Preliminary remarks pp. 105 - 106 pp. 107 – 110 Migraine … · 2018-12-13 · Preliminary...

Preliminary remarks pp. 105 - 106

Methodology pp. 107 – 110

Migraine diagnosis pp. 111 – 116

Management of migraine attacks pp. 117 – 119

Symptomatic treatment of migraine pp. 120 – 146

Prophylactic treatment of migraine pp. 147 – 161

Non-pharmacological therapy of migraine pp. 162 – 167

Diagnosis, symptomatic therapy and preventive therapy of cluster headache pp. 168 – 179

Non-pharmacological treatments for cluster headache pp. 180 – 181

Trigeminal autonomic cephalalgias pp. 182 – 190

Glossary

The Italian Society for the Study of Headaches (SISC) was thefirst scientific society to publish, in 1993, therapeutic guide-lines for migraine [1]. Because of its clarity and conciseness,this document represents a milestone in the history ofheadache societies. The need to provide an updated diagnosticand therapeutic orientation for all experts and physicians ded-icated to headache has become pressing for the Society, notonly because of the remarkable progress made in therapeuticstrategies for headache but also in the wake of the publicationof headache guidelines by the scientific societies of othercountries (e.g. Canada, Denmark, England, U.S.A. etc.) [2–5].

It was, therefore, necessary to publish an edition of diag-nostic-therapeutic guidelines for cluster headache that hadnever been published by other scientific societies or consortiaof different scientific societies. Our attention turned to non-pharmacological therapies that had not been considered in theprevious SISC guidelines. A subcommittee on trigeminalautonomic cephalalgias (TACSs) and unsolved questions wasformed with the objective of identifying or suggesting diag-nostic orientation and, when possible, therapeutic approachesin the tangled world of the new emerging nosographic entities.

For this purpose an Ad Hoc Committee was formed to con-sider the multidisciplinary characteristics of the Society andwas composed of prominent Italian researchers from variousdisciplines. In particular, committee members were selectedfrom the membership of the SISC, the Italian NeurologicalSociety, the Italian Society of Neuropsychiatry of Childhoodand Adolescence, the Italian Society of Internal Medicine, theItalian Society of General Practitioners, the Italian Society ofPain Clinicians, the Italian Society of Clinical Pharmacology,and both the Italian Society and the Association of EmergencyPhysicians. The Ad Hoc Committee was organized into sub-committees, each responsible for a different topic: diagnosis ofmigraine; symptomatic treatment of migraine; prophylactictreatment of migraine; non-pharmacological treatment ofmigraine; diagnosis, symptomatic and prophylactic treatmentof cluster headache; and lastly trigeminal autonomic cephalal-gias (TACs) and unsolved questions.

Additionally, two headache patients were invited to par-ticipate in the committee and give their opinion on the diag-nostic and therapeutic approaches proposed. This also reflectsour line of conduct when writing the guidelines which respectthe new norms of bioethics that have to be always taken intoaccount when giving diagnostic-therapeutic orientation.

The activity of the Ad Hoc Committee took into consid-eration the fact that the guidelines had to be, in final analy-sis, applied in clinical practice. To meet this objective theCommittee indicated precise and practical guidelines to beused by specialists and general practitioners. The guidelineswill be regularly revised on an annual basis as new infor-mation is acquired.

From a methodological point of view, it was decided thatall information reported in the guidelines would be evidence-based [6]. Keeping this in mind, the subcommittee memberscarried out a thorough research in Medline (on PubMed), tak-ing into consideration all articles concerning clinical, labora-tory and instrumental examinations, as well as therapeuticapproaches. Abstracts were excluded from the analysis. Thesubcommittees then proceeded to assess the studies selectedby attributing a score in decreasing value to: controlled, ran-domized, double-blind and placebo-controlled studies, car-ried out according to good clinical practice (GCP); meta-analyses; prospective and cross-sectional studies; reviews;case reports and lastly anecdotal experiences [7].

Statistical assessment involved the evaluation of the sig-nificance of each study, with the aim of establishing thestrength of the evidence. Lastly, the members of each sub-committee, based on their personal clinical experience,expressed an evaluation on the efficacy of diagnostic proce-dures or drugs. The differences with other guidelines, insome points, above all with those from the United States [5],are substantial, and specifically regard the use of opioidsand barbiturates, as well as the use of drugs in association.

The opinion of international experts is important, inorder to develop a broad and constructive debate. It is fun-damental not to pause on the single attacks experienced by

J Headache Pain (2001) 2:105–106© Springer-Verlag 2001

Preliminary remarks

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the patient, but to consider each patient as a “person” affect-ed by a pathology which occurs for a certain period ofhis/her life, and which can become chronic, with the poten-tial risk of drug abuse.

Our patient fights against pain and we must help him todefeat it. A short digression: the term “patient” should beabsolutely abolished because it refers to “patience”(patience etymologically means a person who suffers, but, ingeneral use, it means a person who can serenely wait),meaning that one can wait and which can unconsciouslycontribute to creating a muddled, and static health system.Whoever suffers, meaning every patient, cannot and shouldnot have to wait; but a strong revolt of all the subjects whoare no longer “patients” can help improve the organizationof the health environment. If I demolish I have to immedi-ately reconstruct; therefore, from this moment onward I willcall the patients with the name of “urgent” and this term willhave to enter into general use (it is clear that the urgency canbe immediate or deferred according to the cases). In thebeginning each change can be seen as ridiculous; in this caseit is a strong cultural advancement.

We hope that our efforts have produced a useful, com-plete and easy to consult document, which will be periodi-cally revised.

Virgilio Gallai (President of the Ad Hoc Committee)

References

1. Italian Society for the Study of Headaches (SISC) (1993)Guidelines and recommendations for the treatment ofmigraine. Funct Neurol 8(6):441–446

2. – (1997) Guidelines for the diagnosis and management ofmigraine in clinical practice. Can Med Assoc J156:1273–1287

3. Danish Neurological Society and The Danish HeadacheSociety (1998) Guidelines for the management of headaches.Cephalalgia 18:9–22

4. British Association for the Study of Headache (2000)Guidelines for all doctors in the diagnosis and managementof migraine and tension-type headache, 2nd edition.http://www.bash.org.uk/guidelines.htm (consulted 17December 2001)

5. McCrory DC, Matchar DB, Rosenberg JH, Silberstein SD(2000) Evidence-based guidelines for migraine headache. USHeadache Consortium. http://www.ahsnet.org/guidelines.php,http://www.aoa-net.org/MembersOnly/headachemain.htm(consulted 17 December 2001)

6. Becker WJ (2000) The challenge of evidence-based migrainetherapy. Cephalalgia 20[Suppl 2]:1–4

7. Tfelt-Hansen P, Block G, Dahlof C, Diener HC, Ferrari MD,Goadsby PJ, Guidetti V, Jones B, Lipton RB, Massiou H,Meinert C, Sandrini G, Steiner T, Winner PB (2000)Guidelines for controlled trials of drugs in migraine, secondedition. Cephalalgia 20(9):765–786

General procedure

The search was actually conducted on both Medline andPubMed for all publications from 1966 to 2001 on diagnosisand therapy of migraine and from 1975 to 2001 on diagnosisand therapy of cluster headache. For migraine, the followingkey words were given: migraine/diagnosis; migraine/MRI;migraine/CT; migraine/EEG; migraine/evoked potentialsand event-related potentials; migraine/laboratory parameters;migraine/management; migraine/acute treatment; migraine/prophylactic treatment; migraine/symptomatic and preventivedrugs; migraine non-pharmacological treatment; migraine/behavioral treatment; migraine/biofeedback; migraine/acupuncture; and lastly migraine/hypnotherapy. For clusterheadache, the following key words were used: clusterheadache/diagnosis; cluster headache/MRI; cluster headache/CT; cluster headache/EEG; cluster headache/nitroglycerinetest; cluster headache/histamine test; cluster headache/acutetreatment; cluster headache/prophylactic treatment; clusterheadache/symptomatic and preventive drugs; clusterheadache/non-pharmacological treatment; cluster headache/surgical procedure; cluster headache/Gasser ganglion rhizol-ysis; and cluster headache/gamma knife.

The most recent articles have also been retrieved throughIndex Medicus, and the consultation of the latest issues of inter-national scientific journals in the field was carried out up toMarch 2001. Every article has been examined in its entirety,and the references of all the articles were analyzed, with thepurpose of consulting every other possible related article.Abstracts were excluded from the definitions of the levels ofevidence, scientific strength of evidence and recommendations.

Diagnosis of migraine and cluster headache

All articles concerning the specificity, sensitivity, predic-tive value of the clinical history, general medical exami-

nation, neurological examination, as well as laboratory,radiological, neuroradiological and other instrumentalinvestigations for migraine and cluster headache weretaken into account, especially those aimed at demonstrat-ing significant intracranial or extracranial abnormalities,excluding a secondary headache. As far as migraine diag-nosis is concerned, all papers cited on Medline andPubMed have been considered, regarding studies carriedout on at least 20 patients with primary headaches. Forthese studies at least one of the following two criteriashould have been fulfilled:1. Comparison of clinical history, neurological or general

examination, laboratory tests, radiological or otherinstrumental investigations with a neurological exami-nation with a gold standard (computed tomography(CT) or magnetic resonance imaging (MRI) of thebrain),

2. Description of the results of neuroradiological examina-tions in consecutive series of patients or randomizedsamples. For cluster headache diagnosis, the clinical articles

including less than 30 patients and the articles concerninginstrumental investigations including less than 10 patientswere excluded. The grading of the levels of evidence andscientific strength was done according to those suggestedin the American guidelines [1] for migraine (Tables 1, 2).For the diagnostic procedures for migraine and clusterheadache, four levels of recommendation obtained fromthe consensus of the members of the Ad Hoc Committeewere introduced.

Treatment of migraine and cluster headache

The members of the Ad Hoc Committee defined the levelsof evidence, scientific strength of evidence and clinicalassessment. The latter was derived from the consensus ofthe committee members concerning each symptomatic and


Methodology

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prophylactic drug available or unavailable in Italy for whichthere are data supporting their efficacy or their use inmigraine or cluster headache.

Criteria used for the levels of evidence, scientificstrength of evidence and assessment of the clinical effec-tiveness are reported in Tables 4, 5 and 6, respectively. Asfar as the scientific strength of evidence is concerned, theAd Hoc Committee members tried to define the level ofstatistical significance and the rate of clinical response ina more precise manner with respect to those given by theAmerican guidelines [1].

For assessment of the clinical effectiveness, some per-centages were fixed with the aim of better defining the

scores, in an attempt to overcome generic terms such as“most” and “few” reported in the definition of the “clinicalimpression” in the American guidelines for migraine [1].

Four levels of recommendations have been defined bythe members of the Ad Hoc Committee on the basis of thelevels and the scientific strength of the evidence for the useof drugs in the symptomatic and prophylactic treatment ofmigraine and cluster headache (Table 7).

The clinical judgement expressed by the members ofthe Ad Hoc Committee refers to defined time points for thesymptomatic treatment (2 h for migraine and 30 min forcluster headache). For the prophylactic treatment ofmigraine, this judgement refers to at least 2 months of

Table 1 Levels of evidence for the diagnosis of migraine and cluster headache

Level A evidence: Independent, blind comparison with a “gold standard” of anatomy, physiology, diagnosis or prognosis among a largenumber of consecutive patients suspected of having the target condition. The following definitions apply:

Independent: Neither the test nor the gold standard result were used to select patients for the studyBlind: The test and gold standard were each applied and interpreted without knowledge of the result of the otherGold standard: The results of biopsy, angiography, autopsy, plain radiography, sonography, physiological study, follow-up, therapeutic

response, etc. established the true anatomy, physiology, diagnosis or outcome of the target conditionTarget condition: The anatomical or physiological state, disease, syndrome, prognosis, or therapeutic response that the sign

or symptom identifiesLarge number: Sufficient numbers of patients to have narrow confidence limits on the resulting sensitivity, specificity or likelihood ratio

Level B evidence: Independent, blind comparison with a “gold standard” among a small number of consecutive patients suspected ofhaving the target condition

Small number: Insufficient numbers of patients to have narrow confidence limits for sensitivity, specificity or likelihood ratio

Level C evidence: Independent, blind comparison with a “gold standard” among nonconsecutive patients suspected of havingthe target condition

Level D evidence: Included studies which did not meet criteria for at least Level C of evidence

Table 2 Scientific strength of evidence for the diagnosis of migraine and cluster headache

Grade +++ At least 2 well-designed, randomized clinical trials, directly related to the recommendation yielded a consistent pattern of results

Grade ++ One well-designed, randomized clinical trial directly related to the recommendation or evidence from 2 or more randomizedclinical trials which support the recommendation, but the scientific support was not optimal. For instance, the randomizedtrials available were somewhat inconsistent, or the trials were not directly relevant to the recommendation. An example ofthe last point would be the case where trials were conducted using a study group that differed from the target group for therecommendation

Grade + The Ad Hoc Committee achieved consensus on the recommendation in the absence of relevant controlled trials or based on studies carried out using study groups that differ from the group directly related to the recommendation

Grade 0 No evidence or consensus from the members of the Ad Hoc Committee

Table 3 Levels of recommendation for the diagnosis of migraine and cluster headache

Level I: Indispensable for a correct diagnosisLevel II: Strongly recommendedLevel III: To take into consideration relative to the specific caseLevel IV: Not recommended

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treatment (reduction by at least 50% of the frequency orintensity of the attacks). For the prophylactic treatment ofcluster headache, the judgement of efficacy refers to theability of the drug to induce a rapid disappearance of the

attacks and the resolution of the cluster phase. This judge-ment may be difficult for the episodic forms, in which thespontaneous resolution of the cluster period may not beexcluded.

Table 4 Levels of evidence for the treatment of migraine and cluster headache

Level A: Two or more clinically controlled, randomized studies carried out according to good clinical practice (GCP), versus placebo orversus active treatment of proven efficacy

Level B: One clinically controlled, randomized study carried out according to GCP or more than one well-designed clinical case-controlstudy or cohort study

Level C: Favorable judgement of two-thirds of the Ad Hoc Committee members, historical controls, non-randomized studies, case reports

Table 5 Scientific strength of evidence for the treatment of migraine and cluster headache

Grade +++ The difference in the parameters of efficacy registered with the study drug and with placebo or another active drug has a highlevel of statistical significance (p<0.01; p<0.001; p<0.0001). Adverse events are rare or occasional and of moderate or slightintensity

Grade ++ The difference between the parameter of efficacy registered with the study drug and those registered with placebo or anotheractive drug reaches the minimum level of significance (p<0.05) or the minimum clinically significant level (difference inthe parameters <15%)a

Grade + The difference in the efficacy parameters between the study drug and placebo or another active drug is not statistically significantGrade 0 The drug is not efficacious or is characterized by severe adverse events

a Even drugs for which the difference in the efficacy parameters compared with placebo is higher than the minimum level of statistical sig-nificance, but have frequent yet no severe adverse events, are included in this group

Table 6 Assessment of the clinical effectiveness of treatments for migraine and cluster headache

+++ Greatly effective: The majority (more than 60%) of the patients had a clinical benefit. More than 30% of the patients were pain free(symptomatic treatment) or had no more attacks (prophylactic treatment)

++ Effective: Many patients (from 40% to 60%) had a clinical benefit, or 20%–30% of the patients were pain free (symptomatic treatment)or had no more attacks (prophylactic treatment)

+ Partially effective: Some of the patients (from 20% to 40%) had a clinical benefit, were pain free (symptomatic treatment) or hadno more attacks (prophylactic treatment)

0 Ineffective: Less than 20% of the patients received a clinical benefit

? Undetermined: The members of the Ad Hoc Committee were unable to express any judgement on effectiveness based on theirpersonal clinical impressions

Table 7 Levels of recommendation for the treatment of migraine and cluster headache

Level I: Drugs with high efficacy supported by statistically significant data (evidence of at least two controlled, randomized studiesversus placebo or versus active drugs of proven efficacy) or very high clinical benefit for patients (clinical assessment +++)and with no severe adverse events

Level II: Drugs whose value of efficacy is statistically of lower significance compared to drugs of group I and with a less significantclinical benefit for patients (clinical assessment ++) and no severe adverse events

Level III: Drugs showing efficacy from a statistical point of view but not from a clinical point of view (contrasting results or evidenceis not conclusive). The drugs belonging to this group were further subdivided into two subgroups:

(a) Drugs with no severe adverse events;(b) Unsafe drugs or with complex indications for use (e.g. special diets) or important pharmacological interactions

Level IV: Drugs of proven efficacy but with frequent and severe adverse events or drugs whose efficacy has not been proven from a clinicalor statistical point of view (no difference with respect to placebo). Drugs with unknown clinical patient benefit or statisticalsignificance of efficacy (data unavailable or insufficient)

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Non-pharmacological treatment

From the evaluation of the studies in the literature,reviews included (i.e. acupuncture used in migraine treat-ment of the Cochrane Collaborative Group), the level of

evidence, scientific strength of evidence, and clinicalassessment could not be defined. The results of the singlestudies are therefore reported, and when possible, a judge-ment is expressed by the members of the Ad HocCommittee.

Reference

1. McCrory DC, Matchar DB, Gray RN,Rosenberg JH, Silberstein SD (2000)Overview of program description andmethodology. In: Evidence-basedguidelines for migraine headache. USHeadache Consortium.http://www.aan.com/public/practiceguidelines/01.pdf (consulted 17December 2001)

Introduction

Numerous epidemiological studies have demonstrated thatmigraine affects approximately 15%–18% of women and6% of men in the course of their lives, with a peak preva-lence between the ages of 25 and 55 years, in the period ofmaximum productivity [1–3]. Its disabling nature makes it asocial disease with elevated direct and indirect economiccosts [4–7]. Therefore, it is necessary to make an early diag-nosis and to provide a correct treatment.

Migraine diagnosis has been up to now based on diagnos-tic criteria in the international classification deriving from clin-ical and epidemiological data, because of the incompleteknowledge of pathophysiological mechanisms and lack of spe-cific “markers” [8]. The great merits of the InternationalHeadache Society (IHS) classification consist in having identi-fied a set of diagnostic criteria specific for each headache form,in having edited the previous terminology, introducing, whennecessary, a new terminology and creating a uniform interna-

tional dictionary in the matter of head pain. Twelve years fromits publication, the classification of headache proposed by theIHS [8] is in many aspects still current even if its use hasbrought to light, which always happens when passing fromtheory to practice, some defective aspects. As an example, allthe criteria have a high level of specificity or a high level ofsensitivity, but never both; moreover, specific criteria were notprovided for menstrual headache or chronic headache.

The lacking aspects of headache classification are beingre-evaluated by an appropriate international committee forthe purpose of publishing a revised version.

Clinical history

Case history data are necessary for diagnosis and questionsshould be oriented to: 1. Determine if headache fulfills the set of diagnostic cri-

teria for migraine. Tables 1 and 2 summarize the IHS


Migraine diagnosis

Table 1 International Headache Society diagnostic criteria for migraine without aura. (From [8] with permission)

A. At least 5 attacks fulfilling criteria B-D

B. Headache attacks lasting 4–72 hours* (untreated or unsuccessfully treated)a

C. Headache has at least two of the following characteristics:1. Unilateral location2. Pulsating quality3. Moderate or severe intensity (inhibits or prohibits daily activities)4. Aggravation by walking stairs or similar routine physical activity

D. During headache at least one of the following:1. Nausea and/or vomiting2. Photophobia and phonophobia

E. At least one of the following:1. History, physical and neurological examinations do not suggest one of the disorders listed in groups 5–11 of the IHS classification2. History and/or physical and/or neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations3. Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder

*In children below age 15, attacks may last 2–48 hours. If the patient falls asleep and wakes up without migraine, duration of attack isuntil time of awakeninga In the classification, at points 5–11, secondary headaches are listed

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criteria for migraine without aura and migraine withaura, respectively. To improve the reliability of the diag-nosis, the use of semistructured interviews is recom-mended [9, 10].

2. Formulate additional questions to improve specificityand sensitivity of IHS diagnostic criteria. Additionalinformation can be:(i) Favorable to migraine diagnosis,(ii) Unfavorable to migraine diagnosis.When not otherwise specified, all statements have Level

of evidence D; strength of evidence grade +. For the clinicalhistory, level of recommendation is I.

(i) Additional information favorable to migraine diagnosis

1. Alternating side in the case of unilateral pain.Migrainous pain is unilateral in more than 50% of cases,and generally alternating [11–16]. A side-locked unilat-erality of pain suggests another type of headache.

2. Severe intensity of nausea, phonophobia and photopho-bia. As these symptoms can also be present in tension-type headache, although with milder intensity, the use of agraded scale is recommended to distinguish the two forms(0, absent; 1, mild; 2, moderate; 3, severe) [13, 17, 18].

3. Family history. First-degree relatives of migrainepatients show a 1.9-times higher risk than the generalpopulation to develop migraine without aura and a 1.4-times higher risk to develop migraine with aura [19].

4. Prodromal symptoms (irritability, mood changes, diffi-culty in concentrating, etc.). The incidence of prodromalsymptoms varies from 7% to 88% in different studies onthis topic [20].

5. Triggers or aggravating factors. These include food (notenough or too much), sleep, stress factors, relaxationafter stress as in week-end migraine, etc. In particular, apositive likelihood ratio of 3.6 was calculated for foodtriggers (CI, 2.8–4.6) [21].

6. Osmophobia and hyperosmia. Both are sensitive andspecific markers of migraine attack [18, 22, 24], even ifthey are not included in the present IHS classification.

7. Recurrence of crises in the perimenstrual period. Mostwomen affected by migraine complain of crises in themenstrual period [24].

8. Motion sickness. Several studies have demonstrated thatmigraineurs are more susceptible to motion sicknessthan non-migraineurs [25].

9. History of recurrent abdominal pain, cyclic vomiting,and benign paroxysmal vertigo in juvenile age. Thesesituations are common in this period of life but are morefrequent in families of migraineurs [26].

(ii) Additional information unfavorable to migrainediagnosis

1. Changes in attack severity. Particular attention should begiven when the crisis is referred to as “the worst headacheof one’s life”. In these cases, a secondary headache mustalways be suspected. In a study carried out on adultpatients visited in the emergency room in a 16-monthperiod, 17% of those reporting “the worst headache of mylife” revealed the signs of a subarachnoid hemorrhage oncomputed tomography (CT) [18, 27, 28].

2. Changes of pain features. One has to suspect a sec-ondary headache [18, 28].

3. Changes in frequency, in particular when frequencyrapidly increases. Also in this case, a secondaryheadache must be suspected [28, 29]. A rapidly increas-ing attack frequency significantly increases the odds ofdetecting significant lesions by neuroimaging [29].Level of evidence A; strength of evidence grade ++.

4. Progressively worsening course. In this case a secondaryheadache should always be suspected [18, 28].

5. History of headache causing awakening from sleep.Although both migraine and cluster headache can occur

Table 2 International Headache Society diagnostic criteria for migraine with aura. (From [8] with permission)

A. At least 2 attacks fulfilling B.

B. At least 3 of the following 4 characteristics:1. One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction.2. At least one aura symptom developing gradually over more than 4 minutes, or 2 or more symptoms occurring in succession.3. No aura symptom lasting more than 60 minutes. If more than one aura symptom is present, accepted duration is proportionally

increased.4. Headache following aura with a free interval of less than 60 minutes. (It may also begin before or simultaneously with the aura.)

C. At least one of the following:1. History, physical and neurological examinations do not suggest one of the disorders listed in groups 5–112. History and/or physical and/or neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations3. Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder.

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during sleep, it is important not to underestimate the pos-sibility of a secondary headache [30–32].

6. Headache worsening after Valsalva maneuver. The pre-cipitation of headache by coughing, sneezing or bendingdown can hide a secondary headache disorder [18].

7. Association with systemic symptoms. The presence ofsystemic symptoms such as myalgia, fever and weightloss indicates that a more serious underlying cause maybe present [18].

8. Association with further neurological symptoms. Thecomplaint of any impairment in the level of conscious-ness, seizures, somnolence or confusional state suggeststhe need for further investigations [18].

9. Headache not responding to adequate pharmacologicaltreatments (symptomatic or prophylactic). After exclud-ing the possibilities of poor therapeutic compliance andof symptomatic abuse, it is necessary to consider analternative diagnosis.

10. New onset after 40 years of age. Only 8% of migraineursreport a new-onset headache after 40 years of age, so inthis case, further investigations are needed [33]. Meanage at onset positively correlates with both significant(e.g. brain tumors, arteriovenous malformations, hydro-cephalus) and insignificant (e.g. white matter lesions,brain atrophy) lesions detectable by neuroimaging tech-niques [29].

11. Recent onset. Two studies demonstrated the relevanceof this factor. The former, by Duarte et al. [34], showeda shorter mean duration of disease (2.9 months) inpatients with significant intracranial lesions than inpatients without (8.2 months). When reviewing paperspublished after 1998, the Italian Ad Hoc Committeefound one study which confirmed the shorter headacheduration as a risk factor for intracranial lesions [35].Although in Spanish, the study had been carried out inagreement with the criteria stated by the Americanguidelines [29]. In fact, that study was prospective,was carried out on a series of 299 consecutive patientsand compared the clinical evaluation with CT, demon-strating that in subjects with headache onset over onemonth the prevalence of intracranial lesions was 1%,while in those cases with headache onset of less than orup to 1 month prevalence was 36% [35]. Level of evi-dence A; strength of evidence grade ++.

Additional recommendations

1. It is recommended to grade pain severity through ascale ranging from 0 to 3 (0, absent; 1, mild withoutany limitation of routine activities; 2, moderate andrestraining daily activities but not requiring bed rest; 3,

severe, prohibiting daily activities and compelling bedrest). The exact assessment of pain is important inchoosing the right treatment and in evaluating theeffects of therapy.

2. It is strongly recommended to use a headache diary tobetter define diagnosis, to follow the course of diseaseand to evaluate the effects of therapy.

3. Menstrual headache is not recognized as a nosographicentity in the current international classification [29]. Thisunderscores the need for an exact definition of trueforms and their characteristics. This should be one of thegoals of the future revised classification.

4. History of syncope. A study investigating the occurrenceof syncope in comorbidity with other diseases, in a sam-ple of 16 809 inpatients from 3 Florence hospitals in 1998,demonstrated a significant association between migraineand syncope; these results support the hypothesis of thenon-predictive value of syncope toward the detection ofintracranial abnormalities in migraineurs [36].

5. Vertigo. Among papers published from 1996 through2001, a study carried out on 400 patients (200 referringto a vertigo center and 200 to a headache center) showedan epidemiological association between vertigo andmigraine (the prevalence of migraine was 38% inpatients from the vertigo center while in the general pop-ulation it was 24%) [37].After the clinical history, the physician must perform

general and neurological examinations, and request appro-priate laboratory and radiological tests to exclude all the pos-sible forms of secondary headache as stated by IHS criteria.1. General physical examination. A complete general phys-

ical examination is mandatory. In particular, blood pres-sure, heart rate and body temperature should be mea-sured. Paranasal sinuses, cervical and paraspinal mus-cles, as well as temporomandibular joints should be eval-uated. Level of recommendation I.

2. Neurological examination. A complete neurologicalexamination is mandatory. Particular attention must begiven to exclude any impairment in the level of con-sciousness, the presence of meningeal irritation, abnor-malities of the optic fundi and focal signs. Level of rec-ommendation I.

3. Neuroimaging tests (CT, MRI, angio-MRI) are notwarranted as routine diagnostic procedures, but mustalways be performed in patients with neurologicalsigns. The presence of focal signs increases the likeli-hood of finding significant intracranial lesions such asbrain tumors, arteriovenous malformations and hydro-cephalus, while the absence of abnormalities revealedby the neurological examination decreases the odds offinding significant intracranial lesions with neu-roimaging [29, 38]. Level of evidence C; strength ofevidence grade ++; level of recommendation I.

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Neuroimaging tests (CT, MRI, angio-MRI) should beconsidered in the following cases:– Patients with neurological symptoms. In a 1996

review, Evans [39] confirmed the poor diagnostic con-tribution of neuroimaging in patients with recurrentheadache and normal neurological examination whichhad already been stated in the American guidelines[29]. In a series of 3026 MRI scans performed since1977, the overall prevalence of intracranial lesionswas 0.8% for brain tumors, 0.2% for arteriovenousmalformations, 0.3% for hydrocephalus, 0.1% foraneurysm, 0.2% for subdural hematoma and 1.2% forstroke [39]. Level of evidence D; strength of evidencegrade ++, level of recommendation II.

– Patients complaining of headache or with other riskfactors (see section entitled Additional informationunfavorable toward the diagnosis of migraine). Levelof recommendation II. Brain MRI has a higher sensitivity than brain CT in

detecting white matter abnormalities, arteriovenous mal-formations and posterior cranial fossa lesions, so thechoice between these two techniques should be madeaccording to the clinical suspicion [29, 39]. According toEvan’s review, white matter abnormalities can beobserved by MRI in 12%–46% of cases [39]. The resultsconcerning a presumed higher frequency of white matterabnormalities in migraineurs than in controls are stillcontradictory [39]. As both white matter abnormalitiesand cortical atrophy are non-specific lesions, their detec-tion does not furnish a consistent contribution tomigraine diagnosis [39].

4. Electroencephalography (EEG) is not useful in the rou-tine diagnosis of headache patients. EEG continues tobe recommended in headache patients whose symp-toms suggest a seizure (e.g. atypical migraine aura, lossof consciousness), but is not warranted to excludeintracranial lesions. These recommendations werealready formulated in the American guidelines [29] andremain the same in the present guidelines. A report onEEG practice parameters for headache evaluation waspublished in 1995 [40]. The American guidelines [29]were based upon that document, which was realizedafter reviewing the scientific literature published from1966 through 1994.

As for the possible increased prevalence of EEGabnormalities in migraineurs, published results are con-tradictory. Although no higher prevalence has beendemonstrated in migraineurs than in controls, in the for-mer there is a prominent photic driving for high frequen-cies of stimulus (H-response) that differentiated themfrom controls. This reported sensitivity of H-responsevaries from 26% to 100% and its specificity varies from80% to 91%; in spite of this one cannot affirm that this

test is useful for diagnosis [40]. A recent study concern-ing H-response confirmed the presence of a more promi-nent photic driving in migraineurs than in controls [41].Few studies have been carried out on the identification ofa subgroup of headache sufferers by EEG features, andevidence is not sufficient to confirm that EEG can dif-ferentiate headaches [40]. Similarly, H-response seemsnot to be useful for differentiating migraine and tension-type headache [41]. Data regarding the possible role ofEEG in identifying patients with secondary headachesuggest that EEG is not useful to exclude intracranialdisorders in patients with headache [42].No scientific evidence exists to affirm that further labo-

ratory and instrumental examinations (on blood, cere-brospinal fluid or other biological fluids) or electrophysio-logical, ultrasound, radiological and histological tests candetect sensitive and specific abnormalities in migraine froma diagnostic point of view. Each test should be used everytime that the clinical suspicion suggests its utility.

Some abnormalities reported by scientific papers do nothave a diagnostic value but a research aim

As for visual evoked potentials, an abnormal visual reactiv-ity by steady state stimulus in the frequency range of 15–21Hz was confirmed in the interictal phase of migrainepatients compared to controls [42]. The linear discriminantanalysis and, even more, the neural network method statedthe absolute similarity of migraine and tension-typeheadache concerning that abnormal neurophysiological pat-tern, thus explaining both the difficulties in differentialdiagnosis and the pathophysiological affinity [43]. Duringthe attack of migraine without aura, the visual potentialsteady state was suppressed, then increased in amplitudeduring the interictal phase: such pattern can be explained byan interictal abnormality, probably genetically defined andpredisposing to migraine attacks. The potential suppressionduring the ictal phase is in agreement with a phenomenonsimilar to the spreading depression descibed in migrainewith aura [43].

By studying the trigeminal pathways by using the blinkreflex, a specific hyperexcitability of such circuits wasfound in both adult and juvenile migraineurs without auraduring the interictal phase. That hyperexcitability may pre-dispose to trigeminal activation and to the consequent pre-cipitation of migraine attack [44]. Ictally, the delayed com-ponent of the blink reflex has been shown to be suppressedby the administration of triptans with activity also on thecentral nervous system, thus suggesting that the abnormali-ties of the blink reflex in migraine may be due to a specificserotonergic modulation [45].

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References

1. Henry P, Michel P, Brochet B,Dartigues JF, Tison S, Salamon R(1992) A nationwide survey ofmigraine in France: prevalence andclinical features in adults. GRIM.Cephalalgia 12(4):229–237

2. D’Alessandro R, Benassi G, Lenzi PL,Gamberini G, Sacquegna T, De CarolisP, Lugaresi E (1988) Epidemiology ofheadache in the Republic of SanMarino. J Neurol Neurosurg Psychiatry51(1):21–27

3. Stewart WF, Lipton RB, CelentanoDD, Reed ML (1992) Prevalence ofmigraine headache in the UnitedStates. Relation to age, income, race,and other sociodemographic factors.JAMA 267(1):64–69

4. Ferrari MD (1998) The economic bur-den of migraine to society.Pharmacoeconomics 13(6):667–676

5. Hu XH, Markson LE, Lipton RB,Stewart WF, Berger ML (1999) Burdenof migraine in the United States: dis-ability and economic costs. Arch InternMed 159(8):813–818

6. de Lissovoy G, Lazarus SS (1994) Theeconomic cost of migraine. Presentstate of knowledge. Neurology 44[6Suppl 4]:56–62

7. Holmes WF, MacGregor EA, DodickD (2001) Migraine-related disability:impact and implications for sufferers’lives and clinical issues. Neurology56[6 Suppl 1]:S13–S19

8. Headache Classification Committee ofthe International Headache Society(1988) Classification and diagnosticcriteria of headache disorders, cranialneuralgias and facial pain. Cephalalgia8[Suppl 7]:1–96

9. Rasmussen BK, Jensen R, Olesen J(1991) Questionnaire versus clinicalinterview in the diagnosis of headache.Headache 31(5):290–295

10. Lipton RB, Stewart WC, Solomon S(1992) Questionnaire versus clinicalinterview in the diagnosis of headache.Headache 32(1):55–56

11. Campbell JK (1990) Manifestations ofmigraine. Neurol Clin 8(4):841–855

12. Lance JW, Anthony M (1966) Someclinical aspects of migraine. A prospec-tive survey of 500 patients. ArchNeurol 15(4):356–361

13. Rasmussen BK, Jensen R, Olesen J(1991) A population-based analysis ofthe diagnostic criteria of theInternational Headache Society.Cephalalgia 11(3):129–134

14. Rasmussen BK, Olesen J (1992)Migraine with aura and migraine with-out aura: an epidemiological study.Cephalalgia 12(4):221–228

15. Leone M, D’Amico D, Frediani F,Torri W, Sjaastad O, Bussone G(1993) Clinical considerations onside-locked unilaterality in long-last-ing primary headaches. Headache33(7):381–384

16. Biousse V, D’Anglejan J, Touboui PG,Evrard S, Amarenco P, Bousser MG(1991) Headache in 67 patients withinternal carotid dissection. Cephalalgia11:232–233

17. Iversen HK, Langemark M, AnderssonPG, Hansen PE, Olesen J (1990)Clinical characteristics of migraine andepisodic tension-type headache in rela-tion to old and new diagnostic criteria.Headache 30(8):514–519

18. Pryse-Phillips WE, Dodick DW,Edmeads JG, Gawel MJ, Nelson RF,Purdy RA, Robinson G, Stirling D,Worthington I (1997) Guidelines forthe diagnosis and management ofmigraine in clinical practice. CanadianHeadache Society. Can Med Assoc J156(9):1273–1287

19. Russell MB (1997) Genetic epidemiol-ogy of migraine and cluster headache.Cephalalgia 17(6):683–701

20. Zagami AS, Rasmussen BK (2000)Symptomatology of migraine withoutaura. In: Olesen J, Tfelt-Hansen P,Welch KMA (eds) The headaches, 2ndedn. Lippincott Williams Wilkins,Philadelphia, pp 337–343

21. Smetana GW (2000) The diagnosticvalue of historical features in primaryheadache syndromes: a comprehensivereview. Arch Intern Med160(18):2729–2737

22. Silberstein SD (1995) Migraine symp-toms: results of a survey of self-report-ed migraineurs. Headache35(7):387–396

23. Merikangas KR, Dartigues JF,Whitaker A, Angst J (1994) Diagnosticcriteria for migraine. A validity study.Neurology 44[6 Suppl 4]:S11–S16

24. MacGregor EA, Chia H, Vohrah RC,Wilkinson M (1990) Migraine andmenstruation: a pilot study.Cephalalgia 10(6):305–310

25. Grunfeld E, Gresty MA (1998)Relationship between motion sickness,migraine and menstruation in crewmembers of a “round the world” yachtrace. Brain Res Bull 47(5):433–436

26. Abu-Arafeh I, Hamalainen M (2000)Childhood syndromes related tomigraine. In: Olesen J, Tfelt-Hansen P,Welch KMA (eds) The headaches, 2ndedn. Lippincott Williams Wilkins,Philadelphia, pp 517–523

27. Morgenstern LB, Luna-Gonzales H,Huber JC Jr, Wong SS, Uthman MO,Gurian JH, Castillo PR, Shaw SG,Frankowski RF, Grotta JC (1998)Worst headache and subarachnoidhemorrhage: prospective, modern com-puted tomography and spinal fluidanalysis. Ann Emerg Med 32(3 Pt1):297–304

28. Silberstein SD (1992) Evaluation andemergency treatment of headache.Headache 32(8):396–407

29. McCrory D, Matchar DB, Gray RN,Rosenberg JH, Silberstein SD (2000)Overview of program description andmethodology. In: Evidence-basedguidelines for migraine headache. USHeadache Consortium.http://www.aan.com/public/practiceguidelines/01.pdf (consulted 17December 2001)

30. Sahota PK, Dexter JD (1990) Sleepand headache syndromes: a clinicalreview. Headache 30(2):80–84

31. Kuriztky A (1984) Cluster headache-like pain caused by un upper cervicalmeningioma. Cephalalgia 4:185–186

32. Kennedy CR, Nathwani D (1995)Headache as a presenting symptomfeature of brain tumours in children.Cephalalgia 15[Suppl 16]:A14

33. Steiner TF, Guha P, Capildeo R, RoseFC (1980) Migraine in patients attend-ing a migraine clinic: an analysis bycomputer of age, sex and family histo-ry. Headache 20:190–195

34. Duarte J, Sempere AP, Delgado JA,Naranjo G, Sevillano MD, Claveria LE(1996) Headache of recent onset inadults: a prospective population-basedstudy. Acta Neurol Scand 94(1):67–70

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35. Ortin Castano A, Lopez AlburquerqueT, Adeva Bartolome MT, GonzalezBuitrago JM (1999) [Recent-onsetheadache is a risk factor of intracraniallesion. A prospective study of 299patients.] Ann Med Interna16(4):167–170 (article in Spanish)

36. Bandinelli G, Cencetti S, Bacalli S,Lagi A (2000) Disease-related syncope.Analysis of a community-based hospi-tal registry. J Intern Med247(4):513–516

37. Neuhauser H, Leopold M, Von BrevernM, Arnold G, Lempert T (2001) Theinterrelations of migraine, vertigo andmigrainous vertigo. Neurology56(4):436–441

38. – (1994) Report of the QualityStandards Subcommittee of theAmerican Academy of Neurology.Practice parameter: the utility of neu-roimaging in the evaluation ofheadache in patients with normal neu-rologic examinations (summary state-ment). Neurology 44(7):1353–1354

39. Evans RW (1996) Diagnostic testingfor the evaluation of headaches. NeurolClin 14(1):1–26

40. – (1995) Practice parameter: the elec-troencephalogram in the evaluation ofheadache (summary statement). Reportof the Quality Standards Subcommitteeof the American Academy ofNeurology. Neurology45(7):1411–1413

41. de Tommaso M, Sciruicchio V, BellottiR, Guido M, Sasanelli G, SpecchioLM, Puca FM (1999) Photic drivingresponse in primary headache: diag-nostic value tested by discriminantanalysis and artificial neural networkclassifiers. Ital J Neurol Sci20(1):23–28

42. de Tommaso M, Sciruicchio V, BellottiR, Castellano M, Tota P, Guido M,Sasanelli G, Puca F (1997)Discrimination between migrainepatients and normal subjects based onsteady state visual evoked potentials:discriminant analysis and artificialneural network classifiers. FunctNeurol 12(6):333–338

43. de Tommaso M, Sciruicchio V, GuidoM, Sasanelli G, Puca F (1999) Steady-state visual evoked potentials inheadache: diagnostic value in migraineand tension-type headache patients.Cephalalgia 19(1):23–26

44. de Tommaso M, Guido M, Libro G,Sciruicchio V, Puca F (2000) The threeresponses of the blink reflex in adultand juvenile migraine. Acta NeurolBelg 100(2):96–102

45. de Tommaso M, Guido M, Libro G,Sciruicchio V, Puca F (2000)Zolmitriptan reverses blink reflexchanges induced during the migraineattack in humans. Neurosci Lett289(1):57–60

The management of migraine attacks is based on the carefulcollection of a clinical history, to optimize the choice anduse of drugs for symptomatic treatment, and to best informthe patients and involve them; these are essential prerequi-sites of the “therapeutic alliance” [1–4].

Clinical history

A correct diagnosis of migraine is crucial so that the drugsfor migraine attacks can be effective. After excluding a sec-ondary headache [5], it is useful to conduct a semistructuredinterview with a computerized record [6].

It is necessary to have a documented retrospective clini-cal history of at least 2 months or a registration of a prospec-tive clinical history of at least one month. For this purpose,the headache diary is fundamental and should be filled in forat least three months, in which the frequency, duration andintensity of migraine attacks are registered. Understandingthe characteristics of the crises orients the choice of drug forthe attack. The total number of hours with headache permonth, the intensity, the time it took to reach the peak, thepresence of accompanying symptoms and the use of symp-tomatic therapy are all essential information and should beindicated. On the basis of the frequency, intensity and dura-tion of the crises, the clinician may evaluate if the patientneeds, in addition to a symptomatic treatment, also prophy-lactic treatment.

The use of a diary allows the identification of eventualoccurrences of triggering or aggravating factors. Some ofthem cannot be eliminated (e.g. menstruation, weatherchanges, week-ends), while others can be partially or total-ly removed (e.g. physical fatigue, alteration in the sleep-wake cycle, bad eating habits and fasting, and certain foods,in particular fermented cheese, alcoholic beverages andchocolate, for which the relationship between intake andonset of headache has been established with certainty).

Before beginning any symptomatic or prophylactic treat-ment, it is necessary to eliminate, whenever possible, eachtriggering or aggravating factor. This can, by itself, reducethe frequency or intensity of the crises.

The characteristics of each attack may vary even in thesame patient, who, in some cases, can distinguish attacks ofslight intensity from those of severe intensity from the onsetof the attack, which may positively influence the therapeu-tic choices. The priorities of the patients should also bedefined: in migraine with aura attacks, the patient identifiesthe aura as disabling rather than the head pain phase.Sometimes migraine attacks are accompanied by neuroveg-etative symptoms, such as nausea and vomiting, which maybe, in some cases, more disabling than headache.

For the therapeutic choice, the clinical history of thepatient and the drugs previously taken are fundamental (e.g.efficacy, inefficacy, loss of efficacy, adverse events) for amore precise orientation, since the different crises may havedifferent responses in different patients, and also in the samepatients. The quantity of drugs taken in symptomatic thera-py should always be measured, to identify potential or cur-rent situations of abuse which, in addition to possible phar-macological adverse effects, may induce the transformationof migraine into a chronic daily headache and make thetreatment less efficient or make the eventual prophylactictreatment inefficient.

The coexistence of other pathological conditions(comorbidities) should be investigated, because it influencesthe therapeutic choices, i.e. uncontrolled hypertension andischemic cardiopathy are contraindications to the use of trip-tans and ergot derivatives, whereas gastroduodenal ulcer isa contraindication to the use of analgesics and non-steroidalanti-inflammatory drugs (NSAIDs). Drugs taken for otherdiseases should not be overlooked; they may interfere withantimigraine drugs or favor the onset of attacks (i.e. takingpropranolol increases the levels of rizatriptan; the vaso-dilatatory action of nitroglycerin may facilitate the onset ofa migraine attack).


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The occurrence of other concomitant headache types,together with migraine, should be considered. For these con-comitant headache types, the choice of symptomatic treat-ment may be different. In this regard it is also necessary toteach the patient to recognize the different headache forms,by providing informative pamphlets. This material shouldbe available at each center dedicated to headache treatment.

Therapy

Symptomatic therapy alone is used when the number ofattacks per month is less than 3 or when headache occursless than 4 days per month. Prophylactic treatment may beadopted even when attacks are particularly disabling orwhen these attacks negatively condition the patient’s quali-ty of life. The appropriate choice of drug is based on thecareful and critical evaluation of the clinical history. For thetreatment of migraine attacks, several specific and non-spe-cific therapeutic tools are available. Some of them havebeen in use for a long time, while others have been onlyrecently introduced, and still others, which belong to thegroup of triptans, will soon be available.

Drugs for migraine attacks are distinguished into the fol-lowing groups: triptans; analgesics and NSAIDs; ergotderivatives; and antiemetics [7–9]:– Triptans are indicated for the treatment of migraine

attacks of severe (grade 3) or moderate (grade 2) inten-sity. They are effective not only for headache but also forassociated symptoms. In the majority of cases, the con-temporary administration of antiemetics is not necessary.

– Analgesics and NSAIDs are indicated for the treatmentof migraine crises of slight or moderate intensity(grades 1 and 2) or when triptans are contraindicated orineffective. For certain drugs of this category, no pre-scription is required and over-the-counter drugs may beused, only if the physician has previously formulated acorrect diagnosis.

– Ergot derivatives are indicated for the treatment of dis-abling attacks unresponsive to other drugs and with alow frequency (1–2 attacks per month), due to the poten-tial risk of abuse. They should almost always be admin-istered with antiemetics, since they can increase nauseaand vomiting.

– Antiemetics are indicated as adjuvants in the sympto-matic treatment of migraine attack, when nausea andvomiting are present.The strategies for treating migraine attacks are two: the

step approach and the stratified approach [10, 11]. The stepapproach is based on changes in therapeutic strategiesthrough successive steps, in the case of inefficacy of onestrategy. The stratified approach is based on the preliminary

assessment of the intensity of the headache attacks in a cer-tain patient, which from the beginning allows the choice ofthe most adequate therapy, while separately taking intoaccount the patient and the attacks. The effectiveness of thisapproach in obtaining the most important objective, i.e. totalrecovery of the patient to normal functioning with theadministration of analgesics and NSAIDs for slight-moder-ate crises and of the triptans for moderate-severe crises, hasbeen demonstrated [12]. When the patient is able to recog-nize from the onset the evolution of the attack, he should betaught to choose the most adequate treatment.

The most appropriate drug should be taken at the lowestdosage useful for a complete and early resolution of thecrises. Preparations with only one active drug should be pre-ferred. Moreover, it is convenient to prescribe different ther-apeutic alternatives for attacks of different intensities for thepatient in search of the most effective drug, always consid-ering any eventual comorbidities. Moreover, it is advisableto provide the patients with rescue drugs, in case those indi-cated as first-choice do not produce the desired effects.Prescribing both a triptan and an ergot derivative to the samepatient should be avoided.

The efficacy of the prescribed treatment should be mon-itored over time. Even in this case, the use of the headachediary is advisable. With the aid of this tool, it is possible tocarefully assess the characteristics of the relapses, theeffects of the treatment on head pain and accompanyingsymptoms, the use of the prescribed drugs and the eventualuse of rescue drugs and occurrence of adverse events. In thisway, it is possible not only to assess the efficacy of the ther-apeutic intervention, but also to collect information missingin the initial case chart, to correct any information erro-neously given by the patients or erroneously interpreted bythe physician, and also to identify a possible change in thepattern of attacks (e.g. seasonal variations, aggravation inthe presence of stressful conditions).

Information and patient education

One of the most relevant aspects in defining the treatment ofmigraine attacks is the information given to the patients, towhom the nature of the headache and the measures availablefor both the symptomatic treatment and the prophylaxis ofmigraine attacks, if indicated, should be explained. Theimportance of the pharmacological history should be clarified(i.e. reliability of the information given; exhibiting the previ-ous prescriptions, when available; the opportunity of keepingthe prescriptions even in the future). After these preliminaryremarks, the patient’s experience regarding the efficacy andtolerability of drugs already used should be taken into consid-eration, with the aim of prescribing the most appropriate drug.

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The aims of the ideal treatment for the resolution ofmigraine attacks and associated symptoms and for the rapidrecovery to normal functioning, without adverse events andrelapses or recurrences cannot always be obtained, neitherin all patients nor in all crises. For this reason, correct infor-mation is needed to establish a solid therapeutic alliance.This will give the best results, and avoid creating unrealis-tic expectations that may hinder the patient-physician rela-tionship or reduce patient compliance. Therefore, thepatient should be informed of the reasoning behind the ther-apeutic choice and should be instructed on the appropriateuse of the drugs and the possible adverse effects. The pur-poses and the eventual need for different drugs for differentcrises should be clarified. Lastly, the patient should active-ly participate in the entire treatment of the attacks. Thepatient should learn to appropriately use the headache diaryand to identify and avoid possible triggering factors. Each

patient should avoid aggravating factors and choose theappropriate conditions during the attacks to favor the reso-lution of the crises, such as resting in a quite room withoutlights and noise, attempting to sleep, avoiding excessivelycold or warm environments, and using simple maneuverswhich may give relief.

The physician should explain to the patient that satisfac-tory results can be obtained by avoiding the use of drugs thatmay cause dependency.

The previously mentioned points may contribute to thefundamental therapeutic patient-physician alliance. Thedoctor should be aware of the complexity of head painreferred by the patient and should try to place it in the con-text of the individual patient’s experience. This contributesto establishing a relationship based on trust which is indis-pensable for the patient’s compliance and for the success ofeach therapy.

References

1. Matchar DB, Young WB, RosenbergJH, Pietrzak MP, Silberstein SD,Lipton RB, Ramadan NM (2000)Pharmacological management of acuteattacks. In: Evidence-based guidelinesfor migraine headache. US HeadacheConsortium. http://www.aan.com/pub-lic/practiceguidelines/03.pdf (consulted17 December 2001)

2. Silberstein SD (2000) Practice parame-ter: evidence-based guidelines formigraine headache (an evidence-basedreview). Report of the QualityStandards Subcommittee of theAmerican Academy of Neurology.Neurology 55(6):754–762

3. Tfelt-Hansen P, Mathew NT (2000)General approach to treatment. In:Olesen J, Tfelt-Hansen P, Welch KMA(eds) The headaches, 2nd edn.Lippincott Williams Wilkins,Philadelphia, pp 367–369

4. Becker WJ (2000) The challenge ofevidence-based migraine therapy.Cephalalgia 20[Suppl 2]:1–4

5. Silberstein SD, Goadsby PJ, LiptonRB (2000) Management of migraine:an algorithmic approach. Neurology55[9 Suppl 2]:S46–S52

6. Gallai V, Sarchielli P, Alberti A, RossiC, Cittadini E, and the CollaborativeGroup for the Application of IHSCriteria of the Italian Society for theStudy of Headache (2002) Applicationof the 1988 IHS criteria in the clinicalsetting: results from 10 Italianheadache centers using a reliable andsimple computerized record. Headache(in press)

7. Morey SS (2000) Guidelines onmigraine: Part 3. Recommendations forindividual drugs. Am Fam Physician62(9):2145–2148

8. Diener HC, Limmroth V (1999) Acutemanagement of migraine: triptans andbeyond. Curr Opin Neurol12(3):261–267

9. Ferrari MD, Haan J (1997) Drug treat-ment of migraine attacks. In: GoadsbyPJ, Silberstein SD (eds) Headache.Butterworth-Heinemann, Boston, pp 117–130

10. Sheftell FD, Fox AW (2000) Acutemigraine treatment outcome measures:a clinician’s view. Cephalalgia20[Suppl 2]:14–24

11. Lipton RB, Silberstein SD (2001) Therole of headache-related disability inmigraine management: implications forheadache treatment guidelines.Neurology 56[Suppl 1]:S35–S42

12. Lipton RB, Stewart WF, Stone AM,Lainez MJ, Sawyer JP, for theDisability in Strategies of Care StudyGroup (2000) Stratified care vs stepcare strategies for migraine: theDisability in Strategies of Care (DISC)study. A randomized trial. JAMA284(20):2599–2605

5-HT1B/1D agonists

Efficacy data

Controlled studies have demonstrated the efficacy of 5-HT1B/1D agonists, not only on headache but also on accompa-nying symptoms (e.g. photophobia and phonophobia, nauseaand vomiting) and on functional disability [1–64]. The con-sistency of efficacy in the treatment of multiple attacks andthe long-term efficacy have also been demonstrated, especial-ly for sumatriptan administered subcutaneously or in tablets,zolmitriptan, rizatriptan, naratriptan, eletriptan, and almotrip-tan [55–77]. Slightly higher percentages of headacheresponse were found for subcutaneously administered suma-triptan compared with the other formulations of sumatriptan[78, 79]. Although studies comparing the oral formulations oftriptans are available, it is not possibile at the moment to iden-tify a parameter of overall efficacy which establishes thegreater efficacy of one triptan compared to the others [80–90].

As far as the speed of onset is concerned, a statistically sig-nificant headache response compared with placebo was foundat 15–30 minutes for sumatriptan subcutaneously administeredand at 30–60 min for every other triptan formulation [91, 92].

The administration of sumatriptan during aura appearedto neither shorten the aura duration nor prevent the subse-quent headache [93]. The administration of zolmitriptanduring aura has been shown to be effective on head pain butnot on aura symptoms and was not accompanied by signifi-cant adverse events [94]. No data in this regard are availablefor the other triptans. The percentages of headache recur-rence, emerging from the various efficacy studies, vary from20% to 40%, with slightly greater values for subcutaneous-ly given sumatriptan [95–97]. For all triptans, in any formu-lation, the efficacy of a second dose on recurrent headachehas been demonstrated [98–102]. The efficacy of the differ-ent triptans has also been confirmed on migraine attacksrelated to the menstrual cycle [103–113].

Two recent, prospective studies demonstrated that earlyoral administration of a triptan gives a better headacheresponse [114, 115]. One study showed the possibility ofpreventing migraine attack when naratriptan was taken dur-ing prodromic symptoms [116].

Observations

If headache only slightly improves after the administrationof a triptan, one should wait at least two hours before takinga second dose [117]. If no response is observed within twohours, an additional dose is not useful.

Rapid-dissolving oral formulations of rizatriptan andzolmitriptan are now available. They have an efficacy simi-lar to the tablet formulations, and pharmacokinetic data donot suggest that the highest plasma levels are reached morerapidly [118, 119]. The formulations could, however, beuseful because they are easier to take.

Approximately 25%–35% of patients do not respond totriptans. These percentages may be influenced by incorrectdiagnoses. In fact, even in specialized headache centersdiagnoses not in agreement with IHS criteria are in fact for-mulated in about 28% of the cases [120]. When the diagno-sis of migraine is confirmed, in the case of no response toone of the triptans, the use of another triptan may be con-sidered. Recent open studies have demonstrated the possi-bility of using another triptan with success, when one trip-tan fails [121, 122]. In the case of no response to one trip-tan, however, it is mandatory to reconsider the diagnosis.

Cases of daily use or abuse of triptans have been record-ed, and this may cause migraine to become a chronicheadache [123–128]. It is advisable not to exceed the rec-ommended doses.

Although use of oral triptan formulations is not recom-mended below 18 years of age, recent studies suggest theirefficacy and safety in this age group [129–136].


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Studies on the effects of different triptans in the treatmentof migraine crises during pregnancy are not available, with theexception of results of international prospective studies[137–139] relative to the monitoring of migrainous pregnantwomen who used sumatriptan. These studies did not show agreater incidence of malformations in the newborns of womenwho treated their migraine attacks with sumatriptan duringpregnancy compared to those in the general population, but inone of these studies a higher percentage of low birth-weightnewborns was associated with the use of sumatriptan as wellas a greater incidence of preterm deliveries [137–139]. Theresults available at the moment do not lead to definitive con-clusions. The use of triptans during pregnancy or by womenwho intend to become pregnant is not recommended.

Insufficient data are available to evaluate the safety oftriptan use after 65 years of age. In this case, their use is notrecommended.

Contraindications, adverse events and pharmacologicalinteractions

The use of triptans is contraindicated in the case of positivehistory or suspicion of ischemic cardiopathy, coronaryvasospasm, peripheral vascular disease, uncontrolled hyper-tension, or basilar or hemiplegic migraine [140]. Recentstudies showed that an adjustment of the zolmitriptan doseis unnecessary in the case of mild hypertension or renalinsufficiency [141–143]. If coronary disease or risk factorsfor cardiovascular diseases are suspected, an electrocardio-gram (ECG) should be carried out before beginning treat-ment with a triptan [144, 145].

The percentages of adverse events are variable in clini-cal trials and in post-marketing studies. They are frequentfor the subcutaneous formulation of sumatriptan and occa-sionally for the other triptan formulations. In the majority ofcases, they are not clinically relevant, and of short duration(generally 10–15 min) [146–165]. The most frequentadverse events are: local reactions in relationship with theroute of administration (e.g. subcutaneous, rectal, nasalspray), sensation of chest tightness, constriction or pain,flushing of the face and chest, asthenia, myalgia, somno-lence, warm or cold sensation of the head or arms, paresthe-sias, postural instability, dizziness and, sometimes, neckpain or sensation of neck stiffness. Among the severeadverse events, which occur rarely, unstable angina,myocardial infarction, cardiac arrest and ischemic strokeshould be mentioned [166–171]. Other rare adverse eventsare akathisia, dystonic crises and euphoria.

In particular, the sensation of chest tightness or pain isreferred by 4%–5% of patients treated with sumatriptan,subcutaneously administered, and by a lower percentage of

patients treated with other formulations. It can mimic anangina crisis and alarm a patient who is not adequatelyinformed. The mechanism underlying these chest symptomsis unknown: a spasm of esophageal muscles has been sug-gested [172–176]. ECG modifications have rarely beenrecorded [177]. In a recent study carried out on healthy vol-unteers with positron emission tomography (PET), no sig-nificant variations in myocardial perfusion were shown aftersubcutaneous administration of sumatriptan [178].

The most significant pharmacological interactions, froma clinical point of view, are with ergot derivatives, selectiveserotonin-reuptake inhibitors (SSRIs), monoamine oxidase(MAO) inhibitors, propranolol and drugs which are sub-strates of CYP450.

After taking a triptan, it is necessary to wait at least sixhours before taking an ergot derivative. Conversely, aftertaking an ergot derivative it is recommended to wait at least24 hours before taking a triptan [139]. Likewise for coad-ministration of the different triptans, it is advisable to wait atleast 24 hours between doses.

In the case of the coadministration of one triptan withantidepressants of the SSRI class, the occurrence of a sero-tonergic syndrome is possibile. It is characterized by motorincoordination, marked asthenia and hypereflexia [179–182].

MAO-A inhibitors should be suspended at least twoweeks before initiating treatment with a triptan [183–187].

The contemporary administration of propranolol increas-es the plasma concentration of rizatriptan [188]. In the caseof the contemporary use of propranolol, the administrationof the 5-mg dose of rizatriptan for the attack and the maxi-mum daily dose of 10 mg are recommended. Rizatriptanshould be taken at least two hours after taking propranolol.

Theoretically, rizatriptan and zolmitriptan interact withdrugs which are metabolized by CYP450 [189, 190]. Theclinical relevance of this observation should be clarified.

Administration and dosages

The following paragraphs summarize the mode of adminis-tration and the dosages of common triptans. Readers arecautioned to consult the packaging for specific governmen-tal regulations (e.g. rules, warnings, norms).

Sumatriptan is administered as follows:– Subcutaneous route: 6-mg ampoule; maximum daily

dose, 12 mg.– Oral route: 50–100 mg tablets; maximum daily dose, 200

mg.– Rectal route: 25-mg suppository; maximum daily dose,

50 mg.– Nasal spray: 1 single-dose spray (20 mg); maximum

daily dose, 40 mg.

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Zolmitriptan is administrated orally as a:– 2.5-mg tablet; maximum daily dose, 5 mg; or– 2.5-mg rapimelt formulation; maximum daily dose,

5 mg.Rizatriptan is given orally as a:

– 10-mg tablet; maximum daily dose, 20 mg; or– 10-mg rapidly dissolving wafer; maximum daily dose,

20 mg.Naratriptan is unavailable in Italy; it is marketed in other

countries as a 2.5-mg tablet; maximum daily dose, 5 mg.Eletriptan is now available in Italy in the 20-mg and 40-

mg dosages. The starting dose is 40 mg; the 80-mg dose is rec-ommended when a satisfactory response is not achieved afteran appropriate trial with 40 mg (failure to respond in 2 of 3attacks) and the drug is well tolerated. The dosage of 20 mg isrecommended in the case of liver or kidney insufficiency.

Almotriptan is now marketed in Italy as a 12.5-mg tablet;maximum daily dose, 25 mg.

Analgesics and non-steroidal anti-inflammatory drugs

Efficacy data

The most consistent evidence of efficacy is available foracetylsalicylic acid (ASA), salicylates, naproxen sodium,ibuprofen and diclofenac potassium, whereas the evidence ofefficacy for other non-steroidal anti-inflammatory drugs(NSAIDs) is more limited and weaker [191–232]. Only a fewstudies have investigated the efficacy of analgesics andNSAIDs on associated symptoms. The most consistent datasupporting the efficacy on associated symptoms concernASA, salicylates, ibuprofen and diclofenac [197–199, 207,208]. Studies into the long-term efficacy of the majority ofNSAIDs are lacking. Only one study, carried out on ASA,demonstrated the maintenance of efficacy in the treatment ofmultiple, subsequent attacks [233]. The association of certainNSAIDs with metoclopramide (aspirin, salicylates, tolfenam-ic acid, etc.) or domperidone (acetaminophen) does not sig-nificantly improve their anti-migraine effect [194, 196, 199,201, 202, 218, 222]. The association of certain NSAIDs (i.e.ASA, tolfenamic acid) with caffeine does not increase theirefficacy [220, 221, 234].

Studies comparing the various NSAIDs did not reachconclusions about the greater efficacy of any one drug ofthis class [192, 193, 205, 221, 223]. Ketoprofen, naproxensodium and tolfenamic acid showed a similar efficacy com-pared with ergotamine in association with or without caf-feine [190, 191, 213, 215, 217, 231, 235].

The use of ASA is characterized by a low percentage ofheadache recurrence [198, 200, 201]. For the other anal-gesics and NSAIDs, studies supporting their efficacy formigraine did not investigate the percentages of recurrence.

The efficacy of ASA and other NSAIDs on migraineaura has not been investigated.

In migraine crises associated with the menstrual cycle,only the efficacy of mefenamic acid has been assessed. Thedrug appeared to be significantly more effective on head painand associated symptoms compared with placebo [236].

Observations

ASA is recommended for patients with cardiovascular andcerebrovascular diseases.

Acetaminophen is the first-choice drug for the treatmentof migraine during pregnancy [237].

Studies supporting the efficacy of ketorolac by the intra-muscular route in the treatment of migraine attacks areavailable. These non placebo-controlled studies were car-ried out in the hospital setting with a limited number ofpatients [226–228].

A recent study showed that the administration of naprox-en sodium in association with sumatriptan reduces the per-centage of recurrence of migraine attacks [238]. This find-ing suggests the potential advantage of the contemporaryadministration of one NSAID and one triptan, although fur-ther studies confirming this observation are needed.

The use of the rapid dissolving formulation of ASA,even if not in association with metoclopramide, results inhigher plasma levels in comparison with the non-chewabletablet formulations [239–241].

The daily or almost daily intake of analgesics orNSAIDs can induce a chronic daily headache [242–246].This risk has also been pointed out in children and adoles-cents affected by migraine [247]. Cases of abuse of a com-bination drug containing indomethacin, caffeine andprochlorperazine associated with a chronic daily headachehave been reported [248]. Until now there is little evidencesupporting the efficacy of this combination drug onmigraine attack [249].

It should be noted that the abuse of symptomatic drugsin general, with the exception of barbiturates and narcotics,depends more consistently on the personality of the patientthan on the drug abused.


Analgesics and NSAIDs are contraindicated, other than inthe case of known hypersensitivity to these products or cor-related drugs, in patients with hemorrhagic diatheses orhemocoagulative pathologies, gastric or duodenal ulcer andsevere liver or kidney insufficiency [250–255]. Ibuprofen,

123

naproxen sodium, tolfenamic acid, piroxicam, diclofenac andketorolac are contraindicated in the case of chronic conges-tive heart failure. They are not to be given during pregnancy(especially in the first trimester). The only analgesic which isindicated during pregnancy is acetaminophen [237].Acetaminophen should not be administered to patients withglucose-6-phosphate-dehydrogenase deficiency and patientswith severe hemolytic anemia. Several NSAIDs should notbe used in patients under 14 years of age, and particularattention should be given to their administration in the elder-ly [249, 250]. Products containing acetylsalicylic acid shouldnot be used continuously in children, because of the potentialoccurrence of Reye’s syndrome [252].

The percentages of adverse events, found in clinical trialswith the aim of measuring the efficacy of analgesics andNSAIDs in the treatment of migraine attacks, is consistentlylower than those found in long-term studies which investi-gated the adverse events due to their chronic administration[252]. These adverse events are generally occasional inmigraine patients, but they may reach the percentages report-ed in the chronic administration of NSAIDs for other dis-eases, when they are taken daily or almost daily for migraine.Adverse events consist of gastrointestinal symptoms, such asgastralgias, gastric pyrosis, nausea, vomiting, and rarely gas-tric or duodenal ulcers [253, 254]. The incidence of thesedose-dependent adverse events could be reduced by the useof buffered effervescent tablets (e.g. ASA). Symptoms, suchas somnolence, asthenia, or disturbances of blood cell crasisoccur less frequently [250]. The occurrence of skin rashes orurticarial reactions, asthmatic crises, and anaphylactic reac-tions are rare [256–258]. Kidney or liver intolerance to ASAis similar to that of acetaminophen [259–262]. Other rareadverse events have been reported for each analgesic andNSAIDs. Sedation, polyuria and xerostomia have beendescribed after the administration of ketorolac. The dailyadministration of ketorolac should not exceed 7 days. Rare

adverse events due to acetaminophen are neutropenia, throm-bocytopenia or pancytopenia, as well as liver or kidneynecrosis (massive ingestion). After the administration ofketoprofen, flurbiprofen and diclofenac, hydrosaline reten-tion and an increase in creatinine levels have been reported.Also for tolfenamic/mefenamic acid, intestinal disturbancesand autoimmune hemolytic anemia have been observed [250,259]. The adverse events of indomethacin include visual dis-turbances and hematological disturbances (aplastic orhemolytic anemia, agranulocytosis, thrombocytopenia), dis-turbances of the central nervous system (CNS) such as con-fusion,vertigo, and less frequently, edema, hyperglycemiaand glycosuria.

As far as the pharmacological interactions are con-cerned, analgesics and NSAIDs should be carefully admin-istered in the case of concomitant use of anticoagulants(dicumarolic derivatives or heparin except for low molecu-lar weight heparin) and steroids because of the greater riskof bleeding consequent to their concomitant use. Their useshould be avoided in association with alcohol. NSAIDsincrease the plasma concentration of digoxin, barbituratesand lithium, whereas they reduce the effect of aldosteroneand potassium-sparing diuretics and antihypertensive drugs.Other pharmacological interactions are specific for eachanalgesic and NSAIDs, and this information should be con-sulted in the package insert.


Only the formulations for which there is evidence of efficacyin the treatment of migraine attacks are reported in Table 1.Studies supporting the efficacy of other routes of administra-tion and dosages are lacking. These formulations may be usedaccording to the indication of the physician or specialist.

Table 1 Route of administration and dosages of analgesics and non-steroidal anti-inflammatory drugs, including combination drugs avail-able in Italy

Drug Indication Administration mode and dosage

Acetylsalicylic acid Migraine Oral route: 500- or 1000-mg tablet; maximum daily dose, 2000 mg

Lysine acetylsalicylate Not indicated Oral route: 900–1800 mg powder, equivalent to 500–1000 mg acetylsalicylic acid;maximum daily dose, equivalent to 2000 mg acetylsalicylic acidIntravenous route: 900–1800 mg ampoule, equivalent to 500–1000 mg acetyl-salicylic acid; maximum daily dose, equivalent to 2000 mg acetylsalicylic acidIntramuscular route: 900–1800 mg ampoule, equivalent to 500–1000 mg acetyl-salicylic acid; maximum daily dose, equivalent to 2000 mg acetylsalicylic acid

Acetaminophen Headache Oral route: 500-mg tablet, 1000-mg effervescent tablet, 125-mg effervescentpowder, 300-mg powder; maximum daily dose, 2000 mg

Diclofenac Not indicated Oral route: 46.5-mg soluble tablet; maximum daily dose, 186 mg

the table continues �

124

Continuation of Table 1

Drug Indication Administration mode and dosage

Diclofenac potassium Not indicated Oral route: 50-mg tablet or 50-mg powder; maximum daily dose, 200 mgDiclofenac sodium Not indicated Oral route: 50-mg gastroresistant tablet, 75-mg tablet; 100-mg slow-acting

tablet; maximum daily dose, 200 mgRectal route: 100-mg suppository; maximum daily dose, 200 mgIntramuscular route: 75-mg ampoule; maximum daily dose, 150 mg

Ketoprofen Not indicated Oral route: 25-mg tablet; 50- or 100- or 200-mg capsule; 200-mg slow-actingcapsule; maximum daily dose, 200 mgRectal route: 100- or 200-mg suppository; maximum daily dose, 200 mgIntramuscular route: 50–100 mg ampoule; maximum daily dose, 200 mgIntravenous route: 100-mg ampoule; maximum daily dose, 200 mg

Ketoprofen sucralfate Not indicated Oral route: 225-mg tablet; maximum daily dose, 450 mgKetorolac tromethamine Not indicated Oral route: 10-mg tablet; maximum daily dose, 30 mg

Rectal route: 30-mg suppository; maximum daily dose, 60 mgIntramuscular route: 10-mg or 30-mg ampoule; maximum daily dose, 60 mg

Ibuprofen Headache; Oral route: 200-mg effervescent tablet, 200-mg pill, 400- or 600-mg tablet,migraine 200–600-mg powder; maximum daily dose, 1800 mg

Ibuprofen sodium salt Headache Oral route: 200-mg effervescent tablet; maximum daily dose, 1200 mgRectal route: 600-mg suppository; maximum daily dose, 1800 mg

Ibuprofen lysine salt Headache Oral route: 500-mg tablet; maximum daily dose, 1500 mgIntramuscular route: 400-mg ampoule; maximum daily dose, 1200 mg

Ibuprofen/arginine Headache Oral route: 400-mg powder; maximum daily dose, 1200 mgFlurbiprofen Not indicated Oral route: 100-mg tablet or capsule; maximum daily dose, 300 mgNaproxen Not indicated Oral route: 250-, 500- or 750-mg tablet; 500-mg powder; maximum daily dose,

1500 mgRectal route: 500-mg suppository; maximum daily dose, 1500 mg

Naproxen sodium Migraine Oral route: 220- or 550-mg tablet; 275- or 550-mg capsule; 550-mg powder;maximum daily dose, 1650 mgRectal route: 550-mg suppository; maximum daily dose, 1650 mg

Nimesulide Not indicated Oral route: 100-mg tablet, 50–100-mg powder, 100-mg capsule;maximum daily dose, 300 mgRectal route: 200-mg suppository; maximum daily dose, 400 mg

Nimesulide beta-cyclodextrin Not indicated Oral route: 400-mg powder; maximum daily dose, 800 mgPiroxicam Not indicated Oral route: 20-mg tablet, 20-mg soluble tablet, 20-mg capsule;

maximum daily dose, 40 mgIntramuscular route: 20-mg ampoule; maximum daily dose, 40 mgRectal route: 20-mg suppository; maximum daily dose, 40 mg

Mefenamic acid Not indicated Oral route: 250-mg capsule; maximum daily dose, 1500 mgIndomethacin Not indicated Oral route: 25- or 50-mg capsule; maximum daily dose, 150 mg

Rectal route: 50- or 100-mg suppository; maximum daily dose, 150 mgIndomethacin, meglumine salt Not indicated Intramuscular route: 50-mg ampoule; maximum daily dose, 100 mgPirprofen Not available in Italy Oral route: tablet. Dose tested, 400 mgTolfenamic acid Not available in Italy Oral route: tablet. Doses tested, 200–1000 mg

Combination drugsLysine acetylsalicylate + Migraine Oral route: 1620-mg tablet, equivalent to 900 mg acetylsalicylic acid + 10 mgmetoclopramide metoclopramide; maximum daily dose, 3240 mg equivalent to 1800 mg acetyl-

salicylic acid + 20 mg metoclopramideIndomethacin + prochlorperazine Migraine Oral route: pill containing 25 mg indomethacin, 2 mg prochlorperazine and+ caffeine 75 mg caffeine; maximum daily dose, 100 mg indomethacin + 8 mg

prochlorperazine + 300 mg caffeineRectal route: suppository containing 25 mg indomethacin, 4 mg prochlorperazineand 75 mg caffeine (a double-dose suppository is also available); maximumdaily dose, 100 mg indomethacin + 16 mg prochlorperazine + 300 mg caffeine

125

Combination analgesics

Combination analgesics have the same indications of sim-ple analgesics and NSAIDs. There are few well-conduct-ed studies in this regard, and the majority of them aredated [263–267]. Recent studies are available only for thecombination of acetylsalicylic acid, acetaminophen andcaffeine, and they show significant efficacy on head painin the treatment of migraine attack [268, 269]. This com-bination has been demonstrated to be effective in the treat-ment of migraine attacks associated with the menstrualcycle [270].

The combination analgesics available in Italy containacetylsalicylic acid, acetaminophen, indomethacin, with orwithout caffeine, or acetylsalicylic acid, acetaminophen andpropiphenazone.

The efficacy of the combination compounds containingacetylsalicylic acid, acetaminophen, propiphenazone has notbeen assessed for the treatment of migraine attacks,although these drugs have, at least in Italy, the generic indi-cation for headache.

The combination analgesics have the same contraindica-tions and adverse effects of each component. Caffeine inthese combination analgesics may induce agitation andinsomnia. See the single active components for their instruc-tions for use. The risk of abuse of combination analgesicshas been widely emphasized; this can lead to a chronic dailyheadache [271].

Ergot derivatives

Effectiveness data

Ergotamine tartrate, in association with caffeine or not, hasbeen shown to be significantly effective in numerous con-trolled studies, versus placebo or versus active drug, in alle-viating head pain in a migraine attack [272–277].Ergotamine tartrate does not seem to be effective on theassociated symptoms of nausea and vomiting; rather,because of the interaction with dopaminergic receptors, itmay itself induce or increase nausea and vomiting. Data tosupport the effectiveness of the association of ergotamine,caffeine and aminophenazone in the treatment of a migraineattack are lacking.

Ergotamine tartrate administration is associated with alow incidence of headache recurrence (<30%). Its use iscontroversial for migraine aura, but studies in this regardare lacking.

Up to the advent of the triptans, dihydroergotamineby parenteral route (no longer distributed in Italy) hadbeen the first-choice treatment for migraine attack,

because it was better tolerated than ergotamine tartrate,especially in out-patient settings, in the emergencydepartment or hospital setting. In controlled studies vs.either placebo or active drugs, dihydroergotamine waseffective in alleviating head pain during a migraineattack [278–283].

Dihydroergotamine nasal spray is effective in thecourse of migraine attacks with percentages analogous tothose found for ergotamine plus caffeine in relievinghead pain, but with fewer side effects [284–294]. Lessconclusive results have been obtained for ergotamineadministered intramuscularly or intravenously, althoughthey are indicative of a discrete but significant effective-ness in the symptomatic treatment of migraine attack[282, 283].

Dihydroergotamine, both in the subcutaneous and nasalspray formulations, is less effective than subcutaneouslyadministered sumatriptan in relieving head pain and accom-panying symptoms, but is associated with a small percent-age of headache recurrence [15].

A single trial with dihydroergotamine nasal sprayhas shown its greater effectiveness statistically com-pared to placebo, in reducing prodromic symptoms ofmigraine [292].

Observations

Caffeine doubles the rate of absorption of ergotamine andincreases its peak blood concentration. This prompted thedevelopment of combination formulations containing ergot-amine and caffeine.

Because nausea and vomiting may be worsened bythe administration of ergot derivatives, the contempo-rary administration of an antiemetic is generally indicat-ed. The formulation of dihydroergotamine nasal spraymay be more manageable if nausea and vomiting arepresent.

The intravenous formulation of dihydroergotamine is notavailable in Italy. In America and in other European coun-tries this treatment is recommended: for migraine crisesresistant to treatment, especially in an in-patient setting, inthe emergency department, in the treatment of statusmigrainosus and in chronic daily headache associated withanalgesic or NSAIDs abuse [295, 296].

Patients who regularly use ergot derivatives for morethan 2–3 days/week can develop rebound headache [248,297–300]. The abuse of ergot derivatives may induce anincrease in the frequency of the attacks and develop into achronic daily headache. Their use is not recommended in thetreatment of attacks of medium/high frequency, for thepotential risk of abuse.

126


Ergotamine tartrate and dihydroergotamine are contraindi-cated in pregnancy, in uncontrolled hypertension, and inthe presence of arteriovenous shunts, mitral stenosis,ischemic cardiopathy, cerebrovascular disease, or liver orrenal failure [301].

The principal adverse events due to the use of ergota-mine tartrate are nausea and vomiting (10%). Abdominalpain, diarrhea and muscular cramps have also been record-ed, and, rarely, distal paresthesias [302].

Its chronic administration may induce ergotism, acro-cyanosis, ulcerous distal necrosis, ischemic neuropathies,and pericardial, pleural or retroperitoneal fibrosis [303].

The adverse events consequent to the administration ofdihydroergotamine are analogous to those detected for ergo-tamine tartrate but they occur less frequently [304]. Thenasal spray formulation of dihydroergotamine induces rareadverse events that include nasal obstruction and muscularcramps [293].

As far as pharmacological interactions are concerned,ergot derivatives should not be administered within 6 hoursafter the administration of a triptan.

An increase in the risk of peripheral vasoconstriction canbe observed in patients who are concomitantly treated withbeta-blockers. Although the majority of the patients are ableto tolerate such association, caution is necessary in particu-larly sensitive patients.

Erythromycin, josamycin and other macrolide antibioticsslow the metabolization of the ergot derivatives, increasingtheir plasma levels. Both ergotamine and dihydroergotamineshould not be administered together or temporally near toother vasoconstrictive drugs, including triptans.


Ergotamine is administered via the:– Oral route: 1-mg tablet; daily maximum dose, 6 mg, not

to be repeated on the following four days, not to exceeda total dose of 10 mg/week

– Rectal route: 0.5–2.0 mg doses have been tested; dailymaximum dose, 4 mg, not to be repeated on the follow-ing four days, not to exceed a total dose of 10 mg/week

– Subcutaneous route: 0.25-mg vial; daily maximum dose,0.50 mg

– Intramuscular route: 0.25- or 0.50-mg ampoule; dailymaximum dose, 0.50 mgDihydroergotamine is administered as an intranasal

spray at a dosage of 1–2 mg (1 spray of 0.5 mg per nostril);if necessary sprays can be repeated after 10–15 minutes, 1spray per nostril; daily maximum dose, 2 mg.

Ergotamine and caffeine are administered as follows:– Oral route: tablet containing 1 mg ergotamine and 100

mg caffeine; daily maximum dose, 4 mg ergotamine and400-mg caffeine

– Rectal route: suppository containing 2.0 mg ergotamineand 100 mg caffeine; daily maximum dose, 4 mg ergot-amine and 200 mg caffeine Ergotamine, caffeine and aminophenazone are adminis-

tered via the rectal route: in suppositories containing 0.5 or2.0 mg ergotamine, 100 mg caffeine and 250 mgaminophenazone; daily maximum dose, 4 mg ergotamine,200 mg caffeine, 500 mg aminophenazone.

Antiemetics

Efficacy data

Such a heterogeneous class includes various drugs, whichdiffer pharmacologically from each other. Relatively fewstudies have investigated their effectiveness in migrainecrises, particularly for the oral formulations. Such studiesconcern, in the majority of cases, the combinations withASA and other NSAIDs (e.g. naproxen, ketorolac, aceta-minophen, tolfenamic acid) and dihydroergotamine [64,194, 196, 200–202, 220, 305–308]. These associations havebeen proposed to improve the absorption of the sympto-matic drugs and to act as adjuvants in reducing the nauseaand vomiting accompanying a migraine attack.

No data are available for domperidone. The only find-ings have been obtained in a limited number of migrainepatients, which suggest a potential moderate effectiveness inpreventing and reducing head pain intensity during amigraine attack [309]. There is no evidence in this sense forother antiemetics.

Metoclopramide and prochlorperazine, administered byrectal route, have also been shown to have a bland anti-migraine effect, besides a clear antiemetic effect [310–312].A modest effectiveness in the treatment of migraine attackshas also been found for metoclopramide administered intra-muscularly or intravenously [313–316].

There are also data supporting a partial efficacy in thesymptomatic treatment of migraine of prochlorperazine andchlorpromazine administered intramuscularly or intra-venously [317–322].

Observations

The oral and rectal antiemetic formulations are to be con-sidered adjuvants in the symptomatic therapy of migraine.The intramuscular and intravenous formulations may be

127

used for the treatment of attacks of moderate or severe inten-sity, in which nausea and vomiting prevail and when othersymptomatic drugs are contraindicated or sedation is neces-sary. Prochlorperazine and chlorpromazine may also be con-sidered as monotherapy for the treatment of migraineattacks, especially in determined clinical settings (i.e. emer-gency departments).

Current evidence is not enough to include drugs of theclass of the 5-HT3 antagonists (e.g. granisetron, zatosetron)among the symptomatic treatments for migraine attacks asmonotherapy. In particular clinical settings (i.e. emergencydepartments) and in selected patients, it is possible, however,to consider such drugs as adjuvants in relieving nausea andvomiting in the course of a migraine attack [323, 324]. It isimportant to remember that cases of headache induced by theadministration of ondansetron have been reported [325].

Contraindications, adverse events, pharmacological inter-actions

Metoclopramide is contraindicated in patients affected bypheochromocytoma or epilepsy and in patients receivingdrugs which can potentially induce extrapyramidal reactions(e.g. monoamine oxidase inhibitors, neuroleptics such asphenothiazines, butyrophenones). The use of domperidoneis not recommended in patients with prolactinoma. The useof metoclopramide, chlorpromazine and prochlorperazinemust be limited only to cases of extreme necessity in preg-nancy and during breast feeding.

The occurrence of adverse events following administra-tion of metoclopramide is rare and is represented byextrapyramidal symptoms (particularly dystonia) [326].Such eventuality has not been found for domperidone thatdoes not cross the blood-brain barrier [327]. The principaladverse events emerging from various studies concerningthe administration of chlorpromazine and prochlorperazineare drowsiness and sedation [328, 329]. Acute dystoniccrises and akathisia have been rarely recorded [330–333].An adverse event rarely found with chlorpromazine is pos-tural hypotension, particularly if the drug is coadministeredwith an antihypertensive drug [334, 335].

The occurrence of adverse events due to the administra-tion of phenothiazines is facilitated by the consumption ofalcohol or by the administration of propranolol, which raisesits plasma levels [330].

As far as pharmacological interactions are concerned, itis important to note that anticholinergic drugs, antacids andantisecretory drugs may antagonize the effects of metoclo-pramide and domperidone on gastric motility.Metoclopramide, prochlorperazine and chlorpromazinemust not be coadministered with analgesic narcotics, seda-

tives, hypnotics and tranquilizers due to their synergisticdepressive effect on the CNS [328].

Prochlorperazine and chlorpromazine may lower theanticonvulsive threshold. They should therefore be usedwith caution in the epileptic patients [336]. For other inter-actions see the relative information for each active drug.


Metoclopramide is administered as follows:– Oral route: 10-mg tablet, 0.4% drops, 0.1% syrup, 5-mg

granular effervescent powder; maximum daily dose, 30 mg – Intramuscular or intravenous route: 10-mg ampoule;

maximum daily dose, 30 mgDomperidone is given via the:

– Oral route: 10-mg tablet, 0.1% syrup, 5-mg effervescentpowder; daily maximum dose, 30 mg

– Rectal route: 30-mg suppository; daily maximum dose,30 mg Prochlorperazine can be administered by the:

– Oral route: available as a 5-mg dimaleate tablet; has notbeen tested for the symptomatic treatment of migraine

– Rectal route: 10-mg suppository; daily maximum dose,20 mg

– Intramuscular route: 10-mg dose has been tested– Intravenous route: 10-mg dose has been tested

Chlorpromazine is given via the:– Oral route: available as 25- or 50-mg tablet, not tested

for the symptomatic treatment of migraine – Intramuscular route: tested at 0.1 mg/kg up to 3 doses

every 30 min; maximum dosage administered 1 mg/kg– Intravenous route: tested from 12.5 mg to 37.5 mg

Granisetron is administered intravenously. A dose of 40mg/kg body weight has been tested.

Zatosetron, although not available in Italy, is given intra-venously. The 13-mg dose has been tested.

Other therapeutic strategies

Analgesic opioids

Different controlled studies have shown the effectiveness ofacetaminophen in association with codeine, or with doxyl-amine and buclizine on migraine headache [223, 264–267].Such association has been shown, nevertheless, to be no moreeffective than acetaminophen alone. In a more recent studythe combination of acetaminophen and codeine has not beenshown to be more effective than acetylsalicylic acid in reliev-ing the head pain of migraine attack [195]. A further study has

128

not shown the superiority of the association of acetylsalicylicacid with dextropropoxiphene and phenazone in comparisonto ergotamine [275]. Also, butorphanol (not available in Italy)by intramusular route has not been shown to be more effec-tive than dihydroergotamine administered intramuscularly inassociation with metoclopramide [280]. Research comparingbutorphanol nasal spray with other symptomatic therapies formigraine are lacking [337–340]. Clinical trials which com-pared mepiramine with ketorolac administered by intramus-cular route, dihydroergotamine, chlorpromazine ormetrotrimetazine in the treatment of migraine attacks havenot reached conclusive results on their real effectiveness onhead pain [224, 225, 282, 284, 302, 341].

The Ad Hoc Committee has unanimously decided that sucha class of drugs does not represent a valid option for the treat-ment of migraine crises. This is due to the absence of a moresignificant headache response compared to that found for othersymptomatic antimigraine drugs and because of the potentialrisk of developing a chronic daily headache [342–344].

Patients who frequently use analgesic opioids and con-sult different physicians for their prescriptions are generallycharacterized by a particular personality trait that may con-tribute to maintain or to worsen abuse. In this sense, theyshould be directed to and followed by specialized centers.

Barbiturates

Data are not available to support the effectiveness of barbi-turates in the treatment of migraine attacks. Their use shouldbe avoided for the potential occurrence of abuse or reboundheadache, and for the development of a chronic dailyheadache.

Lidocaine

There is no evidence to support the effectiveness of lidocaineadministered intravenously for the treatment of migraineattack. The results of two prospective studies point out a mod-est, but significant effectiveness, although it is accompaniedby too frequent and early headache recurrence [345–347].

Dexamethasone and hydrocortisone

Three studies have been carried out on limited numbers ofpatients. They have furnished conflicting results that do notallow definitive conclusions to be drawn on the effective-ness of intravenously administered steroids in the treatment

of migraine attacks, especially in the case of headachesresistant to treatment [348–351]. Steroids are therapeuticoptions for the treatment of status migrainosus.

Diazepam

One study has shown that neither diazepam norclormezanone significantly improve the antimigraine effectof the association of metoclopramide, intramuscularlyadministered, and acetaminophen, orally administered[352]. The members of the Ad Hoc Committee concur not torecommend such a drug for migraine attack.

Isometheptene and combination drugs containingisometheptene mucate

Isometheptene has shown a modest effectiveness onmigraine crises of moderate intensity in dated studies[353–355]. Combination drugs containing isometheptenemucate, acetaminophen and dichlorphenazone appeared tobe more effective than the combination of ergotamine andcaffeine (midrin) in relieving head pain, with a lower inci-dence of side effects, such as nausea and vomiting[356–358]. Such compounds are not available in Italy.

Level of evidence, scientific strength of evidence,assessment of clinical effectiveness

Drugs used in the symptomatic treatment of migraine arereported in Table 2 with the respective level of evidence, sci-entific strength of evidence and assessment of clinical effec-tiveness. The frequency of adverse events is also shown.

The definitions of frequency and severity of adverseevents are given in the Glossary. Information on frequencyand severity of adverse events from post-marketing studiescarried out on large samples of migraineurs is available onlyfor triptans. For the other drugs, only the percentages ofadverse events registered on a limited number of patients areavailable. These percentages may also differ consistentlyfrom those registered in the case of chronic use of certaindrugs, such as non-steroidal anti-inflammatory drugs.

The recommendation groups, based on the level of evi-dence, scientific strength of evidence, assessment of clinicaleffectiveness as well as on the frequency and severity ofadverse events for symptomatic antimigraine therapy arereported in Table 3. The principal pharmacological interactionsof these drugs in migraine treatment are reported in Table 4.

129

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eaD

T, 6

.5, 1

2.5,

25,

100

mg

or v

omiti

ng p

reva

il) o

r is

not

pre

ferr

edSE

D, 2

5-m

g su

ppos

itory

Sum

atri

ptan

A+

++

++

Occ

asio

nal,

not s

ever

eU

sefu

l whe

n or

al r

oute

is n

ot p

ossi

ble

(whe

n na

usea

DT,

1–4

0 m

gor

vom

iting

pre

vail)

or

is n

ot p

refe

rred

.SE

D, 2

0-m

g na

sal s

pray

Zol

mitr

ipta

nA

++

++

++

Occ

asio

nal,

not s

ever

eG

ood

tole

rabi

lity

prof

ileD

T, 2

.5–5

.0 m

gSE

D, 2

.5-m

g ta

blet

Zol

mitr

ipta

nA

++

++

++

Occ

asio

nal,

not s

ever

eE

asy

to u

seD

T, 2

.5 m

gSE

D, 2

.5 m

g ra

pim

elt

Riz

atri

ptan

A+

++

++

+O

ccas

iona

l, no

t sev

ere

Goo

d to

lera

bilit

y pr

ofile

DT,

5–4

0 m

gSE

D, 1

0-m

g ta

blet

Riz

atri

ptan

RPD

A

++

++

++

Occ

asio

nal,

not s

ever

eE

asy

to u

seD

T, 1

0 m

gE

letr

ipta

nA

++

+N

AO

ccas

iona

l, no

t sev

ere

Goo

d to

lera

bilit

y pr

ofile

and

low

rec

urre

nce

DT,

20–

80 m

gSE

D, 2

0- o

r 40

-mg

tabl

eta

Alm

otri

ptan

A+

++

NA

Occ

asio

nal,

not s

ever

eG

ood

tole

rabi

lity

prof

ile a

nd lo

w r

ecur

renc

eD

T, 2

–150

mg

SED

, 12.

5-m

g ta

blet

a

Nar

atri

ptan

A+

+N

AO

ccas

iona

l, no

t sev

ere

Les

s ra

pid

onse

t of

actio

n an

d a

low

er r

ecur

renc

eD

T, 1

–25

mg

SED

, 2.5

-mg

tabl

eta

Ana

lges

ics

and

non-

ster

oida

l an

ti-i

nfla

mm

ator

y dr

ugs

(NSA

IDs)

Ace

tyls

alic

ylic

aci

dA

++

++

+O

ccas

iona

l, no

t sev

ere

Goo

d ef

fica

cy/to

lera

bilit

y pr

ofile

DT,

500

–100

0 m

gSE

D, 5

00–1

000

mg

per

os

the

tabl

e co

ntin

ues

�

130C

onti

nuat

ion

of T

able

2

Dru

gL

evel

of

Scie

ntif

ic s

tren

gth

Clin

ical

A

dver

se e

vent

sO

bser

vatio

nsev

iden

ceof

evi

denc

eef

fect

iven

ess

Lysi

ne a

cety

lsal

icyl

ate

(dos

ages

equ

ival

ent

A+

++

++

Occ

asio

nal,

not s

ever

eFo

r us

e pr

edom

inan

tly in

a c

linic

al s

ettin

gto

500

-100

0 m

g of

ace

tyls

alic

ylic

aci

d) p

er o

sb

Lysi

ne a

cety

lsal

icyl

ate,

equ

ival

ent t

o 10

00 m

gA

++

++

+O

ccas

iona

l, no

t sev

ere

For

use

pred

omin

antly

in a

clin

ical

set

ting

ASA

IVD

T,do

seeq

uiva

lent

to10

00 m

gac

etyl

salic

ylic

aci

dC

alci

um c

arba

sala

te +

met

oclo

pram

ide

B+

NA

Occ

asio

nal,

not s

ever

eFo

r us

e pr

edom

inan

tly in

a c

linic

al s

ettin

gD

T, e

quiv

alen

t to

900

mg

ASA

+10

mg

met

oclo

pram

ide,

per

osa

Dic

lofe

nac

pota

ssiu

m

A+

++

+O

ccas

iona

l, no

t sev

ere

DT,

50–

100

mg

SED

, 100

mg

per

osD

iclo

fena

c so

dium

B

++

++

+O

ccas

iona

l, no

t sev

ere

SED

, 75

mg

IMFl

urbi

prof

en

B+

+O

ccas

iona

l, no

t sev

ere

SED

, 100

–300

mg

per

osIb

upro

fen

A+

++

+O

ccas

iona

l, no

t sev

ere

DT,

400

–240

0 m

gSE

D, 4

00–1

200

mg

per

osIn

dom

etha

cin

C+

+Fr

eque

nt, n

ot s

ever

eSE

D, 2

5–50

mg

per

os o

r su

ppos

itory

Indo

met

haci

n +

proc

lorp

eraz

ine

+C

++

Tho

se o

f ea

ch a

ctiv

e R

isk

of a

buse

and

CD

Hca

ffei

ne, p

er o

sco

mpo

und.

Ins

omni

a D

T, 2

5 m

g +

2 m

g +

75

mg

poss

ible

Indo

met

haci

n +

proc

lorp

eraz

ine

+ c

affe

ine,

C+

+T

hose

of

each

act

ive

Ris

k of

abu

se a

nd C

DH

supp

osito

ryco

mpo

und.

Ins

omni

a D

T, 2

5–50

mg

+ 4

–8 m

g +

75–

150

mg

poss

ible

Ket

opro

fen

B+

++

+Fr

eque

nt, n

ot s

ever

eD

T, 1

00 m

g IM

SED

, 100

mg

IMK

etor

olac

B

++

++

+Fr

eque

nt, n

ot s

ever

eIn

pub

lishe

d st

udie

s it

was

pre

dom

inan

tly u

sed

inD

T, 3

0–60

mg

IMpa

rtic

ular

clin

ical

set

tings

(em

erge

ncy

depa

rtm

ent)

SED

, 30–

60 m

g IM

Mef

enam

ic a

cid

B+

++

++

Occ

asio

nal,

not s

ever

eE

ffec

tive

in m

enst

rual

mig

rain

eSE

D, 5

00 m

g pe

r os

Nap

roxe

n B

++

+O

ccas

iona

l, no

t sev

ere

DT,

750

–125

0 m

gSE

D, 7

50–1

500

mg

per

os

the

tabl

e co

ntin

ues

�

131

Con

tinu

atio

n of

Tab

le 2

Dru

gL

evel

of

Scie

ntif

ic s

tren

gth

Clin

ical

A

dver

se e

vent

sO

bser

vatio

nsev

iden

ceof

evi

denc

eef

fect

iven

ess

Nap

roxe

n so

dium

A

++

++

Occ

asio

nal,

not s

ever

eD

T, 7

50–1

750

mg

SED

, 750

–150

0 m

g pe

r os

Nim

esul

ide

C0

+O

ccas

iona

l, no

t sev

ere

Use

d in

a s

ingl

e st

udy

in th

e in

term

itten

t pro

phyl

axis

SED

, 200

mg

per

osof

men

stru

al m

igra

ine

Ace

tam

inop

hen

B+

++

Rar

e, n

ot s

ever

eD

T, 6

50–1

500

mg

SED

, 500

–100

0 m

g pe

r os

Piro

xica

m

B+

++

Occ

asio

nal,

not s

ever

eD

T, 4

0 m

g R

PD p

er o

sSE

D, 4

0 m

g R

PD p

er o

sPi

rpro

fen

B+

NA

Occ

asio

nal,

not s

ever

eD

T, 4

00 m

g pe

r os

a

Tolf

enam

ic a

cid

B+

NA

Occ

asio

nal,

not s

ever

eD

T, 2

00–4

00 m

g pe

r os

a

Com

bina

tion

ana

lges

ics,

per

os

Ace

tam

inop

hen

+ a

cety

lsal

icyl

ic a

cid

+A

++

++

+T

hose

of

each

act

ive

Eff

ectiv

e in

men

stru

al m

igra

ine.

Ris

k of

CD

H w

ith

caff

eine

com

poun

d. I

nsom

nia

repe

ated

use

DT,

500

mg

+ 50

0 m

g +

130

mg

poss

ible

Opi

oid

anal

gesi

cs, p

er o

sPa

race

tam

ol +

cod

eine

B+

++

+Fr

eque

nt, n

ot s

ever

e;R

isk

of C

DH

with

rep

eate

d us

eD

T, 4

00–6

50 m

g +

6–25

mg

seda

tion,

ast

heni

a,na

usea

, ver

tigo

Ant

iem

etic

sM

etoc

lopr

amid

e C

00

Occ

asio

nal:

Adj

uvan

t for

nau

sea

and

vom

iting

SED

, 10-

mg

supp

osito

ryex

trap

yram

idal

sig

ns

(in

part

icul

ar d

ysto

nia)

and

seda

tion

Met

oclo

pram

ide

C+

+Sa

me

as f

or

Sam

e as

for

met

oclo

pram

ide,

per

os

DT,

10

mg

met

oclo

pram

ide,

per

os

SED

, 10-

mg

supp

osito

ryM

etoc

lopr

amid

e C

++

Sam

e as

for

Sam

e as

for

met

oclo

pram

ide,

per

os

DT,

10

mg

IMm

etoc

lopr

amid

e, p

er o

sSE

D, 1

0 m

g IM

the

tabl

e co

ntin

ues

�

132C

onti

nuat

ion

of T

able

2

Dru

gL

evel

of

Scie

ntif

ic s

tren

gth

Clin

ical

A

dver

se e

vent

sO

bser

vatio

nsev

iden

ceof

evi

denc

eef

fect

iven

ess

Met

oclo

pram

ide,

0.1

mg/

kg b

ody

wei

ght I

VB

++

Mor

e fr

eque

nt th

an

Use

d in

par

ticul

ar c

linic

al s

ettin

gsD

T, 1

- to

3-t

imes

per

day

; w

ith th

e or

al f

orm

ulat

ion

max

imum

dos

e, 1

0 m

gSE

D, 0

.1 m

g/kg

1-

to 3

-tim

es p

er d

ayPr

ochl

orpe

razi

ne, 2

0-m

g su

ppos

itory

B+

++

+R

are.

The

mos

t A

djuv

ant f

or n

ause

a an

d vo

miti

ngfr

eque

nt is

sed

atio

nPr

ochl

orpe

razi

ne

B+

++

+R

are.

The

mos

t A

djuv

ant f

or n

ause

a an

d vo

miti

ng

DT,

10

mg

IMc

freq

uent

is s

edat

ion

SED

, 10

mg

IMc

Proc

hlor

pera

zine

B

++

++

Gre

ater

occ

urre

nce

Mor

e ef

fica

ciou

s th

an m

etoc

lopr

amid

e. U

sed

in

DT,

10

mg

IVc

of s

edat

ion

part

icul

ar c

linic

al s

ettin

gs (

emer

genc

y de

part

men

t)SE

D, 1

0 m

g IV

c

Chl

orpr

omaz

ine

C+

+O

ccas

iona

l, no

t sev

ere:

A

djuv

ant f

or n

ause

a an

d vo

miti

ngD

T, 0

.1 m

g/kg

to 3

dos

es e

very

30

min

;se

datio

n, o

rtho

stat

ic

max

imum

dos

age,

1 m

g/kg

bod

y w

eigh

thy

pote

nsio

nC

hlor

prom

azin

e IV

B+

++

+O

ccas

iona

l, no

t sev

ere:

Adj

uvan

t for

nau

sea

and

vom

iting

. Use

d in

D

T, 1

2.5–

37.5

mg

seda

tion,

ort

host

atic

part

icul

ar c

linic

al s

ettin

gs (

emer

genc

y de

part

men

t)hy

pote

nsio

nD

ompe

rido

ne

C+

+R

are

Adj

uvan

t for

nau

sea

and

vom

iting

DT,

30–

120

mg

per

os o

r su

ppos

itory

SED

, 10–

30 m

g pe

r os

or

supp

osito

ry

Erg

ot a

lkal

oids

and

erg

ot d

eriv

ativ

esE

rgot

amin

e B

+N

AFr

eque

nt, n

ot s

ever

eR

isk

of a

buse

and

dev

elop

ing

CD

H; i

n th

e ca

se o

fD

T, 1

–6 m

g pe

r os

, SC

, IM

; 1–4

mg

abus

e er

gotis

m c

an o

ccur

supp

osito

rySE

D, 1

–2 m

g pe

r os

, sup

posi

tory

, SC

, IM

a

Erg

otam

ine

(2 m

g) +

caf

fein

e (2

00 m

g),

B

+N

AFr

eque

nt, n

ot s

ever

eR

isk

of a

buse

and

dev

elop

ing

CD

H; i

n th

e ca

se o

fpe

r os

or

supp

osito

ry a

abus

e er

gotis

m c

an o

ccur

DT,

2–6

mg

ergo

tam

ine

+20

0–60

0 m

g ca

ffei

neE

rgos

tine

(2 m

g) +

caf

fein

e (2

00 m

g)a

B

+N

AFr

eque

nt, n

ot s

ever

eD

ihyd

roer

gota

min

e A

++

+

++

Occ

asio

nal,

not s

ever

e:Fe

wer

sid

e ef

fect

s th

an w

ith e

rgot

amin

eD

T, 0

.5–4

.0 m

gna

sal c

onge

stio

n,

SED

, 2 m

g na

sal s

pray

naus

ea a

nd v

omiti

ngD

ihyd

roer

gota

min

eB

++

NA

From

fre

quen

t to

DT,

1 m

g IM

occa

sion

al, n

ot s

ever

e:

SED

, 1 m

g IM

naus

ea, v

omiti

ng,

dysp

hori

a, f

lush

ing,

an

xiet

y, r

estle

ssne

ss

the

tabl

e co

ntin

ues

�

133

Con

tinu

atio

n of

Tab

le 2

Dru

gL

evel

of

Scie

ntif

ic s

tren

gth

Clin

ical

A

dver

se e

vent

sO

bser

vatio

nsev

iden

ceof

evi

denc

eef

fect

iven

ess

Dih

ydro

ergo

tam

ine

B

++

+N

AO

ccas

iona

l, no

t sev

ere:

D

T, 1

mg

SCa

naus

ea,v

omiti

ng,

SED

, 1 m

g SC

ady

spho

ria,

flu

shin

g,

anxi

ety,

res

tless

ness

Dih

ydro

ergo

tam

ine,

IV

aB

++

N

AM

ore

freq

uent

than

for

Mor

e ef

fica

ciou

s th

an th

e SC

and

IM

for

mul

atio

nsD

T, 0

.5–4

.0 m

g th

e SC

and

IM

of d

ihyd

roer

gota

min

efo

rmul

atio

nsD

ihyd

roer

gota

min

e +

met

oclo

pram

ide

IVa

B

++

+N

AFr

eque

ntA

ssoc

iatio

n w

ith m

etoc

lopr

amid

e re

duce

s na

usea

D

T, 0

.5–1

.0 m

g di

hydr

oerg

otam

ine

+

and

vom

iting

10 m

g m

etoc

lopr

amid

e

Bar

bitu

rate

hyp

noti

csB

utal

bita

l + a

cety

lsal

icyl

ic a

cid

+

C+

++

From

fre

quen

t to

Ris

k of

abu

se a

nd C

DH

or

rebo

und

head

ache

caff

eine

, per

os

occa

sion

al; t

he m

ost

DT,

50

mg

+ 32

5 m

g +

40 m

gfr

eque

nt is

sed

atio

nB

utal

bita

l + a

cety

lsal

icyl

ic a

cid

+ ca

ffei

ne +

B+

+N

AFr

om f

requ

ent t

oR

isk

of a

buse

and

CD

Hco

dein

e, p

er o

saoc

casi

onal

; the

mos

tD

T, 5

0 m

g +

325

mg

+ 40

mg

+ 30

mg

freq

uent

is s

edat

ion

Oth

er d

rugs

Dex

amet

haso

ne

C+

+R

are

Use

sho

uld

be li

mite

d to

a s

hort

per

iod.

Ind

icat

ed in

DT,

6 m

g IV

stat

us m

igra

inos

usH

ydro

cort

ison

e C

++

Rar

e U

se s

houl

d be

lim

ited

to a

sho

rt p

erio

d. I

ndic

ated

inD

T, 5

0 m

g IV

stat

us m

igra

inos

usL

idoc

aine

, int

rana

sal

B

++

N

AO

ccas

iona

l; na

sal

Shor

t dur

atio

n of

act

ion

and

poss

ible

rec

urre

nce

of

DT,

4%

sol

utio

n, 1

–4 d

rops

irri

tatio

nhe

adac

heIs

omet

hept

ene,

per

osa

B+

NA

Can

indu

ce a

uton

omic

DT,

130

–780

mg

dysf

unct

ion

(e.g

.sy

mpa

thet

ic h

yper

activ

ity)

Isom

ethe

pten

e m

ucat

e +

ace

tam

inop

hen

+B

+

N

AC

an in

duce

aut

onom

ic

dich

lora

lphe

nazo

ne, p

er o

sady

sfun

ctio

n (e

.g.

DT,

65

mg

+ 32

5 m

g +

100

mg,

2-

tosy

mpa

thet

ic h

yper

activ

ity)

6-tim

es p

er d

ay

a N

ot a

vaila

ble

in I

taly

b In

trod

uctio

n of

lysi

ne a

cety

lsal

icyl

ic a

cid,

per

os,

has

bee

n ca

rrie

d ou

t acc

ordi

ng to

the

equi

vale

nt d

oses

for

ace

tyls

alic

ylic

aci

d, d

ue to

the

lack

of

stud

ies

whi

ch d

irec

tly in

vest

igat

-ed

the

oral

form

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ions

with

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e do

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nly

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stud

y as

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ed th

e ef

fica

cy o

f the

equ

ival

ent d

ose

for a

cety

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(900

mg)

in a

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ble,

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ever

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omet

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ne.

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os:

2 m

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ochl

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zine

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mg

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met

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uppo

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ry: 8

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hlor

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zine

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mg

indo

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134

Table 3 Drugs for symptomatic treatment of migraine grouped by level of recommendation, based on the level of evidence, scientificstrength of evidence, and assessment of clinical effectiveness. Drugs are listed in alphabetical order

Level I Level II Level III Level IV

Acetylsalicylic acid, per os Acetaminophen, per os Acetaminophen, per osa Butalbital + propiphenazone +

Almotriptan, per os Acetaminophen + Acetylsalicylic acid + butalbital caffeine, per os, suppository

Dihydroergotamine, nasal spray acetylsalicylic acid + + caffeine, per osa Dexamethasone IV

Dihydroergotamine, IM IV* caffeine, per os* Ergotamine, per osa, * Domperidone, per os

(also in association with Acetaminophen + codeine, per os Ergostine + caffeine, per osa Granisetron IV

an antiemetic) Acetylsalicylic acid + butalbital Ergotamine + caffeine, per osa Hydrocortisone IV

Eletriptan, per os + caffeine + codeine, per osb Indomethacin + prochlorperazine + Metoclopramide, per os

Ibuprofen, per os Chlorpromazine IM, IV caffeine, per os, suppositorya Nimesulide, per os

Lysine acetylsalicylate, per os Diclofenac, per os Isometheptene and isometheptene Zatosetron IV*

Lysine acetylsalicylate + Ergotamine IM, SC mucate, per osa, *

metoclopramide, per os Flurbiprofen, per os Lidocaine IVa

Naproxen sodium, per os Ketoprofen, per os Metoclopramide IM,

Naratriptan, per os* Ketorolac IM suppositorya

Rizatriptan, per os Lidocaine, intranasal Piroxicam, rapidly dissolving

Sumatriptan SC, nasal spray, Metoclopramide IV formulation, per osa

per os, suppository Naproxen, per os Pirprofen, per osa,*

Zolmitriptan, per os Prochlorperazine IM, IVa

* Not available in Italy; a Drugs with no severe adverse eventsIM, intramuscularly; IV, intravenously; SC, subcutaneously

Table 4 Major pharmacological interactions among drugs for the symptomatic treatment of migraine

Triptans Serotonergic agonists Other triptans Ergotamine derivatives Sibutramin

Ergot derivatives Beta-blockers Triptans

NSAIDs Other NSAIDsHeparin

Diclofenac MethotrexateTacrolimus

Ketorolac LithiumSalicylates Oral anticoagulants

Tramadol Tricyclic antidepressants NeurolepticsSSRIs

AntiemeticsDomperidone LithiumPhenothiazines Cisapride

LithiumTramadol

Metoclopramide Digoxin

Butalbital Oral anticoagulants

NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin-reuptake inhibitors

135

References

1. Ensink FB (1991) Subcutaneoussumatriptan in the acute treatment ofmigraine. Sumatriptan InternationalStudy Group. J Neurol 238[Suppl1]:S66–S69

2. Cady RK, Wendt JK, Kirschner JR,Sargent JD, Rothrock JF, Skaggs H Jr(1991) Treatment of acute migrainewith subcutaneous sumatriptan.JAMA 265(21):2831–2835

3. The Subcutaneous SumatriptanInternational Study Group (1991)Treatment of migraine attacks withsumatriptan. N Engl J Med325(5):316–321

4. Sumatriptan Auto-Injector StudyGroup (1991) Self-treatment of acutemigraine with subcutaneous suma-triptan using an auto-injector device.Eur Neurol 31(5):323–331

5. Mathew NT, Dexter J, Couch J,Flamenbaum W, Goldstein J,Rapoport A, Sheftell F, Saper J,Silberstein S, Solomon S et al for theUS Sumatriptan Research Group(1992) Dose ranging efficacy andsafety of subcutaneous sumatriptan inthe acute treatment of migraine. ArchNeurol 49(12):1271–1276

6. Bousser MG, d’Allens H, Richard A(1993) Efficacy of subcutaneoussumatriptan in the acute treatment ofearly-morning migraine: a placebo-controlled trial. Early MorningMigraine Sumatriptan Study Group. JIntern Med 234(2):211–216

7. Cady RK, Dexter J, Sargent JD,Markley H, Osterhaus JT, Webster CJ(1993) Efficacy of subcutaneoussumatriptan in repeated episodes ofmigraine. Neurology43(7):1363–1368

8. Henry P, d’Allens H for the FrenchMigraine Network Bordeaux-Lyon-Grenoble (1993) Subcutaneous suma-triptan in the acute treatment ofmigraine in patients using dihydroer-gotamine as prophylaxis. Headache33(8):432–435

9. Gross ML, Kay J, Turner AM, HalletK, Cleal AL, Hassani H, for theUnited Kingdom Study Group (1994)Sumatriptan in acute migraine usinga novel cartridge system self-injector.Headache 34(10):559–563

10. Russell MB, Holm-Thomsen OE,Rishoj Nielsen M, Cleal A, PilgrimAJ, Olesen J (1994) A randomizeddouble-blind placebo-controlledcrossover study of subcutaneoussumatriptan in general practice.Cephalalgia 14(4):291–296

11. Jensen K, Tfelt-Hansen P, HansenEW, Krois EH, Pedersen OS (1995)Introduction of a novel self-injectorfor sumatriptan. A controlled clinicaltrial in general practice. Cephalalgia15(5):423–429

12. Akpunonu BE, Mutgi AB, FedermanDJ, Volinsky FG, Brickman K, DavisRL, Gilbert C, Asgharnejad M (1995)Subcutaneous sumatriptan for treat-ment of acute migraine in patientsadmitted to the emergency depart-ment: a multicenter study. AnnEmerg Med 25(4):464–469

13. Mushet GR, Cady RK, Baker CC,Clements B, Gutterman DL, Davis R(1996) Efficacy and tolerability ofsubcutaneous sumatriptan adminis-tered using the IMITREX STAT dosesystem. Clin Ther 18(4):687–699

14. Cady RC, Ryan R, Jhingran P,O’Quinn S, Pait DG (1998)Sumatriptan injection reduces pro-ductivity loss during a migraineattack: results of a double-blind,placebo-controlled trial. Arch InternMed 158(9):1013–1018

15. Touchon J, Bertin L, Pilgrim AJ,Ashford E, Bes A (1996) A compari-son of subcutaneous sumatriptan anddihydroergotamine nasal spray in theacute treatment of migraine.Neurology 47(2):361–365

16. Diener HC, for the ASASUMAMIGStudy Group (1999) Efficacy andsafety of intravenous acetylsalicylicacid lysinate compared to subcuta-neous sumatriptan and parenteralplacebo in the acute treatment ofmigraine. A double-blind, double-dummy, randomized, multicenter,parallel group study. Cephalalgia19(6):581–588

17. The Oral Sumatriptan Dose-DefiningStudy Group (1991) Sumatriptan - anoral dose-defining study. Eur Neurol31(5):300–305

18. The Oral Sumatriptan InternationalMultiple-Dose Study Group (1991)Evaluation of a multiple-dose regi-men of oral sumatriptan for the acutetreatment of migraine. Eur Neurol31(5):306–313

19. Nappi G, Sicuteri F, Byrne M,Roncolato M, Zerbini O (1994) Oralsumatriptan compared with placeboin the acute treatment of migraine. JNeurol 241(3):138–144

20. Pini LA, Sternieri E, Fabbri L, ZerbiniO, Bamfi F, for the Oral SumatriptanItalian Study Group (1995) High effi-cacy and low frequency of headacherecurrence after oral sumatriptan. J IntMed Res 23(2):96–105

21. Sargent J, Kirchner JR, Davis R,Kirkhart B (1995) Oral sumatriptan iseffective and well tolerated for theacute treatment of migraine: resultsof a multicenter study. Neurology45[8 Suppl 7]:S10–S40

22. Centonze V, Polito MB, Di Bari M,Fabbri L, Cassiano MA, Bassi A,Albano O (1995) [Evaluation of theefficacy of oral sumatriptan in themanagement of migraine attacks.Clinical results.] Clin Ter146(11):721–728 (article in Italian)

23. Cutler N, Mushet GR, Davis R,Clements B, Whitcher L (1995) Oralsumatriptan for the acute treatment ofmigraine: evaluation of three dosagestrengths. Neurology 45[8 Suppl7]:S5–S9

24. Pfaffenrath V, Cunin G, Sjonell G,Prendergast S (1998) Efficacy andsafety of sumatriptan tablets (25 mg,50 mg, and 100 mg) in the acutetreatment of migraine: defining theoptimum doses of oral sumatriptan.Headache 38(3):184–190

25. Moschiano F, D’Amico D, Grazzi L,Leone M, Bussone G (1997)Sumatriptan in the acute treatment ofmigraine without aura: efficacy of 50-mg dose. Headache 37(7):421–423

26. Savani N, Brautaset NJ, ReunanenM, Szirmai I, Ashford EA, HassaniH, Saiers J (1999) A double-blindplacebo-controlled study assessingthe efficacy and tolerability of 50 mgsumatriptan tablets in the acute treat-ment of migraine. SumatriptanTablets S2CM07 Study Group. Int JClin Pract Suppl 105:7–15

136

27. Pini LA, Fabbri L, Cavazzuti L (1999)Efficacy and safety of sumatriptan 50mg in patients not responding to stan-dard care, in the treatment of mild tomoderate migraine. The Sumatriptan50 mg Italian Study Group. Int J ClinPharmacol Res 19(2):57–64

28. The Finnish Sumatriptan Group andthe Cardiovascular Clinical ResearchGroup (1991) A placebo-controlledstudy of intranasal sumatriptan forthe acute treatment of migraine. EurNeurol 31(5):332–338

29. Salonen R, Ashford E, Dahlof C,Dawson R, Gilhus NE, Luben V,Noronha D, Warter JM, for theInternational Intranasal SumatriptanStudy Group (1994) Intranasal suma-triptan for the acute treatment ofmigraine. J Neurol 241:463–469

30. Ryan R, Elkind A, Baker CC,Mullican W, DeBussey S,Asgharnejad M (1997) Sumatriptannasal spray for the acute treatment ofmigraine. Results of two clinicalstudies. Neurology 49(5):1225–1230

31. Peikert A, Becker WJ, Ashford EA,Dahlof C, Hassani H, Salonen RJ(1999) Sumatriptan nasal spray: adose-ranging study in the acute treat-ment of migraine. Eur J Neurol6(1):43–49

32. Boureau F, Kappos L, Schoenen J,Esperanca P, Ashford E (2000) Aclinical comparison of sumatriptannasal spray and dihydroergotaminenasal spray in the acute treatment ofmigraine. Int J Clin Pract54(5):281–286

33. Dahlof C (1999) Sumatriptan nasalspray in the acute treatment ofmigraine: a review of clinical studies.Cephalalgia 19(9):769–778

34. Dahlof C (2001) Clinical efficacyand tolerability of sumatriptan tabletand suppository in the acute treat-ment of migraine: a review of datafrom clinical trials. Cephalalgia21[Suppl 1]:9–12

35. Tepper SJ, Cochran A, Hobbs S,Woessner M (1998) Sumatriptan sup-positories for the acute treatment ofmigraine. S2B351 Study Group. Int JClin Pract 52(1):31–35

36. Bertin L, Brion N, Farkkila M, GobelH, Wessely P (1999) A dose-definingstudy of sumatriptan suppositories inthe acute treatment of migraine. Int JClin Pract 53(8):593–598

37. Plosker GL, McTavish D (1994)Sumatriptan. A reappraisal of its phar-macology and therapeutic efficacy inthe acute treatment of migraine andcluster headache. Drugs47(4):622–651

38. Tfelt-Hansen P (1998) Efficacy andadverse events of subcutaneous, oral,and intranasal sumatriptan used formigraine treatment: a systematicreview based on number needed totreat. Cephalalgia 18(8):532–538

39. Visser WH, Klein KB, Cox RC,Jones D, Ferrari MD (1996) 311C90,a new central and peripherally acting5-HT1D receptor agonist in the acuteoral treatment of migraine: a double-blind, placebo-controlled, dose-rangefinding study. Neurology46(2):522–526

40. Lobo BL, Cooke SC, Landy SH(1999) Symptomatic pharmacothera-phy of migraine. Clin Ther21(7):1118–1130

41. Dahlof C, Diener HC, Goadsby PJ,Massiou H, Olesen J, Schoenen J,Wilkinson M, Sweet RM, Klein KB(1998) Zolmitriptan, a 5-HT1B/1Dreceptor agonist for the acute oraltreatment of migraine: a multicentre,dose-range finding study. Eur JNeurol 5(6):535–543

42. Tfelt-Hansen P, De Vries P, SaxenaPR (2000) Triptans in migraine: acomparative review of pharmacology,pharmacokinetics and efficacy. Drugs60(6):1259–1287

43. Cutler NR, Claghorn J, Sramek JJ,Block G, Panebianco D, Cheng H,Olah TV, Reines SA (1996) Pilotstudy of MK-462 in migraine.Cephalalgia 16(2):113–116

44. Gijsman H, Kramer MS, Sargent J,Tuchman M, Matzura-Wolfe D, PolisA, Teall J, Block G, Ferrari MD(1997) Double-blind, placebo-con-trolled, dose-finding study of rizatrip-tan (MK-462) in the acute treatmentof migraine. Cephalalgia17(6):647–651

45. Teall J, Tuchman M, Cutler N, GrossM, Willoughby E, Smith B, Jiang K,Reines S, Block G, for theRizatriptan 022 Study Group (1998)Rizatriptan (MAXALT) for the acutetreatment of migraine and migrainerecurrence. A placebo-controlled, out-patient study. Headache38(4):281–287

46. Klassen A, Elkind A, Asgharnejad M,Webster C, Laurenza A, for theNaratriptan S2WA3001 Study Group(1997) Naratriptan is effective andwell tolerated in the acute treatmentof migraine. Results of a double-blind, placebo-controlled, parallel-group study. Headache37(10):640–645

47. Mathew NT, Asgharnejad M,Peykamian M, Laurenza A, for theNaratriptan S2WA3003 Study Group(1997) Naratriptan is effective andwell tolerated in the acute treatmentof migraine. Results of a double-blind, placebo-controlled, crossoverstudy. Neurology 49(6):1485–1490

48. Havanka H, Dahlof C, Pop PH,Diener HC, Winter P, Whitehouse H,Hassani H (2000) Efficacy of nara-triptan tablets in the acute treatmentof migraine: a dose-ranging study.Naratriptan S2WB2004 Study Group.Clin Ther 22(8):970–980

49. Färkkilä M (1996) A dose-findingstudy of eletriptan (UK-116,044)(5–30 mg) for the acute treatment ofmigraine. Cephalalgia 16:387–388

50. Diener HC, McHarg A (2000)Pharmacology and efficacy of eletrip-tan for the treatment of migraineattacks. Int J Clin Pract54(10):670–674

51. Wells NE, Steiner TJ (2000)Effectiveness of eletriptan in reduc-ing time loss caused by migraineattacks. Pharmacoeconomics18(6):557–566

52. Gobel H, Winter P, Boswell D, CrispA, Becker W, Hauge T, Mihout B,Niewold J, Torring J (2000)Comparison of naratriptan and suma-triptan in recurrence-prone migrainepatients. Naratriptan InternationalRecurrence Study Group. Clin Ther22(8):981–989

53. Goadsby PJ (2002) Efficacy, safetyand tolerability of oral eletriptan inthe acute treatment of migraine:results of a Phase III, multicentre,placebo-controlled study across threeattacks. Cephalalgia (in press)

54. Dahlof C, Tfelt-Hansen P, MassiouH, Fazekas A (2001) Dose finding,placebo-controlled study of oralalmotriptan in the acute treatment ofmigraine. Neurology57(10):1811–1817

137

55. Pascual J, Falk RM, Piessens F,Prusinski A, Docekal P, Robert M,Ferrer P, Luria X, Segarra R, ZayasJM (2000) Consistent efficacy andtolerability of almotriptan in the acutetreatment of multiple migraineattacks: results of a large, random-ized, double-blind, placebo-controlledstudy. Cephalalgia 20(6):588–596

56. Ryan R, Keywood C (1998) A prelim-inary study of frovatriptan (VML251),a potent cerebroselective 5-hydroxy-tryptamine (5-HT)1B/1D agonist for theacute treatment of migraine. Eur JNeurol 5[Suppl 3]:S46 (abstract)

57. Easthope SE, Goa KL (2001)Frovatriptan. CNS Drugs15(12):969–976

58. Ferrari MD, Roon KI, Lipton RB,Goadsby PJ (2001) Oral triptans(serotonin 5-HT (1B/1D) agonists) inacute migraine treatment: a meta-analysis of 53 trials. Lancet358(9294):1668–1675

59. The Multinational Oral Sumatriptanand Cafergot Comparative StudyGroup (1991) A randomised, double-blind comparison of sumatriptan andcafergot in the acute treatment ofmigraine. Eur Neurol 31(5):314–322

60. The Multinational Oral Sumatriptanand Aspirin Plus MetoclopramideComparative Study Group (1992) Astudy to compare oral sumatriptanwith oral aspirin plus metoclo-pramide in the acute treatment ofmigraine. Eur Neurol 32:177–184

61. Pfaffenrath V, Scherzer S (1995)Analgesics and NSAIDs in the treat-ment of the acute migraine attack.Cephalalgia 15[Suppl 15]:14–20

62. Myllylä VV, Havanka H, Herrala L,Kangasniemi P, Rautakorpi I, TurkkaJ, Vapaatalo H, Eskerod O (1998)Tolfenamic acid rapid release versussumatriptan in the acute treatment ofmigraine: comparable effect in a dou-ble-blind, randomized, controlled,parallel-group study. Headache38(3):201–207

63. The Diclofenac-K/SumatriptanMigraine Study Group (1999) Acutetreatment of migraine attacks: effica-cy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potas-sium in comparison to oral sumatrip-tan and placebo. Cephalalgia19(4):232–240

64. Dowson A, Ball K, Haworth D (2000)Comparison of a fixed combination ofdomperidone and paracetamol(Domperamol) with sumatriptan 50mg in moderate to severe migraine: arandomised UK primary care study.Curr Med Res Opin 16(3):190–197

65. Gobel H, Heinze A, Stolze H, Heinze-Kuhn K, Lindner V (1999) Open-labeled long-term study of the effica-cy, safety, and tolerability of subcuta-neous sumatriptan in acute migrainetreatment. Cephalalgia 19(7):676–683

66. Zagami AS (1997) 311C90: long-term efficacy and tolerability profilefor the acute treatment of migraine.International 311C90 Long-TermStudy Group. Neurology 48[3 Suppl3]:S25–S28

67. Geraud G, Compagnon A, Rossi A(2002) Zolmitriptan versus a combi-nation of acetylsalicylic acid andmetoclopramide in the acute oraltreatment of migraine: a double-blind, randomised, three-attack study.Eur Neurol 47(2):88–98

68. The International 311C90 Long-termStudy Group (1998) The long-term tol-erability and efficacy of oral zolmitrip-tan (Zomig, 311C90) in the acute treat-ment of migraine. An internationalstudy. Headache 38(3):173–183

69. Tepper SJ, Donnan GA, Dowson AJ,Bomhof MA, Elkind A, Meloche J,Fletcher PE, Millson DS (1999) Along-term study to maximisemigraine relief with zolmitriptan.Curr Med Res Opin 15(4):254–271

70. Tuchman M, Edvinsson L, Geraud G,Korczyn A, Mauskop A, PfaffenrathV (1999) Zolmitriptan provides con-sistent migraine relief when used inthe long-term. Curr Med Res Opin15(4):272–281

71. Kramer MS, Matzura-Wolfe D, PolisA, Getson A, Amaraneni PG, SolbachMP, McHugh W, Feighner J,Silberstein S, Reines SA, for theRizatriptan Multiple Attack StudyGroup (1998) A placebo-controlled,crossover study of rizatriptan in thetreatment of multiple migraineattacks. Neurology 51(3):773–781

72. Block GA, Goldstein J, Polis A,Reines, SA, Smith ME (1998)Efficacy and safety of rizatriptan ver-sus standard care during long-termtreatment for migraine. RizatriptanMulticenter Study Groups. Headache38(10):764–771

73. Silberstein SD (2000) Rizatriptanversus usual care in long-term treat-ment of migraine. Neurology 55[9Suppl 2]:S25–S28

74. Dahlof CG, Lipton RB, McCarrollKA, Kramer MS, Lines CR, FerrariMD (2000) Within-patient consisten-cy of response of rizatriptan for treat-ing migraine. Neurology55(10):1511–1516

75. Saper JR (2000) The use of rizatrip-tan in the treatment of acute, multiplemigraine attacks. Neurology 55[9Suppl 2]:S15–S18

76. Heywood J, Bomhof MA, PradalierA, Thaventhiran L, Winter P, HassaniH (2000) Tolerability and efficacy ofnaratriptan tablets in the acute treat-ment of migraine attacks for 1 year.Naratriptan Long-Term Study Group.Cephalalgia 20(5):470–474

77. Cabarrocas X, Esbri R, Peris F,Ferrer P (2001) Long-term efficacyand safety of oral almotriptan: inter-im analysis of a 1-year open study.Headache 41(1):57–62

78. Carpay HA, Matthijsse P, SteinbuchM, Mulder PG (1997) Oral and sub-cutaneous sumatriptan in the acutetreatment of migraine: an open ran-domized cross-over study.Cephalalgia 17(5):591–595

79. Gruffydd-Jones K, Hood CA, PriceDB (1997) A within-patient compari-son of subcutaneous and oral suma-triptan in the acute treatment ofmigraine in general practice.Cephalalgia 17(1):31–36

80. Geraud G, Olesen J, Pfaffenrath V,Tfelt-Hansen P, Zupping R, DienerHC, Sweet R (2000) Comparison ofthe efficacy of zolmitriptan andsumatriptan: issues in migraine trialdesign. Cephalalgia 20(1):30–38

81. Visser WH, Terwindt GM, Reines SA,Jiang K, Lines CR, Ferrari MD, forthe Dutch/US Rizatriptan StudyGroup (1996) Rizatriptan vs sumatrip-tan in the acute treatment of migraine.A placebo-controlled, dose-rangingstudy. Arch Neurol 53(11):1132–1137

82. Tfelt-Hansen P, Teall J, Rodriguez F,Giacovazzo M, Paz J, Malbecq W,Block GA, Reines SA, Visser WH(1998) Oral rizatriptan versus oralsumatriptan: a direct comparativestudy in the acute treatment ofmigraine. Rizatriptan 030 StudyGroup. Headache 38(10):748–755

138

83. Gallagher RM, Dennish G, SpieringsEL, Chitra R (2000) A comparativetrial of zolmitriptan and sumatriptanfor the acute oral treatment ofmigraine. Headache 40(2):119–128

84. Lines C, Visser WH, Vandormael K,et al (1997) Rizatriptan 5 mg versussumatriptan 50 mg in the acute treat-ment of migraine. Headache37:319–320

85. Goldstein J, Ryan R, Jiang K, GetsonA, Norman B, Block GA, Lines C(1998) Crossover comparison of riza-triptan 5 mg and 10 mg versus suma-triptan 25 mg and 50 mg in migraine.Rizatriptan Protocol 046 StudyGroup. Headache 38(10):737–747

86. Tfelt-Hansen P, Ryan RE Jr (2000)Oral therapy for migraine: compar-isons between rizatriptan and suma-triptan. A review of four randomized,double-blind clinical trials.Neurology 55[9 Suppl 2]:S19–S24

87. Goadsby PJ, Ferrari MD, Olesen J,Stovner LJ, Senard JM, Jackson NC,Poole PH, for the Eletriptan SteeringCommittee (2000) Eletriptan in acutemigraine: a double-blind, placebo-controlled comparison to sumatriptan.Neurology 54(1):156–163

88. Pascual J, Vega P, Diener HC, AllenC, Vrijens F, Patel K (2000)Comparison of rizatriptan 10 mg vs.zolmitriptan 2.5 mg in the acute treat-ment of migraine. Rizatriptan-Zolmitriptan Study Group.Cephalalgia 20(5):455–461

89. Bomhof M, Paz J, Legg N, Allen C,Vandormael K, Patel K (1999)Comparison of rizatriptan 10 mg vsnaratriptan 2.5 mg in migraine. EurNeurol 42(3):173–179

90. Deleu D, Hanssens Y (2000) Currentand emerging second-generation trip-tans in acute migraine therapy: acomparative review. J ClinPharmacol 40(7):687–700

91. Marcus DA (2001) Establishing astandard of speed for assessing theefficacy of the serotonin (1B/1D)agonists (triptans). Arch Neurol58(7):1056–1058

92. Klapper JA, O’Connor S (2000)Rizatriptan wafer-sublingual vs.placebo at the onset of acutemigraine. Cephalalgia 20(6):585–587

93. Bates D, Ashford E, Dawson R,Ensink FB, Gilhus NE, Olesen J,Pilgrim AJ, Shevlin P (1994)Subcutaneous sumatriptan during themigraine aura. Sumatriptan AuraStudy Group. Neurology44(9):1587–1592

94. Dowson A (1996) Can oral 311C90, anovel 5-HT1D agonist, preventmigraine headache when taken dur-ing an aura? Eur Neurol 36[Suppl2]:28–31

95. Solomon GD, Frizelis K, Becker J,Kunkel RS (1998) Dosing of oralsumatriptan: a review of our first 104patients. Headache 38(5):349–351

96. Visser WH, Jaspers NM, de VriendRH, Ferrari MD (1996) Risk factorsfor headache recurrence after suma-triptan: a study in 366 migrainepatients. Cephalalgia 16(4):264–269

97. Cull RE, Price WH, Dunbar A (1997)The efficacy of subcutaneous suma-triptan in the treatment of recurrenceof migraine headache. J NeurolNeurosurg Psychiatry 62(5):490–495

98. Ferrari MD, James MH, Bates D,Pilgrim A, Ashford E, Anderson BA,Nappi G (1994) Oral sumatriptan:effect of a second dose, and incidenceand treatment of headache recur-rences. Cephalalgia 14(5):330–338

99. Scott RJ, Aitchison WR, Barker PR,McLaren GI (1996) Oral sumatriptanin the acute treatment of migraineand migraine recurrence in generalpractice. QJM 89(8):613–622

100. Rapoport AM, Visser WH, CutlerNR, Alderton CJ, Paulsgrove LA,Davis RL, Ferrari MD (1995) Oralsumatriptan in preventing headacherecurrence after treatment ofmigraine attacks with subcutaneoussumatriptan. Neurology45(8):1505–1509

101. Mauskop A, Farkkila M, Hering-Hanit R, Rapoport A, Warner J(1999) Zolmitriptan is effective forthe treatment of persistent and recur-rent migraine headache. Curr MedRes Opin 15(4):282–289

102. Spencer CM, Gunasekara NS, Hills C(1999) Zolmitriptan: a review of itsuse in migraine. Drugs 58(2):347–374

103. Solbach MP, Waymer RS (1993)Treatment of menstruation associatedmigraine headache with subcutaneoussumatriptan. Obstet Gynecol82(5):769–772

104. Facchinetti F, Bonellie G,Kangasniemi P, Pascual J, Shuaib A,for the Sumatriptan MenstrualMigraine Study Group (1995) Theefficacy and safety of subcutaneoussumatriptan in the acute treatment ofmenstrual migraine. Obstet Gynecol86(6):911–916

105. Gross M, Barrie M, Bates D, DowsonA, Erlington G (1995) The efficacyof sumatriptan in menstrual migraine.A prospective study. Cephalalgia15[Suppl 14]:227

106. Leira R, Suarez C, Castillo J, LemaM, Noya M (1995) Sumatriptan sub-cutaneo en el trataméento de les cri-sis de migraña. Analisis de eficacia ytolerancia a largo plazo. Rev Neurol23(122):752–755

107. Salonen R, Saiers J (1999)Sumatriptan is effective in the treat-ment of menstrual migraine: a reviewof prospective studies and retrospec-tive analyses. Cephalalgia19(1):16–19

108. Rapoport AM, Ramadan NM,Adelman JU, Mathew NT, ElkindAH, Kudrow DB, Earl NL (1997)Optimizing the dose of zolmitriptan(Zomig, 311C90) for the acute treat-ment of migraine. A multicenter, dou-ble-blind, placebo-controlled, doserange-finding study. The 017 ClinicalTrial Study Group. Neurology49(5):1210–1218

109. Solomon GD, Cady RK, Klapper JA,Earl NL, Saper JR, Ramadan NM(1997) Clinical efficacy and tolerabil-ity of 2.5 mg zolmitriptan for theacute treatment of migraine. The 042Clinical Trial Study Group.Neurology 49(5):1219–1225.

110. Silberstein S, Norman B, Jiang K etal (1999) Rizatriptan is effective inmenstrual migraine. Neurology52[Suppl 2]:A208

111. Silberstein SD, Massiou H, Le JeunneC, Johnson-Pratt L, McCarroll KA,Lines CR (2000) Rizatriptan in thetreatment of menstrual migraine.Obstet Gynecol 96(2):237–242

112. Massiou H, Pitei D, Poole PH, SikesC (2000) Efficacy of eletriptan forthe treatment of migraine in womenwith menstrually associated migraine,and in women on contraceptives orhormone replacement therapy: meta-analyses of randomized clinical trials.Pfizer (Data on file)

139

113. Pitei D, Hettiarachchi J (2000)Efficacy of eletriptan in treatingwomen with menstrually associatedmigraine and women on oral contra-ceptives hormone replacement thera-py. Obstet Gynecol 95[4 Suppl 1]:S32

114. Cady RK, Lipton RB, Hall C,Stewart WF, O’Quinn S, GuttermanD (2000) Treatment of mild headachein disabled migraine sufferers: resultsof the Spectrum Study. Headache40(10):792–797

115. Cady RK, Sheftell F, Lipton RB,O’Quinn S, Swidan S, Jones M,Putnam DG, Crisp A, Metz A,McNeal S (2000) Effect of earlyintervention with sumatriptan onmigraine pain: retrospective analysesof data from three clinical trials. ClinTher 22(9):1035–1048

116. Luciani R, Carter D, Mannix L,Hemphill M, Diamond M, Cady R(2000) Prevention of migraine duringprodrome with naratriptan.Cephalalgia 20(2):122–126

117. Millson DS (2000) Rational migrainemanagement: optimising treatmentwith the triptans. Funct Neurol15[Suppl 3]:182–191

118. Ahrens SP, Farmer MV, WilliamsDL, Willoughby E, Jiang K, BlockGA, Visser WH (1999) Efficacy andsafety of rizatriptan wafer for theacute treatment of migraine.Rizatriptan Wafer Protocol 049 StudyGroup. Cephalalgia 19(5):525–530

119. Oldman AD, Smith LA, McQuay HJ,Moore RA (2001) Rizatriptan foracute migraine (Cochrane Review).Cochrane Database Syst Rev3:CD003221

120. Gallai V, Sarchielli P, Alberti A,Rossi C, Cittadini E, and theCollaborative Group for theApplication of IHS Criteria of theItalian Society for the Study ofHeadache (2002) Application of the1988 IHS criteria in the clinical set-ting: results from 10 Italianheadache centers using a reliableand simple computerized record.Headache (in press)

121. Stark S, Spierings EL, McNeal S,Putnam GP, Bolden-Watson CP,O’Quinn S (2000) Naratriptan effica-cy in migraineurs who respond poor-ly to oral sumatriptan. Headache40(7):513–520

122. Mathew NT, Kailasam J, Gentry P,Chernyshev O (2000) Treatment ofnon responders to oral sumatriptanwith zolmitriptan and rizatriptan: acomparative open trial. Headache40(6):464–465

123. Sullivan JT, Preston KL, Testa MP,Busch M, Jasinski DR (1992)Psychoactivity and abuse potential ofsumatriptan. Clin Pharmacol Ther52(6):635–642

124. Osborne MJ, Austin RC, Dawson KJ,Lange L (1994) Is there a problemwith long-term use of sumatriptan inmigraine. BMJ 308(6921):113

125. Catarci T, Lenzi GL, Cerbo R,Fieschi C (1995) Sumatriptan anddaily headache. J Neurol NeurosurgPsychiatry 58(4):508

126. Ottervanger JP, Valkenburg HA,Grobbee DE, Stricker BH (1996)Pattern of sumatriptan use andoveruse in general practice. Eur JClin Pharmacol 50(5):353–355

127. Goadsby PJ (1998) Sumatriptan isnot the only analgesic used inappro-priately. BMJ 317(7164):1016

128. Limmroth V, Kazarawa Z, FritscheG, Diener HC (1999) Headache afterfrequent use of serotonin agonistszolmitriptan and naratriptan. Lancet353(9150):378

129. MacDonald JT (1994) Treatment ofjuvenile migraine with subcutaneoussumatriptan. Headache34(10):581–582

130. Hämäläinen ML, Hoppu K,Santavuori P (1997) Sumatriptan formigraine attacks in children: a ran-domized placebo-controlled study.Do children with migraine respond tooral sumatriptan differently fromadults? Neurology 48(4):1100–1103

131. Linder SL (1996) Subcutaneoussumatriptan in the clinical setting: thefirst 50 consecutive patients withacute migraine in a pediatric neurolo-gy office practice. Headache36(7):419–422

132. Dixon R, Engleman K, Kemp J,Ruckle JL (1999) A comparison ofthe pharmacokinetics and tolerabilityof the novel antimigraine compoundzolmitriptan in adolescents andadults. J Child AdolescPsychopharmacol 9(1):35–42

133. Ueberall MA, Wenzel D (1999)Intranasal sumatriptan for the acutetreatment of migraine in children.Neurology 52(7):1507–1510

134. Winner P, Rothner AD, Saper J, NettR, Asgharnejad M, Laurenza A,Austin R, Peykamian M (2000) Arandomized, double-blind placebo-controlled study of sumatriptan nasalspray in the treatment of acutemigraine in adolescents. Pediatrics106(5):989–997

135. Rothner AD, Winner P, Nett R,Asgharnejad M, Laurenza A, AustinR, Peykamian M (2000) One-yeartolerability and efficacy of sumatrip-tan nasal spray in adolescents withmigraine: results of a multicenter,open-label study. Clin Ther22(12):1533–1546

136. Linder SL, Dowson AJ (2000)Zolmitriptan provides effectivemigraine relief in adolescents. Int JClin Pract 54(7):466–469

137. O’Quinn S, Ephross SA, Williams V,Davis RL, Gutterman DL, Fox AW(1999) Pregnancy and perinatal out-comes in migraineurs using sumatrip-tan: a prospective study. ArchGynecol Obstet 263(1–2):7–12

138. Olesen C, Steffensen FH, SorensenHT, Nielsen GL, Olsen J (2000)Pregnancy outcome following pre-scription for sumatriptan. Headache40(1):20–24

139. Reiff-Eldridge R, Heffner CR,Ephross SA, Tennis PS, White AD,Andrews EB (2000) Monitoringpregnancy outcomes after prenataldrug exposure through prospectivepregnancy registries: a pharmaceuti-cal company commitment. Am JObstet Gynecol 182(1 Pt 1):159–163

140. Gardner DM, Lynd LD (1998)Sumatriptan contraindications and theserotonin syndrome. AnnPharmacother 32(1):33–38

141. Dixon R, French S, Kemp J, SellersM, Leclerc V, Delvaux M, RautureauJ (1998) Effect of hepatic impairmenton the pharmacokinetics of zolmitrip-tan. J Clin Pharmacol 38(8):694–701

142. Gillotin C, Bagnis C, Mamet JP, PeckRW, Deray G (1997) No need toadjust the dose of 311C90 (zolmitrip-tan), a novel anti-migraine treatment,in patients with renal failure notrequiring dialysis. Int J ClinPharmacol Ther 35(11):522–526

140

143. Smith DA, Cleary EW, Watkins S,Huffman CS, Dilzer SC, Lasseter KC(1998) Pharmacokinetics and phar-macodynamics of zolmitriptan inpatients with mild to moderate hyper-tension: a double-blind, placebo-con-trolled study. J Clin Pharmacol38(8):685–693

144. Evans RW, Martin V (2000) Expertopinion: assessing cardiac risk priorto use of triptans. Headache 40(7):599–602

145. Hedenmalm K (2000)[Cardiovascular side-effects of trip-tans in migraine exist but are rare. 5-HT receptor mediated extracranialvasoconstriction is the most commoncause.] Lakartidningen97(25):3078–3084 (article inSwedish)

146. Brown EG, Endersby CA, Smith RN,Talbot JC (1991) The safety and tol-erability of sumatriptan: an overview.Eur Neurol 31(5):339–344

147. Grundemar L (1994) [Sumatriptanand cardiac complaints. Careful car-diac anamnesis is needed prior totreatment.] Lakartidningen91(17):1701–1702 (article inSwedish)

148. Marterer A, Wober C, Schnider P,Aull S, Wessely P (1995)[Sumatriptan side-effects and prob-lems in routine clinical practice.]Med Klin 90(11):628–633 (article inGerman)

149. Ottervanger JP, van Witsen TB,Valkenburg HA, Grobbee DE,Stricker BH (1994) Adverse reactionsattributed to sumatriptan. A postmar-keting study in general practice. Eur JClin Pharmacol 47(4):305–309

150. Perry CM, Markham A (1998)Sumatriptan. An updated review ofits use in migraine. Drugs55(6):889–922

151. Welch KM, Mathew NT, Stone P,Rosamond W, Saiers J, Gutterman D(2000) Tolerability of sumatriptan:clinical trials and postmarketingexperience. Cephalalgia20(8):687–695

152. Geraud G, Valette C (2000)[Sumatriptan nasal spray 20 mg:efficacy, tolerance and quality of lifein migraine patients.] Rev Neurol(Paris) 156(6–7):646–653 (article inFrench)

153. Moore KH, Hussey EK, Shaw S,Fuseau E, Duquesnoy C, Pakes GE(1997) Safety, tolerability, and phar-macokinetics of sumatriptan inhealthy subjects following ascendingsingle intranasal doses and multipleintranasal doses. Cephalalgia17(4):541–550

154. Kunka RL, Hussey EK, Shaws S,Warner P, Aubert B, Richard I,Fowler PA, Pakes GE (1997) Safety,tolerability, and pharmacokinetics ofsumatriptan suppositories followingsingle and multiple doses in healthyvolunteers. Cephalalgia17(4):532–540

155. Göbel H, Boswell D, Winter P et al(1997) A comparison of the efficacy,safety and tolerability of naratriptanand sumatriptan. Cephalalgia 17:426

156. Pfaffenrath V, Diener HC (1994) Sideeffects and tolerabily of sumatriptan(review article). Munch MedWochenschr 136:560–565

157. Goa KL, Balfour JA (1997)Management of acute migraineattack: defining the role of sumatrip-tan. Dis Manage Health Outcomes2(3):141–155

158. Edmeads JG, Millson DS (1997)Tolerability profile of zolmitriptan(Zomig; 311C90), a novel dual cen-tral and peripherally acting 5-HT1B/1D agonist. International clini-cal experience based on >3000 sub-jects treated with zolmitriptan.Cephalalgia 17[Suppl 18]:41–52

159. Earl NL (1996) Clinical safety of311C90: aggregated data frompatients and volunteers to date. EurNeurol 36[Suppl 2]:8–12

160. Schoenen J, Klein KB, MultinationalOral 311C90 and SumatriptanComparative Study Group (1996)311C90 and sumatriptan produceindistinguishable CNS adverse eventprofiles. Cephalalgia 16:389–390

161. Zeneca Pharmaceuticals (1997)Zomig (zolmitriptan) tablets: profes-sional information brochure. ZenecaPharmaceuticals. Wilmington,Delaware, USA

162. Sakai F (2000) Safety and tolerabilityof rizatriptan. Cephalalgia 20[Suppl1]:16–18

163. Fox AW (2000) Comparative tolera-bility of oral 5-HT1B/1D agonists.Headache 40(7):521–527

164. Deleu D, Hanssens Y (1999) Profilesof 5-HT1B/1D agonists in acutemigraine with special reference tosecond generation agents. ActaNeurol Belg 99(2):85–95

165. Tepper SJ (2001) Safety and rationaluse of the triptans. Med Clin NorthAm 85(4):959–970 (review)

166. Lippolis A, Castini D, Cirino D,Ornaghi M (1994) [Coronaryvasospasm secondary to subcuta-neous administration of sumatriptan.]G Ital Cardiol 24(7):883–886 (articlein Italian)

167. Walton-Shirley M, Flowers K,Whiteside JH (1995) Unstable anginapectoris associated with Imitrex ther-apy. Cathet Cardiovasc Diagn34(2):188

168. Mueller L, Gallagher RM, Ciervo CA(1996) Vasospasm-induced myocar-dial infarction with sumatriptan.Headache 36(5):329–331

169. O’Connor P, Gladstone P (1995) Oralsumatriptan-associated transmuralmyocardial infarction. Neurology45(12):2274–2276

170. Kelly KM (1995) Cardiac arrest fol-lowing use of sumatriptan. Neurology45(6):1211–1213

171. Tfelt-Hansen P, Ferrari MD, Olesen J(1993) Association between suma-triptan and stroke. Lancet342(8866):303

172. Ottervanger JP, Valkenburg HA,Grobbee DE, Stricker BH (1997)Characteristics and determinants ofsumatriptan-associated chest pain.Arch Neurol 54(11):1387–1392

173. Visser WH, Jaspers NM, de VriendRH, Ferrari MD (1996) Chest symp-toms after sumatriptan: a two-yearclinical practice review in 735 con-secutive migraine patients.Cephalalgia 16(8):554–559

174. Foster JM, Houghton LA, WhorwellPJ (1997) Further evidence thatsumatriptan induced chest pain isoesophageal in origin: effect onoesophageal visceral sensation. Gut40[Suppl 1]:A31

175. Houghton LA, Foster JM, WhorwellPJ, Morris J, Fowler P (1995) Is chestpain after sumatriptan oesophageal inorigin? Lancet 344(8928):985–986

176. Foster JM, Houghton LA, WhorwellPJ (1997) Sumatriptan at a therapeu-tic dose alters oesophageal motility.Gut 40[Suppl 1]:A44

141

177. Pearce H, Shakir S,Wright S et al(1996) Postmarketing surveillance ofsumatriptan in the treatment of acutemigraine. Pharmacoepidemiol DrugsSaf 5[Suppl 1]:86

178. Lewis PJ, Barrington SF, MarsdenPK, Maisey MN, Lewis LD (1997) Astudy of the effects of sumatriptan onmyocardial perfusion in healthyfemale migraineurs using 13NH3

positron emission tomography.Neurology 48(6):1542–1550

179. Van Hecken AM, Depre M, DeSchepper PJ, Fowler PA, Lacey LF,Durham JM (1992) Lack of effect offlunarizine on the pharmacokineticsand pharmacodynamics of sumatrip-tan in healthy volunteers. Br J ClinPharmacol 34(1):82–84

180. Blier P, Bergeron R (1995) The safe-ty of concomitant use of sumatriptanand antidepressant treatments. J ClinPsychopharmacol 15(2):106–109

181. Szabo CP (1995) Fluoxetine andsumatriptan: possibly a counterpro-ductive combination. J ClinPsychiatry 56(1):37–38

182. Mathew NT, Tietjen GE, Lucker C(1996) Serotonin syndrome compli-cating migraine pharmacotherapy.Cephalalgia 16(5):323–327

183. Diamond S (1995) The use of suma-triptan in patients on monoamine oxi-dase inhibitors. Neurology45(6):1039–1040

184. Van Haarst AD, Van Gerven JM,Cohen AF, De Smet M, Sterrett A,Birk KL, Fisher AL, De Puy ME,Goldberg MR, Musson DG (1999) Theeffects of moclobemide on the phar-macokinetics of the 5-HT1B/1D agonistrizatriptan in healthy volunteers. Br JClin Pharmacol 48(2):190–196

185. Williams P, Fuseau E, Cosson V et al(1997) Sumatriptan pharmacokineticsare significantly altered bymonoamine oxidase inhibitor co-administration. Cephalalgia 17:408

186. Rolan P (1997) Potential drug interac-tions with the novel antimigraine com-pound zolmitriptan (Zomig, 311C90).Cephalalgia 17[Suppl 18]:21–27

187. Shadle CR, Liu G, Goldberg MR(2000) A double-blind, placebo-con-trolled evaluation of the effect of oraldoses of rizatriptan 10 mg on oralcontraceptive pharmacokinetics inhealthy female volunteers. J ClinPharmacol 40(3):309–315

188. Wild MJ, McKillop D, Butters CJ(1999) Determination of the humancytochrome P 450 isoforms involvedin the metabolism of zolmitriptan.Xenobiotica 29(8):847–857

189. Dooley M, Faulds D (1999)Rizatriptan: a review of its efficacy inthe management of migraine. Drugs58(4):699–723

190. Hakkarainen H, Gustafsson B,Stockman O (1978) A comparativetrial of ergotamine tartrate, acetylsali-cylic acid and a dextropropoxyphenecompound in acute migraine attacks.Headache 18(1):35–39

191. Hakkarainen H, Quiding H, StockmanO (1980) Mild analgesics as an alter-native to ergotamine in migraine. Acomparative trial with acetylsalicylicacid, ergotamine tartrate, and a dextro-propoxyphene compound. J ClinPharmacol 20(10):590–595

192. Tfelt-Hansen P, Olesen J (1980)Paracetamol (acetaminophen) versusacetylsalicylic acid in migraine. EurNeurol 19(3):163–165

193. Peters BH, Fraim CJ, Masel BE(1983) Comparison of 650 mg aspirinand 1,000 mg acetaminophen witheach other, and with placebo in mod-erately severe headache. Am J Med74(6A):36–42

194. Tfelt-Hansen P, Olesen J (1984)Effervescent metoclopramide andaspirin (Migravess) versus efferves-cent aspirin or placebo for migraineattacks:a double-blind study.Cephalalgia 4(2):107–111

195. Boureau F, Joubert JM, Lasserre V,Prum B, Delecoeuillerie G (1994)Double-blind comparison of an aceta-minophen 400 mg - codeine 25 mgcombination versus aspirin 1000 mgand placebo in acute migraine attack.Cephalalgia 14(2):156–161

196. Henry P, Hiesse-Provost O,Dillenschneider A, Ganry H, InsuastyJ (1995) Efficacitè et tolèrance del’association effervescente aspirine-metoclopramide dans le traitement dela crise de migraine sans aura essairandomisè en double aveugle contreplacebo. Presse Mèd 24:254–258

197. – (1999) Multicentre, randomised,double-blind, single-dose, placebo-controlled parallel-group study on theanalgesic efficacy of acetylsalicylicacid effervescent 1000 mg (2x500mg) in patients with acute migraineattacks. Medical Research Report,Bayer, Leverkusen, Germany

198. Lange R, Schwarz JA, Hohn M(2000) Acetylsalicylic acid efferves-cent 1000 mg (Aspirin) in acutemigraine attacks; a multicentre, ran-domized, double-blind, single-dose,placebo-controlled parallel groupstudy. Cephalalgia 20(7):663–667

199. Chabriat H, Joire JE, Danchot J,Grippon P, Bousser MG (1994)Combined oral lysine acetylsalicylateand metoclopramide in the acutetreatment of migraine: a multicentredouble-blind placebo-controlledstudy. Cephalalgia 14(4):297–300

200. Tfelt-Hansen P, Henry P, Mulder LJ,Scheldewaert RG, Schoenen J,Chazot G (1995) The effectiveness ofcombined oral lysine acetylsalicylateand metoclopramide compared withoral sumatriptan for migraine. Lancet346(8980):923–926

201. Tfelt-Hansen P (2000) The effective-ness of combined oral lysine acetyl-salicylate and metoclopramide(Migpriv) in the treatment ofmigraine attacks. Comparison withplacebo and oral sumatriptan. FunctNeurol 15[Suppl 3]:196–201

202. Le Jeunne C, Gomez JP, Pradalier A,Titus i Albareda F, Joffroy A, LianoH, Henry P, Lainez JM, Geraud G(1999) Comparative efficacy andsafety of calcium carbasalate plusmetoclopramide versus ergotaminetartrate plus caffeine in the treatmentof acute migraine attacks. Eur Neurol41(1):37–43

203. Taneri Z, Petersen-Braun M (1995)Therapie des akuten Migränean-fallsmit intravenös applizierterAcetysalicylsäure. Eine placebokon-trollierte Doppelblindstudie. DerSchmers 9:124–129

204. Limmroth V, Katsarava Z, Diener HC(1999) Acetylsalicylic acid in thetreatment of headache. Cephalalgia19(6):545–551

205. Pearce I, Frank GJ, Pearce JM (1983)Ibuprofen compared with paraceta-mol in migraine. Practitioner227(1377):465–467

206. Havanka-Kanniainen H (1989)Treatment of acute migraine attack:ibuprofen and placebo compared.Headache 29(8):507–509

207. Kloster R, Nestvold K, Vilming ST(1992) A double-blind study ofibuprofen versus placebo in the treat-ment of acute migraine attacks.Cephalalgia 12(3):169–171

142

208. Kellstein DE, Lipton RB, Geetha R,Koronkiewicz K, Evans FT, StewartWF, Wilkes K, Furey SA,Subramanian T, Cooper SA (2000)Evaluation of a novel solubilized for-mulation of ibuprofen in the treat-ment of migraine headache: a ran-domized, double-blind placebo-con-trolled, dose-ranging study.Cephalalgia 20(4):233–243

209. Del Bene E, Poggioni M, GaragiolaU, Maresca V (1987) Intramusculartreatment of migraine attacks usingdiclofenac sodium: a crossover clini-cal trial. J Int Med Res 15(l):44–48

210. Karachalios GN, Fotiadou A, ChrisikosN, Karabetsos A, Kehagioglou K (1992)Treatment of acute migraine attack withdiclofenac sodium: a double-blind study.Headache 32(2):98–100

211. Dahlöf C, Björkman R (1993)Diclofenac-K (50 and 100 mg) andplacebo in the acute treatment ofmigraine. Cephalalgia 13(2):117–123

212. McNeely W, Goon KL (1999)Diclofenac potassium in migraine: areview. Drugs 57(6):991–1003

213. Pradalier A, Rancurel G, Dordain G,Verdure L, Rascol A, Dry J (1985)Acute migraine attack therapy: com-parison of naproxen sodium and anergotamine tartrate compound.Cephalalgia 5(2):107–113

214. Johnson ES, Ratcliffe DM, WilkinsonM (1985) Naproxen sodium in thetreatment of migraine. Cephalalgia5(1):5–10

215. Sargent JD, Baumel B, Peters K,Diamond S, Saper JR, Eisner LS,Solbach P (1988) Aborting a migraineattack: naproxen sodium vs ergotamineplus caffeine. Headache 28(4):263–266

216. Andersson PG, Hinge HH, JohansenO, Andersen CU, Lademann A,Gotzsche PC (l989) Double-blindstudy of naproxen vs placebo in thetreatment of acute migraine attacks.Cephalalgia 9(l):29–32

217. Treves TA, Streiffler M, Korczyn AD(1992) Naproxen sodium versusergotamine tartrate in the treatmentof acute migraine attacks. Headache32(6):280–282

218. Hamalainen ML, Hoppu K, ValkeilaF, Santavuori P (1997) Ibuprofen oracetaminophen for the acute treat-ment of migraine in children: a dou-ble-blind, randomized, placebo-con-trolled, crossover study. Neurology48(1):103–107

219. Lipton RB, Baggish JS, Stewart WF,Codispoti JR, Fu M (2000) Efficacyand safety of acetaminophen in thetreatment of migraine: results of arandomized, double-blind, placebo-controlled, population-based study.Arch Intern Med 160(22):3486–3492

220. Tokola RA, Kangasniemi P,Neuvonen PJ, Tokola O (1984)Tolfenamic acid, metoclopramide,caffeine and their combinations in thetreatment of migraine attacks.Cephalalgia 4(4):253–263

221. Hakkarainen H, Parantainen J,Gothoni G, Vapaatalo H (1982)Tolfenamic acid and caffeine: a use-ful combination in migraine.Cephalalgia 2(4):173–177

222. Larsen BH, Christiansen LV, AndersenB, Olesen J (1990) Randomized dou-ble-blind comparison of tolfenamicacid and paracetamol in migraine.Acta Neurol Scand 81(5):464–467

223. Gawel MJ, Szalai JF, Stiglick A,Aimola N, Weiner M (1990)Evaluation of analgesic agents inrecurring headache compared withother clinical pain models. ClinPharmacol Ther 47(4):504–508

224. Larkin GL, Prescott JE (1992) A ran-domized, double-blind, comparativestudy of the efficacy of ketorolactromethamine versus meperidine inthe treatment of severe migraine. AnnEmerg Med 21(8):919–924

225. Duarte C, Dunaway F, Turner L,Aldag J, Frederick R (1992)Ketorolac versus meperidine andhydroxyzine in the treatment of acutemigraine headache: a randomizedprospective, double-blind trial. AnnEmerg Med 21(9):1116–1121

226. Davis CP, Torre PR, Williams C,Gray C, Barrett K, Krucke G, PeakeD, Bass B Jr (1995) Ketorolac versusmeperidine-plus-promethazine treat-ment of migraine headache: evalua-tions by patients. Am J Emerg Med13(2):146–150

227. Kinnunen E, Erkinjuntti T, FärkkiläM, Palomäki H, Porras J, Teirmaa H,Freudenthal Y, Andersson P (1988)Placebo-controlled double-blind trialof pirprofen and an ergotamine tar-trate compound in migraine attacks.Cephalalgia 8(3):175–179

228. Awidi AS (1982) Efficacy of flurbipro-fen in the treatment of acute migraineattacks: a double-blind cross-overstudy. Curr Ther Res 32(3):492–497

229. Micieli G, Iannacchero R, TassorelliC, Russano G, Sibilla L, Nappi G(1989) Effetto antalgico del complessopiroxicam-beta-ciclodestrina nel tratta-mento dell’emicrania comune. Studiocontrollato vs. naprossene sodico adosaggio elevato (550 mg). GNeuropsicofarmacol 11(4):170–173

230. Nappi G, Micieli G, Tassorelli C,Viotti E, Altavilla T (1993)Effectiveness of a piroxicam fast dis-solving formulation sublinguallyadministered in the symptomatictreatment of migraine without aura.Headache 33(6):296–300

231. Kangasniemi P, Kaaja R (1992)Ketoprofen and ergotamine in acutemigraine. J Intern Med231(5):551–554

232. Karabetsos A, Karachalios G,Bourlinou P, Reppa A, Koutri R,Fotiadou A (1997) Ketoprofen versusparacetamol in the treatment of acutemigraine. Headache 37(1):12–14

233. Hugues FC, Lacoste JP, Danchot J,Joire JE (1997) Repeated doses ofcombined oral lysine acetylsalicylateand metoclopramide in the acutetreatment of migraine. Headache37(7):452–454

234. Engelhardt G, Mauz AB, Pairet M(1997) Role of caffeine in combinedanalgesic drugs from the point ofview of experimental pharmacology.Arzneimittelforschung 47(8):917–927

235. Hakkarainen H, Vapaatalo H,Gothoni G, Parantainen J (1979)Tolfenamic acid is as effective asergotamine during migraine attacks.Lancet 2(8138):326–328

236. Al-Waili NS (2000) Treatment ofmenstrual migraine withprostaglandin synthesis inhibitormefenamic acid: double-blind studywith placebo. Eur J Med Res5(4):176–182

237. Pfaffenrath V, Rehm M (1998)Migraine in pregnancy: what are thesafest treatment options? Drug Saf19(5):383–388

238. Krymchantowski AV (2000)Naproxen sodium decreases migrainerecurrence when administered withsumatriptan. Arq Neuropsiquiatr58(2B):428–430

239. Cooke AR, Hunt JN (1970)Absorption of acetylsalicylic acidfrom unbuffered and buffered gastriccontents. Am J Dig Dis15(2):95–102

143

240. Ross-Lee LM, Eadie MJ,Heazlewood V, Bochner F, Tyrer JH(1983) Aspirin pharmacokinetics inmigraine. The effect of metoclo-pramide. Eur J Clin Pharmacol24(6):777–785

241. Volans GN (1974) Absorption ofeffervescent aspirin during migraine.Br Med J 4(5939):265–268

242. Diener HC, Dichgans J, Scholz E,Geiselhart S, Gerber WD, Bille A(1989) Analgesic-induced chronicheadache: long-term results of with-drawal therapy. J Neurol 236(1):9–14

243. Edmeads J (1990) Analgesic-inducedheadaches: an unrecognized epidem-ic. Headache 30(9):614–615

244. Adelman JU (1991) Analgesicinduced headache. N C Med J52(7):345–346

245. Dowson A (1999) Drug-inducedheadaches. Lancet354(9174):254–255

246. Silberstein SD, Lipton RB (2000)Chronic daily headache. Curr OpinNeurol 13(3):277–283

247. Hämäläinen ML, Hoppu K,Santavuori P (1998) Twelve cases ofanalgesic headache. Arch Dis Child78(6):555–556

248. Bonuccelli U, Nuti A, Lucetti C,Pavese N, D’Agnello G, Muratorio A(1996) Amitriptyline and dexametha-sone combined treatment in drug-induced headache. Cephalalgia16(3):198–200

249. Tassorelli C, Cavallini A,Iannacchero R, Blandini F, Micieli G,Rollero M (1984) Terapia e profilassidel mal di testa di tipo emicranico:efficacia dell’indometacina-caffeina-proclorfenazina (Difmetrè). Studioclinico in doppio cieco cross-overversus indometacina a differentidosaggi. Clin Trials J 26(5):345–355

250. Gray RN, McCrory DC, Eberlein K,Westman EC, Hasselblad V (1999)Self-administered drug treatments foracute migraine headache. Technicalreview (Prepared for the Agency forHealth Care Policy and Researchunder Contract No. 290-94-2025.Available from the NationalTechnical Information Service, NITSaccession no. 127854)

251. Pradalier A, Vincent D (1992)[Migraine and non-steroidal anti-inflammatory agents.] Pathol Biol(Paris) 40(4):397–405 (article inFrench)

252. de Almeida MA, Gaspar AP,Carvalho FS, Nogueira JM, Pinto JE(1997) Adverse reactions to aceta-minophen, ASA, and NSAIDs inchildren: what alternatives? AllergyAsthma Proc 18(5):3l3–318

253. Henry D, Lim LL, Garcia LA,Gutthann SP, Carson JL, Griffin M,Savage R, Moride Y, Logan R,Hawkey C, Hill S, Fries JT (1996)Variability in risk of gastrointestinalcomplications with individual non-steroidal anti-inflammatory drugs:results of a collaborative meta-analy-sis. BMJ 312:1563–1566

254. Hawkey CJ (2000) Nonsteroidal anti-inflammatory drug gastropathy.Gastroenterology 119(2):521–535

255. Bjorkman D (1998) Nonsteroidalanti-inflammatory drug-associatedtoxicity of the liver, lower gastroin-testinal tract, and esophagus. Am JMed 105(5A):17S–21S

256. Ayonrinde OT, Saker BM (2000)Anaphylactoid reactions to paraceta-mol. Postgrad Med J 76(898):501–502

257. de Paramo BJ, Gancedo SQ, CuevasM, Camo IP, Martin JA, Cosmes EL(2000) Paracetamol (acetaminophen)hypersensitivity. Ann Allergy AsthmaImmunol 85(6 Pt 1):508–511

258. Babu KS, Salvi SS (2000) Aspirinand asthma. Chest 118(5):1470–1476

259. McCarthy DM (1999) Comparativetoxicity of nonsteroidal anti-inflam-matory drugs. Am J Med 107(6A):37S–46S

260. Lindgren A, Aldenborg F, NorkransG, Olaison L, Olsson R (1997)Paracetamol-induced cholestatic andgranulomatous liver injuries. J InternMed 241(5):435–439

261. McClain CJ, Price S, Barve S,Devalarja R, Shedlofsky S (1999)Acetaminophen hepatotoxicity: anupdate. Curr Gastroenterol Rep1(1):42–49

262. Whelton A (1999) Nephrotoxicity ofnonsteroidal anti-inflammatory drugs:physiologic foundations and clinicalimplications. Am Med J106(5B):13S–24S

263. General Practitioner Research Group(1973) Migraine treated with an anti-histamine-analgesic combination.Practitioner 211(263):357–361

264. Somerville BW (1976) Treatment ofmigraine attacks with an analgesiccombination (Mersyndol). Med JAust 1(23):865–866

265. Carasso RL, Yehuda S (1984) Theprevention and treatment of migrainewith an analgesic combination. Br JClin Pract 38(1):25–27

266. Uzogara E, Sheehan DV, ManschreckTC, Jones KJ (1986) A combinationdrug treatment for acute commonmigraine. Headache 26(5):231–236

267. Adam EI (1987) A treatment for theacute migraine attack. J Int Med Res15(2):71–75

268. Lipton RB, Stewart WF, Ryan RE Jr,Saper J, Silberstein S, Sheftell F(1998). Efficacy and safety of aceta-minophen, aspirin and caffeine inalleviating migraine headache pain:three double-blind, randomized,placebo-controlled trials. Arch Neurol55(2):210–217

269. Goldstein J, Hoffman HD, ArmellinoJJ, Battikha JP, Hamelsky SW, CouchJ, Blumenthal H, Lipton RB (1999)Treatment of severe, disablingmigraine attacks in an over-the-counter population of migraine suf-ferers: results from three randomized,placebo-controlled studies of thecombination of acetaminophen,aspirin, and caffeine. Cephalalgia19(7):684–691

270. Silberstein SD, Armellino JJ,Hoffman HD, Battikha JP, HamelskySW, Stewart WF, Lipton RB (1999)Treatment of menstruation-associatedmigraine with the nonprescriptioncombination of acetaminophen,aspirin, and caffeine: results fromthree randomized, placebo-controlledstudies. Clin Ther 21(3):475–491

271. Evans RW (1999) Warning: theexcedrin migraine warning label isinadequate to warn consumers of therisk of medication rebound headache.Headache 39(9):679–680

272. Yuill GM, Swinburn WR, LiversedgeLA (1972) A double-blind crossovertrial of isometheptene mucate com-pound and ergotamine in migraine.Br J Clin Pract 26(2):76–79

273. Hakkarainen H, Allonen H (1982)Ergotamine vs metoclopramide vstheir combination in acute migraineattacks. Headache 22:10–12

274. Tfelt-Hansen P, Saxena PR, DahlofC, Pascual J, Lainez M, Henry P,Diener H, Schoenen J, Ferrari MD,Goadsby PJ (2000) Ergotamine in theacute treatment of migraine: a reviewand European consensus. Brain123(Pt 1):9–18

144

275. Waters WE (1970) A randomizedcontrolled trial of ergotamine tartrate.Br J Prev Soc Med 24(1):65

276. Friedman AP, Di Serio FJ, HwangDS (1989) Symptomatic relief ofmigraine: multicenter comparison ofCafergot P-B, Cafergot, and placebo.Clin Ther 11(1):170–182

277. Ryan RE (1970) Double-blind clini-cal evaluation of the efficacy andsafety of ergostine-caffeine, ergota-mine-caffeine, and placebo inmigraine headache. Headache9(4):212–220

278. Callaham M, Raskin N (1986) A con-trolled study of dihydroergotamine inthe treatment of acute migraineheadache. Headache 26(4):168–171

279. Belgrade MJ, Ling LJ, SchleevogtMB, Ettinger MG, Ruiz E (1989)Comparison of single-dose meperi-dine, butorphanol, and dihydroergota-mine in the treatment of vascularheadache. Neurology 39(4):590–592

280. Klapper JA, Stanton JS (1991)Ketorolac versus DHE and metoclo-pramide in the treatment of migraineheadaches. Headache 31(8):523–524

281. Mathew NT (1997) Dosing andadministration of ergotamine tartrateand dihydroergotamine. Headache37[Suppl 1]:S26–S32

282. Klapper JA, Stanton J (1993) Currentemergency treatment of severemigraine headaches. Headache33(10):560–562

283. Carleton SC, Shesser RF, PietrzakMP, Chudnofsky CR, Starkman S,Morris DL, Johnson G, Rhee KJ,Barton CW, Chelly JE, Rosenberg J,Van Valen MK (1998) Double-blind,multicenter trial to compare the effi-cacy of intramuscular dihydroergota-mine plus hydroxyzine versus intra-muscular meperidine plus hydroxy-zine for the emergency departmenttreatment of acute migraine headache.Ann Emerg Med 32(2):129–138

284. Bousser MG, Loria Y (1985)Efficacy of dihydroergotamine nasalspray in the acute treatment of acutemigraine attacks. Cephalalgia5[Suppl 3]:554–555

285. Krause KH, Bleicher MA (1985)Dihydroergotamine nasal spray in thetreatment of migraine attacks.Cephalalgia 5[Suppl 3]:138–139

286. Hirt D, Lataste X, Taylor P (1989) Acomparison of the DHE nasal sprayand cafergot in acute migraine.Cephalalgia 9[Suppl 10]:410–411

287. Massiou H (1985)Dihydroergotamine nasal spray inprevention and treatment of migraineattacks: two controlled trials versusplacebo. Cephalalgia 5[Suppl3]:131–133

288. Paiva T, Esperanca P, Marcelino L,Assis G (1985) A double-blind trialwith dihydroergotamine nasal sprayin migraine crisis. Cephalalgia5[Suppl 3]:140–141

289. Rohr J, Dufresne J (1985)Dihydroergotamine nasal spray forthe treatment of migraine attacks: acomparable double-blind crossoverstudy with placebo. Cephalalgia5[Suppl 3]:142–143

290. Tulunay FC, Karan O, Aydin N,Culcuoglu A, Guvener A (1987)Dihydroergotamine nasal spray dur-ing migraine attacks. A double-blindcrossover study with placebo.Cephalalgia 7(2):131–133

291. DiSerio F, Patin J, Friedman A (1989)USA trials of dihydroergotaminenasal spray in the acute treatment ofmigraine headache. Cephalalgia9[Suppl 10]:344–345

292. Ziegler D, Ford R, Kriegler J,Gallagher RM, Peroutka S,Hammerstad J, Saper J, Hoffert M,Vogel B, Holtz N et al (l994)Dihydroergotamine nasal spray forthe acute treatment of migraine.Neurology 44[3 pt 1]:447–453

293. Dihydroergotamine Nasal SprayMulticenter Investigators (1995)Efficacy, safety, and tolerability ofdihydroergotamine nasal spray asmonotherapy in the treatment of acutemigraine. Headache 35(4):177–184

294. Gallagher RM and theDihydroergotamine Working Group(1996) Acute treatment of migrainewith dihydroergotamine nasal spray.Arch Neurol 53(12):1285–1291

295. Silberstein SD, Schulman EA,Hopkins MM (1990) Repetitive intra-venous DHE in the treatment ofrefractory headache. Headache30(6):334–339

296. Silberstein SD (1995) Status migrain-osus. In: Gilman S, Goldstein GW,Waxman SG (eds) Neurobase. Arbor,La Jolla

297. Evers S, Gralow I, Bauer B, Suhr B,Buchheister A, Husstedt IW,Ringelstein EB (1999) Sumatriptanand ergotamine overuse and drug-induced headache: a clinicoepidemio-logic study. Clin Neuropharmacol22(4):201–206

298. Zed PJ, Loewen PS, Robinson G(1999) Medication-induced headache:overview and systematic review oftherapeutic approaches. AnnPharmacother 33(1):61–72

299. Evers S, Suhr B, Bauer B,Grotemeyer KH, Husstedt IW (1999)A retrospective long-term analysis ofthe epidemiology and features ofdrug-induced headache. J Neurol246(9):802–809

300. Evers S, Schmidt F, Bauer B, Voss H,Grotemeyer KH, Husstedt IW (1999)The impact of ergotamine-inducedheadache and ergotamine withdrawalon information processing.Psychopharmacology (Berl)142(1):61–67

301. Lipton RB (1997) Ergotamine tartrateand dihydroergotamine mesylate:safety profiles. Headache 37[Suppl1]:S33–S41

302. Meyler WJ (1996) Side effects ofergotamine. Cephalalgia 16(1):5–10

303. Enriquez E, Rangel A, Velasco CE,Basave MN, Lopez-Rodriguez R(2000) [Ergotism caused byautomedication.] Arch Inst CardiolMex 70(6):603–608 (article inSpanish)

304. Scott AK (1992)Dihydroergotamine: a review of itsuse in the treatment of migraine andother headaches. ClinNeuropharmacol 15(4):289–296

305. Saadah HA (1992) Abortive migrainetherapy with oral naproxen sodiumplus metoclopramide plus ergotaminetartrate with caffeine. Headache32(2):95–97

306. Becker A, Berner G, Leuschner F,Vogtle-Junkert U (1992)[Pharmacokinetic aspects of a com-bination of metoclopramide andparacetamol. Results of a humankinetic study and consequences formigraine patients.]Arzneimittelforschung42(4):552–555 (article in German)

145

307. Pradalier A, Guerard des Lauriers A,Scheck F, Peraudeau P, Lacoste JP,Cajfinger F (1995) [Calcium car-basalate-metoclopramide combina-tion versus dihydroergotamine in thetreatment of migraine attacks.] PatholBiol (Paris) 43(9):806–813 (article inFrench)

308. Scherl ER, Wilson JF (1995)Comparison of dihydroergotaminewith metoclopramide versus meperi-dine with promethazine in the treat-ment of acute migraine. Headache35(5):256–259

309. Waelkens J (1984) Dopamine block-ade with domperidone: bridgebetween prophylactic and abortivetreatment of migraine? A dose-find-ing study. Cephalalgia 4(2):85–90

310. Amery WK, Waelkens J (1983)Prevention of the last chance: analternative pharmacologic treatmentof migraine. Headache 23(1):37–38

311. Bell R, Montoya D, Shuaib A, LeeMA (1990) A comparative trial ofthree agents in the treatment of acutemigraine headache. Ann Emerg Med19(10):1079–1082

312. Ellis GL, Delaney J, DeHart DA,Owens A (1993) The efficacy ofmetoclopramide in the treatment ofmigraine headache. Ann Emerg Med22(2):191–195

313. Coppola M, Yearly DM, Leibold RA(1995) Randomized, placebo-con-trolled evaluation of prochlorperazineversus metoclopramide for emer-gency department treatment ofmigraine headache. Ann Emerg Med26(5):541–546

314. Cameron JD, Lane PL, Speechley M(1995) Intravenous chlorpromazinevs intravenous metoclopramide inacute migraine headache. AcadEmerg Med 2(7):597–602

315. Tek DS, McClellan DS, Olshaker JS,Allen CL, Arthur DC (1990) Aprospective, double-blind study ofmetoclopramide hydrochloride forthe control of migraine in the emer-gency department. Ann Emerg Med19(10):1083–1087

316. Tfelt-Hansen P, Olesen J, Aebelholt-Krabbe A, Melgaard B, Veilis B(1980) A double blind study of meto-clopramide in the treatment ofmigraine attacks. J Neurol NeurosurgPsychiatry 43(4):369–371

317. Jones EB, Gonzalez ER, Boggs JG,Grillo JA, Elswick RK Jr (1994)Safety and efficacy of rectal prochlor-perazine for the treatment of migrainein the emergency department. AnnEmerg Med 24(2):237–241

318. McEwen JI, O’Connor HM, DinsdaleHB (1987) Treatment of migrainewith intramuscular chlorpromazine.Ann Emerg Med 16 (7):758–763

319. Shrestha M, Singh R, Moreden J,Hayes JE (1996) Ketorolac vs chlor-promazine in the treatment of acutemigraine without aura. A prospective,randomized, double-blind trial. ArchIntern Med 156(15):1725–1728

320. Kelly AM, Ardagh M, Curry C,D’Antonio J, Zebic S (1997)Intravenous chlorpromazine versusintramuscular sumatriptan for acutemigraine. J Accid Emerg Med14(4):209–211

321. Jones J, Pack S, Chun E (1996)Intramuscular prochlorperazine ver-sus metoclopramide as single agenttherapy for the treatment of acutemigraine headache. Am J Emerg Med14(3):262–264

322. Lane PL, McLellan BA, Baggoley CJ(1989) Comparative efficacy ofchlorpromazine and meperidine withdimenhydrinate in migraineheadache. Ann Emerg Med18(4):360–365

323. Rowat BM, Merrill CF, Davis A,South V (1991) A double-blind com-parison of granisetron and placebofor the treatment of acute migraine inthe emergency department.Cephalalgia 11(5):207–213

324. Chappell AS, Bay JM, Botzum GD,Cohen ML (1994) Zatosetron, a 5-HT3 receptor antagonist in a multi-center trial for acute migraine.Neuropharmacology33(3–4):509–513

325. Veneziano M, Framarino DeiMalatesta M, Bandiera AF, FiorelliC, Galati M, Paolucci A (1995)Ondansetron-induced headache. Ourexperience in gynecological cancer.Eur J Gynaecol Oncol16(3):203–207

326. Bateman DN, Darling WM, Boys R,Rawlins MD (1989) Extrapyramidalreactions to metoclopramide andprochlorperazine. Q J Med71(264):307–311

327. Barone JA (1999) Domperidone: aperipherally acting dopamine 2-receptor antagonist. AnnPharmacother 33(4):429–440

328. Owens DG (1996) Adverse effects ofantipsychotic agents. Do neweragents offer advantages? Drugs51(6):895–930

329. Green JF, McElholm A, King DJ(1996) A comparison of the sedativeand amnestic effects of chlorpro-mazine and lorazepam.Psychopharmacology (Berl)128(1):67–73

330. Olsen JC, Keng JA, Clark JA (2000)Frequency of adverse reactions toprochlorperazine in the ED. Am JEmerg Med 18(5):609–611

331. Drotts DL, Vinson DR (1999)Prochlorperazine induces akathisia inemergency patients. Ann Emerg Med34(4 Pt 1):469–475

332. Higgins BC (1999) Emergency!Prochlorperazine-induced dystonia.Am J Nurs 99(11):34

333. Pesola GR, Quinto C (1996)Prochlorperazine-induced neurolepticmalignant syndrome. J Emerg Med14(6):727–729

334. White WB (1986) Hypotension withpostural syncope secondary to thecombination of chlorpromazine andcaptopril. Arch Intern Med146(9):1833–1834

335. Byrne A, Zibin T, Chimich W,Hnatko G (1994) Severe hypotensionassociated with combined lithium andchlorpromazine therapy: a case reportand a review. Can J Psychiatry39(5):294–296

336. Markowitz JC, Brown RP (1987)Seizures with neuroleptics and anti-depressants. Gen Hosp Psychiatry9(2):135–141

337. Elenbaas RM, Iacono CU, KoellnerKJ, Priddle JP, Gratton M, Racz G,Evens RP (1991) Dose effectivenessand safety of butorphanol in acutemigraine headache. Pharmacotherapy11(1):56–63

338. Diamond S, Freitag FG, DiamondML, Urban G (1992) Transnasalbutorphanol in the treatment ofmigraine headache pain. Headache Q3(2):164–171

146

339. Hoffert MJ, Couch JR, Diamond S,Elkind AH, Goldstein J, KohlermanNJ 3rd, Saper JR, Solomon S (1995)Transnasal butorphanol in the treat-ment of acute migraine. Headache35(2):65–69

340. Melanson SW, Morse JW, PronchikDJ, Heller MB (1997) Transnasalbutorphanol in the emergency depart-ment management of migraineheadache. Am J Emerg Med15(1):57–61

341. Linbo L, Bartleson JD, Morgan-Thompson D, Greff L, Naessens JM(1998) Acute treatment of periodicsevere headache: comparison of threeoutpatient care facilities. Headache38(2):105–111

342. Ziegler DK (1997) Opioids inheadache treatment. Is there a role?Neurol Clin 15(1):199–207

343. Donnadieu S, Djian MC (1998) [Paintherapy.] Presse Med27(39):2062–2069 (article in French)

344. Ducharme J (1999) CanadianAssociation of Emergency PhysiciansGuidelines for the acute managementof migraine headache. J Emerg Med17(1):137–144

345. Reutens DC, Fatovich DM, Steward-Wynne EG, Prentice DA (1991) Isintravenous lidocaine clinically effec-tive in acute migraine? Cephalalgia11(6):245–247

346. Maizels M, Scott B, Cohen W, ChenW (1996) Intranasal lidocaine fortreatment of migraine: a randomized,double-blind, controlled trial. JAMA276(4):319–321

347. Maizels M (1998) Intranasal lido-caine for migraine in an outpatientpopulation. Headache 38(5):391

348. Kozubski W (1992) Metamizole andhydrocortisone for the interruption ofa migraine attack - preliminary study.Headache Q 3(3):326–328

349. Klapper J, Stanton J (1991) Theemergency treatment of acutemigraine headache: a comparison ofintravenous dihydroergotamine, dex-amethasone, and placebo.Cephalalgia 11[Suppl 11]:159–160

350. Saadah HA (1994) Abortive migrainetherapy in the office with dexametha-sone and prochlorperazine. Headache34(6):366–370

351. Gallagher R (1986) Emergency treat-ment of intractable migraine.Headache 26(2):74–75

352. Tfelt-Hansen P, Jensen K, VendsborgP, Lauritzen M, Olesen J (1982)Chlormezanone in the treatment ofmigraine attacks: a double-blindcomparison with diazepam and place-bo. Cephalalgia 2(4):205–210

353. Ogden HD (1963) Controlled studiesof a new agent in vascular headache.Headache 3(1):29–31

354. Ryan RE (1974) A study of midrinin the symptomatic relief ofmigraine headache. Headache14(1):33–42

355. Diamond S, Medina JL (1975)Isometheptene: a non-ergot drug inthe treatment of migraine. Headache15(3):211–213

356. Behan PO (1978) Isometheptenecompound in the treatment of vascu-lar headache. Practitioner221(1326):937–939

357. Diamond S (1976) Treatment ofmigraine with isometheptene, aceta-minophen, and dichloralphenazonecombination: a double-blind,crossover trial. Headache15(4):282–287

358. Freitag FG, Cady R, DiSerio F,Elkind A, Gallagher RM, Goldstein J,Klapper JA, Rapoport AM,Sadowsky C, Saper JR, Smith TR(2001) Comparative study of a com-bination of isometheptene mucate,dichloralphenazone with aceta-minophen and sumatriptan succinatein the treatment of migraine.Headache 41(4):391–398

Introduction

The opportunity to choose a specific prophylactic therapyfor a patient depends upon the severity of the attacks andhow these headaches alter the quality of life. Prophylactictreatment is usually recommended in the case of 3 or moresevere attacks per month incompletely responding to symp-tomatic treatment and in the case of more than 4 days withheadache per month.

The main goals for preventive agents in migrainetreatment are to reduce the frequency and severity ofmigraine attacks and improve the quality of life. It is gen-erally accepted that a good response to prophylactic treat-ment is at least a 50% reduction in the frequency orseverity of migraine attacks. Others goals are to expandthe knowledge of preventive treatments, to promote stud-ies in this field, and to avoid the development of a chron-ic daily headache as well as symptomatic drug abuse ormisuse [1].

As for all therapeutic strategies, even the prophylacticdrugs for migraine should undergo a careful evaluation oftheir benefit/risk ratio. This implies that each treatmentshould be used at the dosage with the least number ofadverse drug reactions (ADRs) in order to reduce the num-ber and severity of attacks for an adequate period until thetreatment can be stopped.

The presence of any comorbid conditions should be con-sidered in the choice of a preventive medication formigraine.

From evidence-based medicine to recommendations

Recommendations for the prophylactic treatment ofmigraine should be not just the simple sum of the findingsof clinical trials from evidence-based papers, obtained from

Medline, but also the result of the critical evaluation by agroup of experts who discuss the results available in the lit-erature, taking into account their own experiences. In fact,clinical reports may not be sufficient for giving a stepapproach to treatment choice, particularly for drugs not yetadequately evaluated, even if they are used by patients orprescribed by physicians [2–4].

Management of pharmacological treatment

To minimize the risk and improve the patient’s compli-ance, prophylactic treatment should be started at lowdoses, possibly as a monotherapy. Doses can be slowlyincreased until therapeutic goals are achieved in theabsence of side effects. The treatment should be main-tained for at least 3 months before stopping it. In fact, clin-ical benefit may take as long as 1–3 months after the onsetof response. To use a monotherapy at adequate doses andfor an adequate period of time is necessary in order tounderscore the relationship between drug efficacy and sideeffects.

Long-acting or depot formulations can improve patientcompliance. When pharmacological resistance appears, anew prophylactic treatment with another drug should be pre-ceded by a washout period.

Drugs contraindicated for any comorbid conditions (i.e.beta-blockers in patients with asthma) and drugs that couldworsen migraine (i.e. nifedipine for hypertension) should beavoided, when possible.

Particular attention should be devoted to drug-drug ordrug-food interactions, and it should be remembered thatmany prophylactic treatments may cause teratogeniceffects. Therefore, prophylactic treatment during pregnan-cy should be limited to special situations, and in these rarecases, drugs with the lowest risk to the fetus should beselected.


Prophylactic treatment of migraine

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Patient recommendations

The main problem in preventive therapies is always patientcompliance. The compliance in prolonged treatments isinversely related to the length of treatment and the numberof pills taken every day. Therefore, when possible, the num-ber of drugs taken should be reduced and the patients shouldbe involved in the choice of their own treatment. Patientsshould be carefully informed about how and when to takedrugs, and about the potential adverse effects. Another rele-vant point to address is the patient’s expectations of the actu-al therapeutic efficacy of the drug, and about the impact ofthe treatment on the quality of life and disease evolution.

For the evaluation of the efficacy of the treatment,patients should be educated to follow a formal managementplan and to carefully fill out headache diaries that recordthe frequency and duration of attacks, the severity of pain,the functional impairment, disability and the drugs taken aswell as any adverse events. These parameters are necessaryto assess the modifications in migraine due to preventivetreatment.

Primary prevention of migraine

Migraine can be considered as a particular response of thehuman brain to a number of triggers, both internal andexternal. Such response is probably genetically deter-mined. Migraine patients seem to present a lower thresh-old for attacks in certain brain areas compared with thoseof non-migraineurs. In this regard, the primary prophylax-is of migraine should be focused on identifying the trig-gers and carefully avoiding them by changing the patient’slifestyle. Therefore, patients should be provided a list ofcommon triggers to avoid. Another easy method isencouraging patients to note all the migraine attacks andthe potential triggers for each attack in their headachediary.

The most frequent trigger factors are listed in Table 1.However, even a correct lifestyle cannot prevent allmigraine attacks in all patients.

It has been hypothesized that migraine patients have alowered threshold for trigger factors, perhaps geneticallydetermined. So, a rational prophylactic treatment should befocused to enhance this threshold and this, together with theremoval of trigger factors, when possible, should result inthe reduction of the number and intensity of attacks.

Precipitating factors are those factors able to elicit amigraine attack, after a short time of exposure. They are notthe cause of migraines. They often need cofactors to precip-itate the attacks and, even in the same patients, one factor isnot enough to always induce the attack.

One or more precipitating factors are reported in64%–90% of patients with migraine, and these are morefrequent in those with migraine without aura than withaura. The most frequent factors are stress and psychologi-cal tension.

A trivial trigger is considered food. Many people believethat by avoiding some specific foods it is possible to reducethe frequency of migraine attacks. Putative allergic factorsare often considered responsible for migraine attacks,whereas, only in rare cases, a specific food directly causesmigraine. From 20% to 52% of patients report that alcoholicdrinks precipitate migraine, and conflicting data have beenreported with respect to differences between beer or red andwhite wine. Also, some foods are involved as precipitatingfactors in percentages varying from 10% to 45%, namely:chocolate, cheese, some fruits, citrus fruits, fatty foods andfried foods. Peatfield [5] recorded 19% of patients reportingsensitivity to cheese, chocolate, or both, and 11% of patientssensitive to citrus fruits. The exact mechanism of thesemigraine attacks is unknown, although migraine is general-ly believed to be caused by a chemical reaction consisting inthe release of serotonin from the intestinal wall, or by anenzymatic defect, and not by allergic reactions.

By contrast, fasting has been described to be a precipi-tating factor in 25% of children and in 40% of adults affect-ed by migraine.

Menstruation is a common precipitating factor in24%–64% of women suffering from migraine without aura.In fact, hormonal factors can be considered as both precipi-tating and predisposing factors.

Both too much or too little sleep as well as fatigue arebelieved to be precipitating factors.

Moreover, weather changes are often considered to beprecipitating factors for migraine in a percentage rangingfrom 7% to 43%, and patients even say that they are able topredict the forecast. By contrast, specific studies did notshow a relationship between migraine attacks and eitherweather conditions or barometric changes.

Glaring, blinding and psychedelic lights are also report-ed to be precipitating factors for migraine, and in a recentstudy these lights were recognized as precipitating factorsonly in migraine with aura [6].

Other triggers could be angiographic procedures, headinjuries, physical exercise, and altitude. By contrast, sexual activity does not seem able to cause a migraineattack.

Behavior modifications

The first recommendation for patients should be to avoidtrigger factors. To obtain this result, patients need to recog-

149

nize their specific trigger factors; therefore, it is necessary tocarefully fill out the diary that should be evaluated at everymedical visit.

When stress is identified as the main trigger factor, it isuseful to begin a formal behavioral treatment program toavoid stressors, since pharmacological therapy alone isunable to control migraine attacks. For this purpose, musclerelaxation techniques, including biofeedback, are recom-mended. In some cases physical exercise can be useful toreduce stress.

Drug treatment should be used together with behaviormodifications to obtain a significant reduction of migraineattacks and an improvement in the quality of life.

Re-evaluation of the diagnosis

The diagnosis should be re-evaluated when:– there is a case of high frequency of migraine attacks– there are changes in migraine characteristics (i.e. focal

symptoms, variation of frequency, intensity or length ofattacks, etc.)

– there is a lack of effects after three treatments with dif-ferent drugs

– there is an analgesic abuse

Drugs for prophylactic treatment

A few drugs for the prophylactic treatment of migraine havebeen studied in adequate clinical trials according to evi-dence-based medicine (EBM) criteria. The level and qualityof evidence for their use, and the overall recommendationlevel, are presented in Tables 2 and 3 respectively. Clinicallyrelevant drug-drug interactions are given in Table 4.

Beta-blockers

How beta-blockers can reduce attack frequency in mi-graneurs is not clear, although it is probably by acting on thecentral monoaminergic system and serotonin receptors. Notall these drugs are effective, and those used in migraine pro-phylaxis include atenolol, metoprolol, nadolol and propra-nolol [7–56]. Beta-blockers are contraindicated in patientswith chronic obstructive pulmonary disease, diabetes melli-tus, heart failure and peripheral vascular diseases. There is arelative contraindication in pregnancy.

Atenolol and nadolol are excreted by the kidneys andshow fewer adverse effects in the central nervous system

(CNS). Failure of prophylactic treatment with one beta-blocker is not predictive of the activity of other beta-block-ers, so that consecutive trials with these drugs are appropri-ate. Physicians should start with low doses and increasethem slowly, if necessary.

When migraine attacks are controlled, doses can bereduced slowly. The abrupt suspension of beta-blockers caninduce rebound effects both increasing migraine attacks andinducing adrenergic side effects and hypertension.

Calcium channel blockers

Calcium channel blockers act by modulating neurotrans-mission, inducing vasodilatation and exerting a cytopro-tective effect by preventing the influx of calcium ions intothe cells and reducing cell damage due to hypoxia. Thetherapeutic effects become evident only after somemonths of treatment, and are associated with a number ofside effects. Among all available drugs of this class, themost used are flunarizine (level of evidence A, recom-mendation level I) and verapamil (level of evidence B,recommendation level II) [57–77]. The efficacy of thesedrugs in reducing migraine attacks by at least 50% andimproving the quality of life is comparable with thatobtained by beta-blockers at least for flunarizine. Lessconsistent are the findings with nimodipine and nifedip-ine [78–82].

Some calcium channel blockers are contraindicated inpregnancy, hypotension, heart failure, atrioventricular (AV)block, Parkinson’s disease and depression (e.g. flunarizine)and in patients in therapy with beta-blockers and mono-amine oxidase inhibitors (MAOI) (e.g. verapamil).

Serotonin antagonists

Pizotifen is one of the serotonin receptor antagonists withweak antihistaminic and cholinergic effects. Despite itseffectiveness in migraine, with a clinical benefit in50%–64% of the cases, it has side effects which includeweight gain and asthenia (level of evidence A, recom-mendation level IIIb) [83–86]. Methysergide is a semi-synthetic ergometrine derivative with activity as 5-HT1

and 5-HT2 receptor antagonists. It has been shown to beactive, particularly in cases with high frequency of attacksnot responsive to treatment [86]. Contraindicationsinclude pregnancy, peripheral vascular disorders, severearteriosclerosis, coronary artery disease, severe hyperten-sion, thrombophlebitis or cellulitis of the legs, pepticulcer disease, fibrotic disorders, lung diseases, connective

150

tissue disease, liver or renal function impairment, valvu-lar heart disease, cachexia, or serious infection.Methysergide can induce retroperitoneal fibrosis andpleural and heart valve fibrosis with an estimated inci-dence of 1 in 5000 treated patients. Therefore, it should bereserved for severe cases in which other migraine preven-tive drugs are not effective, taking carefully into accountthe risk-benefit ratio. Today this drug is not available inItaly.

Tricyclic antidepressants

Amitriptyline is useful in migraine, especially in patientswith concomitant tension-type headache (level of evidenceA, recommendation class I). The mechanism of action isnot related to its antidepressant activity. Amitriptylinemodulates monoaminergic pathways, by inhibiting thereuptake of both adrenaline and serotonin. Moreover, itfunctionally down-regulates β-adrenergic and serotonergicreceptor expression in the central nervous system Theeffective dose varies [27, 87–91], starting with an initialdose of 10 mg, per os, every night, to be increased by 10mg per week, up to a maximum of 50 mg per day. Highdoses could be necessary in the case of concomitantdepression.

A lower risk of developing asthenia and anticholinergicside effects has been observed for nortriptyline compared toamitriptyline (level of evidence C). The contraindicationsinclude: severe cardiac, liver, renal, prostatic and thyroiddiseases, glaucoma, hypotension, convulsive disorders andconcomitant use of MAOI.

Tricyclic antidepressants should be used with caution inelderly patients because of anticholinergic effects.

Selective serotonin-reuptake inhibitors

Few studies are available on the use of this class of drugs inthe prophylaxis of migraine [92–98]. At the moment, thereis no definitive evidence supporting the use of these drugs inpreventing migraine attacks.

Alpha-2 agonists

The majority of the studies on the prophylactic treatment ofmigraine concern clonidine but failed to show more effica-cy compared with placebo [99–113]. Negative results werealso obtained with guanfacine [114].

Antiepileptic drugs

Sodium valproate shows excellent results in preventingmigraine in clinical trials (level of evidence A; recommen-dation level I) [115–120].

Care should be used when this drug is associated withacetylsalicylic acid (ASA) and warfarin, because of thepossibility of bleeding. The main side effects are nausea,alopecia, tremors and weight gain; chronic use mayinduce liver damage, mostly in children. This drug is ter-atogenic and should not be administered to pregnantwomen.

Gabapentin, a GABAergic drug, has been shown to beeffective in preventing migraine attacks [121, 122]. In arecent multicenter double-blind placebo-controlled study,this drug was significantly more effective than placebo inreducing the frequency of migraine attacks [122]. Themore frequent adverse effects were somnolence anddizziness.

Topiramate and lamotrigine have been used with moder-ate efficacy in migraine prophylaxis [123–130]. The mostfrequent side effects of topiramate were cognitive dysfunc-tion, sedation, diarrhea, weight loss, and dizziness. Recently,it has been reported that after one month of therapy with top-iramate, some patients reported an acute reduction of vision,myopia and acute narrow-angle glaucoma.

Lamotrigine showed less efficacy in preventing migrainewithout aura, whereas it was efficacious in preventingattacks in the case of a high frequency of migraine with auracrises [128–130]. The most frequent side effects were: rash(some fatal), fatigue, dizziness, headache, Stevens-Johnsonsyndrome, toxic epidermal necrolysis and hypersensitivityreactions.

No recent studies have been carried out on carba-mazepine as a prophylactic antimigraine drug and data areinconclusive about its efficacy [131, 132].

Non-steroidal anti-inflammatory drugs

The main mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition ofcyclooxygenase in both isoforms, whereas, even in theabsence of inflammation, NSAIDs are active in reducingmigraine pain (level of evidence B, recommendation levelII). Among this class of drugs, acetylsalicylic acid, flur-biprofen, lornoxicam, mefenamic acid, ketoprofen andboth naproxen and naproxen sodium show a discrete effec-tiveness in migraine prophylaxis [2, 133–146]. Bothnaproxen and naproxen sodium are useful in the preventionof menstrual migraine (level of evidence B; recommenda-tion level II) [147, 148].

151

NSAIDs should be used for intermittent prophylaxis inmenstrual migraine and not for prolonged periods of timebecause of their gastric and intestinal side effects (level ofevidence B) [149, 150].

Dihydroergotamine

Dihydroergotamine in slow-release formulations at various doses was effective in preventing migraineattacks [151, 152]. Dihydroergokryptine also appeared tobe an effective drug for the prophylaxis of migraineattacks [153].

Lisuride

Lisuride has been proved to be effective and well-toleratedfor migraine prophylaxis in some studies [154, 155]. In anopen study, a reduction of more than 50% of attacks wasobserved in 61.4% of patients treated for a 3-month period,with good tolerance [154].

Riboflavin

Riboflavin at high doses (up to 400 mg) showed goodeffectiveness in preventing migraine attacks [156] with alow rate of unwanted side effects, such as mild abdominal

pain and diarrhea. This drug at these doses is not avail-able in Italy.

Estrogens

Some clinical trials showed the efficacy of high doses ofestradiol (1.5 mg/day in gel) in the prophylactic treat-ment of menstrual migraine. They have been demonstrat-ed to significantly reduce the number of attacks [157,158]. Lower doses (50 mg/day) were ineffective.Preliminary studies suggest a possible effectiveness ofthe association of estradiol with flumedroxone andmethysergide [86].

Tanacetum parthenium

The efficacy of feverfew in preventing migraine is not uni-versally accepted. Some studies show a reduction in painintensity and associated symptoms, whereas others show anincrease in the frequency of attacks or no differences incomparison with placebo [159–162].

Magnesium

Magnesium showed efficacy in preventing migraine in threeclinical trials [163–165].

Table 1 Common trigger factors for migraine

Hormonal Menstruation, ovulation, oral contraceptives

Diet Alcohol, nitrites, monosodium glutamate, aspartame, chocolate, cheeses, fasting

Psychological Stress, post-stress (weekends and holidays), anxiety, fear, depression

Environmental Flashing lights, blinding lights, fluorescent lights, weather changes, perfumes, altitude

Sleep Lack of or excessive sleep

Drugs Nitroglycerin, histamine, reserpine, hydralazine, ranitidine, estrogens, cocaine, marijuana

Others Head injuries, physical exercise

152Ta

ble

2E

vide

nce

for

prop

hyla

ctic

dru

g tr

eatm

ents

in m

igra

ine.

Dos

e ra

nges

are

indi

cativ

e on

ly. R

ecom

men

datio

ns a

re n

ot m

ade

for

regi

men

dos

ing.

Ref

er to

pub

lishe

d lit

era-

ture

for

spe

cifi

c do

sing

info

rmat

ion.

No

dosi

ng in

form

atio

n is

pro

vide

d fo

r tr

eatm

ents

not

evi

denc

e-ba

sed

(Lev

el C

)

Dru

gL

evel

of

Scie

ntif

ic s

tren

gth

Clin

ical

Adv

erse

eve

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Com

men

tsev

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ceof

evi

denc

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fect

iven

ess

Bet

a-bl

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teno

lol

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100

mg/

day

A+

++

++

Occ

asio

nal,

not s

ever

eFr

eque

nt A

Es

are

asth

enia

, fat

igue

and

diz

zine

ss.

ED

, 100

mg/

day

Use

ful i

n pa

tient

s w

ith h

yper

tens

ion,

anx

iety

and

pani

c at

tack

s. S

houl

d no

t be

used

in p

atie

nts

with

coex

istin

g as

thm

a, c

ardi

ac f

ailu

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r R

ayna

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dis

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ay e

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not u

se w

ith

ergo

tam

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reas

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rano

lol

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l, no

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e as

for

ate

nolo

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us e

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tial t

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hen

DT,

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240

mg/

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rano

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ith r

izat

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min

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asio

nal,

not s

ever

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me

as f

or a

teno

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DT,

80–

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day

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ate

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Cal

cium

cha

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eA

++

++

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asio

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not s

ever

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ost f

requ

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ide

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are

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and

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ptom

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ay b

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–10

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day

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rved

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lder

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atie

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rec

omm

ende

d do

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ness

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150

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120

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vate

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++

Occ

asio

nal,

not s

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onst

ipat

ion

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omm

on. D

o no

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in th

e pr

esen

ceE

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40 m

g/da

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AV

bloc

k. C

ould

be

a go

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lock

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in a

thle

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omm

ende

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pat

ient

sw

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trok

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pro

long

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ura,

and

in p

atie

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with

coex

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pert

ensi

on a

nd ta

chyc

ardi

a. A

void

asso

ciat

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bet

a-bl

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rs

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iaze

ma

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asio

nal,

not s

ever

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lera

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oth

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ss.

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omm

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imiz

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5 m

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the

tabl

e co

ntin

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�

153

Con

tinu

atio

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le 2

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idep

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cycl

ic a

ntid

epre

ssan

ts (

TC

As)

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itrip

tylin

eA

++

++

++

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uent

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ere

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wsi

ness

, wei

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and

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ergi

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Es

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25–

150

mg/

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mon

. Par

ticul

arly

use

ful i

n pa

tient

s w

ith

ED

, 30–

150

mg/

day

depr

essi

on, m

igra

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and

tens

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type

hea

dach

e.

Apr

ogre

ssiv

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crea

se in

dos

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rec

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tilm

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enan

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10–

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NA

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eque

nt, n

ot s

ever

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ette

r to

lera

ted

than

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itrip

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, 10–

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eque

nt, n

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ever

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her

TC

As

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ctiv

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++

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ccas

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l, no

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Inso

mni

a, f

atig

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rem

or a

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n ad

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n de

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nts.

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re a

re d

rug

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ract

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ts

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ine,

par

oxet

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CN

A+

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asio

nal,

not s

ever

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me

as f

or f

luox

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ese

rtra

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oam

ine

oxid

ase

inhi

bito

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spe

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ever

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stri

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ns; s

how

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high

ris

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sev

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drug

-dru

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ns. B

enef

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an p

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ld b

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atie

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with

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alpr

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A

++

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nt, n

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ever

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men

ded

for

patie

nts

with

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long

ed o

rD

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00–1

550

mg/

day

atyp

ical

mig

rain

e au

ra. N

ot r

ecom

men

ded

in p

atie

nts

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m le

vel,

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with

live

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e an

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prog

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is r

ecom

men

ded

with

repe

ated

mon

itori

ng o

f dr

ug p

lasm

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in th

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rly

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ent.

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like

nau

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ast

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aan

d so

mno

lenc

e ar

e fr

eque

ntly

see

n w

hen

high

erdo

ses

are

used

. Oth

er s

ide

effe

cts

incl

ude

wei

ght

gain

, hai

r lo

ss, t

rem

or, a

nd te

rato

geni

c po

tent

ial

Gab

apen

tinA

++

++

Occ

asio

nal,

not s

ever

eD

T, 9

00–1

200

mg/

day

Topi

ram

atea

B+

+?

Occ

asio

nal,

not s

ever

eO

ccas

iona

l CN

S A

E, k

idne

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ones

and

wei

ght l

oss

(100

mg/

day)

. Acu

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a an

d na

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-ang

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com

a

the

tabl

e co

ntin

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�

154C

onti

nuat

ion

of T

able

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of

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ic s

tren

gth

Clin

ical

Adv

erse

eve

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Com

men

tsev

iden

ceof

evi

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otri

gine

B

++

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eque

nt, n

ot s

ever

eR

ecom

men

ded

for

mig

rain

e w

ith a

ura

with

a h

igh

DT,

100

mg/

day

freq

uenc

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atta

cks

Car

bam

azep

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Freq

uent

, not

sev

ere

Com

mon

adv

erse

eve

nts

are

dizz

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s, v

ertig

o,

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600

mg/

day

drow

sine

ss. N

ot r

ecom

men

ded

beca

use

of p

oor

effi

cacy

and

a h

igh

inci

denc

e of

sid

e ef

fect

s

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eque

nt, n

ot s

ever

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adve

rse

even

ts f

requ

ent,

no c

linic

al b

enef

it fo

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T, 0

.05–

0.22

5 m

g/da

ypr

even

tion

of m

igra

ine

ED

, 0.0

75–0

.15

mg/

day

Sero

toni

n an

tago

nist

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zotif

enA

++

++

+Fr

eque

nt, n

ot s

ever

eSo

mno

lenc

e an

d w

eigh

t gai

n ar

e co

mm

onD

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50 m

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yE

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50 m

g/da

y

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A+

Freq

uent

, not

sev

ere

Use

d in

ped

iatr

ic m

igra

ine.

Wei

ght g

ain

and

fatig

ue

are

com

mon

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Lis

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eaA

++

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ccas

iona

l, no

t sev

ere

Not

ava

ilabl

e in

Ita

ly. A

t low

dos

es u

sefu

l for

mig

rain

epr

ophy

laxi

s

Dih

ydro

ergo

tam

ine

TR

A+

++

++

Rar

e, n

ot s

ever

eA

ltern

ativ

e dr

ug f

or m

oder

ate

to s

ever

e m

igra

ine

DT,

10

mg/

day

atta

cks

of lo

w f

requ

ency

and

in c

ase

of n

o re

spon

seE

D, 1

0 m

g/da

yto

trip

tans

. Do

not u

se w

ithin

6 h

aft

er tr

ipta

ns. T

o be

used

in m

ild to

mod

erat

e m

igra

ine

atta

cks

whe

nN

SAID

s ar

e no

t tol

erat

ed. U

sefu

l for

sho

rt-t

erm

prop

hyla

ctic

ther

apy

NSA

IDs A

cety

lsal

icyl

ic a

cid

B+

?O

ccas

iona

l, no

t sev

ere

Abd

omin

al d

isco

mfo

rt, g

astr

itis

and

occu

lt G

I bl

eedi

ngD

T, 3

25–1

300

mg/

day

are

freq

uent

. May

be

usef

ul f

or p

atie

nts

with

art

hriti

sE

D, 1

300

mg/

day

and

prev

ious

str

oke

Lor

noxi

cam

aB

++

?O

ccas

iona

l, no

t sev

ere

–

Nap

roxe

n, n

apro

xen

sodi

umB

++

?O

ccas

iona

l, no

t sev

ere

Use

d as

sho

rt-t

erm

pro

phyl

axis

in m

enst

rual

mig

rain

e D

T, 1

100

mg/

day

ED

, 110

0 m

g/da

y

Ket

opro

fen

B+

+?

Occ

asio

nal,

not s

ever

e–

DT,

150

mg/

day

ED

, 150

mg/

day

the

tabl

e co

ntin

ues

�

155

Con

tinu

atio

n of

Tab

le 2

Dru

gL

evel

of

Scie

ntif

ic s

tren

gth

Clin

ical

Adv

erse

eve

nts

Com

men

tsev

iden

ceof

evi

denc

eef

fect

iven

ess

Oth

ers

Est

radi

olB

++

++

Rar

e, n

ot s

ever

eU

sed

for

the

shor

t-te

rm p

reve

ntio

n of

men

stru

alD

T, 1

5 m

g/da

y fo

r 1

wee

km

igra

ine.

Per

cuta

neou

s us

eE

D, 1

5 m

g/da

y fo

r 1

wee

k

Vita

min

B2

B+

++

++

Rar

e, n

ot s

ever

eR

are

AE

. Unk

now

n dr

ug-d

rug

inte

ract

ions

D

T, 4

00 m

g/da

yE

D, 4

00 m

g/da

y

Mag

nesi

umB

++

Rar

e, n

ot s

ever

eN

on-c

hela

ted

form

ulat

ions

can

indu

ce d

iarr

hea.

D

T, 4

00–6

00 m

g/da

yM

ay b

e us

eful

in p

atie

nts

with

men

stru

al m

igra

ine

ED

, 400

–600

mg/

day

Tana

cetu

m p

arth

eniu

mB

++

?R

are,

not

sev

ere

Mild

sid

e ef

fect

s. W

ithdr

awal

cou

ld b

e as

soci

ated

DT,

50–

82 m

g/da

yw

ith r

ebou

nd f

requ

ency

of

head

ache

s E

D, 5

0–82

mg/

day

Bot

ulin

um to

xin

AB

++

++

Rar

e, n

ot s

ever

eTe

chni

ques

of

adm

inis

trat

ion

are

not e

asy

and

appl

icab

leev

eryw

here

Dru

gs n

ot a

vail

able

or

not

used

in

Ital

y

Vig

abat

rina

B+

+?

Occ

asio

nal

Clin

ical

exp

erie

nce

and

publ

ishe

d da

ta a

re la

ckin

gD

T, 1

000–

2000

mg/

day

and

furt

her

stud

ies

are

need

ed. V

isua

l fie

ld c

onst

rict

ion

has

been

des

crib

ed a

s A

E

Phen

elzi

nea

CN

A?

Freq

uent

Req

uire

s co

mpl

ex m

anag

emen

t with

spe

cial

die

tary

rest

rict

ions

. Hig

h po

tent

ial f

or d

rug-

drug

inte

ract

ions

.M

ay b

e he

lpfu

l in

patie

nts

with

coe

xist

ing

depr

essi

onor

whe

n an

tidep

ress

ants

fro

m o

ther

cla

sses

fai

l.A

E in

clud

e or

thos

tatic

hyp

oten

sion

, fat

igue

, ver

tigo

and

psyc

hotic

dis

turb

ance

s

Tim

olol

A+

+?

Infr

eque

nt–

DT,

20–

30 m

g/da

yE

D, 2

0–30

mg/

day

Dih

ydro

ergo

kryp

tinea

B+

?N

ot s

ever

eM

ild s

ide

effe

cts.

With

draw

al c

ould

be

asso

ciat

ed w

ithD

T, 2

0 m

g/da

yre

boun

d fr

eque

ncy

of h

eada

ches

Met

hyle

rgon

ovin

eaC

NA

?Fr

eque

ntM

ay b

e us

ed in

men

stru

al-a

ssoc

iate

d m

igra

ine

Met

hyse

rgid

ebA

++

+?

Rar

e bu

t pot

entia

llySh

ould

be

rese

rved

for

sev

ere

case

s in

whi

ch o

ther

DT,

2–1

0 m

g/da

yse

vere

mig

rain

e pr

even

tive

drug

s ar

e no

t eff

ectiv

eE

D, 6

mg

Flum

edro

xone

B+

?O

ccas

iona

l to

freq

uent

Rar

e A

E a

re h

epat

ic d

isea

se, h

emor

rhag

e, c

hole

stat

ic

DT,

10–

30 m

g/da

yja

undi

ce, p

orph

yria

, men

stru

al d

istu

rban

ces

inE

D, 1

0–30

mg/

day

wom

en, a

nd d

row

sine

ss a

nd d

ecre

ased

libi

do in

men

aE

ffic

acio

us d

ose

not e

stab

lishe

d in

con

trol

led

tria

ls; b

Bas

ed o

n bo

dy w

eigh

tC

NS,

cen

tral

ner

vous

sys

tem

; AE

, adv

erse

eve

nts;

TC

As,

tric

yclic

ant

idep

ress

ants

; AV

, atr

iove

ntri

cula

r; N

SAID

s, n

on-s

tero

idal

ant

i-in

flam

mat

ory

drug

s; G

I, g

astr

oint

estin

al; D

T,

dose

s te

sted

; ED

, eff

icac

ious

dos

es in

clin

ical

tria

ls; T

R, t

ime-

rele

ased

; NR

, not

rec

omm

ende

d; N

A, n

ot a

pplic

able

; ?, u

ndet

erm

ined

156

Table 4 Clinically relevant drug-drug interactions among antimigraine drugs

Drug 1 Drug 2 Effect Onset Probable mechanism of action

Acetylsalicylic acid (ASA) Diclofenac GI lesions Rapid Gastric irritationIndomethacin GI lesions Delayed Gastric irritationCOX-2 inhibitors Increased risk of GI bleeding Delayed Gastric irritation

Ergotamine Triptans Vasoconstriction Rapid Additive vasoconstrictive effects

Methysergide Triptans Prolonged vasoconstriction Rapid Additive vasoconstrictive effects

NSAIDs NSAIDs Peptic ulcer; gastritis; Rapid Gastric irritationGI bleeding

Propranolol Rizatriptan Increased rizatriptan levels Rapid Inhibition of rizatriptan metabolism

SSRIs Triptans Serotonin syndrome Rapid Excessive 5-HT stimulationMAOI Serotonin syndrome Rapid Excessive 5-HT stimulation

TCAs Sertraline Serotonin syndrome Rapid Excessive 5-HT stimulation

Triptans Triptans Prolonged vasoconstriction Rapid Additive vasoconstrictive effectsMAOI Serotonin syndrome Rapid Excessive 5-HT stimulation

Valproate Amitriptyline Increased amitriptyline levels Delayed Inhibition of amitriptyline metabolism

Verapamil Beta-blockers Hypotension, bradycardia Rapid Additive cardiovascular effects,reduced metabolism of beta-blockers

GI, gastrointestinal; NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin-reuptake inhibitors; TCAs, tricyclic anti-depressants; MAOI, monoamine oxidase inhibitors

Table 3 Drugs for prophylactic treatment of migraine grouped by level of recommendation

Level I Level II Level III (a, b) Level IV

Amitriptyline Cinnarizine Acetylsalicylic acidb BupropionAtenolol Dihydroergotamine TR Botulinum toxin Aa CarbamazepineFlunarizine Fluoxetine Diltiazema ClonidinePropranolol Gabapentin Fluvoxaminea Dihydroergokryptine*Sodium valproate Lamotrigine Lisuridea Doxepin

Lornoxicam Magnesiuma EstradiolMetoprolol Methylergonovineb* Flumedroxone*Nadolol Nimodipinea ImipramineNaproxen Nortriptylinea KetoprofenNaproxen sodium Paroxetinea MertazepineTopiramate Pizotifenb Methysergide*Verapamil Sertralinea Phenelzine*Vitamin B2 Tanacetum parthenium

Timolol*TrazodoneVenlafaxineVigabatrin*

The names of the drugs are listed in alphabetical order* Drugs unavailable or not used in Italya and b refer to the two subgroups of Level 3 reported in Table 7 “Levels of recommendation for the treatment of migraine and clusterheadache” of the Methodology section

a Drugs with no severe adverse eventsb Unsafe drugs or with complex indication for use (e.g. special diets) or important pharmacological interactions

157

1. Tfelt-Hansen P, Welch KMA (1993)General principles of pharmacologi-cal treatment. In: Olesen J, Tfelt-Hansen P, Welsh KMA (eds) Theheadaches. Raven, New York, pp299–303

2. Gray RN, Goslin RE, McCrory DC,Eberlein K, Tilsky J, Hasselbald V(1999) Drug treatment for the pre-vention of migraine headache.Technical Review 2.3 (prepared forthe Agency for Health Care Policyand Research under Contract No.290-94-2025. Available from theNational Technical InformationService; NTIS accession no.127953)

3. McCrory DC, Matchar DB,Rosenberg JH, Silberstein SD (2000)Evidence-based guidelines formigraine headache. US HeadacheConsortium.http://www.ahsnet.org/guidelines.php,http://www.aoa-net.org/MembersOnly/headachemain.htm(consulted 17 December 2001)

4. Silberstein SD, Lipton RB (1997)Chronic daily headache. In:Goadsby PJ, Silberstein SD (eds)Blue books of practical neurology:headache. Butterworth-Heinemann,Boston, pp 201–225

5. Peatfield RC (1995) Relationshipsbetween food, wine, and beer-precip-itated migrainous headaches.Headache 35(6):355–357

6. Martin VT, Behbehani MM (2001)Toward a rational understanding ofmigraine trigger factors. Med ClinNorth Am 85(4):911–941

7. Ahuja GK, Verma AK (1985)Propranolol in prophylaxis of migraine.Indian J Med Res 82:263–265

8. Børgesen SE, Nielsen JL, Møller CE(1974) Prophylactic treatment ofmigraine with propranolol. A clinicaltrial. Acta Neurol Scand 50(5):651–656

9. Dahlöf C (1987) No clearcut long-term prophylactic effect of onemonth of treatment with propranololin migraineurs. Cephalalgia 7[Suppl6]:459–460

10. Forssman B, Henriksson KG,Johannsson V, Lindvall L, Lundin H(1976) Propranolol for migraineprophylaxis. Headache16(5):238–245

11. Johnson RH, Hornabrook RW,Lambie DG (1986) Comparison ofmefenamic acid and propranolol withplacebo in migraine prophylaxis.Acta Neurol Scand 73(5):490–492

12. Mikkelsen B, Pedersen KK,Christiansen LV (1986) Prophylactictreatment of migraine with tolfe-namic acid, propranolol and place-bo. Acta Neurol Scand73(4):423–427

13. Pita E, Higueras A, Bolaños J, PerezN, Mundo A (1977) Propranolol andmigraine. A clinical trial. ArchFarmacol Toxicol 3(3):273–278

14. Pradalier A, Serratrice G, Collard M,Hirsch E, Feve J, Masson M, MassonC, Dry J, Koulikovsky G, Nguyen Get al (1989) Long-acting propranololin migraine prophylaxis: results of adouble-blind, placebo-controlledstudy. Cephalalgia 9(4):247–253

15. Holroyd KA, Penzien DB,Cordingley GE (1991) Propranolol inthe management of recurrentmigraine: a meta-analytic review.Headache 31(5):333–340

16. Stensrud P, Sjaastad O (1976) Short-term clinical trial of propranolol inracemic form (Inderal), D-propra-nolol, and placebo in migraine. ActaNeurol Scand 53(3):229–232

17. Tfelt-Hansen P, Standnes B,Kangasneimi P, Hakkarainen H,Olesen J (1984) Timolol vs. propra-nolol vs. placebo in common migraineprophylaxis: a double-blind multicen-ter trial. Acta Neurol Scand 69(1):1–8

18. Gerber WD, Schellenberg R, ThomM, Haufe C, Bolsche F, Wedekind W,Niederberger U, Soyka D (1995)Cyclandelate versus propranolol inthe prophylaxis of migraine - a dou-ble-blind placebo-controlled study.Funct Neurol 10(1):27–35

19. al-Qassab HK, Findley LJ (1993)Comparison of propranolol LA 80mg and propranolol LA 160 mg inmigraine prophylaxis: a placebo-con-trolled study. Cephalalgia13(2):128–131

20. Carroll JD, Reidy M, Savundra PA,Cleave N, McAinsh J (1990) Long-acting propranolol in the prophylaxisof migraine: a comparative study oftwo doses. Cephalalgia10(2):101–105

21. Havanka-Kanniainen H, Hokkanen E,Myllylä VV (1988) Long-acting pro-pranolol in the prophylaxis ofmigraine: comparison of the dailydoses of 80 mg and 160 mg.Headache 28(9):607–611

22. Gawel MJ, Kreeft J, Nelson RF,Simard D, Arnott WS (1992)Comparison of the efficacy and safe-ty of flunarizine to propranolol in theprophylaxis of migraine. Can JNeurol Sci 19(3):340–345

23. Lücking CH, Oestreich W, Schmidt R,Soyka D (1988) Flunarizine vs. pro-pranolol in the prophylaxis ofmigraine: two double-blind compara-tive studies in more than 400 patients.Cephalalgia 8[Suppl 8]:21–26

24. Ludin HP (1989) Flunarizine andpropranolol in the treatment ofmigraine. Headache 29(4):219–224

25. Shimell CJ, Fritz VU, Levien SL(1990) A comparative trial of flunar-izine and propranolol in the preven-tion of migraine. S Afr Med J77(2):75–77

26. Rao BS, Das DG, Taraknath VR,Sarma Y (2000) A double-blind con-trolled study of propranolol andcyproheptadine in migraine prophy-laxis. Neurol India 48(3):223–226

27. Mathew NT (1981) Prophylaxis ofmigraine and mixed headache. A ran-domized controlled study. Headache21(3):105–109

28. Steardo L, Bonuso S, Di Stasio E,Marano E (1982) Selective and non-selective beta-blockers: are botheffective in prophylaxis of migraine?A clinical trial versus methysergide.Acta Neurol (Napoli) 4(3):196–204

29. Kjærsgåard Rasmussen MJ, HoltLarsen B, Borg L, SoelbergSørensen P, Hansen PE (1994)Tolfenamic acid versus propranololin the prophylactic treatment ofmigraine. Acta Neurol Scand89(6):446–450

30. Kaniecki RG (1997) A comparison ofdivalproex with propranolol andplacebo for the prophylaxis ofmigraine without aura. Arch Neurol54(9):1141–1145

31. Behan PO, Reid M (1980)Propranolol in the treatment ofmigraine. Practitioner224(1340):201–203

References

158

32. Andersson PG, Dahl S, Hansen JH,Hansen PE, Hedman C, KristensenTN, de Fine Olivarius B (1983)Prophylactic treatment of classicaland non-classical migraine withmetoprolol: a comparison with place-bo. Cephalalgia 3(4):207–212

33. Bordini CA, Arruda MA, CiciarelliMC, Speciali JG (1997) Propranololvs flunarizine vs flunarizine plus pro-pranolol in migraine without auraprophylaxis. A double-blind trial. ArqNeuropsiquiatr 55(3B):536–541

34. Kangasniemi P, Hedman C (1984)Metoprolol and propranolol in theprophylactic treatment of classicaland common migraine. A double-blind study. Cephalalgia 4(2):91–96

35. Olsson JE, Behring HC, Forssman B,Hedman C, Hedman G, Johansson F,Kinnman J, Palhagen SE,Samuelsson M, Strandman E (1984)Metoprolol and propranolol inmigraine prophylaxis: a double-blindmulticentre study. Acta Neurol Scand70(3):160–168

36. Ryan RE Sr (1984) Comparativestudy of nadolol and propranolol inprophylactic treatment of migraine.Am Heart J 108(4 Pt 2):1156–1159

37. Cortelli P, Albani F (1994) Propranololin prophylaxis of migraine. ArchNeurol 51(12):1181–1182

38. Olerud B, Gustavsson CL, Furberg B(1986) Nadolol and propranolol inmigraine management. Headache26(10):490–493

39. Goslin RE, Gray RN, McCrory DC,Penzien D, Rains J, Hasselblad V(1999) Behavioral and physical treat-ments for migraine headache.Technical Review 2.2 (prepared forthe Agency for Health Care Policyand Research under Contract No.290-94-2025. Available from theNational Technical InformationService; NTIS accession no. 127946)

40. Ekbom K, Lundberg PO (1972)Clinical trial of LB-46 (d, 1-4-(2-hydroxy-3-isopropyl-aminopropoxy)indol. An adrenergic beta-receptorblocking agent in migraine prophy-laxis. Headache 12(1):15–17

41. Kuritzky A, Hering R (1987)Prophylactic treatment of migrainewith long acting propranolol. A com-parison with placebo. Cephalalgia7[Suppl 6]:457–478

42. Solomon GD (1986) Verapamil andpropranolol in migraine prophylaxis:a double-blind crossover study.Headache 26:325

43. Forssman B, Lindblad CJ,Zbornikova V (1983) Atenolol formigraine prophylaxis. Headache23(4):188–190

44. Johannsson V, Nilsson LR, WideliusT, Javerfalk T, Hellman P, AkessonJA, Olerud B, Gustafsson CL, RaakA, Sandahl G et al (1987) Atenolol inmigraine prophylaxis: a double-blindcross-over multicentre study.Headache 27(7):372–374

45. Freitag FG, Diamond S (1984)Nadolol and placebo comparisonstudy in the prophylactic treatment ofmigraine. J Am Osteopath Assoc84(4):343–347

46. Ryan RE Sr, Ryan RE Jr, SudilovskyA (1983) Nadolol: its use in the pro-phylactic treatment of migraine.Headache 23(1):26–31

47. Sudilovsky A, Elkind AH, Ryan RESr, Saper JR, Stern MA, Meyer JH(1987) Comparative efficacy ofnadolol and propranolol in the man-agement of migraine. Headache27(8):421–426

48. Ryan RE Sr, Ryan RE Jr, SudilovskyA (1982) Nadolol and placebo com-parison study in the prophylactictreatment of migraine. PanminervaMed 24(2):89–94

49. Langohr HD, Gerber WD, KoletzkiE, Mayer K, Schroth G (1985)Clomipramine and metoprolol inmigraine prophylaxis - - a double-blind crossover study. Headache25(2):107–113

50. Diener HC, Hartung E, Chrubasik J,Evers S, Schoenen J, Eikermann A,Latta G, Hauke W; Study Group(2001) A comparative study of oralacetylsalicyclic acid and metoprololfor the prophylactic treatment ofmigraine. A randomized, controlled,double-blind, parallel group phaseIII study. Cephalalgia21(2):120–128

51. Kangasniemi P, Andersen AR,Andersson PG, Gilhus NE, HedmanC, Hultgren M, Vilming S, Olesen J(1987) Classic migraine: effectiveprophylaxis with metoprolol.Cephalalgia 7(4):231–238

52. Steiner TJ, Joseph R, Hedman C,Rose FC (1988) Metoprolol in theprophylaxis of migraine: parallel-groups comparison with placebo anddose-ranging follow-up. Headache28(1):15–23

53. Wideroe TE, Vigander T (1974)Propranolol in the treatment ofmigraine. Br Med J 2(921):699–701

54. Stellar S, Ahrens SP, Meibohm AR,Reines SA (1984) Migraine preven-tion with timolol. A double-blindcrossover study. JAMA252(18):2576–2580

55. Limmroth V, Michel MC (2001) Theprevention of migraine: a criticalreview with special emphasis onbeta-adrenoceptor blockers. Br J ClinPharmacol 52(3):237–243

56. Vilming S, Standnes B, Hedman C(1985) Metoprolol and pizotifen inthe prophylactic treatment of classi-cal and common migraine. A double-blind investigation. Cephalalgia5(1):17–23

57. al Deeb SM, Biary N, Bahou Y, alJaberi M, Khoja W (1992)Flunarizine in migraine: a double-blind placebo-controlled study (in aSaudi population). Headache32(9):461–462

58. Diamond S, Freitag FG, Luis P(1981) A double-blind placebo-con-trolled prophylactic study of flunar-izine (Sibelium) in migraine.Headache 21(6):235–239

59. Mendenopoulos G, Manafi T,Logothetis I, Bostantjopoulou S(1985) Flunarizine in the preventionof classical migraine: a placebo-con-trolled evaluation. Cephalalgia5(1):31–37

60. Pini LA, Ferrari A, Guidetti G,Galetti G, Sternieri E (1985)Influence of flunarizine on the alteredelectronystagmographic (ENG)recordings in migraine. Cephalalgia5[Suppl 2]:173–175

61. Sorensen PS, Hansen K, Olesen J(1986) A placebo-controlled, double-blind, cross-over trial of flunarizinein common migraine. Cephalalgia6(1):7–14

62. Thomas M, Behari M, Ahuja GK(1991) Flunarizine in migraine pro-phylaxis: an Indian trial. Headache31(9):613–615

159

63. Bussone G, Cerbo R, Martucci N,Micieli G, Zanferrari C, Grazzi L,Fabbrini G, Cavallini A, Granella F,Ambrosoli L, Mailland F, Poli A,Manzoni G (1999) Alpha-dihydroer-gocryptine in the prophylaxis ofmigraine: a multicenter double-blindstudy versus flunarizine. Headache39(6):426–431

64. Sorensen PS, Larsen BH, RasmussenMJ, Kinge E, Iversen H, Alslev T,Nohr P, Pedersen KK, Schroder P,Lademann A et al (1991) Flunarizineversus metoprolol in migraine prophy-laxis: a double-blind, randomized par-allel group study of efficacy and toler-ability. Headache 31(10):650–657

65. Grotmeyer KH, Schlake HP, HusstedtIW, Rolf LH (1987) Metoprolol versusflunarizine: a double-blind cross-overstudy. Cephalalgia 7[Suppl 6]:465–466

66. Cerbo R, Casacchia M, Formisano R,Feliciani M, Cusimano G, Buzzi MG,Agnoli A (1986) Flunarizine-pizo-tifen single-dose double-blind cross-over trial in migraine prophylaxis.Cephalalgia 6(1):15–18

67. Louis P, Spierings EL (1982)Comparison of flunarizine (Sibelium)and pizotifen (Sandomigran) inmigraine treatment: a double-blindstudy. Cephalalgia 2(4):197–203

68. Rascol A, Montastruc JL, Rascol O(1986) Flunarizine versus pizotifen: adouble-blind study in the prophylaxisof migraine. Headache 26(2):83–85

69. Agnoli A, Bussone G, Mailland F,Manzoni GC, Martucci N, Nappi G(1991) Dihydroergokryptine vs. flu-narizine in the basic treatment ofmigraine without aura. Cephalalgia11(11):216–217

70. Bussone G, Baldini S, D’Andrea G,Cananzi A, Frediani F, Caresia L,Ferro Milone F, Boiardi A (1987)Nimodipine versus flunarizine incommon migraine: a controlled pilottrial. Headache 27(2):76–79

71. Lamsudin R, Sadjimin T (1993)Comparison of the efficacy betweenflunarizine and nifedipine in the pro-phylaxis of migraine. Headache33(6):335–338

72. Nappi G, Sandrini G, Savoini G,Cavallini A, de Rysky C, Micieli G(1987) Comparative efficacy ofcyclandelate versus flunarizine inthe prophylactic treatment ofmigraine. Drugs 33[Suppl2]:103–109

73. Lucetti C, Nuti A, Pavese N,Gambaccini G, Rossi G, BonuccelliU (1998) Flunarizine in migraineprophylaxis: predictive factors for apositive response. Cephalalgia18(6):349–352

74. Markley HG, Cheronis JC, PiephoRW (1984) Verapamil in prophylactictherapy of migraine. Neurology34(7):973–976

75. Solomon GD, Steel JC, SpaccaventoLJ (1983) Verapamil prophylaxis ofmigraine: a double-blind, placebo-controlled study. JAMA250(18):2500–2502

76. Ansel E, Fazzone T, Festenstein R etal (1988) Nimodipine in migraine pro-phylaxis. Cephalalgia 8(4):269–272

77. Migraine-Nimodipine EuropeanStudy Group (MINES) (1989)European multicenter trial ofnimodipine in the prophylaxis ofclassic migraine (migraine with aura).Headache 29(10):639–642

78. Gelmers HJ (1983) Nimodipine, anew calcium antagonist in the pro-phylactic treatment of migraine.Headache 23(3):106–109

79. Havanka-Kanniainen H, Hokkanen E,Myllyla VV (1985) Efficacy ofnimodipine in the prophylaxis ofmigraine. Cephalalgia 5(1):39–43

80. McArthur JC, Marek K, Pestronk A,McArthur J, Peroutka SJ (1989)Nifedipine in the prophylaxis of clas-sic migraine: a crossover, double-masked, placebo-controlled study ofheadache frequency and side effects.Neurology 39(2 Pt 1):284–286

81. Shukla R, Garg RK, Nag D, AhujaRC (1995) Nifedipine in migraineand tension headache: a randomizeddouble-blind crossover study. JAssoc Physicians India43(11):770–772

82. Gerber WD, Diener HC, Scholz E,Niederberger U (1991) Respondersand non-responders to metoprolol,propranolol and nifedipine treatmentin migraine prophylaxis: a dose-rangestudy based on time-series analysis.Cephalalgia 11(1):37–45

83. Cleland PG, Barnes D, ElringtonGM, Loizou LA, Rawes GD (1997)Studies to assess if pizotifen prophy-laxis improves migraine beyond thebenefit offered by acute sumatriptantherapy alone. Eur Neurol38(1):31–38

84. Mastrosimone F, Iaccarino C, deCaterina G (1992) Efficacy and toler-ance of cyclandelate versus pizotifenin the prophylaxis of migraine. J Med23(1):1–16

85. Spierings EL, Messinger HB (1988)Flunarizine vs. pizotifen in migraineprophylaxis: a review of comparativestudies. Cephalalgia 8[Suppl8]:27–30

86. Silberstein SD (1998) Methysergide.Cephalalgia 18(7):421–435

87. Couch JR, Hassanein RS (1976)Migraine and depression: effect ofamitriptyline prophylaxis. Trans AmNeurol Assoc 101:234–237

88. Couch JR, Hassanein RS (1979)Amitriptyline in migraine prophylax-is. Arch Neurol 36(11):695–699

89. Gomersall JD, Stuart A (1973)Amitriptyline in migraine prophylaxis.Changes in pattern of attacks during acontrolled clinical trial. J NeurolNeurosurg Psychiatry 36(4):684–690

90. Ziegler DK, Hurwitz A, HassaneinRS, Kodanaz HA, Preskorn SH,Mason J (1987) Migraine prophylax-is. A comparison of propranolol andamitriptyline. Arch Neurol44(5):486–489

91. Bonuso S, Di Stasio E, Barone P,Steardo L (1983) Timed-release dihy-droergotamine in the prophylaxis ofmixed headache. A study versusamitriptyline. Cephalalgia 3[Suppl1]:175–178

92. Adly C, Straumanis J, Chesson A(1992) Fluoxetine prophylaxis ofmigraine. Headache 32(2):101–104

93. Saper JR, Silberstein SD, Lake AE3rd, Winters ME (1994) Double-blindtrial of fluoxetine: chronic dailyheadache and migraine. Headache34(9):497–502

94. Steiner TJ, Ahmed F, Findley LJ,MacGregor EA, Wilkinson M(1998) S-fluoxetine in the prophy-laxis of migraine: a phase II double-blind randomized placebo-con-trolled study. Cephalalgia18(5):283–286

95. Bánk J (1994) A comparative studyof amitriptyline and fluvoxamine inmigraine prophylaxis. Headache34(8):476–478

96. Oguzhanoglu A, Sahiner T, Kurt T,Akalin O (1999) Use of amitriptylineand fluoxetine in prophylaxis ofmigraine and tension-type headaches.Cephalalgia 19(5):531–532

160

97. Andersson PG, Petersen EN (1981)Propranolol and femoxetine, a HT-uptake inhibitor, in migraine prophy-laxis. A double-blind crossover study.Acta Neurol Scand 64(4):280–288

98. Kangasniemi PJ, Nyrke T, Lang AH,Petersen E (1983) Femoxetine - anew 5-HT uptake inhibitor - and pro-pranolol in the prophylactic treatmentof migraine. Acta Neurol Scand68(4):262–267

99. Adam EI, Gore SM, Price WH(1978) Double-blind trial of clonidinein the treatment of migraine in a gen-eral practice. J R Coll Gen Pract28(195):587–590

100. Boisen E, Deth S, Hübbe P, Jansen J,Klee A, Leunbach G (1978) Clonidinein the prophylaxis of migraine. ActaNeurol Scand 58(5):288–295

101. Bredfeldt RC, Sutherland JE, Kruse JE(1989) Efficacy of transdermal cloni-dine for headache prophylaxis andreduction of narcotic use in migrainepatients. A randomized crossover trial.J Fam Pract 29(2):153–156

102. Das SM, Ahuja GK, NarainaswamyAS (1979) Clonidine in prophylaxisof migraine. Acta Neurol Scand60(4):214–217

103. Kallanranta T, Hakkarainen H,Hokkanen E, Tuovinen T (1977)Clonidine in migraine prophylaxis.Headache 17(4):169–172

104. Mondrup K, Møller CE (1977)Prophylactic treatment of migrainewith clonidine. A controlled clinicaltrial. Acta Neurol Scand56(5):405–412

105. Ryan RE Sr, Diamond S, Ryan RE Jr(1975) Double-blind study of cloni-dine and placebo for the prophylactictreatment of migraine. Headache15(3):202–210

106. Shafar J, Tallett ER, Knowlson PA(1972) Evaluation of clonidine inprophylaxis of migraine. Double-blind trial and follow-up. Lancet1(7747):403–407

107. Sjaastad O, Stensrud P (1971) 2-(2,6-dichlorophenylamino)-2-imidazolinehydrochloride (ST 155 orCatapresan) as a prophylactic remedyagainst migraine. Acta Neurol Scand47(1):120–122

108. Stensrud P, Sjaastad O (1976)Clonidine (Catapresan)-double-blindstudy after long-term treatment withthe drug in migraine. Acta NeurolScand 53(3):233–236

109. Wilkinson M (1970) Preliminaryreport on the use of clonidine(Boehringer Ingelheim) in the treat-ment of migraine. Res Clin StudHeadache 3:315–320

110. Louis P, Schoenen J, Hedman C(1985) Metoprolol vs. clonidine inthe prophylactic treatment ofmigraine. Cephalalgia 5(3):159–165

111. Kåss B, Nestvold K (1980)Propranolol (Inderal) and clonidine(Catapressan) in the prophylactictreatment of migraine. A comparativetrial. Acta Neurol Scand61(6):351–356

112. – (1990) No authors listed. Clonidinein migraine prophylaxis - now obso-lete. Drug Ther Bull 28(20):79–80

113. Behan PO (1985) Prophylactic treat-ment for migraine: a comparison ofpizotifen and clonidine. Cephalalgia5[Suppl 3]:524–525

114. Elkind AH, Webster C, HerbertsonRK (1989) Efficacy of guanfacine ina double-blind parallel study formigraine prophylaxis. Cephalalgia9[Suppl 10]:369–370

115. Klapper JA (1994) An open labelcross-over comparison of divalproexsodium and propranolol HCl in theprevention of migraine headaches.Headache Q 5(1):50–53

116. Klapper J (1997) Divalproex sodiumin migraine prophylaxis: a dose-con-trolled study. Cephalalgia17(2):103–108

117. Kinze S, Clauss M, Reuter U, Wolf T,Dreier JP, Einhaupl KM, Arnold G(2001) Valproic acid is effective inmigraine prophylaxis at low serumlevels: a prospective open-labelstudy. Headache 41(8):774–778

118. Mathew NT, Saper JR, SilbersteinSD, Rankin L, Markley HG,Solomon S, Rapoport AM, Silber CJ,Deaton RL (1995) Migraine prophy-laxis with divalproex. Arch Neurol52(3):281–286

119. Mathew NT, Rapoport A, Saper J,Magnus L, Klapper J, Ramadan N,Stacey B, Tepper S (2001) Efficacyof gabapentin in migraine prophylax-is. Headache 41(2):119–128

120. Jensen R, Brinck T, Olesen J (1994)Sodium valproate has a prophylacticeffect in migraine without aura: atriple-blind, placebo-controlledcrossover study. Neurology44(4):647–651

121. Wessely P, Baumgartner C, KlinglerD et al (1987) Preliminary results ofa double-blind study with the newmigraine prophylactic druggabapentin. Cephalalgia 7[Suppl6]:477–478

122. Di Trapani G, Mei D, Marra C,Mazza S, Capuano A (2000)Gabapentin in the prophylaxis ofmigraine: a double-blind randomizedplacebo-controlled study. Clin Ther151(3):145–148

123. Edwards KR, Glantz MJ, Norton A,Cross N (2000) Prophylactic treat-ment of episodic migraine with topi-ramate: a double-blind, placebo-con-trolled trial in 30 patients.Cephalalgia 20:316

124. Potter DL, Hart DE, Calder CS,Storey JR (2000) A double-blind, ran-domized, placebo controlled, parallelstudy to determine the efficacy oftopamax (Topiramate) in the prophy-laxis of migraine Neurology54[Suppl 3]:A14 (abstract)

125. Di Trapani G, Mei D, Marra C,Mazza S, Capuano A (2000) Use oftopiramate as prophylactic treatmentin migraine: result of a pilot study.Cephalalgia 20:338–357

126. Randal L, Von Seggern RL, Lisa K,Mannix LK, James U (2000) Efficacyof topiramate in migraine prophylax-is: a retrospective chart analysis.Neurology 54[Suppl 3]:A267(abstract)

127. Young WB, Hopkins MM, SanchezDel Rio M, Shechter AL (2000) Theeffect of topiramate on weight inchronic daily headache and episodicmigraine patients. Cephalalgia20:338–357

128. Steiner TJ, Findley LJ, Yuen AW(1997) Lamotrigine versus placebo inthe prophylaxis of migraine with andwithout aura. Cephalalgia17(2):109–112

129. D’Andrea G, Granella F, CadaldiniM, Manzoni GC (1999)Effectiveness of lamotrigine in theprophylaxis of migraine with aura:an open pilot study. Cephalalgia19(1):64–66

130. Lampl C, Buzath A, Klinger D,Neumann K (1999) Lamotrigine inthe prophylactic treatment ofmigraine aura - a pilot study.Cephalalgia 19(1):58–63

161

131. Rompel H, Bauermeister PW (1970)Aetiology of migraine and preventionwith carbamazepine (Tegretol):results of a double-blind, cross-overstudy. S Afr Med J 44(4):75–80

132. Anthony M, Lance JW, Somerville B(1972) A comparative trial ofprindolol, clonidine and carba-mazepine in the interval therapy ofmigraine. Med J Aust1(26):1343–1346

133. O’Neill BP, Mann JD (1978) Aspirinprophylaxis in migraine. Lancet2(8101):1179–1181

134. Ryan RE SR, Ryan RE Jr (1981)Migraine prophylaxis: a newapproach. Laryngoscope 91(9 Pt1):1501–1506

135. Masel BE, Chesson AL, Peters BH,Levin HS, Alperin JB (1980) Plateletantagonists in migraine prophylaxis.A clinical trial using aspirin anddipyridamole. Headache 20(1):13–18

136. Couch JR, Bears CM, Verhulst S(1987) Fenoprofen in migraine pro-phylaxis. Headache 27(5):289

137. Diamond S, Solomon GD, FreitagFG, Mehta ND (1987) Fenoprofen inthe prophylaxis of migraine: a dou-ble-blind, placebo-controlled study.Headache 27(5):246–249

138. Salomon GD, Kunkel RS (1993)Flurbiprofen in the prophylaxis ofmigraine. Cleve Clin J Med60(1):43–48

139. Sternieri E, Bussone G, Manzoni GC,Martucci N, Nappi G (1991)Lornoxicam, a new non-steroidalanti-inflammatory drug in migraineprophylaxis: a double blind multicen-tric study. Cephalalgia 11[Suppl11]:154–155

140. Carrieri PB, Orefice G, Sorge F(1988) A double-blind placebo-con-trolled trial of indobufen in the pro-phylaxis of migraine. Acta NeurolScand 77(6):433–436

141. Stensrud P, Sjaastad O (1974)Clinical trial of a new anti-bradykinin, anti-inflammatory drug,ketoprofen (19.583 r.p.) in migraineprophylaxis. Headache 14(2):96–100

142. Sargent J, Solbach P, Damasio H,Baumel B, Corbett J, Eisner L, JessenB, Kudrow L, Mathew N, Medina Jet al (1985) A comparison of naprox-en sodium to propranolol hydrochlo-ride and a placebo control for theprophylaxis of migraine headache.Headache 25(6):320–324

143. Bellavance AJ, Meloche JP (1990) Acomparative study of naproxen sodi-um, pizotyline and placebo inmigraine prophylaxis. Headache30(11):710–715

144. Lindegard KF, Ovrelid L, Sjaastad O(1980) Naproxen in the prevention ofmigraine attacks: a double-blindplacebo-controlled cross-over study.Headache 20(2):96–98

145. Ziegler DK, Ellis DJ (1985)Naproxen in prophylaxis in migraine.Arch Neurol 42(6):582–584

146. Sances G, Martignoni E, Fioroni L,Blandini F, Facchinetti F, Nappi G(1990) Naproxen sodium in menstru-al migraine prophylaxis: a double-blind placebo controlled study.Headache 30(11):705–709

147. Szekel B, Merryman S, Croft H, PostG (1989) Prophylactic effect ofnaproxen sodium on perimenstrualheadache: a double-blind placebocontrolled study. Cephalalgia 9[Suppl10]:452–453

148. Welch KM, Ellis DJ, Keenam PA(1985) Successful migraine prophy-laxis with naproxen sodium.Neurology 35(9):1304–1310

149. Garcia-Rodriguez LA (1998)Variability in risk of gastrointestinalcomplications with different non-steroidal anti-inflammatory drugs.Am J Med 104:30S–34S

150. Henry D (1997) Meta-analysis of riskof gastrointestinal complications withNSAIDs. Authors should not haveincluded data from one study. BMJ314(7078):445

151. Bousser MG, Chick J, Fuseau E,Soisson T, Thevenet R (1998)Combined low-dose acetylsalicylicacid and dihydroergotamine inmigraine prophylaxis. A double-blind, placebo-controlled crossoverstudy. Cephalalgia 8(3):187–192

152. Buscaino GA, Sorge F, Bussone G,Frediani F (1991) Preventive treat-ment of headache with slow-releasedihydroergotamine: comparison ofdosage protocols. Curr Ther Res49:925–935

153. Frediani F, Grazzi L, Zanotti A,Mailland F, Zappacosta BM, BussoneG (1991) Dihydroergokryptine versusdihydroergotamine in migraine pro-phylaxis: a double-blind clinical trial.Cephalalgia 11(3):117–121

154. Soyka D, Frieling B (1989) [Lisuridefor the prevention of migraine.Results of a multicenter study.]Fortschr Med 107(35):763–766 (arti-cle in German)

155. Diener HC, Kaube H, Limmroth V(1998) A practical guide to the man-agement and prevention of migraine.Drugs 56(5):811–824

156. Schoenen J, Jacquy J, Lenaerts M(1998) Effectiveness of high-doseriboflavin in migraine prophylaxis. Arandomized controlled trial.Neurology 50(2):466–470

157. de Lignières B, Vincens M, Mauvais-Jarvis P, Mas JL, Touboul PJ,Bousser MG (1986) Prevention ofmenstrual migraine by percutaneousoestradiol. Br Med J 293(6561):1540

158. MacGregor A (2000) Migraine asso-ciated with menstruation. FunctNeurol 15[Suppl 3]:143–153

159. Johnson ES, Kadam NP, HylandsDM, Hylands PJ (1985) Efficacy offeverfew as prophylactic treatment ofmigraine. Br Med J291(6495):569–573

160. Murphy JJ, Heptinstall S, Mitchell JR(1988) Randomised double-blindplacebo-controlled trial of feverfewin migraine prevention. Lancet2(8604):189–192

161. Palevitch D, Earon G, Carusso R(1997) Feverfew (Tanacetum parthe-nium) as a prophylactic treatment formigraine: a double-blind placebo-controlled study. Phytother Res11:508–511

162. De Weerdt CJ, Bootsma HPR,Hendriks H (1996) Herbal medicinesin migraine prevention: randomizeddouble-blind placebo-controlledcrossover trial of feverfew prepara-tion. Phytomedicine 3:225–230

163. Peikert A, Wilimzig C, Köhne-VollandR (1996) Prophylaxis of migraine withoral magnesium: results from aprospective, multi-center, placebo-controlled and double-blind random-ized study. Cephalalgia 16(4):257–263

164. Pfaffenrath V, Wessely P, Meyer C,Isler HR, Evers S, Grotemeyer KH,Taneri Z, Soyka D, Gobel H, FischerM (1996) Magnesium in the prophy-laxis of migraine – a double-blindplacebo-controlled study. Cephalalgia16(6):436–440

165. Facchinetti F, Sances G, Borella P,Genazzani AR, Nappi G (1991)Magnesium prophylaxis of menstrualmigraine: effects on intracellular mag-nesium. Headache 31(5):298–301

Acupuncture

The efficacy of acupuncture in migraine has been recentlyevaluated by the Cochrane Collaborative Group [1]. After arigorous selection, the Cochrane Collaborative Group tookinto consideration 11 publications which investigated theeffectiveness of acupuncture toward a sham procedure in theprophylaxis of migraine. Five studies concluded thatacupuncture is significantly more effective than the shamstimulation, 4 studies showed a positive trend in favor ofacupuncture, while in 2 other trials acupuncture appeared tobe no more effective than placebo. In three studies, theeffectiveness of acupuncture was compared with that ofpharmacological preventive treatments. In all three studiesthe efficacy of acupuncture was underscored (equally effec-tive to the study drug in one study and more effective thanthe study drugs in the other two studies), but the Cochranereviewers expressed some methodological doubts relative tothese 3 trials.

Another recent, systematic review reached conclusionssimilar to those of the Cochrane Collaborative Group, regard-ing the role of acupuncture in migraine prophylaxis [2].

Electromyographical biofeedback and relaxation training

The majority of the studies in this regard compared activetreatments vs. a control group represented by patients in anout-patient setting. It is, in fact, extremely difficult to designstudies with matching placebo, since double-blinding isimpossible to use and a single-blinding is complicated toachieve. In the trials analyzed, the effect size in the patientgroups receiving the control treatment appeared to be lessthan half of the minimum value of the effect size of thepatient groups who received the active treatments. Thesedata suggest that electromyographical biofeedback and

relaxation training have a certain effectiveness in the pre-vention of adult migraine. A bias to be considered is that themajority of the patients included in these studies wererecruited in specialized centers and, therefore, they werepatients with severe migraine or nonresponders to pharma-cological therapies.

1. Electromyographical biofeedback: prospective, con-trolled randomized or quasi-randomized studies in adultmigraine patients

Five studies have been published on this topic between 1978and 1986. In three of the studies it was possible to calculatean overall effect size score of 0.77 and mean headacheimprovement using the headache index was 51% (range,36%–58%) [3–5]. In 2 further studies, for which it wasimpossible to calculate the effect size, the mean headacheimprovement was 23% (20%–24%) [6, 7]. Studies notincluded in this analysis reported lower percentages ofheadache improvement.

2. Relaxation training: prospective, controlled randomizedor quasi-randomized studies in adult migraine patients

Techniques aimed at controlling muscle tension or inducingmental relaxation with the help of a therapist have been ana-lyzed. These techniques include: progressive muscle relax-ation, autogenic training, and relaxation through meditationor visual imagery techniques.

In 5 studies it was possible to calculate the effect size, andthe mean headache improvement was 41% (range,6.2%–78%) [3, 8–11]. In one study, progressive musclerelaxation was compared with autogenic training but no dif-ference was found between the two treatments [12].


Non-pharmacological therapy of migraine

Thermal biofeedback and relaxation training

The use of thermal biofeedback for preventive headachetreatment consists in teaching the patient to warm thehands (vasodilatation) by using rapid sensory feedback,even though the distal vasodilatation of the upper limbsdoes not seem to be the most relevant factor in the antimi-graine effect of this procedure. No significant differencewas found on the effects of thermal biofeedback on handwarming compared with that on cooling, on thermal stabi-lization or on the suppression of the alpha rhythm on theEEG [13].

Indeed, both a regular participation at these sessions andthe belief of the patient in obtaining good results throughmeaningful control over headache (vasodilatation) can sig-nificantly influence the anti-migraine effect of this tech-nique. The studies show, in fact, that the effectiveness ofthermal biofeedback is enhanced if it is also practiced athome [14], and if the degree of feedback is reinforced bypositive results such as hand warming [15].

1. Thermal biofeedback

In 4 studies, the mean improvement of the headache indexwas 37% [16–19]. The modest value of the effect size(0.38) inferred by three studies [17–19] failed to support asignificant clinical benefit. However, studies not includedin the meta-analysis showed a greater improvement (50%and more).

2. Thermal biofeedback plus relaxation training

Nine studies showed a mean improvement in theheadache index of 33% [3, 7–9, 20–24]. The value of theeffect size (meta-analysis carried out on 8 of 9 studies) [3,4, 8, 9, 20–23] was modest (0.40), but still statisticallysignificant. The association of this technique with med-ication therapy can further improve the headache index,as seen in one study which showed a positive effect of theaddition of propranol to the treatment [24]. A comparisonwith drug therapy alone did not show significant differ-ences [25].

Thermal biofeedback has often been used in combina-tion with progressive muscle relaxation, and this combina-tion (TBR) has given the best results. On the other hand,TBR has been associated with pharmacological therapy andthis gave better results compared to the two techniques usedseparately. Recently, thermal biofeedback associated withrelaxation techniques has been recommended as a first-

choice nonpharmacological treatment for migraine, andphysical therapy has been indicated as a second-choicetreatment for migraineurs who do not sufficiently improvewith TBR [26].

Many studies on thermal biofeedback, associated or notwith relaxation techniques, involve young patients affectedby migraine. A meta-analysis study based on the compari-son of different types of behavioral treatment demonstratedthat thermal biofeedback and TBR are much more effectivethan other behavioral treatments, psychological approach-es, placebo and the most frequently used drugs [27].However, this conclusion was not confirmed by anothermeta-analysis in the same study carried out taking intoaccount only those studies comparing patients in therapywith control groups [27].

Thermal biofeedback alone can be effective in the pre-vention of migraine. TBR is also an effective treatment inthe prevention of recurrent migraine attacks. TBR can beeffectively associated with traditional pharmacologicaltreatment; moreover, the association of TBR with physio-therapy (e.g. active and passive movements, correction ofposture) can be considered in those patients who do notrespond to TBR alone. However, it should be pointed outthat thermal biofeedback is no more effective in migraineprevention than other types of biofeedback. The resultsobtained with electromyographic biofeedback and TBRshowed that neither technique is superior.

Hyperbaric oxygen therapy

The hypothesis of a therapeutic role for oxygen in migrainedates back to the 1930s. Wolff and Lenox in fact, believedthat oxygen inhalation was able to abort migraine attacksdue to the vasoconstrictive activity of oxygen on intra- andextracranial vessels [28]. Some decades later, Kudrow intro-duced therapy with normobaric oxygen for cluster headache[29], but unlike for this form of headache, the administrationof oxygen represents today a little explored technique for thetreatment of migraine.

The effectiveness of hyperbaric oxygen at two atmos-pheres of pressure was compared to the effect of normobar-ic oxygen at one atmosphere of pressure in patients affectedby migraine [30]. The study found a statistically significantdifference in effectiveness in favor of hyperbaric oxygen.The principal criticism of this study is that it was an opendesign with a small number of patients.

Another study compared the effectiveness of hyperbaricoxygen with normobaric oxygen in patients suffering frommigraine with aura [31]. The results supported the greaterefficacy of hyperbaric oxygen therapy, even though this,too, was an open study with few patients.

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Hypnosis

Hypnosis has a long tradition but few controlled studies areavailable regarding its effectiveness in migraine treatment.Given the difficulty in identifying sham techniques, potentialstudy strategies included comparison with pharmacologicaltreatments or with behavioral techniques such as biofeedback,or comparison between patient status before and after hypno-sis. Two studies based on this last approach suggested a highefficacy, but the results should be taken with caution [32, 33].In the first case [32], a randomized study compared hyp-notherapy (six sessions) with prochlorperazine (10 mg/dayfirst month, then 20 mg/day for 11 months). During the firstsix months, patients treated with hypnotherapy showed areduction in headache frequency compared to the group treat-ed with prochlorperazine, and this difference reached statisti-cal significance during months 6-12 of treatment. A possiblecriticism of this study is that prochlorperazine as administeredin this study cannot be considered an antimigraine drug.

In the second case [33], the effectiveness of self-hypno-sis was compared with thermal biofeedback plus relaxationtraining. Both approaches were effective in improvingheadache symptoms, but no significant difference was foundbetween the two groups.

In considering the possibility of combining hypnosiswith other non-pharmacological therapies, a meta-analysisof a broad number of controlled studies suggested that hyp-nosis can be of benefit in the treatment of headache whencombined with cognitive-behavioral therapy [34].

Orthodontic and stomatognathic treatments

A single trial investigated the effectiveness of dental occlusalequilibration [35] in migraine prevention. Headache diagnosiswas made according to the criteria of the Ad Hoc Committeeon Classification of Headache of 1962 [36]. Of the 96 patientsstudied, a subgroup of 36 suffered from migraine. No signifi-cant benefit was observed in the group of migraineurs [35].The studies of Wenneberg et al. [37] and Vallon et al. [38] aredifficult to interpret since they lacked sufficient data formigraine diagnosis according to IHS criteria. Tsolka et al. [39]treated 51 patients with orthognathodontic or sham tech-niques. No significant differences were observed in the per-centage reduction of migraine crises between the groups treat-ed with either genuine therapy or sham treatment.

Cervical manipulation techniques

A single study from 1978 carried out by Parker et al. [40]treating migraine patients with cervical mobilization

(movement of a joint within the normal range of move-ment) and cervical manipulation (movement of a jointbeyond its normal range of oscillation) provided littleadvantage for the use of these techniques in patients withmigraine (criteria not clearly defined). The study comparedthree interventions in 85 subjects: cervical manipulationperformed by a physician or physiotherapist, cervicalmanipulation performed by a chiropractor, and cervicalmobilization performed by a physician or physiotherapist(control). In all three groups, the post-treatment scores ofmigraine patients for frequency, severity and disabilitywere better than pre-treatment scores. No statistically sig-nificant differences were observed between groups treatedwith cervical manipulation and simple cervical mobiliza-tion. The same authors [41], in a follow-up study of thesepatients, reported a reduction in the average number ofattacks, from 29 to 19.

In 1998, Nelson et al. [42], in a prospective controlledstudy in parallel investigated migraine prophylaxis in 218patients. They were subdivided into three groups: the firstone received amitriptyline, the second one cervical manipu-lation plus amitriptyline, and the third one only cervicalmanipulation. Using index scores based on pre-treatmentvalues, a statistically significant improvement was observedin 49% of patients treated with amitriptyline, in 41% ofthose treated with drug plus cervical manipulation, and in40% of those treated with cervical manipulation alone. Astatistically significant improvement was seen in theamitriptyline-treated group compared to the other twogroups.

Behavioral therapy

Non-pharmacological treatment of headache, in general andparticularly of migraine, and especially in childhood andadolescence should not be viewed as an alternative to phar-macological intervention, but rather as an integral part of theapproach. This is based on the well known individual varia-tion in response to pharmacological treatments, both inadults [43, 44], and in children and adolescents [45, 46],since the pharmacogenetic, pharmacodynamic and pharma-cokinetic characteristics of the drugs vary with age. A non-pharmacological intervention is based first of all on the cor-rect identification of the headache disturbance, as well as thepossible trigger factors of the crises. Non-pharmacologicalintervention is crucial in childhood and adolescence, espe-cially when the well-recognized negative role of analgesicabuse in developing a chronic headache is taken intoaccount [47–49].

Even though non-pharmacological interventions cannotbe considered tout court an alternative strategy to pharma-cological interventions, some aspects support the use of

165

non-pharmacological interventions as treatments “ofchoice” or treatments to be integrated into symptomatic andprophylactic therapy:– Ineffectiveness or inadequate response to pharmacologi-

cal treatment – Inadequate compliance– Resistance of parents or patients (especially if adoles-

cents) to the use of drugs – A previous history of frequent analgesics use– Former preventive treatments– Psychiatric comorbidity (e.g. anxiety disturbances,

mood disturbances, social phobias, sleep disturbances)– Environmental trigger factors temporally related to the

onset of the crises – Family problems– Excessive involvement in school- and work-related matters

Relaxation techniques gave good results, especially whencombined with biofeedback, as shown in a case-control study[50]. After 10 years, biofeedback still seems to be more effec-tive than relaxation training alone [51, 52]. Relaxation train-ing, nevertheless, seems no more effective than less-struc-tured interventions, such as therapy sessions carried out “dis-cussing” potential trigger factors of the crises, or sessionsbased on the recognition of underlying emotional factors [53].

In synthesis, the treatments that have received greaterempirical support are those based on biofeedback(thermal/autogenic feedback and electromyographicalbiofeedback). Recently, promising results were obtained withbiofeedback based on training of slow cortical potentials [54].

There has been a lack of controlled studies using psy-chodynamic models of psychotherapy (individual) or a fam-ily therapy approach, even though the efficacy of such inter-ventions is widely supported by clinical experience.

Two relevant reviews [29, 55] further underscore theeffectiveness of biofeedback, but the advantage of integrat-

ing this technique with cognitive-behavioral interventionsneeds to be more clearly established.

Cognitive-behavioral techniques are based on theassumption that specific learning experiences can modifymaladaptive behaviors, replacing them with others moresuitable to the subject and different situations. Techniquesaimed at modifying stress-coping strategies and effecting amore adaptive response to stress have been successfullyused in childhood and adolescence [56, 57].Future research should consider the following issues:– Patient groups have been selected from the clinical set-

ting (above all patients attending specialized centers).– The tendency to spontaneous headache remission espe-

cially in childhood and adolescence has been widelydemonstrated [58] and its contribution to the results oftherapeutic trials should be assessed.

– The role and the mechanisms of placebo need to be clar-ified, for the implications regarding both pharmacologi-cal and non-pharmacological treatments.

– Further studies are needed to identify the discriminatingfactors (i.e. headache diagnosis and psychological pro-file) which support or not the choice of various non-pharmacological interventions.

– The influence of age-related factors needs to be furtherinvestigated.

– The influence of factors such as psychiatric comorbidityand personality characteristics should be clarified.

– The interactions between pharmacological and non-pharmacological interventions need to be determined.

– The influence of different learning settings (clinical andresearch laboratories) and training programs (individualor group) for different interventions should be betterinvestigated.

– Predictive variables for the clinical outcomes should beidentified.

References

1. Melchart D, Linde K, Fischer P,Berman B, White A, Vickers A, AllaisG (2001) Acupuncture for idiopathicheadache (Cochrane Review). In: TheCochrane Library, 4. Update Software,Oxford

2. Goslin RE, Gray RN, McCrory DC,Penzien D, Rains J, Hasselblad V (1999)Behavioral and physical treatments formigraine headache. Technical review 2.2(prepared for the Agency for HealthExpensive Policy and Research underContract No. 290-94-2025. Availablefrom the National Technical InformationService; NTIS accession no. 127946)

3. Daly EJ, Donn PA, Galliher MJ,Zimmerman JS (1983) Biofeedbackapplications to migraine and tensionheadaches: a double-blinded outcomestudy. Biofeedback Self Regul8(1):135-152

4. Lake A, Rainey J, Papsdorf JD (1979)Biofeedback and rational-emotive ther-apy in the management of migraineheadache. J Appl Behav Anal12(1):127–140

5. Bild R, Adams HE (1980) Modificationof migraine headaches by cephalic bloodvolume pulse and EMG biofeedback. JConsult Clin Psychol 48(1):51–57

6. Lacroix JM, Clarke MA, Bock JC,Doxey N, Wood A, Lavis S (1983)Biofeedback and relaxation in thetreatment of migraine headaches: com-parative effectiveness and physiologi-cal correlates. J Neurol NeurosurgPsychiatry 46(6):525–532

7. Sargent J, Solbach P, Coyne L, SpohnH, Segerson J (1986) Results of a con-trolled, experimental, outcome study ofnon drug treatments for the control ofmigraine headaches. J Behav Med9(3):291–323

166

8. Barrios FX (1980) Social skills andpsychosomatic disorders. In: RathjenDP, Foreyt JP (eds) Social competence:interventions for children and adults.Pergamon, New York, pp 271–301

9. Blanchard EB, Theobald DE,Williamson DA, Silver BV, Brown DA(1978) Temperature biofeedback in thetreatment of migraine headaches: acontrolled evaluation. Arch GenPsychiatry 35(5):581–588

10. Brown JM (1984) Imagery copingstrategies in the treatment of migraine.Pain 18(2):157–167

11. Sorbi M, Tellegen B (1986)Differential effects of training in relax-ation and stress-coping in patients withmigraine. Headache 26(9):473–481

12. Janssen K, Neutgens J (1986)Autogenic training and progressiverelaxation in the treatment of threekinds of headache. Behav Res Ther24(2):199–208

13. Blanchard EB, Peters ML, Hermann C,Turner SM, Buckley TC, Barton K,Dentinger MP (1997) Direction of tem-perature control in the thermal biofeed-back treatment of vascular headache.Appl Psychophysiol Biofeedback22(4):227–245

14. Gauthier J, Cote G, French D (1994)The role of home practice in the ther-mal biofeedback treatment of migraineheadache. J Consult Clin Psychol62(1):180–184

15. Allen KD, Shriver MD (1997)Enhanced performance feedback tostrengthen biofeedback treatment out-come with childhood migraine.Headache 37(3):169–173

16. Friedman H, Taub HA (1984) Briefpsychological training procedures inmigraine treatment. Am J Clin Hypn26(3):187–200

17. Gauthier J, Lacroix R, Cote A, DoyonJ, Drolet M (1985) Biofeedback con-trol of migraine headaches: a compari-son of two approaches. BiofeedbackSelf Regul 10(2):139–159

18. Kewman D, Roberts AH (1980) Skintemperature biofeedback andmigraine headaches. A double-blindstudy. Biofeedback Self Regul5(3):327–345

19. Mullinix JM, Norton BJ, Hack S,Fishman MA (1978) Skin temperaturebiofeedback and migraine. Headache17(6):242–244

20. Blanchard EB, Appelbaum KA,Radnitz CL, Morrill B, Michultka D,Kirsch C, Guarnieri P, Hillhouse J,Evans DD, Jaccard J et al (1990) Acontrolled evaluation of thermalbiofeedback and thermal biofeedbackcombined with cognitive therapy in thetreatment of vascular headache. JConsult Clin Psychol 58(2):216–224

21. Blanchard EB, Appelbaum KA,Nicholson NL, Radnitz CL, Morrill B,Michultka D, Kirsch C, Hillhouse J,Dentinger MP (1990) A controlledevaluation of the addition of cognitivetherapy to a home-based biofeedbackand relaxation treatment of vascularheadache. Headache 30(6):371–376

22. Blanchard EB, Nicholson NL,Radnitz CL, Steffek BD, AppelbaumKA, Dentinger MP (1991) The role ofhome practice in thermal biofeed-back. J Consult Clin Psychol59(4):507–512

23. McGrady A, Wauquier A, McNeil A,Gerard G (1994) Effect of biofeed-back-assisted relaxation on migraineheadache and changes in cerebralblood flow velocity in the middlecerebral artery. Headache34(7):424–428

24. Holroyd KA, France JL, CordingleyGE, Rokicki LA, Kvaal SA, LipchikGL, McCool HR (1995) Enhancing theeffectiveness of relaxation-thermalbiofeedback training with propranololhydrochloride. J Consult Clin Psychol63(2):327–330

25. Sovak M, Kunzel M, Sternbach RA,Dalessio DJ (1981) Mechanism of thebiofeedback therapy of migraine: voli-tional manipulation of the psychophys-iological background. Headache21(3):89–92

26. Marcus DA, Scharff L, Mercer S, TurkDC (1998) Nonpharmacological treat-ment for migraine: incremental utilityof physical therapy with relaxation andthermal biofeedback. Cephalalgia18(5):266–272

27. Hermann C, Kim M, Blanchard EB(1995) Behavioral and prophylacticpharmacological intervention studiesof paediatric migraine: an exploratorymeta-analysis. Pain 60(3):239–255

28. Wolff HG, Lenox WG (1930) Cerebralcirculation. The effects on pial vesselof variations in the oxygen and carbondioxide concentration of the blood.Arch Neurol Psychiatry 23:1097

29. Kudrow L (1981) Response of clusterheadache attacks to oxygen inhalation.Headache 21(1):1–4

30. Myers DE, Myers RA (1995) A prelim-inary report on hyperbaric oxygen inthe relief of migraine headache.Headache 35(4):197–199

31. Wilson JR, Foresman BH, GamberRG, Wright T (1998) Hyperbaric oxy-gen in the treatment of migraine withaura. Headache 38(2):112–115

32. Anderson JA, Basker MA, Dalton R(1975) Migraine and hypnotherapy. IntJ Clin Exp Hypn 23(1):48–58

33. Graham GW (1975) Hypnotic treat-ment for migraine headaches. Int JClin Exp Hypn 23(3):165–171

34. Kisch I (1995) Hypnosis as an adjunctto cognitive-behavioral psychotherapy:a meta-analysis. J Consult ClinPsychol 63:214–220

35. Forssel H, Kirveskari P, KangasniemiP (1985) Changes in headache aftertreatment of mandibular dysfunction.Cephalalgia 5(4):229–236

36. Ad Hoc Committee on Classificationof Headache (1962) Classification.JAMA 179:717–718

37. Wenneberg B, Nystrom T, Carlsson GE(1988) Occlusal equilibration and otherstomatognathic treatment in patientswith mandibular dysfunction andheadache. J Prosthet Dent59(4):478–483

38. Vallon D, Ekberg EC, Nilner M, KoppS (1991) Short-term effect of occlusaladjustment on craniomandibular disor-ders including headaches. ActaOdontol Scand 49(2):89–96

39. Tsolka P, Morris R, Preiskel H (1994)Occlusal adjustment therapy for cran-iomandibular disorders: a clinicalassessment by a double-blind method.J Prosthet Dent 68:957–962

40. Parker GB, Tupling H, Pryor DS(1978) A controlled trial of cervicalmanipulation of migraine. Aust N Z JMed 8(6):589–593

41. Parker GB, Pryor DS, Tupling H (1980)Why does migraine improve during aclinical trial? Further results from a trialof cervical manipulation for migraine.Aust N Z J Med 10(2):192–198

42. Nelson CF, Bronfort G, Evans R,Boline P, Goldsmith C, Anderson AV(1998) The efficacy of spinal manipula-tion, amitriptyline and the combinationof both therapies for the prophylaxis ofmigraine headache. J ManipulativePhysiol Ther 21(8):511–519

167

43. Nies AS (1990) Principles of thera-peutics. In: Gilman AG, Rall TW,Nies AS, Taylor P (eds) Goodman andGillman’s: the pharmacological basisof therapeutics, 8th edn. Pergamon,New York, pp 62–83

44. Vesell ES (1986) Pharmacogeneticapproaches to the prediction of drugresponse. In: Braude MC, Chao HM(eds) Genetic and biological markersin drug abuse and alcoholism. NationalInstitute on Drug Abuse, Washington,DC, pp 25–40 (Research monographseries no. 66)

45. Leeder, JS, Kearns GL (1997)Pharmacogenetics in pediatrics. PediatrClin North Am 44(1):55–77

46. Laughren TP (1996) Regulatory issuesin pediatric psychopharmacology. JAm Acad Child Adolesc Psychiatry34(10):1276–1282

47. Mathew NT, Stubits E, Nigam MR(1982) Transformation of episodicmigraine into daily headache: analysisof factors. Headache 22(2):66–68

48. Silberstein SD (1991) Appropriate useof abortive medications in headachetreatment. Pain Management 4:22–28

49. Vasconcellos E, Pina-Garza JE, MillanEJ, Warner JS (1998) Analgesicrebound headache in children and ado-lescents. J Child Neurol 13(9):443–447

50. Fentress DW, Masek BJ, Mehegan JE,Benson H (1986) Biofeedback andrelaxation-response training in thetreatment of pediatric migraine. DevMed Child Neurol 28(2):139–146

51. Bussone G, Grazzi L, D’Amico D,Leone M, Andrasik F (1998)Biofeedback-assisted relaxation train-ing for young adolescents with ten-sion-type headache: a controlled study.Cephalalgia 18(7):463–467

52. Dooley J, Bagnell A (1995) The prog-nosis and treatment of headaches inchildren – a ten-year follow-up. Can JNeurol Sci 22(1):47–49

53. McGrath PJ, Humphreys P, GoodmanJT, Keene D, Firestone P, Jacob P,Cunningham SJ (1988) Relaxation pro-phylaxis for childhood migraine: a ran-domized placebo-controlled trial. DevMed Child Neurol 30(5):626–631

54. Siniatchkin M, Hierundar A, Kropp P,Kuhnert R, Gerber WD, Stephani U(2000) Self-regulation of slow corticalpotentials in children with migraine: anexploratory study. Appl PsychophysiolBiofeedback 25(1):13–32

55. Holden EW, Deichmann MM, Levy JD(1999) Empirically supported treat-ments in pediatric psychology: recur-rent pediatric headache. J PediatrPsychol 24(2):91–109

56. Chen E, Joseph MH, Zeltzer LK(2000) Behavioral and cognitive inter-ventions in the treatment of pain inchildren. Pediatr Clin North Am47(3):513–525

57. Richter IL, McGrath PJ, HumphreysPJ, Goodman JT, Firestone P, Keene D(1986) Cognitive and relaxation treat-ment of paediatric migraine. Pain25(2):195–203

58. Guidetti V, Galli F (1998) Evolution ofheadache in childhood and adoles-cence: an 8-year follow-up.Cephalalgia 18(7):449–454

Introduction

The term cluster headache (CH) was introduced for the firsttime in 1952 by Kunkle et al. [1] who underscored, with theterm cluster, one of the principal characteristics of this par-ticular form of headache, i.e. occurrence of attacks in clus-ters. However, CH was certainly already known in the1930s, when Horton et al. [2] clearly described thisheadache form in a broad patient population, and, perhapseven earlier, under different terms [3–6].

The few epidemiological studies in the literature carriedout on the general population indicate a prevalence of CH ofaround 0.1% [7, 8]. CH clearly predominates in males [9–12],even if in the cases with onset beginning from the 1980sonward, a clear male predominance appears to have decreased[13, 14]. The average age at onset of CH is 29–30 years of age,but an onset after 50 years of age is possible and also, althoughrare, an onset in childhood may not be excluded [9–12].

Despite the fact that the clinical picture of CH is extreme-ly typical, past cases of CH were underestimated becausemany patients with this form of headache were misdiagnosedas having trigeminal neuralgia, sinusitis or dental disease.The diffusion and general acceptance of the InternationalHeadache Society’s classification [15] have led to specificand precise clinical criteria necessary for the diagnosis of theindividual headache forms. This has led, fortunately, to areduction in misdiagnoses of CH in clinical practice.

Diagnosis

Cluster headache is easy to diagnose because it is distin-guished by attacks that present clear and specific clinicalcharacteristics. The attacks tend to recur over time with fea-tures which remain constant, both in the same patient andbetween different patients.

The diagnosis of CH is founded essentially on the histo-ry of the patient, and clinical information should be careful-ly collected in detail. The questions for the patient and thesubsequent clinical history which emerge should be focusednot only on the clinical characteristics of the individualattacks but also on the way they recur over time.

For the diagnosis of individual attacks, it is advisable touse a semistructured interview based on the diagnostic cri-teria of the IHS [15].A. At least 5 attacks, fulfilling criteria B-D of the IHS clas-

sification for CH.B. Severe, unilateral pain, with orbital, supraorbital and/or

temporal location, lasting from 15 to 180 minutes (with-out treatment).Pain in CH is of a particularly severe intensity. Using avisual analogical scale, 87% of the patients indicatedthat the maximum pain intensity experienced during theattack was scored between 8 and 10 centimeters on thescale, with an average score of 9.17 [16]. CH is, by def-inition, headache with a strictly unilateral distribution.Even though cases with a bilateral location of pain havebeen described, they are sporadic, not exceeding 1%–2%of a broad and diverse CH patient population [9–12].In addition to those cranial-facial areas affected by pain,as indicated in the diagnostic criteria of the IHS classifi-cation, other locations not infrequently involved are inthe occipital and frontal regions (and not only supraor-bital area) [17]. It is also advisable to ask the patient ifpain is felt in the zygomatic and dental regions. Thisfinding can be an additional element supporting thediagnosis [11].The duration of a spontaneous CH attack can exceed 3hours but only occasionally, and in a limited number ofpatients.

C. Headache associated with at least one of the following 8signs ipsilateral to the pain:1. Conjunctival injection 2. Lacrimation


Diagnosis, symptomatic therapy and preventivetherapy of cluster headache

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3. Nasal congestion 4. Rhinorrhea 5. Facial perspiration6. Miosis7. Ptosis 8. Eyelid edema Subsequent to the publication of the IHS classification[15], careful revision of a large number of CH patientsidentified cases of CH without associated symptoms[18, 19]. However, the elimination of this criterioncould run the risk of overestimating the number of casesof CH.During a CH attack, a clear majority of patients displaya characteristic behavior: they cannot stay still, theyseem restless, they must keep moving and pace back andforth [10, 11, 16]. Psychomotor agitation could be con-sidered to be a possible ninth factor associated with pain.The inclusion of this additional factor in the diagnosis ofCH may help account for some cases which otherwisewould not have been considered [17]. It is thereforeadvisable, while gathering the medical history, to inquireabout the patient’s behavior during the attack.Of the eight associated signs, those with the better sensi-tivity and specificity indexes are lacrimation, nasal con-gestion and rhinorrhea, all ipsilateral to the pain.Although ptosis and miosis ipsilateral to the pain have agood specificity, they are not easily perceived by thepatient, and consequently there is little chance of thembeing reported not even during a thorough patient histo-ry write up.

D. Attack frequency is between 1 attack every 2 days and 8attacks daily. The CH attacks occur, in the majority ofcases, 1–3 times per day. Attacks lasting a relatively longtime (2–3 hours) have a lower rate of recurrence (onceevery 1–2 days). It is useful to ask patients if their crisesmanifest themselves at particular times, keeping in mindthat there are certain times of the day (e.g. 2–3 p.m.,9–10 p.m.) and of the night (e.g. 1–2 a.m. or, however,in relation to the first REM phase of sleep) in which thepossibility of an attack is greater [11, 20].

E. The clinical history, the general and neurological exam-inations, and eventual laboratory, neurophysiologicaland imaging testing exclude an organic cause of theheadache under study.As more unusual elements emerge from the clinical his-

tory, it is advisable to think of a possible underlying organ-ic condition. It therefore becomes essential to carry out athorough general and neurological examination and, if nec-essary, to resort to appropriate and specific testing. Dozensof patients have been described since the late 1970s whowere considered to be symptomatic cases of CH [21]. Forsome of these cases, however, the clinical characteristics ofthe headache have not been reported in detail or those

described do not correspond to CH. For the others, the fol-low-up, after the exclusion of organic pathologies, is notenough to eliminate the doubt between a causal role and asimple concomitance. The possibility remains, however,although remote, that a cerebral organic pathology (e.g. arte-riovenous malformations, aneurysms, hypophyseal expan-sive processes) or cervical pathology (e.g. meningiomas,aspergillomas) produces head pain similar to that of CH.Neuroradiological investigations should, however, be con-sidered in particular cases even in the absence of specificindications, for example, in those patients who are exces-sively worried that they may have a serious, organic pathol-ogy underlying their headache.

The accurate gathering of the clinical history distin-guishes two principal subtypes of CH that may be differen-tiated on the basis of their different temporal pattern:episodic CH (around 90% of the total cases of CH) andchronic CH (around 10% of the cases).

Diagnosis of episodic CH

The following criteria are the same as those indicated in theIHS classification level [15]:– All the criteria listed for the diagnosis of CH should be

fulfilled.– At least 2 active headache periods (clusters) lasting from

7 days to 1 year (without treatment), separated by remis-sion periods of at least 14 days.

– In the majority of the cases the active period lasts 1–2months and the alternating remission period lastsfrom a few months to 2 years. Active periods mayrarely occur for less than a week, the so-called mini-clusters [22].

– At the beginning of an active period, the attack frequen-cy may be less than the minimum time limit (1/2 day)indicated in the IHS diagnostic criteria [15].

Diagnosis of chronic CH

The following criteria are the same reported in the IHS clas-sification [15]:– All the criteria reported for the diagnosis of CH must be

fulfilled.– Absence of remission periods, or remission periods last-

ing less than 14 days, for at least one year.The absence of interval phases without headache may

characterize CH from its onset (primary chronic CH) or mayintervene more or less after a long history of episodic CH(secondary chronic CH).

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Further elements

The patient should be questioned about personal behavioralchoices, in particular cigarette smoking. In fact, over 80% ofpatients with CH smoke, and more than half of smokers withCH smoke more than 20 cigarettes per day [10, 11, 23]. It isalso advisable to ask the patient if he has succeeded in iden-tifying possible trigger factors for the single attacks, withparticular attention to the consumption of alcoholic drinks.

In the past, in the cases in which the diagnosis of CH wasin doubt, pharmacological induction tests were carried outwith vasodilatatory substances, such as nitroglycerin [24]and histamine [25, 26]. With these substances, the attackmay be triggered during the active period of CH, but not inthe interval phase of remission. The test with nitroglycerin(1 mg by sublingual route) shows an appreciable sensitivitybut a scarce specificity, while the test with histamine(0.3–0.5 mg by subcutaneous route) appears to be burdenedby strongly conflicting results [25–27]. Of the two inductiontests, the one with nitroglycerin is also used today forresearch purposes to study CH attack, since it is not easy fora researcher to investigate a spontaneous CH crisis.

Since the diagnosis of CH does not present particulardifficulties if the clinical history is complete and accurate, itis not necessary to use pharmacological induction tests fordiagnostic purposes.

General examination

The general physical examination, carried out at the firstvisit for a headache, should include at least the followingelements: vital signs (arterial pressure and heart rate), car-diac status, extracranial (paranasal sinuses, extracranialarteries, paraspinal cervical muscles and temporomandibu-lar articulations) and cervical motility.

A neurological examination should be carried out, evaluat-ing in particular: the ocular fundi, pupillary size and reactivity,extrinsic ocular motility, the eyelids, sensitivity in the area ofinnervation of the fifth cranial nerve and the corneal reflex.

Laboratory and neurophysiological testing, and imaging

Abnormal findings at the general examination unusual inCH suggest that neuroradiological investigations be carriedout. An exception is possible bradycardia and a partialBernard-Horner sign, ipsilateral to the pain. It should beremembered that MRI may be more sensitive than CT inrevealing abnormalities of irrelevant clinical significance,but not more sensitive in identifying clinically significantabnormalities.

Many studies have been carried out during the pastdecades, with the purpose of clarifying the pathophysiologicalmechanisms of CH and, on the basis of these results, differentetiopathogenetic hypotheses have been formulated. Interestingfindings have concerned the carotid circulation [28], neu-rovegetative [29–32] and neuroendocrine functions [33–39],the immune system [40–42], neurophysiological [43, 44] andbiochemical [45, 46] aspects, as well as the trigeminovascularsystem [47, 48]. In the last few years, sophisticated neu-roimaging techniques (e.g. positron emission tomography)have shown hypothalamic activation during a CH attackinduced by nitroglycerin [49] and, more recently, a stablestructural alteration of the posterior hypothalamus [50].

Unfortunately, however, until now notable progress inthe knowledge of the inner mechanisms underlying CH hasnot been confirmed through instrumental examinationswhich may be potentially applied for diagnostic purposes.There is no evidence to support the use of electroen-cephalography [51], transcranial Doppler [52], CT [53] orMRI [54, 55] in the diagnosis of CH. Neuroradiologicalinvestigations should be avoided if they do not allow forvariations in the therapeutic approach and are not recom-mended if the patient is not more likely to present significantabnormalities compared to the general population.

Level of evidence, strength of evidence and recommenda-tions for CH diagnosis

For the diagnosis of individual attacks the members of theAd Hoc Committee assigned a level of evidence D, astrength of evidence + and recommendation II. The use ofpharmacological induction tests for diagnostic purposes wasjudged as having a strength of evidence ++ and recommen-dation III. Both general and neurological examinationsreceived a level of evidence D, strength of evidence +, andrecommendation I. Neurological investigations, even in theabsence of specific indications, received a strength of evi-dence + and recommendation III, when patients thought thata serious pathology was responsible for CH. A strength ofevidence + was attributed to the need of a neuroradiologicalinvestigation in the case of abnormal findings at generalexamination.

Symptomatic treatment

The objectives of symptomatic therapy for CH are thefollowing:– Treat the attack at the onset;– Promote resolution and significant relief of pain and

associated vegetative phenomena;

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– Obtain this result in the shortest time (within 15 minutesafter initiating treatment)

– Minimize side effects.

Sumatriptan

Sumatriptan belongs to the pharmacological class of trip-tans. Two clinical trials, controlled versus placebo, investi-gated the effectiveness of this molecule in relieving a CHcrisis [56, 57]. The significant effectiveness of subcuta-neously administered sumatriptan found in these studieshas been confirmed by the clinical experience of the mem-bers of the Ad Hoc Committee. The drug was used by sub-cutaneous route at a dose of 6 mg. As indicated in the chap-ter “Symptomatic treatment of migraine”, the side effectsare certainly more numerous than those occurring withplacebo, but they are generally of slight or moderate enti-ty. The most common side effect is transitory pain at theinjection site. Other collateral effects reported includepain, tingling, and sensations of warmth, heaviness, pres-sure or tightness. These symptoms, defined as “triptansymptoms”, are transitory and may involve any part of thebody, including the chest and throat. The members of theAd Hoc Committee believe that these symptoms, whenpresent, are milder than those observed in patients withmigraine. Such characteristics render subcutaneouslyadministered sumatriptan the first-choice drug for thesymptomatic treatment of CH.

Observational studies have confirmed the effectivenessof sumatriptan in treating multiple attacks over time, witha good safety profile [58, 59]. Indications from the ItalianMinistry of Health foresee that this formulation should notbe taken more than 2 times per day, with at least one hourbetween doses, even if data in the literature point out thatdosages up to 3–4 times per day do not induce additionalor particularly severe side effects [60]. Another observa-tional study has also shown the effectiveness of sumatrip-tan on the accompanying vegetative symptoms [61]. Nasalcongestion, rhinorrhea, lacrimation and photophobia gen-erally disappear with the pain, while conjunctival hyper-emia, miosis and ptosis resolve a little later.

Particular attention should be noted regarding the asso-ciation of sumatriptan with drugs containing ergotamine forthe possible appearance of prolonged vasospastic reactions.Sumatriptan should not be taken within 24 hours afteradministration of an ergot derivative. Conversely, ergot-con-taining medication should not be used within 6 hours afteradministration of sumatriptan.

The efficacy of sumatriptan nasal spray, at the dosage of20 mg, has been investigated in only 1 open controlledstudy, in comparison to the 6-mg subcutaneous formulation

[62]. The results indicate a lower efficacy of sumatriptannasal spray compared to subcutaneously given sumatriptan.The side effects are not severe, but are of light intensity andare infrequent.

Sumatriptan nasal spray, at the dosage of 20 mg, maybe taken only two times in the same day, and in any casenot within 2 hours of the first dose. The contraindicationsand pharmacological interactions are the same as for thesubcutaneous formulation. The majority of the membersof the Ad Hoc Committee have not enough experience toexpress a judgement of therapeutical efficacy of nasalspray formulation.

Zolmitriptan

Only one controlled clinical trial versus placebo has beenreported [63]. The primary end point was the reduction ofpain intensity by at least 2 points on a verbal scale from 0 to4 in 30 minutes; the drug at the dosage of 10 mg, per os,appeared to be efficacious only in episodic cluster headache.The members of the Ad Hoc Committee believe that thedrug tested at 5 mg is inefficacious.

The dosage of 10 mg exceeds the maximum level rec-ommended (5 mg) by the Italian Health Ministry.

Oxygen by inhalation

There is only one clinical trial [64] and one open study [65]in the literature on the use of inhalatory oxygen in CH.Oxygen, at 100%, is administered for 15 min with a facialmask at a rate of 6–7 l/min. These studies concur in attribut-ing a high level of evidence to this therapeutic intervention.The members of the Ad Hoc Committee, on the basis oftheir clinical impression, also expressed a positive consen-sus on its effectiveness. The drug may therefore be consid-ered a valid second-choice therapeutic option in cases inwhich there are contraindications to the use of sumatriptan,or if the daily crises are numerous, while waiting for thebeneficial effect from a prophylactic treatment.

Today the possibility of having gaseous or liquid oxygenat home presents no particular problems since this gas isavailable in any pharmacy. After oxygen use, a new unex-pected crisis of CH may recur.

There is only one controlled clinical trial of hyperbaricoxygen therapy versus placebo [66] and two observationalstudies [67, 68]. This therapy is generally carried out byadministering 100% O2 for 30 minutes, in a hyperbaric cham-ber at 2 atmospheres pressure. A shorter duration of crises hasbeen reported in treated patients compared to those treated

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with placebo [66]. The results do not reach, however, a clearstatistical significance. No side effects have been reported.The members of the Ad Hoc Committee could not express anevaluation of the clinical efficacy of this procedure.

The administration of hyperbaric oxygen is a difficultprocedure to carry out; a hyperbaric chamber should beavailable at the moment of the onset of the crisis.

Ergotamine in association with caffeine

Clinical research on the use of ergotamine in the symptomatictreatment of CH, at least in the preparations available in Italy,was carried out many years ago. In these open studies theeffectiveness of the association between ergotamine and caf-feine, both in tablets (1 mg ergotamine + 100 mg caffeine) [69]and suppositories (2 mg ergotamine + 100 mg caffeine), wastested [70]. The results do not demonstrate a clear effective-ness of these associations and the members of the Ad HocCommittee, on the basis of their personal clinical experience,did not judge these drugs, in these combinations, to be activein the treatment of a CH attack. The association between ergo-tamine and caffeine in their different formulations was, there-fore, not recommended in the symptomatic treatment of CH.

Dihydroergotamine

Only one placebo-controlled clinical trial has been carriedout, which investigated the effectiveness of dihydroergota-mine in the nasal spray formulation at a dose of 0.5 mg perspray per nostril in the attack of CH [71]. In this study, dihy-droergotamine was not able to stop the CH crisis, but onlyto reduce the intensity of the symptoms. On the basis of theirclinical experience, the members of the Ad Hoc Committeeconsidered this molecule to be completely ineffective in thisformulation. The dihydroergotamine nasal spray was, there-fore, not recommended in the symptomatic treatment of CH.

Lidocaine

Only two uncontrolled open studies have been carried out[72, 73]. In the first [72], 1 ml of a 4% lidocaine solution (40mg) was instilled in the nostril, ipsilaterally to the pain. Allthe treated attacks were, however, provoked by the adminis-tration of nitroglycerin. In the second study [73], 4% lido-caine in the nasal spray formulation was administered, 4sprays immediately and another 2 after 15 min (however thedose of the drug administered per spray was not defined).

The data that emerged from these two studies do not providedefinite clinical evidence of effectiveness, considering thefact that the first study [72] did not refer to spontaneous CHattacks. The members of the Ad Hoc Committee believe, onthe basis of their clinical evaluation, that this drug is inef-fective. Lidocaine is therefore not recommended for thesymptomatic treatment of CH.

Prophylactic treatment

In the last few years important innovations have been intro-duced in the therapy of CH. The principal objectives of pro-phylactic therapy are to achieve the rapid disappearance ofthe attacks and consequently to end the cluster phase.Secondary objectives are aimed at reducing the frequency,the intensity and the duration of the attacks. Preventivetreatment is judged effective and safe only in chronic CH,because in the recurrent and episodic CH forms there isalways doubt that the crisis period resolves spontaneouslyrather than as a consequence of the established treatment.Accordingly, the principles of prophylactic treatment are:– Begin treatment early, particularly in the episodic forms – Continue treatment for at least 10–14 days after the dis-

appearance of the crises– Gradually suspend treatment– If the crises reappear, increase dosages to therapeutic

levels– Begin treatment again with the onset of a subsequent

cluster phaseThe drug choice depends on different factors:

– Age and lifestyle of the patient (eliminate alcohol andsmoking during crisis periods)

– Expected duration of the cluster phase– Type of CH (episodic or chronic)– Response to previous treatments– Possible reported side effects– Contraindications to the use of recommended drugs – Comorbid pathologies

Verapamil

Today, verapamil is considered the first-choice drug for theprophylactic treatment of CH, in both the episodic andchronic forms. The effectiveness of verapamil at the dosageof 360 mg/day, per os, has been demonstrated, and the drugis currently the most widely used [74, 75]. It is effective, inthe majority of patients and with few side effects at higherdoses. In an open study involving 48 patients, 69% reportedan improvement greater than 75% during treatment with

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verapamil [74]. In another recent study, double-blind versusplacebo, the effectiveness of verapamil (360 mg/day) wasinvestigated in 30 patients, for a period of 2 weeks. In thepatients treated with verapamil (N=15), a statistically signif-icant reduction in the frequency of the crises and in the useof analgesics was shown, which was more evident in thesecond week of treatment [75].

The initial dose of a delayed-release preparation is 120mg, 3-times per day. Two-thirds of patients show an improve-ment greater than 50% with the daily dose of 240 mg.

Verapamil should be associated with lithium with cau-tion in the most severe cases; otherwise, it is generally welltolerated and there are no interactions with sumatriptan, cor-ticosteroids or other prophylactic drugs.

The most annoying side effect is constipation. An elec-trocardiogram is advisable before administering this drug toexclude an atrial-ventricular block.

It should be remembered that the drugs belonging to thiscategory must be used with caution if administered togetherwith β-blockers.

Prednisone

Prednisone is effective and has a rapid preventive action in thetreatment of episodic CH. It should be considered a second-choice drug. In chronic CH the drug induces a rapid relief ofthe crises, and is useful in the early phase of treatment, whenthe preventive drugs are still not yet effective. The associationprednisone + lithium was much more effective in a study of 56patients affected by chronic CH followed for 3.2 years [76].

A large open study [77] showed a marked improvementin 77% of 77 patients suffering from episodic CH and a par-tial benefit in another 12%, both treated with prednisoneadministered per os.

Prednisone is used at doses of 50–60 mg/day for 2–3days, decreasing the dose by 10 mg/day every 2–3 days.

Until side effects appear, this drug can be used only forinducing the remission of the most serious cases with highattack frequency and intensity, particularly in the centralphase of the cluster.

Headache may reappear when the dose of prednisone islowered to less than 25 mg/day. In this case, another first-choice prophylactic drug may be associated with prednisone.

The treatment period should not exceed 3 weeks.

Dexamethasone

In an open study [78] carried out on 15 patients with episod-ic CH, dexamethasone, parenterally administered, at a doseof 4 mg two times per day in the first two weeks, and then 4

mg per day the following week, was able to interrupt thecluster phase. The members of the Ad Hoc Committee couldnot express a judgement of efficacy.

Lithium

Lithium has been used in different psychiatric and medicalpathologies, and is effective in the prophylaxis of both chron-ic and episodic CH. Today it is widely used in clinical prac-tice, although only open clinical studies have been performed.

Overall, in 28 clinical studies involving 428 patients, sat-isfactory results have been obtained in 304 (78%) of thepatients affected by chronic CH [79]. After the suspensionof treatment, a shift from the chronic to the episodic formwas demonstrated in this group of patients [79].

Even in a group of 164 patients affected by episodic CH,lithium has been shown to be effective, with a significantimprovement observed in 63% of the patients [80]. A dou-ble-blind study, carried out in a group of 30 patients affect-ed by chronic CH, compared verapamil (360 mg/day) andlithium (900 mg/day), and found an equal effectiveness ofthe two drugs, but fewer side effects and a shorter latencyperiod with verapamil [81].

One double-blind clinical study versus placebo wasunable to show a greater effectiveness of lithium (800 mg,delayed-release formulation) than placebo; this study wasinterrupted after 1 week of treatment and, unexpectedly, aresponse to placebo equal to 31% was noticed [82].

The initial dose is on average 300 mg, 3-times per day,while the maximum dose is generally 1200 mg/day.Effectiveness is seen after a few days of treatment (atdosages of 600–900 mg/day).

Lithium is effective at serum concentrations of 0.4–1.2mEq/l, lower than those necessary for treatment of bipolardisorders. Serum levels should be measured 12 hours afterthe last dose, and should not exceed 1.2 mEq/l.

It is necessary to periodically measure serum lithiumlevels and to check for thyroid and renal functional parame-ters both before and during treatment. The most frequentside effects associated with lithium treatment are tremors,diarrhea, and mental confusion. It must be used with cautionin association with calcium channel blockers, some selectiveserotonin-reuptake inhibitors (SSRIs), thiazide diuretics,indomethacin and diclofenac.

Melatonin

Serum and urinary levels of melatonin are reduced in patientsaffected by CH, particularly during the cluster phase [38, 83].On the basis of these observations, the periodicity of CH and

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the hypothalamic involvement in its pathogenesis, the effec-tiveness of the oral administration of 10 mg melatonin per oswas demonstrated through a double-blind study versus placeboin 20 patients affected by episodic CH [84]. The remissionphase was obtained in 3–5 days in half of the patients treatedwith melatonin, in contrast to CH patients treated with placebo.

Pizotifen

In the only single-blind study carried out on 28 patients suf-fering from episodic CH, the disappearance of the crises hasbeen reported in 21% of patients and 36% showed animprovement of the crises greater than 50% [85]. The main-tenance dose of pizotifen was 3 mg/day, which should bereached progressively.

Clonidine

Clonidine was used in only one open short-term study, in agroup of 13 patients affected by CH (N=8 episodic form; N=5chronic form) and was administered by transdermal route atdoses of 5.0–7.5 mg/day for 1 week. It induced a 50% reduc-tion of the frequency, duration and intensity of the crises [86].

In another open study, clonidine was administered bytransdermal route for 2 weeks (5 mg/day the first week, 7.5mg/day the second week), to 16 patients affected by episod-ic CH [87]. The disappearance of the crises, after 7 days oftreatment, was noticed in only 5 of 16 patients examined.

The members of the Ad Hoc Committee were not able toexpress any judgement on the clinical efficacy of transder-mal clonidine in chronic CH.

Valproic acid

In an open clinical study, valproic acid has been used for thetreatment of 13 patients with episodic CH [88]. In 9 of thesepatients the disappearance of the crises was observed after 1–4days of treatment, and the drug was, in any case, well tolerat-ed. The dosage varied from 600 to 2000 mg/day, given in twodoses. Even if the drug may cause several adverse effects, theyare, however, infrequent [89]. They include: weight gain, tem-porary hair loss, gastrointestinal disturbances, sedation andcognitive impairment. These adverse effects tend to disappearwith decreasing dosages. Valproic acid is contraindicated inpregnancy due to the potentially dangerous effects on the neur-al tube and should also not be used when there are liver distur-bances. While the drug may increase the serum levels of ben-

zodiazepines and barbiturates if contemporarily administered,these associations should be used carefully in clinical practice.

Monitoring of drug blood levels, hematic crasis andhepatic and pancreatic functional parameters is necessary.

The members of the Ad Hoc Committee could notexpress any judgement on the efficacy of the drug.

Topiramate

In a recent open study [90], an improvement of 10 patientsaffected by CH was demonstrated after the administration of50–125 mg topiramate, fractioned in two daily doses. Innine patients the remission phase occurred after 2 weeks oftreatment; two of them were affected by chronic CH. Thedosage and the eventual adverse events were reduced whentreatment began with low doses which were graduallyincreased. The adverse events reported are somnolence, stu-por, ataxia, and cognitive disturbances.

The members of the Ad Hoc Committee could notexpress any judgement on the efficacy of the drug.

Capsaicin

In a double-blind study, capsaicin, at a concentration of0.025%, applied 2-times per day for 7 days in the ipsilateralnostril, has been shown to be more efficacious than placebo inreducing the frequency and intensity of the crises [91]. Theunpleasant local reactions induced by the drug make it difficultto manage in the long-term treatment of cluster headache. Thepatients affected by episodic CH seemed to have greater clini-cal benefit compared to those affected by the chronic form.

The drug, used in galenic form, is not available in Italy.Moreover, the members of the Ad Hoc Committee did notbelieve it necessary to express any judgement on the effica-cy of this preparation.

Dihydroergotamine

Dihydroergotamine, intravenously administered, has beendemonstrated to induce the rapid disappearance of clusterattacks when administered daily, for a short time period(0.5–0.8 mg in 8 h, until the disappearance of the crises)[92]. This retrospective study was carried out on 54 patients,of whom 23 had episodic CH and the remaining 31 hadchronic CH. This drug is contraindicated in patients affect-ed by peripheral vasculopathies, coronary disease andhypertension. It should not be associated with triptans.

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Dihydroergotamine, formulated for intravenous admin-istration, is not available in Italy.

Methysergide

Methysergide is a semisynthetic ergot alkaloid. Old, openstudies demonstrated that the drug is efficacious in50%–70% of cases [93, 94]. According to the study ofCurran et al. [95], which reviewed all the studies availablein the literature before 1967, for a total of 451 patients, thepercentage of the efficacy data was about 73%. On the con-trary both Kudrow [10] (who only investigated patients withchronic CH) and Krabbe [96] found efficacy percentagesranging from 20% to 30%. The dosages varied from 4 to 10mg/day. The drug, however, needs to be suspended for at

least two months after a treatment period of 4 months, dueto the adverse effects of retroperitoneal, pleuropulmonaryand endocardiac fibrosis.

The drug is no longer commercially available in Italy.

Level of evidence, scientific strength of evidence, andassessment of clinical effectiveness

Drugs used in the symptomatic treatment of clusterheadache are listed in Table 1, together with scores regard-ing evidence towards their use. Drugs used in the prophy-laxis of episodic and chronic cluster headaches are given inTables 2 and 3, respectively. The recommendation groups ofdrugs for the symptomatic and prophylactic treatments ofcluster headache are shown in Tables 4 and 5, respectively.

Table 1 Characteristics of drugs used in the symptomatic treatment of cluster headache

Level Scientific strength Clinical Adverse eventsof evidence of evidence effectiveness

Sumatriptan, 6 mg SC A +++ +++ Occasional, not severe

Sumatriptan, 20-mg nasal spray C ++ ? Rare, not severe

Zolmitriptan, 10 mg per os B ++ ? Occasional, not severe

Oxygen inhalation, 100% O2, B ++ ++ Rare, not severe6–7 l/min for 15 min

Hyperbaric oxygen therapy, 100% O2 B + ? Not reportedfor 30 min at 2 atm

Ergotamine + caffeine, C + + Occasional, not severe1 mg + 100 mg per os

Ergotamine + caffeine, 2 mg + 100 mg C + + Occasional, not severesuppository

Dihydroergotamine, 0.5 mg nasal spray B + 0 Occasional, not severe

Lidocaine, 4% solution applied intranasally C + + Occasional, severe

Valproic acid, C ++ ? Occasional, not severe600–1200 mg/day per os

Topiramate, 50–125 mg/day C + ? Frequent, not severein 2 administrations

Capsaicin, 0.025% solution C ++ ? Frequent, not severeapplied intranasally bid, ipsilaterallyto the paina

Dihydroergotamine, 0.5–1.0 mg C ++ ++ Frequent, not severein 8 h until crises enda

Methysergide, 4–10 mg/day per osa C + + Rare, not severe

The efficacy dose tested is indicated after each drugSC, subcutaneously administereda Not available in Italy

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Table 2 Characteristics of drugs used in the prophylaxis of episodic cluster headache


Verapamil, 120 mg per os, bid or tid B +++ +++ Rare, not severe

Prednisone, 50–60 mg/day per os, C +++ +++ Rare, not severetapering over a maximum of 3 weeks

Dexamethasone, 4 mg bid IM or IV C ++ ? Rare, not severefor 2 weeks, then 4 mg/day for 1 week

Lithium, 30 mg per os, tid or qid C +++ +++ Rare, severe

Melatonin, 10 mg/day per os B ++ ? Not reported

Pizotifen, 3 mg/day per os B ++ ? Rare, not severe

Clonidine, 5.0–7.5 mg/day transdermally C + 0 Frequent, not severe

The efficacy dose tested is indicated after each drugIM, intramuscularly; IV, intravenously; bid, 2 times a day; tid, 3 times a day; qid, 4 times a day

Table 3 Characteristics of drugs used in the prophylaxis of chronic cluster headache


Verapamil, 120 mg per os, bid or tid C +++ +++ Rare, not severe

Prednisone, 50–60 mg/day per os, C ++ ? Rare, not severetapering over a maximun of 3 weeks

Lithium, 300 mg per os, tid or qid C +++ +++ Rare, severe

Clonidine, 5.0–75 mg/day transdermally C ++ ? Frequent, not severe

Capsaicin, 0.025% solution applied B + ? Frequent, not severeintranasally bid for 7 days, ipsilateralto the paina

Dihydroergotamine, 0.5–1.0 mg in 8 h C ++ ++ Frequent, severeuntil crises end

Methysergide, 4–10 mg/day per os C + + Rare, severe

The efficacy dose tested is indicated after each druga Not available in Italy

Table 4 Recommendation groups of drugs for the symptomatic treatment of cluster headache

Group I Group II Group IIIa Group IV

Sumatriptan, Oxygen therapy Ergotamine + caffeine, per os Sumatriptan, nasal spraysubcutaneously administered (inhalatory) Ergotamine + caffeine, suppository Zolmitriptan, per os

Lidocaine 4%, intranasally Hyperbaric oxygen therapyDihydroergotamine, nasal spray

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Table 5 Recommendation groups of drugs for the prophylaxis of episodic and chronic cluster headache (CH). No drugs fall into recom-mendation group I for cluster headache

Group II Group IIIa Group IIIb Group IV

Episodic CH Verapamil, per os Prednisone, per os Lithium, per os Dexamethasone, per osMethysergide, per os Melatonin, per os

Pizotifen, per osClonidine, transdermal routeValproic acid, per osTopiramate, per osCapsaicin, intranasal routeDihydroergotamine, intravenous route

Chronic CH – Verapamil, per os Lithium, per os Prednisone, per osMethysergide, per os Clonidine, transdermal route

Capsaicin, intranasal routeDihydroergotamine, intravenous route

References

1. Kunkle EC, Pfeiffer JB Jr, WilhoitWM, Hamrick LW Jr (1952) Recurrentbrief headaches in “cluster pattern”.Trans Am Neurol Assoc 77:240–243

2. Horton BT, MacLean AR, Craig WM(1939) A new syndrome of vascularheadache: results of treatment with his-tamine; preliminary report. Mayo ClinProc 14:257–260

3. Moellendorff (1867) Ueber hemikranie.Virchow Arch Path Anat 41:385–395

4. Eulenburg A (1883) Ueber Hemikranie.Dtsch Med Wochenschr 9:637–639

5. Bing R (1913) Lehrbuch desNervenkrankheiten. Urban &Schwarzenberg, Berlin, p 418

6. Harris W (1926) Neuritis and neural-gia. Oxford University, London

7. Ekbom K, Ahlborg B, Schele R (1978)Prevalence of migraine and clusterheadache in Swedish men of 18.Headache 18(1):9–19

8. D’Alessandro R, Gamberini G,Benassi G, Morganti G, Cortelli P,Lugaresi E (1986) Cluster headache inthe Republic of San Marino.Cephalalgia 6(3):159–162

9. Ekbom K (1970) A clinical comparisonof cluster headache and migraine. ActaNeurol Scand [Suppl 41]:1–44

10. Kudrow L (1980) Cluster headache.Mechanisms and management. OxfordUniversity, New York

11. Manzoni GC, Terzano MG, Bono G,Micieli G, Martucci N, Nappi G (1983)Cluster headache - clinical findings in180 patients. Cephalalgia 3(1):21–30

12. Sjaastad O (1992) Cluster headachesyndrome. WB Saunders, London

13. Manzoni GC (1997) Male preponder-ance of cluster headache is progres-sively decreasing over the years.Headache 37(9):588–589

14. Manzoni GC (1998) Gender ratio ofcluster headache over the years: a pos-sible role of changes in lifestyle.Cephalalgia 18(3):138–142

15. Headache Classification Committee ofthe International Headache Society(1988) Classification and diagnosticcriteria for headache disorders, cranialneuralgias and facial pain. Cephalalgia8[Suppl 7]:1–96

16. Torelli P, Manzoni GC (2002) Pain andbehavior in cluster headache. Brain (inpress)

17. Torelli P, Cologno D, Cademartiri C,Manzoni GC (2001) Application of theInternational Headache Society classi-fication criteria in 652 cluster headachepatients. Cephalalgia 21(2):145–150

18. Ekbom K (1990) Evaluation of clinicalcriteria for cluster headache with spe-cial reference to the classification ofthe International Headache Society.Cephalalgia 10(4):195–197

19. Nappi G, Micieli G, Cavallini A,Zanferrari C, Sandrini G, Manzoni GC(1992) Accompanying symptoms ofcluster attacks: their relevance to thediagnostic criteria. Cephalalgia12(3):165–168

20. Dexter JD, Riley TL (1975) Studies innocturnal migraine. Headache15(1):51–62

21. Nappi G, Manzoni GC (1996)Primary headaches. In: Nappi G,Manzoni GC (eds) Clinical approachand management. Smith-Gordon,London, pp 127-208

22. Sjaastad O, de Souza Carvalho D,Fragoso YD, Zhao JM (1988) Clusterheadache: on the significance of so-calledminibouts. Cephalalgia 8(4):285–291

23. Manzoni GC (1999) Cluster headacheand lifestyle: remarks on a populationof 374 male patients. Cephalalgia19(2):88–94

24. Ekbom K (1968) Nitroglycerin as aprovocative agent in cluster headache.Arch Neurol 19(5):487–493

25. Horton BT (1961) Histaminic cephal-gia (Horton’s headache or syndrome).Md Med J 10:178–203

26. Peters GA (1953) Migraine: diagnosisand treatment with emphasis on themigraine-tension headache: provoca-tion tests and use of rectal supposito-ries. Mayo Clin Proc 28:673–686

27. Symonds CP (1956) A particular vari-ety of headache. Brain 79:217–232

28. Ekbom K, Greitz T (1970) Carotidangiography in cluster headache. ActaRadiol Diagn (Stockh) 10(3):177–186

29. Fanciullacci M, Pietrini U, Gatto G,Boccuni M, Sicuteri F (1982) Latentdysautonomic pupillary lateralizationin cluster headache. A pupillometricstudy. Cephalalgia 2(3):135–144

178

30. Saunte C, Russell D, Sjaastad O(1983) Cluster headache: on the mech-anism behind attack-related sweating.Cephalalgia 3(3):175–185

31. Drummond PD (1988) Autonomic dis-turbances in cluster headache. Brain111(Pt 5):1199–1209

32. Salvesen R, Sand T, Sjaastad O (1988)Cluster headache: combined assess-ment with pupillometry and evapor-imetry. Cephalalgia 8(3):211–218

33. Kudrow L (1976) Plasma testosteronelevels in cluster headache preliminaryresults. Headache 16(1):28–31

34. Nelson RF (1978) Testosterone levelsin cluster and non-cluster migrainousheadache patients. Headache18(5):265–267

35. Romiti A, Martelletti P, Gallo MF,Giacovazzo M (1983) Low plasmatestosterone levels in cluster headache.Cephalalgia 3(1):41–44

36. Facchinetti F, Nappi G, Cicoli C,Micieli G, Ruspa M, Bono G,Genazzani AR (1986) Reduced testos-terone levels in cluster headache: astress-related phenomenon?Cephalalgia 6(1):29–34

37. Waldenlind E, Gustafsson SA, EkbomK, Wetterberg L (1987) Circadiansecretion of cortisol and melatonin incluster headache during active clusterperiods and remission. J NeurolNeurosurg Psychiatry 50(2):207–213

38. Leone M, Maltempo C, Gritti A,Bussone G (1994) The insulin toler-ance test and ovine corticotrophin-releasing-hormone test in episodiccluster headache. II: comparison withlow back pain patients. Cephalalgia14(5):357–364

39. Leone M, Lucini V, D’Amico D,Moschiano F, Maltempo C, FraschiniF, Bussone G (1995) Twenty-four-hourmelatonin and cortisol plasma levels inrelation to timing of cluster headache.Cephalalgia 15(3):224–229

40. Visintini D, Trabattoni G, ManzoniGC, Lechi A, Bortone L, Behan PO(1986) Immunological studies in clus-ter headache and migraine. Headache26(8):398–402

41. Giacovazzo M, Martelletti P, Valeri M,Piazza A, Monaco PI, Casciani CU(1987) Variations in the Leu7+ andLeuM3+ leukocyte subpopulationsobserved in cluster headache aredependent on HLA-DR antigens.Headache 27(1):35–38

42. Giacovazzo M, Stirparo G, De StefanoL, Martelletti P, Rinaldi-Garaci C (1989)Lymphokine-activated killer (LAK) cellphenomenon in cluster headache. “Invitro” activation by recombinant inter-leukin-2. Headache 29(3):177–179

43. Sandrini G, Alfonsi E, Ruiz L, Pavesi G,Micieli G, Manzoni GC, Mancia D,Nappi G (1991) Impairment of cornealpain perception in cluster headache. Pain47(3):299–304

44. Lozza A, Schoenen J, Wang W,Delwaide PJ (1995) The trigeminalpathway is hyperexcitable on thepainful side in cluster headache: a studyof the recovery curve of the blink reflexR2 component. Cephalalgia 15:197

45. D’Andrea G, Cananzi AR, Toldo M,Ferro-Milone F (1986) Platelet activityin cluster headache. Cephalalgia6:163–167

46. D’Andrea G, Granella F, Alecci M,Manzoni GC (1998) Serotonin metabo-lism in cluster headache. Cephalalgia18(2):94–96

47. Hardebo JE (1984) The involvement oftrigeminal substance P neurons in clus-ter headache. A hypothesis. Headache24(6):294–304

48. Moskowitz MA (1990) Basic mecha-nisms in vascular headache. NeurolClin 8(4):801–815

49. May A, Bahra A, Buchel C, FrackowiakRS, Goadsby PJ (1998) Hypothalamicactivation in cluster headache attacks.Lancet 352(9124):275–278

50. May A, Bahra A, Buchel C,Frackowiak RS, Goadsby PJ (2000)PET and MRA findings in clusterheadache and MRA in experimentalpain. Neurology 55(9):1328–1335

51. Hasan Z, Sjaastad O, Lundervold A(1976) An electroencephalographicinvestigation of patients with clusterheadache. Clin Electroencephalogr7:203–207

52. Dahl A, Russell D, Nyberg-Hansen R,Rootwelt K (1990) Cluster headache:transcranial Doppler ultrasound andrCBF studies. Cephalalgia 10(2):87–94

53. Russell D, Nakstad P, Sjaastad O(1978) Cluster headache - pneumoen-cephalographic and cerebral computer-ized axial tomography findings.Headache 18(5):272–273

54. Sjaastad O, Rinck P (1990) Clusterheadache: MRI studies of the cav-ernous sinus and the base of the brain.Headache 30(6):350–351

55. Hannerz J, Greitz D (1992) MRI ofintracranial arteries in nitroglycerin-induced cluster headache attacks.Headache 32(10):485–488

56. The Sumatriptan Cluster HeadacheStudy Group (1991) Treatment ofacute cluster headache with sumatrip-tan. N Engl J Med 325(5):322–326

57. Ekbom K, Monstad I, Prusinski A,Cole JA, Pilgrim AJ, Noronha D(1993) Subcutaneous sumatriptan inthe acute treatment of clusterheadache: a dose comparison study.The Sumatriptan Cluster HeadacheStudy Group. Acta Neurol Scand88(1):63–69

58. Ekbom K, Krabbe E, Micieli G,Prusinski A, Cole JA, Pilgrim AJ,Noronha D (1995) Cluster headacheattacks treated for up to three monthswith subcutaneous sumatriptan (6 mg).Sumatriptan Cluster Headache Long-Term Study Group. Cephalalgia15(3):230–236

59. Göbel H, Lindner V, Heinze A, RibbatM, Deuschl G (1998) Acute therapyfor cluster headache with sumatriptan:findings of a one-year long-term study.Neurology 51(3):908–911

60. Ekbom K, Waldenlind E, Cole J,Pilgrim A, Kirkham A (1992)Sumatriptan in chronic clusterheadache: results of continuous treat-ment for eleven months. Cephalalgia12(4):254–256

61. Hardebo JE (1993) Subcutaneous suma-triptan in cluster headache: a time studyof the effect on pain and autonomicsymptoms. Headache 33(1):18–21

62. Hardebo JE, Dahlöf C (1998)Sumatriptan nasal spray (20 mg/dose)in the acute treatment of clusterheadache. Cephalalgia 18(7):487–489

63. Bahra A, Gawel MJ, Hardebo JE,Millson D, Breen SA, Goadsby PJ(2000) Oral zolmitriptan is effective inthe acute treatment of clusterheadache. Neurology 54(9):1832–1839

64. Fogan L (1985) Treatment of clusterheadache. A double-blind comparisonof oxygen vs. air inhalation. Arch neu-rol 42(4):362–363

65. Kudrow L (1981) Response of clusterheadache attacks to oxygen inhalation.Headache 21(1):1–4

66. Di Sabato F, Fusco BM, Pelaia P,Giacovazzo M (1993) Hyperbaric oxy-gen therapy in cluster headache. Pain52(2):243–245

179

67. Weiss LD, Ramasastry SS, EidelmanBH (1989) Treatment of a clusterheadache patient in a hyperbaric cham-ber. Headache 29(2):109–110

68. Porta M, Granella F, Coppola A,Longoni C, Manzoni GC (1991)Treatment of cluster headache attackswith hyperbaric oxygen. Cephalalgia11[Suppl 11]:236–237

69. Horton BT, Ryan R, Reynolds JL(1948) Clinical observations on the useof E.C. 110, a new agent for the treat-ment of headache. Proc Mayo Clin23:105–108

70. Magee KR, Westerberg MR, DeJongRM (1952) Treatment of headachewith ergotamine caffeine suppositories.Neurology 2:477–480

71. Andersson PG, Jespersen LT (1986)Dihydroergotamine nasal spray in thetreatment of attacks of clusterheadache. A double-blind trial versusplacebo. Cephalalgia 6(1):51–54

72. Kittrelle JP, Grouse DS, Seybold ME(1985) Cluster headache. Local anes-thetic abortive agents. Arch Neurol42(5):496–498

73. Robbins L (1995) Intranasal lidocainefor cluster headache. Headache35(2):83–84

74. Gabai IJ, Spierings EL (1989)Prophylactic treatment of clusterheadache with verapamil. Headache29(3):167–168

75. Leone M, D’Amico D, Frediani F,Moschiano F, Grazzi L, Attanasio A,Bussone G (2000) Verapamil in theprophylaxis of episodic clusterheadache: a double-blind study versusplacebo. Neurology 54(6):1382–1385

76. Boiardi A, Bussone G, Merati B,Tansini E, Boeri R (1983) Course ofchronic cluster headache. Ital J NeurolSci 4(1):75–77

77. Prusinsky A, Kozubsky W, Szulc-Kuberska J (1987) Steroid treatment inthe interruptions of clusters in clusterheadache patients. Cephalalgia 7[Suppl6]:332–333

78. Anthony M, Daher BM (1992)Mechanism of action of steroids incluster headache. In: Rose FC (ed)New advances in headache research.Smith-Gordon, London, pp 271–274

79. Ekbom K, Olivarius B (1971) Chronicmigrainous nevralgia: diagnostic andtherapeutic aspects. Headache11:97–101

80. Ekbom K (1981) Lithium for clusterheadache: review of the literature andpreliminary results of long-term treat-ment. Headache 21(4):132–139

81. Bussone G, Leone M, Peccarisi C,Micieli G, Granella F, Magri M,Manzoni GC, Nappi G (1990) Double-blind comparison of lithium and vera-pamil in cluster headache prophylaxis.Headache 30(7):411–417

82. Steiner TJ, Hering R, Couturier EG,Davies PT, Whitmarsh TE (1997)Double-blind placebo-controlled trialof lithium in episodic cluster headache.Cephalalgia 17(6):673–675

83. Waldenlind E, Ekbom K, WetterbergL, Fanciullacci M, Marabini S, SicuteriF, Polleri A, Murialdo G, Filippi U(1994) Lowered circannual urinarymelatonin concentrations in episodiccluster headache. Cephalalgia14(3):199–204

84. Leone M, D’Amico D, Moschiano F,Fraschini F, Bussone G (1996)Melatonin versus placebo in the pro-phylaxis of cluster headache: a double-blind pilot study with parallel groups.Cephalalgia 16(7):494–496

85. Ekbom K (1969) Prophylactic treat-ment of cluster headache with a newserotonin antagonist, BC 105. ActaNeurol Scand 45(5):601–610

86. D’Andrea G, Perini F, Granella F,Cananzi A, Sergi A (1995) Efficacy oftransdermal clonidine in short-termtreatment of cluster headache: a pilotstudy. Cephalalgia 15(5):430–433

87. Leone M, Attanasio A, Grazzi L, LibroG, D’Amico D, Moschiano F, BussoneG (1997) Transdermal clonidine in theprophylaxis of episodic clusterheadache: an open study. Headache37(9):559–560

88. Hering R, Kuritzky A (1989) Sodiumvalproate in the treatment of clusterheadache: an open clinical trial.Cephalalgia 9(3):195–198

89. Wheeler S (1998) Significance ofmigrainous features in clusterheadache: divalproex responsiveness.Headache 38:547–551

90. Wheeler SD, Carrazana EJ (1999)Topiramate-treated cluster headache.Neurology 53(1):234–236

91. Marks DR, Rapoport A, Padla D,Weeks R, Rosum R, Sheftell F,Arrowsmith F (1993) A double-blindplacebo-controlled trial of intranasalcapsaicin for cluster headache.Cephalalgia 13(2):114–116

92. Mather PJ, Silberstein SD, SchulmanEA, Hopkins MM (1991) The treat-ment of cluster headache with repeti-tive intravenous dihydroergotamine.Headache 31(8):525–532

93. Friedman AP, Elkind AH (1963)Appraisal of methysergide in treatmentof vascular headache of migraine-type.JAMA 184:125–128

94. Graham JR (1964) Methysergide forprevention of headache: experience infive hundred patients over three years.N Engl J Med 270:67–72

95. Curran DA, Hinterberger H, Lance JW(1967) Methysergide. Res Clin StudHeadache 1:74–122

96. Krabbe A (1989) Limited efficacy ofmethysergide in cluster headache: Aclinical experience. Cephalalgia9[Suppl 10]:404–405

In patients with chronic cluster headache, surgical treatmentmay be the only alternative when medical therapy, either inan in-patient or an out-patient setting, is ineffective, is lim-ited by contraindications, or is poorly tolerated [1]. Patientsto be treated surgically must be carefully selected and meetthe following mandatory criteria:1. Total resistance to pharmacological treatment (severe

side-effects and contraindications to the treatments);2. Headache strictly located on the same side, since in

patients where the headache alternates sides, there is arisk of recurrence after surgical treatment;

3. Pain primarily in the region of the ophthalmic branch ofthe trigeminal nerve;

4. Patients with stable personality and psychological pro-file with little tendency to somatization.Many anatomical sites have been considered in an

attempt to stop cluster attacks. The parasympathetic path-way has been interrupted by sectioning the intermediusnerve, the great superficial petrosal nerve and thesphenopalatine ganglion. In many cases the benefits havebeen inconsistent or, when the procedures appeared to beeffective, there was a risk of recurrence of the clusterheadache. The surgical procedures that give the best resultsare those involving the sensory component of the trigeminalnerve, particularly percutaneous retrogasserian rhizotomywith radiofrequencies (PRFR) [2-6] and percutaneous retro-gasserian rhizolysis with glycerol (PRGR) [7–9].

Rhizotomy with radiofrequencies

This technique, introduced in 1932 by Kirschner [10] with theterm of electrocoagulation, but then immediately abandonedbecause of many complications, was modified by White andSweet in 1986 [11, 12]. It is based on the demonstration thatthe nociceptive C fibers, being thinner than the A fibersresponsible for tactile sensitivity, may be destroyed with agradual thermal lesion, leaving tactile sensitivity intact.

After having placed the patient on the operating table ina supine position, under local anesthesia, a particular needlecannula is introduced about 3 cm from the lip margin,homolaterally to the head pain, for about 5 cm, under con-tinuous fluoroscopic control, until it passes beyond the ovalforamen and reaches the cistern of the Gasserian ganglion.After removing the stylet of the needle, cerebrospinal fluidmay leak from the ganglion cistern. An electrode is thenintroduced and a stimulation is applied; the tingling or burn-ing feeling felt by the patient near the stimulated root con-firms the exact position of the needle cannula. After a briefneuroleptoanalgesia, thermocoagulation is carried out at atemperature of around 70° C for about 2 min.

The results are encouraging: at least 75% of patientsobtain good to excellent results [3, 5]. The duration of theprocedure is also favorable, with recurrence in the long-termfollow-up of only 20%, while some patients remain pain-free for 20 years [6].

The best results were obtained when strong analgesia orstrong hypoalgesia occurred. If pain is predominantly locat-ed in the orbital, retrorbital, infraorbital or supraorbitalareas, a lesion of the V1 and V2 branches of the trigeminalnerve is adequate. If pain also involves the temple and thearea of the ear, a lesion of the V3 branch is needed, becausethe temple and the ear are innervated by the auricular branchof the mandibular nerve.

In the immediate post-surgical period, several complica-tions may occur which are, on the other hand, relatively few.These include: transitory diplopia, piercing pain in the terri-tory of distribution of the trigeminal nerve, difficulty inmastication on the side of the lesion and deviation of thejaw. These complications are usually transitory and, as arule, there is complete recovery. A more annoying compli-cation is painful anesthesia. The incidence of painful anes-thesia is low (less than 4%). Because of the corneal analge-sia caused by the radiofrequencies, patients must beinstructed to pay adequate attention to their eyes after theprocedure. The patients are invited to wear dark glasses andto not allow dust or other foreign bodies to enter their eyes


Non-pharmacological treatments for clusterheadache

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when they are exposed to the wind. Moreover, they are rec-ommended to consult an ophthalmologist, if there are signsof corneal infection. The untreated corneal infections mayeasily cause corneal opacity because of the lack of cornealsensitivity.

Percutaneous retrogasserian rhizolysis with glycerol

An alternative treatment to PRFR is glycerolysis of theGasser ganglion. This method consists of penetrating theGasser ganglion cistern, using the same technique describedpreviously. To be certain of the exact position of the needlecannula, neurostimulation is performed and/or 0.5 mlmetrizamide is injected, with the aim of visualizing thetrigeminal cistern. After removal of the metrizamide, a mix-ture of glycerol (0.15-0.20 ml) and cerebrospinal fluid isintroduced into the cistern, making sure that the patientremains in a semi-seated position for about two hours.

In a recent study [13], 83% of the patients assessed (15out of 18) showed an improvement of the crises after 1-2injections; the patients were followed for 5.2 years and noneof them complained of corneal anesthesia or facial dyses-

thesia. Recurrence was seen in 39% of these patients, whonecessitated a second intervention.

The disadvantages of glycerol injections are:1. Incomplete analgesia in comparison to the lesions

induced with radiofrequencies;2. Difficult control of the lesion with glycerol, while with

the lesions caused by radiofrequencies, a selectivedestruction of the V1, V2 or V3 branches of the trigem-inal nerve is possible;

3. Possible leakage of glycerol from Meckel’s cave withpossible chemical meningitis.Recently gamma-knife surgery has been used in patients

with cluster headache resistant to drug therapy [14]. Reliefwas immediate and within a week the patients were freefrom pain and relief was maintained for more than eightmonths. The complete effectiveness, duration and tolerabil-ity of the technique are not known at the moment. Being anoninvasive procedure with fewer collateral effects thanablative surgery, it may represent a good alternative todestructive procedures.

In conclusion, surgical treatment of cluster headachemay be considered the last resource and should be limited tocases of chronic cluster headache which are disabling andresistant to medical therapies.

References

1. Dodick DW, Rozen TD, Goadsby PJ,Silberstein SD (2000) Clusterheadache. Cephalalgia 20(9):787–803

2. Maxwell RE (1982) Surgical control ofchronic migrainous neuralgia bytrigeminal ganglio-rhizolysis. JNeurosurg 57(4):459–466

3. Onofrio BM, Campbell JK (1986)Surgical treatment of chronic clusterheadache. Mayo Clin Proc61(7):537–544

4. Sweet WH, Wepsic JG (1974)Controlled thermocoagulation oftrigeminal ganglion and rootlets fordifferential destruction of pain fibers.1. Trigeminal neuralgia. J Neurosurg40(2):143–156

5. Mathew NT, Hurt W (1988)Percutaneous radiofrequency trigemi-nal gangliorhizolysis in intractablecluster headache. Headache28(5):328–331

6. Taha JM, Tew JM Jr (1995) Long-termresults of radiofrequency rhizotomy inthe treatment of cluster headache.Headache 35(4):193–196

7. Waltz TA, Dalessio DJ, Ott KH,Copeland B, Abbott G (1985)Trigeminal cistern glycerol injectionsfor facial pain. Headache25(7):354–357

8. Ekbom K, Lindgren L, Nilsson BY,Hardebo JE, Waldenlind E (1987)Retro-gasserian glycerol injection inthe treatment of chronic clusterheadache. Cephalalgia 7(1):21–27

9. Hassenbusch SJ, Kunkel RS,Kosmorsky GS, Covington EC, PillayPK (1991) Trigeminal cisternal injec-tion of glycerol for treatment of chron-ic intractable cluster headaches.Neurosurgery 29(4):504–508

10. Kirschner M (1932) ZueElectrocoagulation des GanglionGasseri. Zentrabl Chir 59:2841

11. White JC, Sweet WH (1969) Pain andthe neurosurgeon: a forty year experi-ence. CC Thomas, Springfield,III:360–372

12. Sweet WH (1988) Surgical treatmentof chronic cluster headache. Headache28:669–670

13. Pieper DR, Dickerson J, HassenbuschSJ (2000) Percutaneous retrogasserianglycerol rhizolysis for treatment ofchronic intractable cluster headaches:long-term results. Neurosurgery46(2):363–368

14. Ford RG, Ford KT, Swaid S, Young P,Jennelle R (1998) Gamma knife treat-ment of refractory cluster headache.Headache 38(1):3–9

Introduction

Trigeminal autonomic cephalalgias (TACs) such as clusterheadache, chronic paroxysmal hemicrania (CPH), episodicparoxysmal hemicrania, short-lasting unilateral neuralgiformheadache with conjunctival injection and tearing (SUNCT)are a group of unilateral painful syndromes all of which arecharacterized by pain attacks in the facial area innervated bythe first branch of the trigeminal nerve and autonomic signson the same side of the head. Overall, these headaches havea common pathogenetic mechanism, consisting in the activa-tion of the trigeminal and autonomic systems by means of atrigeminal-autonomic reflex. The activation of the autonom-ic system is not dependent on the intensity of pain.

Levels of calcitonin gene-related peptide (CGRP) andvasoactive intestinal peptide (VIP) in cluster headache andin CPH are significantly higher during the painful phasecompared to migraine with and without aura. These forms,therefore, have in common a brief period of pain (of varyinglength in the different forms) and the presence of local auto-nomic signs, which are the elements upon which specificdiagnostic criteria are based.

The 1988 classification of the International HeadacheSociety [1] identifies in this group two nosographic entitiesrepresented by cluster headache (in the episodic and chron-ic forms) and CPH, currently classified in group 3.Regarding this, the subcommittee suggested that the defini-tion of the idiopathic headache group be changed from clus-ter headache and CPH to unilateral headache with autonom-ic signs, so that other forms may also be included within thesame group. Even though the diagnostic criteria remainunchanged with respect to those of the international classifi-cation, some modifications to the comment on CPH havebeen proposed by the subcommittee.

As far as SUNCT is concerned, this form should beincluded in the group of unilateral headaches with autonom-ic signs, considering the large number of papers available in

the literature on this topic and the clinical characteristicsthat are sufficiently homogeneous to permit precise diag-nostic criteria to be defined.

The inclusion of episodic paroxysmal hemicrania andhemicrania continua is still debatable. An increase in thenumber of cases and more extensive critical reviews of thelatter are necessary. The presence of analogous clinical pic-tures which are, however, secondary to organic diseases,makes it mandatory that adequate instrumental investiga-tions be carried out for all forms diagnosed as TACs.

We propose the following modifications, hereuponapplicable for cluster headache, chronic paroxysmal hemi-crania and SUNCT to point 3 of the IHS classification [1]:

3. Unilateral headache with autonomic signs3.1 Cluster headaches (no changes)3.2 Chronic paroxysmal migraine

A. At least 50 attacks fulfilling criteria B-E.B. Pain of severe intensity with unilateral, orbital,

supraorbital and/or temporal location, always on thesame side.

C. Frequency, >5 attacks per day for more than half thetime.

D. Pain associated with at least one of the followingsigns on the side of the pain: – Conjunctival injection – Lacrimation – Nasal congestion – Rhinorrhea – Ptosis – Eyelid edema

E. Absolute response to indomethacin F. Exclusion of organic causes through diagnostic

instrumental examinations. 3.3 SUNCTs

A. At least 50 attacks fulfilling criteria B-E.B. Attacks of unilateral pain in the territory of distribu-

tion of the first branch of the trigeminal nerve.


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183

C. Attacks lasting from 5 seconds to 3 minutes.D. Attacks having at least 3 of the following 4 charac-

teristics:1. Stabbing and/or burning and/or neuralgic (like an

electric shock) pain.2. Moderate to very severe pain intensity.3. Frequency varying from less than 1 per day to

more than 30 per hour.4. The crises are triggered from trigeminal or extra-

trigeminal trigger zones.E. Pain is accompanied by lacrimation and conjunctival

injection on the symptomatic side.F. Exclusion of organic causes through diagnostic

instrumental examinations.Few case reports without autonomic signs have been

reported. These need to be further investigated and thenumber of cases should be increased. Few cases of noresponse to indomethacin have been described, whichneed further confirmation. Some cases of the episodicform reported in the literature may represent pre-chronicforms of the same illness. Data are at the moment insuffi-cient to describe the episodic form as a separate noso-graphic entity.

Paroxysmal hemicrania (chronic and episodic)

Although CPH [2–137] is also defined by the presence ofaccompanying autonomic signs, some cases lack these signs[8, 12, 46]. In other cases, the response to indomethacin islacking (further criterion for classification) or, in the samepatient, it was necessary to subsequently increaseindomethacin dosages [13, 123]. This observation makes itnecessary to reconsider the diagnosis in poorly responsivepatients and to exclude organic causes, if this criterion hasnot been previously respected.

The lack of response to indomethacin may be a discrim-inating factor in borderline forms of cluster headache. Infact, the existence of CPH forms, in which painful episodesare of low frequency and long duration, for instance 5episodes lasting 45 minutes, suggests this possibility. Underthese conditions, pharmacological diagnostic tests may beuseful, such as the induction test with nitroglycerin and theevaluation of the clinical response to subcutaneously admin-istered sumatriptan or to steroid treatment.

Cases of apparently non-chronic paroxysmal hemicra-nia have been described. Therefore, a separate nosographicentity (like cluster headache) has been hypothesized. Thelack of long-term follow-up does not allow the possibilityto verify the stability of this episodic form in the samepatient or to say if this form already represents a pre-chron-ic phase of CPH.

SUNCT

The headache form defined as SUNCT (currently notincluded in the IHS classification [1]) has been repeatedlydescribed in the literature [138–176], and the homogeneityof the clinical pictures suggests that it should be includedunder the classification of unilateral headaches at point3.3. The brief duration of pain (not more than 180 seconds)is typical in these patients. Few patients have crises whichare of a longer duration, making a differential diagnosisdifficult with brief episodes of CPH. In this case, theabsolute response to indomethacin, to which SUNCT isunresponsive, should be useful to discriminate between thetwo forms. The lack of a significant response toindomethacin or to other treatments is, in fact, typical ofthis form, whereas treatment with lamotrigine seems togive promising results.

In the cases described in the literature, lacrimation andconjunctival injection were the more frequent autonomicsigns [45]. The exclusion of organic causes (secondaryforms have been already described in the literature) is alsomandatory for this form (as in the other unilateralheadaches) [45].

Hemicrania continua

Another clinical entity described in the literature is hemi-crania continua [3–5, 6–9, 177–226]. This entity deserves tobe included in unilateral headaches due to the location of thepain. Pain is described as continuous and of moderate inten-sity with “exacerbations”, that are sometimes characterized,as far as symptoms and duration are concerned, as more typ-ical of migraine or cluster headache, with accompanyingautonomic signs. In a strict sense, only these exacerbationsshould be classified as unilateral headaches with autonomicsigns. The underlying headache, in fact, is never accompa-nied by autonomic signs.

Such exacerbations should be better characterized andpossibly considered as headache crises superimposed on theunderlying pain. It may be possible, in fact, to recognizeamong them some of the nosographic entities already codi-fied by the IHS (e.g. migraine or cluster headache) or not yetincluded in this classification (e.g. SUNCT, idiopathic stab-bing headache). As such, it is recommended to begin pro-phylactic treatment of these superimposed forms and todetermine the characteristics of the eventual residualheadache.

The observation that indomethacin may relieve theunderlying pain and the exacerbations leads one to think thatthe onset of one of the latter forms is facilitated by thechronic underlying pain.

184

The pain of hemicrania continua may present in a non-periodic, discontinuous way, and in about 20% of thecases described in the literature exacerbations were notpresent [22, 112].

The classification criteria and the recommendations forhemicrania continua which may be included in group 3 ofthe IHS classification [1] are the following:3.4 Hemicrania continua 3.4.1 Continuous hemicrania continua.3.4.2 Discontinuous hemicrania continua.

A. Headache which is present for at least three months.

B. Strictly unilateral location of the pain.C. Pain with the following characteristics:

– Continuous but fluctuating,– Moderate intensity, for at least half the time,– Absence of precipitating factors.

D. Exacerbations of the pain with or without autonomic signs on the side of the pain are frequent.

E. Absolute response to indomethacin.F. Exclusion of organic causes through diagnostic

instrumental examinations.

References

1. – (1988) Classification and diagnosticcriteria for headache disorders, cranialneuralgias and facial pain. HeadacheClassification Committee of theInternational Headache Society.Cephalalgia 18[Suppl 7]:1–96

2. Alberca R, Sureda B, Marquez C,Navarro A (1991) [Episodic ++paroxysmal hemicrania or chronicparoxysmal hemicrania in pre-chron-ic state?] Neurologia 6(6):219–221(article in Spanish)

3. Antonaci F, Pareja JA, Caminero AB,Sjaastad O (1998) Chronic paroxys-mal hemicrania and hemicrania con-tinua: lack of efficacy of sumatriptan.Headache 38(3):197–200

4. Antonaci F, Pareja JA, Caminero AB,Sjaastad O (1998) Chronic paroxys-mal hemicrania and hemicrania con-tinua. Parenteral indomethacin: the“indotest”. Headache 38(2):122–128

5. Antonaci F, Pareja JA, Caminero AB,Sjaastad O (1998) Chronic paroxys-mal hemicrania and hemicrania con-tinua: anesthetic blockades of peri-cranial nerves. Funct Neurol13:11–15

6. Antonaci F, Sand T, Sjaastad O(1992) Hemicrania continua andchronic paroxysmal hemicrania: acomparison of pupillometric findings.Funct Neurol 7(5):385–389

7. Antonaci F, Sandrini G, Danilov A,Sand T (1994) Neurophysiologicalstudies in chronic paroxysmal hemi-crania and hemicrania continua.Headache 34(8):479–483

8. Antonaci F, Sjaastad O (1989)Chronic paroxysmal hemicrania(CPH): a review of the clinical mani-festations. Headache 29(10):648–656

9. Antonaci F (1994) Chronic paroxys-mal hemicrania and hemicrania con-tinua: orbital phlebography and MRIstudies. Headache 34(1):32–34

10. Antonaci F (1991) The sweating pat-tern in “hemicrania continua”. Acomparison with chronic paroxysmalhemicrania. Funct Neurol6(4):371–375

11. Benoliel R, Sharav Y (1998)Paroxysmal hemicrania. Case studiesand review of the literature. OralSurg Oral Med Oral Pathol OralRadiol Endod 85(3):285–292

12. Blau JN, Engel H (1990) Episodicparoxysmal hemicrania: a furthercase and review of the literature. JNeurol Neurosurg Psychiatry53(4):343–344

13. Bogucki A, Niewodniczy A (1984)Case report: chronic cluster headachewith unusual high frequency ofattacks. Differential diagnosis withCPH. Headache 24(3):150–151

14. Bogucki A, Kozubski W (1987)Cluster headache and chronic parox-ysmal hemicrania: how to classifyborderline cases? J Neurol NeurosurgPsychiatry 50(12):1698-1699

15. Bogucki A, Szymanska R, Braciak W(1984) [Newly described form ofidiopathic headache-so-called chronicparoxysmal hemicrania (Sjaastadsyndrome).] Neurol Neurochir Pol18(4):373–377 (article in Polish)

16. Bogucki A, Szymanska R, Braciak W(1984) Chronic paroxysmal hemicra-nia: lack of pre-chronic stage.Cephalalgia 4(3):187–189

17. Boulliat J (1984) [Is chronic paroxys-mal hemicrania due to a chronicinflammatory syndrome?] Presse Med13(40):2453–2454 (article in French)

18. Brandt T, Paulus W, Pollmann W(1991) [Cluster headache and chronicparoxysmal hemicrania: current ther-apy.] Nervenarzt 62(6):329–339 (arti-cle in German)

19. Broeske D, Lenn NJ, Cantos E(1993) Chronic paroxysmal hemicra-nia in a young child: possible relationto ipsilateral occipital infarction. JChild Neurol 8(3):235–236

20. Caminero AB, Pareja JA, Dobato JL(1998) Chronic paroxysmal hemicra-nia-tic syndrome. Cephalalgia18(3):159–161

21. Centonze V, Bassi A, Causarano V,Dalfino L, Centonze A, Albano O(2000) Simultaneous occurrence ofipsilateral cluster headache andchronic paroxysmal hemicrania: acase report. Headache 40(1):54–56

22. Centonze V, Macinagrossa G,Magrone D, Attolini E, Vino M,Tesauro P, Campanozzi F, Albano O(1987) [Chronic paroxysmalmigraine: a new entity or a transientform? Apropos of 3 new clinicalcases.] Minerva Med 78(14):977–979(article in Italian)

23. Christoffersen B (1979) [Chronicparoxysmal hemicrania.] UgeskrLaeger 141(14):930–931 (article inDanish)

24. Comabella M, Titus F, Huguet P(1996) Recurrent paroxysmalheadache associated with facialecchymosis. Cephalalgia16(5):341–343

25. Coria F, Claveria LE, Jimenez-Jimenez FJ, de Seijas EV (1992)Episodic paroxysmal hemicraniaresponsive to calcium channel block-ers. J Neurol Neurosurg Psychiatry55(2):166

185

26. Cumming WJ (1991) Episodic parox-ysmal hemicrania. J NeurolNeurosurg Psychiatry 54(7):666

27. Dahlof C (1993) Subcutaneous suma-triptan does not abort attacks ofchronic paroxysmal hemicrania(CPH). Headache 33(4):201–202

28. De Marinis M (1994) Pupillaryabnormalities due to sympatheticdysfunction in different forms ofidiopathic headache. Clin Auton Res4(6):331–338

29. Delcanho RE, Graff-Radford SB(1993) Chronic paroxysmal hemicra-nia presenting as toothache. J OrofacPain 7(3):300–306

30. Delreux V, Kevers L, Callewaert A(1989) Hemicranie paroxystiqueinaugurant un syndrome de Pancoast.Rev Neurol (Paris) 145(2):151–152

31. Devarrieux L, Chapon F, Viader F,Houtteville P, Lechevalier B (1986)[Paroxysmal hemicrania with homo-lateral mydriasis.] Presse Med15(20):932 (article in French)

32. Di Monda V (1999) Chronic paroxys-mal hemicrania and SUNCT syn-drome. Ital J Neurol Sci 20[2Suppl]:S49–S52

33. Drummond PD (1985) Thermographicand pupillary asymmetry in chronicparoxysmal hemicrania. A case study.Cephalalgia 5(3):133–136

34. Dutta AK (1984) Chronic paroxysmalhemicrania. J Assoc Physicians India32(6):537

35. Evans RW, Olesen J (2000)Remitting chronic paroxysmal hemi-crania or episodic paroxysmal hemi-crania? Headache 40(10):858–859

36. Evers S, Bauer B, Suhr B, Voss H,Frese A, Husstedt IW (1999)Cognitive processing is involved incluster headache but not in chronicparoxysmal hemicrania. Neurology53(2):357–363

37. Evers S, Husstedt IW (1996)Alternatives in drug treatment ofchronic paroxysmal hemicrania.Headache 36(7):429–432

38. Ferrando M, Santamaria J, Peres J(1983) [Paroxysmal hemicrania. Post-stenotic dilatation of the subclavianartery]. Rev Neurol (Paris)139(6–7):451–452 (article in French)

39. Foerderreuther S, von Maydell R,Straube A (1997) A CPH-like picturein two patients with an orbitocav-ernous sinus syndrome. Cephalalgia17(5):608–611

40. Gatzonis S, Mitsikostas DD, Ilias A,Zournas CH, Papageorgiou C (1996)Two more secondary headaches mim-icking chronic paroxysmal hemicra-nia. Is this the exception or the rule?Headache 36(8):511–513

41. Gawel MJ, Rothbart P (1992)Chronic paroxysmal hemicraniawhich appears to arise from eitherthird ventricle pathology or internalcarotid artery pathology. Cephalalgia12(5):327

42. Geaney DP (1983) Indomethacin-responsive episodic cluster headache.J Neurol Neurosurg Psychiatry46(9):860–861

43. Giacovazzo M, Di Sabato F, GalloMF, Granata M, Martelletti P (1992)[“Chronic paroxysmal hemicrania”following ophthalmic herpes zoster.]Riv Eur Sci Med Farmacol14(1):45–47 (article in Italian)

44. Gladstein J, Holden EW, Peralta L(1994) Chronic paroxysmal hemicra-nia in a child. Headache34(9):519–520

45. Goadsby PJ, Edvinsson L (1996)Neuropeptide changes in a case ofchronic paroxysmal hemicrania-evi-dence for trigemino-parasympatheticactivation. Cephalalgia 16(6):448–450

46. Goadsby PJ, Lipton RB (1997) Areview of paroxysmal hemicranias,SUNCT syndrome and other short-lasting headaches with autonomicfeature, including new cases. Brain120(Pt 1):193–209

47. Goadsby PJ (1999) Short-lasting pri-mary headaches: focus on trigeminalautonomic cephalgias andindomethacin-sensitive headaches.Curr Opin Neurol 12(3):273–277

48. Graff-Radford SB (1998) Paroxysmalhemicrania. Oral Surg Oral Med OralPathol Oral Radiol Endod 86(2):138

49. Granella F, Farina S, Manzoni GC(1985) [Chronic paroxysmal hemicra-nia. Description of 5 clinical casesand nosographic considerations.]Acta Biomed Ateneo Parmense56(4–5):207–212 (article in Italian)

50. Guerrero-Peral AL, Marcos-RamosRA, Martin-Perez MV, Herranz-Sanchez MN, Jimenez de la FuenteD, Ponce-Villares MA (1999)[Carotidynia as a form of presenta-tion of paroxysmal hemicrania.] RevNeurol 29(11):1054–1055 (article inSpanish)

51. Hannerz J, Ericson K, Bergstrand G(1987) Chronic paroxysmal hemicra-nia: orbital phlebography and steroidtreatment. A case report. Cephalalgia7(3):189–192

52. Hannerz J, Jogestrand T (1993)Intracranial hypertension and suma-triptan efficacy in a case of chronicparoxysmal hemicrania whichbecame bilateral. (The mechanism ofindomethacin in CPH). Headache33(6):320–323

53. Hannerz J (1993) Trigeminal neural-gia with chronic paroxysmal hemi-crania: the CPH-tic syndrome.Cephalalgia 13(5):361–364

54. Heckl RW (1986) [Cluster headacheand chronic paroxysmal hemicrania-effectiveness of oxygen inhalation].Nervenarzt 57(5):311–313 (article inGerman)

55. Hochman MS (1981) Chronic parox-ysmal hemicrania. A new type oftreatable headache. Am J Med71(1):169–170

56. Horven I, Russell D, Sjaastad O(1989) Ocular blood flow changes incluster headache and chronic parox-ysmal hemicrania. Headache29(6):373–376

57. Jensen NB, Joensen P, Jensen J(1982) Chronic paroxysmal hemicra-nia: continued remission of symp-toms after discontinuation ofindomethacin. Cephalalgia2(3):163–164

58. Jotkowitz S (1978) Chronic paroxys-mal hemicrania and cluster. AnnNeurol 4(4):389

59. Joubert J, Powell D, Djikowski J(1987) Chronic paroxysmal hemicra-nia in a South African black. A casereport. Cephalalgia 7(3):193–196

60. Kaeser HE (1990) [What is yourdiagnosis? Chronic paroxysmal hemi-crania.] Schweiz Rundsch Med Prax79(11):309–310 (article in German)

61. Kayed K, Godtlibsen OB, Sjaastad O(1978) Chronic paroxysmal hemicra-nia IV: “REM sleep locked” nocturnalheadache attacks. Sleep 1(1):91–95

62. Kilpatrick CJ, King J (1982) Chronicparoxysmal hemicrania. Med J Aust1(2):87–88

63. Klassen BD, Dooley JM (2000)Chronic paroxysmal hemicrania-likeheadaches in a child: response to aheadache diary. Headache40(10):853–855

186

64. Kudrow DB, Kudrow L (1989)Successful aspirin prophylaxis in achild with chronic paroxysmal hemi-crania. Headache 29(5):280–281

65. Kudrow L, Esperanca P, Vijayan N(1987) Episodic paroxysmal hemicra-nia? Cephalalgia 7(3):197–201

66. Leon JC, Monton FI (1994)Paroxysmal hemicrania. Neurology44(11):2215–2216

67. Leone M, Filippini G, D’Amico D,Farinotti M, Bussone G (1994)Assessment of InternationalHeadache Society diagnostic criteria:a reliability study. Cephalalgia14(4):280–284

68. MacMillan JC, Nukada H (1989)Chronic paroxysmal hemicrania. N ZMed J 102(868):251–252

69. Manzoni GC, Terzano MG, MorettiG (1981) A new case of “chronicparoxysmal hemicrania”. Ital JNeurol Sci 2(4):411–413

70. Martinez-Salio A, Porta-Etessam J,Perez-Martinez D, Balseiro J,Gutierrez-Rivas E (2000) Case reports:chronic paroxysmal hemicrania-ticsyndrome. Headache 40(8):682–685

71. Mathew NT, Kailasam J, Fischer A(2000) Responsiveness to celecoxibin chronic paroxysmal hemicrania.Neurology 55(2):316

72. Medina JL (1992) Organic headachesmimicking chronic paroxysmal hemi-crania. Headache 32(2):73–74

73. Micieli G, Cavallini A, Facchinetti F,Sances G, Nappi G (1989) Chronicparoxysmal hemicrania: a chronobio-logical study (case report).Cephalalgia 9(4):281–286

74. Moller A, Strian F (1985) [Chronicparoxysmal hemicrania as a postpar-tum headache syndrome.]Geburtshilfe Frauenheilkd 45(7):497(article in German)

75. Moncada E, Graff-Radford SB(1995) Benign indomethacin-respon-sive headaches presenting in the oro-facial region: eight case reports. JOrofac Pain 9(3):276–284

76. Morales Asin F (1997) [Chronicparoxysmal hemicrania.] Neurologia12[Suppl 5]:44–49 (article inSpanish)

77. Morales-Asin F (1995) [Chronicparoxysmal hemicrania.] Rev Neurol23[Suppl 4]:S535–S539 (article inSpanish)

78. Nebudova J (1987) [Chronic parox-ysmal hemicrania.] Cesk NeurolNeurochir 50(2):69–72 (article inCzech)

79. Newman LC, Gordon ML, LiptonRB, Kanner R, Solomon S (1992)Episodic paroxysmal hemicrania: twonew cases and a literature review.Neurology 42(5):964–966

80. Newman LC, Herskovitz S, LiptonRB, Solomon S (1992) Chronicparoxysmal headache: two cases withcerebrovascular disease. Headache32(2):75–76

81. Newman LC, Lipton RB, Solomon S(1993) Episodic paroxysmal hemicra-nia: 3 new cases and a review of theliterature. Headache 33(4):195–197

82. Pareja J, Pareja J (1992) Chronicparoxysmal hemicrania coexistingwith migraine. Differential responseto pharmacological treatment.Headache 32(2):77–78

83. Pareja J, Sjaastad O (1996) Chronicparoxysmal hemicrania and hemicra-nia continua. Interval betweenindomethacin administration andresponse. Headache 36(1):20–23

84. Pareja JA, Palomo T, Gorriti MA,Pareja J, Espejo J (1990) “Hemicraniaepisodica”–a new type of headache ora pre-chronic stage of hemicrania con-tinua? Headache 30(6):344–346

85. Pareja JA (1995) Chronic paroxysmalhemicrania: dissociation of the painand autonomic features. Headache35(2):111–113

86. Pascual J, Quijano J (1998) A case ofchronic paroxysmal hemicraniaresponding to subcutaneous sumatrip-tan. J Neurol Neurosurg Psychiatry65(3):407

87. Pearce SH, Cox JG, Pearce JM(1987) Chronic paroxysmal hemicra-nia, episodic cluster headache andclassic migraine in one patient. JNeurol Neurosurg Psychiatry50(12):1699–1700

88. Pelz M, Merskey H (1982) A case ofpre-chronic paroxysmal hemicrania.Cephalalgia 2(1):47–50

89. Petty RG, Rose FC (1982) Chronicparoxysmal hemicrania: first reportedBritish case. BMJ 286:438

90. Pfaffenrath V, Kufner G, Pollmann W(1984) [Chronic paroxysmal hemicra-nia. A review based on personalcases.] Nervenarzt 55(8):402–406(article in German)

91. Pollmann W, Pfaffenrath V (1986)Chronic paroxysmal hemicrania: thefirst possible bilateral case.Cephalalgia 6(1):55–57

92. Pradalier A, Dry J (1984) [Chronicparoxysmal hemicrania. Treatmentwith indomethacin and diclofenac.]Therapie 39(2):185–188 (article inFrench)

93. Pradalier A, Dry J (1984) [Chronicparoxysmal hemicrania.] Presse Med13(1):48 (article in French)

94. Price RW, Posner JB (1978) Chronicparoxysmal hemicrania: a disablingheadache syndrome responding toindomethacin. Ann Neurol3(2):183–184

95. Rangel Guerra R (1981) [Chronicparoxysmal hemicrania (author’stransl).] Rev Invest Clin 33(1):57–60(article in Spanish)

96. Rapoport AM, Sheftell FD, BaskinSM (1981) Chronic paroxysmal hem-icrania - case report of the secondknown definite occurrence in a male.Cephalalgia 1(2):67–69

97. Raskin NH (1997) Short-lived headpains. Neurol Clin 15(1):143–152

98. Rasmussen BK (1986) [Chronicparoxysmal migraine. A review andpresentation of 4 new cases.] UgeskrLaeger 149(1):10–12 (article inDanish)

99. Robbins L (1991) Chronic paroxys-mal hemicrania successfully treatedwith inhaled heparin therapy.Headache 31:402

100. Robbins L (1992) Prophylaxis ofmigraine, cluster and chronic parox-ysmal hemicrania with low-doseinhaled heparin. Headache32(5):267–268 (abstract)

101. Russell D, Christoffersen B, Horven I(1978) Chronic paroxysmal hemicra-nia: a case report. Headache18(2):99–100

102. Russell D, Storstein L (1984)Chronic paroxysmal hemicrania:heart rate changes and ECG rhythmdisturbances. A computerized analy-sis of 24 h ambulatory ECG record-ings. Cephalalgia 4(2):135–144

103. Russell D (1984) Chronic paroxys-mal hemicrania: severity, durationand time of occurrence of attacks.Cephalalgia 4(1):53–56

104. Saunte C, Russell D, Sjaastad O (1983)Chronic paroxysmal hemicrania. IX.On the mechanism of attack-relatedsweating. Cephalalgia 3(3):191–199

187

105. Saunte C (1984) Chronic paroxysmalhemicrania: salivation, tearing andnasal secretion. Cephalalgia4(1):25–32

106. Schlake HP, Bottger IG, GrotemeyerKH, Husstedt IW, Schober O (1990)Single photon emission computedtomography (SPECT) with 99mTc-HMPAO (hexamethylpropylenamineoxime) in chronic paroxysmal hemi-crania. A case report. Cephalalgia10(6):311–315

107. Shabbir N, McAbee G (1994)Adolescent chronic paroxysmal hem-icrania responsive to verapamilmonotherapy. Headache34(4):209–210

108. Shen JM (1993) Transcranial Dopplersonography in chronic paroxysmalhemicrania. Headache 33(9):493–496

109. Sjaastad O, Dale I (1976) A new (?)clinical headache entity “chronicparoxysmal hemicrania” 2. ActaNeurol Scand 54(2):140–159

110. Sjaastad O, Dale I (1974) Evidencefor a new (?), treatable headache enti-ty. Headache 14(2):105–108

111. Sjaastad O, Aasly J, Fredriksen T,Wysocka Bakowska MM (1986)Chronic paroxysmal hemicrania. X.On the autonomic involvement.Cephalalgia 6(2):113–123

112. Sjaastad O, Antonaci F (1993)Chronic paroxysmal hemicrania(CPH) and hemicrania continua: tran-sition from one stage to another.Headache 33(10):551–554

113. Sjaastad O, Antonaci F (1987) Chronicparoxysmal hemicrania: a case report.Long-lasting remission in the chronicstage. Cephalalgia 7(3):203–205

114. Sjaastad O, Antonaci F (1995) Apiroxicam derivative partly effectivein chronic paroxysmal hemicraniaand hemicrania continua. Headache35(9):549–550

115. Sjaastad O, Apfelbaum R, Caskey W,Christoffersen B, Diamond S, GrahamJ, Green M, Horven I, Lund-Roland L,Medina J, Rogado S, Stein H (1980)Chronic paroxysmal hemicrania(CPH). The clinical manifestations. Areview. Ups J Med Sci Suppl 31:27–33

116. Sjaastad O, Egge K, Horven I, KayedK, Lund-Roland L, Russell D,Sloordahl Conradi I (1979) Chronicparoxysmal hemicrania: mechanicalprecipitation of attacks. Headache19(1):31–36

117. Sjaastad O, Russell D, Saunte C,Horven I (1982) Chronic paroxysmalhemicrania. VI. Precipitation ofattacks. Further studies on the precip-itation mechanism. Cephalalgia2(4):211–214

118. Sjaastad O, Russell D, Saunte C(1983) Chronic paroxysmal hemicra-nia. VIII. The sweating pattern.Cephalalgia 3(1):45–52

119. Sjaastad O, Saunte C, Graham JR(1984) Chronic paroxysmal hemicra-nia. VII. Mechanical precipitation ofattacks: new cases and localization oftrigger points. Cephalalgia4(2):113–118

120. Sjaastad O, Stovner LJ, Stolt-NielsenA, Antonaci F, Fredriksen TA (1995)CPH and hemicrania continua:requirements of high indomethacindosages - a ominous sign? Headache35(6):363–367

121. Sjaastad O (1989) Chronic paroxys-mal hemicrania (CPH): nomenclatureas far as the various stages are con-cerned. Cephalalgia 9(1):1–2

122. Sjaastad O (1987) Chronic paroxys-mal hemicrania: recent developments.Cephalalgia 7(3):179–188

123. Valade D, El Amrani M (2000) Lesalgies de la face idiopathiques autresque l’algie vasculaire de la face. RevNeurol (Paris) 156[Suppl4]:4S57–4S61

124. Sjaastad O (1993) Paroxysmal hemi-crania. Neurology 43(7):1445–1447

125. Skobieranda FG (1997) Episodiccluster headache with a high dailyattack frequency: contrast withepisodic paroxysmal hemicrania.Headache 37:5 (abstract)

126. Solomon S, Newman LC (1995)Chronic paroxysmal hemicrania in achild? Headache 35(4):234

127. Solomon S (1989) Variants of chron-ic paroxysmal hemicrania.Cephalalgia 9(1):79–80

128. de Souza Carvalho D, Salvesen R,Sand T, Smith SE, Sjaastad O (1988)Chronic paroxysmal hemicrania.XIII. The pupillometric pattern.Cephalalgia 8:219–226

129. Spierings EL (1992) Episodic andchronic paroxysmal hemicrania. ClinJ Pain 8(1):44–48

130. Spierings EL (1988) The chronicparoxysmal hemicrania conceptexpanded. Headache 28(9):597–598

131. Stein HJ, Rogado AZ (1980) Chronicparoxysmal hemicrania: two newpatients. Headache 20:72–76

132. Tehindrazanarivelo AD, Visy JM,Bousser MG (1992) Ipsilateral clusterheadache and chronic paroxysmalhemicrania: two case reports.Cephalalgia 12(5):318–320

133. Thevenet JP, Delestrain MC, DordainG (1983) [Chronic paroxysmal hemi-crania sensitive to indomethacin.]Presse Med 12(45):2855–2858 (arti-cle in French)

134. Vijayan N (1992) Symptomaticchronic paroxysmal hemicrania.Cephalalgia 12(2):111–113

135. Warner JS, Wamil AW, McLean MJ(1994) Acetazolamide for the treat-ment of chronic paroxysmal hemicra-nia. Headache 34(10):597–599

136. Zukerman E, Peres MF, Kaup AO,Monzillo PH, Costa AR (2000)Chronic paroxysmal hemicrania-ticsyndrome. Neurology54(7):1524–1526

137. Alberca R, Márquez C, Vila MJ(1991) [Hemicrania paroxistica neu-ralgiforme.] Neurologia6(8):299–301 (article in Spanish)

138. Becser N, Berky M (1995) SUNCTsyndrome: a Hungarian case.Headache 35(3):158–160

139. Benoliel R, Sharav Y (1998) SUNCTsyndrome: case report and literaturereview. Oral Surg Oral Med OralPathol Oral Radiol Endod85(2):158–161

140. Benoliel R, Sharav Y (1998)Trigeminal neuralgia with lacrimationor SUNCT syndrome? Cephalalgia18(2):85–90

141. Bouhassira D, Attal N, Esteve M,Chauvin M (1994) “SUNCT” syn-drome. A case of transformation fromtrigeminal neuralgia? Cephalalgia14(2):168–170

142. Bussone G, Leone M, Dalla Volta G,Strada L, Gasparotti R, Di Monda V(1991) Short-lasting unilateral neural-giform headache attacks with tearingand conjunctival injection: the first“symptomatic“ case? Cephalalgia11(13):123–127

143. D’Andrea G, Granella F, Ghiotto N,Nappi G (2001) Lamotrigine in thetreatment of SUNCT syndrome.Neurology 57(9):1723–1725

188

144. D’Andrea G, Granella F (2001)SUNCT syndrome: the first case inchildhood. Short-lasting unilateralneuralgiform headache attacks withconjunctival injection and tearing.Cephalalgia 21(6):701–702

145. D’Andrea G, Granella F, CadaldiniM (1999) Possible usefulness oflamotrigine in the treatment ofSUNCT syndrome. Neurology53(7):1609

146. De Benedittis G (1996) SUNCT syn-drome associated with cavernousangioma of the brain stem.Cephalalgia 16(7):503–506

147. Graff-Radford SB (2000) SUNCTsyndrome responsive to gabapentin(Neurontin). Cephalalgia20(5):515–517

148. Hannerz J, Greitz D, Hansson P,Ericson K (1992) SUNCT may beanother manifestation of orbitalvenous vasculitis. Headache32(8):384–389

149. Kruszewski P, Zhao JM, Shen JM,Sjaastad O (1993) SUNCT syn-drome: forehead sweating pattern.Cephalalgia 13(2):108–113

150. Kruszewski P (1992) Short-lasting,unilateral, neuralgiform headacheattacks with conjunctival injectionand tearing (SUNCT syndrome): V.Orbital phlebography. Cephalalgia12(6):387–389

151. Lain AH, Caminero AB, Pareja JA(2000) SUNCT syndrome; absence ofrefractory periods and modulation ofattack duration by lengthening of thetrigger stimuli. Cephalalgia20(7):671–673

152. Lanusse S, Senechal O, Rouhart F,Goas JY (1999) [SUNCT syndrome:case report and literature review.]Rev Neurol (Paris)155(12):1071–1073 (article inFrench)

153. Leone M, Rigamonti A, Usai S,Damico D, Grazzi L, Bussone G(2000) Two new SUNCT casesresponsive to lamotrigine.Cephalalgia 20(9):845–847

154. May A, Bahra A, Büchel C, TurnerR, Goadsby PJ (1999) Functionalmagnetic resonance imaging in spon-taneous attacks of SUNCT: short-lasting neuralgiform headache withconjunctival injection and tearing.Ann Neurol 46(5):791–794

155. Morales F, Mostacero E, Marta J,Sanchez S (1994) Vascular malfor-mation of the cerebellopontine angleassociated with “SUNCT” syndrome.Cephalalgia 14(4):301–302

156. Morales-Asin F, Espada F, Lopez-Obarrio LA, Navas I, Escalza I,Iniguez C (2000) A SUNCT casewith response to surgical treatment.Cephalalgia 20(1):67–68

157. Pareja JA, Caballero V, Sjaastad O(1996) SUNCT syndrome. Status-likepattern. Headache 36(10):622–624

158. Pareja JA, Kruszewski P, CamineroAB (1999) SUNCT syndrome versusidiopathic stabbing headache (jabsand jolts syndrome). Cephalalgia19[Suppl 25]:46–48

159. Pareja JA, Kruszewski P, Sjaastad O(1997) SUNCT syndrome. Diagnosismorbi. Short-lasting unilateral neural-giform headache attacks, with con-junctival injection, tearing and rhinor-rhoea. Neurologia 12[Suppl 5]:66–72

160. Pareja JA, Pareja J, Palomo T,Caballero V, Pamo M (1994) SUNCTsyndrome: repetitive and overlappingattacks. Headache 34(2):114–116

161. Pareja JA, Shen JM, Kruszewski P,Caballero V, Pamo M, Sjaastad O(1996) SUNCT syndrome: duration,frequency, and temporal distributionof attacks. Headache 36(3):161–165

162. Pareja JA, Sjaastad O (1994) SUNCTsyndrome in the female. Headache34(4):217–220

163. Poughias L, Aasly J (1995) SUNCTsyndrome: cerebral SPECT imagesduring attacks. Headache35(3):143–145

164. Raimondi E, Gardella L (1998)SUNCT syndrome. Two cases inArgentina. Headache 38(5):369-371

165. Salazar JA, Tamayo JA, Fernández O(1998) [SUNCT type headache. Areport of a new case. Short-lasting,unilateral, neuralgiform, headacheattacks with conjunctival injectionand tearing.] Neurologia13(3):148–150 (article in Spanish)

166. Shen JM, Johnsen HJ (1994) SUNCTsyndrome: estimation of cerebralblood flow velocity with transcranialDoppler ultrasonography. Headache34(1):25–31

167. Sjaastad O, Kruszewski P, Fostad K,Elsas T, Qvigstad G (1992) SUNCTsyndrome: VII. Ocular and relatedvariables. Headache 32(10):489–495

168. Sjaastad O, Pareja JA, Zukerman E,Jansen J, Kruszewski P (1997)Trigeminal neuralgia. Clinical mani-festations of first division involve-ment. Headache 37(6):346–357

169. Sjaastad O, Russell D, Hørven I,Bunaes U (1978) Multiple neuralgi-form unilateral headache attacksassociated with conjunctival injec-tion and appearing in clusters. Anosological problem. In:Proceedings of the ScandinavianMigraine Society, p 31

170. Sjaastad O, Saunte C, Salvesen R,Fredriksen TA, Seim A, Roe OD,Fostad K, Lobben OP, Zhao JM(1989) Short-lasting, unilateral, neu-ralgiform headache attacks with con-junctival injection, tearing, sweating,and rhinorrhea. Cephalalgia9(2):147–156

171. Sjaastad O, Zhao JM, Kruszewski P,Stovner LJ (1991) Short-lasting uni-lateral neuralgiform headache attackswith conjunctival injection, tearing,etc. (SUNCT): III. AnotherNorwegian case. Headache31(3):175–177

172. ter Berg JW, Goadsby PJ (2001)Significance of atypical presentationof symptomatic SUNCT: a casereport. J Neurol NeurosurgPsychiatry 70(2):244–246

173. Wingerchuk, Nyquist PA, RodriguezM, Dodick DW (2000)Extratrigeminal short-lasting unilater-al neuralgiform headache with con-junctival injection and tearing(SUNCT): new pathophysiologicentity or variation on a theme?Cephalalgia 20:127–129

174. Wober C, Wober-Bingol C, WesselyP (1993) Das SUNCT syndrom.Fallbericht und literaturubersicht.Fortschr Neurol Psychiatr61(11):378–382

175. Grecho VE, Dobrovitskaia AM(2000) [A specific form of headachewith neuralgia-like manifestations(SUNCT-syndrome).] Zh NevrolPsikhiatr Im S S Korsakova100:28–31 (article in Russian)

176. Zhao JM, Sjaastad O (1993) SUNCTsyndrome: VIII. Pupillary reactionand corneal sensitivity. Funct Neurol8(6):409–414

189

177. Andermann F, Lugaresi E, DvorkinGS, Montagna P (1986) Malignantmigraine: the syndrome of prolongedclassical migraine, epilepsia partialiscontinua, and repeated strokes; a clin-ically characteristic disorder probablydue to mitochondrial encephalopathy.Funct Neurol 1(4):481–486

178. Antonaci F, Sjaastad O (1992)Hemicrania continua: a possiblesymptomatic case, due to mesenchy-mal tumor. Funct Neurol7(6):471–474

179. Bauherz G (2000) [Chronicheadaches.] Rev Med Brux21(4):A207–A213 (article in French)

180. Bordini C, Antonaci F, Stovner LJ,Schrader H, Sjaastad O (1991)“Hemicrania continua”: a clinicalreview. Headache 31(1):20–26

181. Brilla R, Evers S, Soros P, HusstedtIW (1998) Hemicrania continua in anHIV-infected outpatient. Cephalalgia18(5):287–288

182. Centonze V, Attolini E, CampanozziF, Magrone D, Tesauro P, Vino M,Campanale G, Albano O (1987)“Hemicrania continua”: a new clini-cal entity or a further developmentfrom cluster headache? A case report.Cephalalgia 7(3):167–168

183. Evans RW, Lay CL (2000)Posttraumatic hemicrania continua?Headache 40(9):761–762

184. Evers S, Bahra A, Goadsby PJ (1999)Coincidence of familial hemiplegicmigraine and hemicrania continua? Acase report. Cephalalgia19(5):533–535

185. Forderreuther S, Straube A (1999) [Arare headache syndrome. SUNCTsyndrome, hemicrania continua andred ear syndrome.] Nervenarzt70(8):754–758 (article in German)

186. Fragoso YD, Machado PC (1998)Hemicrania continua with onset at anearly age. Headache 38(10):792–793

187. Hannerz J (2000) Chronic bilateralheadache responding toindomethacin. Headache40(10):840–843

188. Iordanidis T, Sjaastad O (1989)Hemicrania continua: a case report.Cephalalgia 9(4):301–303

189. Joubert J (1991) Hemicrania continuain a black patient – the importance ofthe non-continuous stage. Headache31(7):480–482

190. Jurynczyk J, Weglewski A (1999)[Hemicrania continua: a case report.]Neurol Neurochir Pol33(5):1195–1200 (article in Polish)

191. Kumar KL, Bordiuk JD (1991)Hemicrania continua: a therapeuticdilemma. Headache 31(5):345

192. Kuritzky A (1992) Indomethacin-resistant hemicrania continua.Cephalalgia 12(1):57–59

193. Lainez JM, Pareja Martinez AI(1997) [Hemicrania continua.]Neurologia 12[Suppl 5]:50–55 (arti-cle in Spanish)

194. Marano E, Giampiero V, GennaroDR, di Stasio E, Bonusa S, Sorge F(1994) “Hemicrania continua”: a pos-sible case with alternating sides.Cephalalgia 14(4):307–308

195. Miller LG, Prichard JG (1990)Current issues in NSAID therapy.Prim Care 17(3):589–601

196. Moorjani BI, Rothner AD (2001)Indomethacin-responsive headachesin children and adolescents. SeminPediatr Neurol 8(1):40–45

197. Newman LC, Lipton RB, Russell M,Solomon S (1992) Hemicrania con-tinua: attacks may alternate sides.Headache 32(5):237–238

198. Newman LC, Lipton RB, Solomon S(1994) Hemicrania continua: ten newcases and a review of the literature.Neurology 44(11):2111–2114

199. Olesen J, Rasmussen BK (1996) TheInternational Headache Society clas-sification of chronic daily and near-daily headaches: a critique of the crit-icism. Cephalalgia 16(6):407–411

200. Oser FS 3rd (1995) Hemicrania con-tinua. Neurology 45(10):1948–1949

201. Pareja JA, Espejo J, Trigo M, SjaastadO (1997) Congenital (?) Horners syn-drome and ipsilateral headache. FunctNeurol 12(3–4):123–131

202. Pareja JA, Palomo T, Gorriti MA,Pareja J, Espejo J, Moron B, Trigo M(1990) Hemicrania continua. The firstSpanish case: a case report.Cephalalgia 10(3):143–145

203. Pareja JA (1999) Hemicrania contin-ua: ocular discomfort heraldingpainful attacks. Funct Neurol14(2):93–95

204. Pareja JA (1995) Hemicrania contin-ua: remitting stage evolved from thechronic form. Headache35(3):161–162

205. Pascual J (1995) Hemicrania contin-ua. Neurology 45(12):2302-2303

206. Pasquier F, Leys D, Petit H (1987)“Hemicrania continua”: the firstbilateral case? Cephalalgia7(3):169–170

207. Peres MF, Zukerman E (2000)Hemicrania continua responsive torofecoxib. Cephalalgia20(2):130–131

208. Pfaffenrath V, Kaube H (1990)Diagnostics of cervicogenicheadache. Funct Neurol 5(2):159–164

209. Rothbart P (1992) Unilateral headachewith features of hemicrania continuaand cervicogenic headache–a casereport. Headache 32(9):459–460

210. Sheftell FD, Rapoport AM, CoddonDR (2000) Reply from Sheftell et al.to “Naratriptan prophylaxis of trans-formed migraine or hemicrania con-tinua?” Headache 40(6):500

211. Silberstein SD, Lipton RB, SolomonS, Mathew NT (1994) Classificationof daily and near-daily headaches:proposed revisions to the IHS crite-ria. Headache 34(1):1–7

212. Silberstein SD, Lipton RB, SliwinskiM (1996) Classification of daily andnear-daily headaches: field trial ofrevised IHS criteria. Neurology47(4):871-875

213. Silberstein SD, Lipton RB (2000)Chronic daily headache. Curr OpinNeurol 13(3):277–283

214. Silberstein SD (1994) Tension-typeheadaches. Headache 34(8):S2–S7

215. Sjaastad O, Joubert J, Elsas T, BovimG, Vincent M (1993) Hemicraniacontinua and cervicogenic headache.Separate headaches or two faces ofthe same headache? Funct Neurol8(2):79–83

216. Sjaastad O, Spierings EL, Saunte C,Wysocka Bakowska MM, Sulg I,Fredriksen TA (1984) “Hemicraniacontinua”. An indomethacin respon-sive headache. II. Autonomic func-tion studies. Cephalalgia4(4):265–273

217. Sjaastad O, Spierings EL (1984)“Hemicrania continua”: anotherheadache absolutely responsive toindomethacin. Cephalalgia4(1):65–70

218. Sjaastad O, Tjorstad K (1987)“Hemicrania continua”: a thirdNorwegian case. Cephalalgia7(3):175–177

190

219. Sjaastad O, Vincent M, Stovner LJ(1993) Side alternation of pain inhemicrania continua. Headache33(1):43–45

220. Sjaastad O (1987) “Hemicrania con-tinua”–new developments.Cephalalgia 7(3):163–166

221. Solomon S, Newman LC (1999)Chronic daily bilateral headacheresponsive to indomethacin.Headache 39(10):754–757

222. Trucco M, Antonaci F, Sandrini G(1992) Hemicrania continua: a caseresponsive to piroxicam-beta-cyclodextrin. Headache 32(1):39–40

223. Warner JS (1997) Analgesic reboundas a cause of hemicrania continua.Neurology 48(6):1540–1541

224. Wheeler SD (2000) Naratriptan pro-phylaxis of transformed migraine orhemicrania continua? Headache40(6):498–499

225. Young WB, Silberstein SD (1993)Hemicrania continua and sympto-matic medication overuse. Headache33(9):485–487

226. Zukerman E, Hannuch SN, CarvalhoDde S, Fragoso YD, Jenger KA(1987) “Hemicrania continua”: a casereport. Cephalalgia 7(3):171–173

Good clinical practice (GCP)International standards of ethics andscientific quality used in the plan-ning, execution, and recording ofclinical studies that involve humansubjects. Adhesion to good clinicalpractice (GCP) not only guaranteesthat the laws, safety and well-being ofthe subjects who participate in thestudy, in conformity with the estab-lished principles of the Declaration ofHelsinki are respected, but also thatthe findings of the study are reliable

Intensity of headacheThe degree of head pain is recordedon a verbal analogical scale of 4points: 0, no headache; 1, lightintensity, when headache does notlimit normal daily activities; 2, mod-erate intensity, when headache par-tially limits the normal daily activi-ties of the patient; 3, severe intensi-ty, when pain is of such an intensityto completely prevent a social life

Functional disabilityThe functional impairment of themigraine patient is recorded on a ver-bal analogical scale of 4 points: 0, nodisability, the patient has a normalfunctional ability; 1, the performanceof the patient is slightly impaired buthe can, however, carry out normaldaily activities; 2, the performance ofthe patient is moderately impairedand he can only carry out some dailyroutine activities; 3, the performance

of the patient is severely impaired, hecannot carry out any routine dailyactivities and may need to stay in bed

Efficacy parameters for migraineSymptomatic treatment

Headache responseReduction of pain intensity fromsevere or moderate to light or absent.It is measured in the patient at certaintime points (e.g. 1 hour, 2 hours, 4hours) compared with the baselinetime (before taking the study drug)

Headache-free patientsPercentage of patients withoutheadache at defined time points(e.g. 15 minutes, 30 minutes) aftertaking the study drug

Sustained headache responsePercentage of patients with noheadache at two hours, without tak-ing an escape medication and with noheadache recurrence within 48 hours

Effectiveness on accompanyingsymptomsPercentage of patients free of nau-sea, vomiting, photophobia andphonophobia at defined time pointscompared with baseline (before theadministration of the study drug)

Effectiveness on functional disabilityPercentage of patients with partialor total recovery of functional dis-ability at defined time points com-

pared with baseline (before theadministration of the study drug)

Need for an escape medicationNecessity to take a drug differentfrom the one on which the effec-tiveness is being assessed, due to arecurrence of headache

Headache recurrenceWorsening of headache (to moder-ate or severe pain) within 24 hoursof treatment and subsequent toheadache response (mild or no pain)

Headache relapseHeadache recurrence occurs whenthe patient is pain-free at two hoursand a headache of any intensityreappears within 48 hours

ConsistencyMaintenance in the effectiveness ofthe treatment in subsequent attacks

Prophylactic treatmentEfficacyA treatment is considered efficaciouswhen it reduces the frequency orintensity of the attacks by at least 50%

Efficacy parameters for clusterheadache

Symptomatic treatmentPain-free patientsPercentage of pain-free headachepatients at defined time points (e.g. 1,2, 4 hours) after taking the study drug


Glossary

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Effectiveness on functional disabilityPercentage of patients with partialor total recovery of functional dis-ability at defined time points (e.g. 15minutes, 30 minutes) after taking thestudy drug

Prophylactic treatmentEfficacyA treatment is considered effica-cious when it induces a rapid disap-pearance of the attacks and conse-quently the end of the cluster phase.Secondary objectives are the reduc-tion in the frequency, intensity andduration of the attack by at least 50%

Non-respondersPatients who do not have a signifi-cant headache response to a definedsymptomatic treatment and noresponse is confirmed in otherattacks (at least 3)

Serious side effectsAny unfavorable clinical event that,at any dosage:

- Is fatal- Puts life in danger- Requires the hospitalization of the

patient or a prolonged recovery - Results in a persistent or significant

invalidity

- Causes a congenital abnormality ora defect at birth

Side effects Any unfavorable clinical event that occurs after the administrationof the study drug. Side effects aredistinguished on the basis of the frequency in: rare, <1/10,000;occasional, inclusive between1/10,000 and 1/100; and frequent,>1/100 cases. They may be distin-guished on the basis of the severi-ty into severe and not severe sideeffects

Preliminary remarks pp. 105 - 106 pp. 107 – 110 Migraine … · 2018-12-13 · Preliminary...

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