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Central Nervous System Conditions: Headache

Irene Worthington, BScPhm

Date Prepared: May 2010

Pathophysiology

This chapter focuses on the most common primary headache disorders: tension-type headache, migraine and cluster headache.

An extensive classification of headache disorders has been published by the International Headache Society (IHS).1

Tension-type Headache

Tension-type headache (TTH) is the most common type of headache. It is diagnosed mainly by the absence of features found inother types of headaches (e.g., migraine). Although mental stress and tension are frequently thought to precipitate TTH, the exactpathophysiology is unknown. Both peripheral (myofascial tissues) and central mechanisms are thought to contribute to pain in

TTH.2 Some headache experts believe that TTH is a variant of migraine, since there are significant overlapping features; however,epidemiologic studies have concluded that migraine and TTH are different disorders, which coexist in many patients. TTH can beepisodic or chronic (headache on ≥15 days per month). The lifetime prevalence of TTH is around 80%, and about 3% for chronic

TTH. The prevalence of TTH appears to be higher in women, and declines with age in both sexes.2

Migraine

Migraine is a common, underdiagnosed, often incapacitating neurovascular disorder characterized by attacks of headache pain

(generally moderate to severe), autonomic nervous system dysfunction and neurological symptoms in some patients.3 The IHS

provides diagnostic features for 7 subtypes of migraine.1 The specific cause of migraine is unknown but genetic factors are likelyinvolved. It has been proposed that specific migraine triggers can provoke CNS dysfunction in susceptible individuals, leading todilation of intracranial and extracerebral blood vessels and activation of the trigeminal sensory nerves (resulting in release ofvasoactive peptides such as calcitonin-gene-related peptide), with subsequent relaying of pain signals to the brain. Migraineattacks may be episodic or chronic (≥15 days per month). In approximately 15% of patients, migraine attacks are preceded oraccompanied by transient focal neurologic symptoms (usually visual); this is referred to as migraine with aura (previously knownas classic migraine). Aura is thought to be caused by neuronal dysfunction, not ischemia or vasoconstriction, as previouslybelieved. Migraine without aura is more common than migraine with aura. In North America and Western Europe, the 1-year

prevalence of migraine is 11% overall: 15–18% among women and 6% among men. Attacks may last from 4–72 hours.3 , 4

Cluster Headache

Cluster headache, a rare disorder, was previously thought to be a variant of migraine but is currently classified as a distinctheadache disorder. Prevalence is about 0.1%, predominantly in men. It is characterized by repeated attacks (cluster periods,separated by headache-free interval remission periods lasting for months or years) of strictly unilateral pain in theorbital/temporal region and associated with autonomic signs or symptoms (e.g., lacrimation, conjunctival injection, rhinorrhea,miosis, ptosis). A minority of patients have attacks for longer than a year without remission (or remission lasting <14 days); this isreferred to as chronic cluster headache. Attacks generally last for 15–180 minutes and occur from once every other day to 8 timesa day. Pain tends to be severe (boring, bursting or piercing quality). The exact pathophysiology is unknown. Studies havesuggested that an autosomal dominant gene has a role in some families. Neuroimaging has revealed primary defects in thehypothalamic grey matter. It has been suggested that an inflammatory process in the cavernous sinus and tributary veins results

in cluster headache (nitroglycerin and other vasodilators can induce an attack of cluster headache).5

Goals of Therapy6 , 7 , 8

Identify potentially serious causes of headache and refer patient to physician/emergency room as required fordiagnosis/treatmentRelieve pain and associated symptoms (e.g., nausea/vomiting) so that patient can return to normal functioningPrevent recurrence of headachePrevent complications due to medication overuse

Patient Assessment (Figure 1 - Assessment and Management of Patients with Headache)

There are no diagnostic tests for primary headache disorders (e.g., tension-type headache, migraine, cluster headache).

Diagnosis is based on symptoms, after ruling out any serious underlying disorders.1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13

The IHS has established criteria for the diagnosis of various headache disorders.1 Secondary headache disorders are thoseassociated with organic causes (e.g., trauma, meningitis, space-occupying lesion). Some medical procedures are associated with

headache (e.g., lumbar puncture, rhinoscopy).

Patients with occasional tension-type headache do not need to see a physician unless the headaches become chronic (≥15days/month). Patients with features of migraine should be assessed and diagnosed by a physician to obtain appropriate treatment.Any unusual headache should be diagnosed by a physician; if the headache is very severe, with a sudden onset, referimmediately to an emergency room (see Red Flags for Serious Headache, below). A stepwise approach to headache assessment

and treatment is provided in Figure 1 - Assessment and Management of Patients with Headache.1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ,

11 , 12



Common Signs and Symptoms

Table 1 outlines the clinical features of the more common primary headache disorders.

Differential Diagnosis

In addition to the primary headache disorders in Table 1, other causes of headache include:1 , 10 , 11 , 12 , 14

Other primary headache types such as paroxysmal hemicrania, idiopathic stabbing headache, cold-stimulus headache, benigncough headache, benign exertional headacheInfections such as meningitis; encephalitisTemporal arteritis (an important cause of headache in those over 50 years of age; associated with systemic symptoms andelevated erythrocyte sedimentation rate; if left untreated, often leads to permanent blindness)Subdural hematoma; subarachnoid hemorrhage; cerebral ischemia (stroke); transient ischemic attack (TIA); headachefollowing stroke or TIA; systemic/CNS vasculitides (e.g., systemic lupus erythematosus); space-occupying lesions (e.g., braintumor) and others

Note: “sinus” headaches occur only in the presence of a sinus infection (fever, purulent nasal discharge)14

Medications (see Table 2)

Table 1: Clinical Features of Tension-type Headache, Migraine and Cluster Headache

ClinicalFeature Tension-type Headache Migraine Cluster Headache

Quality ofheadache

Pressing/tightening(nonpulsating)

Throbbing/pulsating (atleast part of the time)

Penetrating

Severity Mild to moderate Usually moderate tosevere, although can bemild

Excruciating

Location Bilateral Usually unilateral (can bebilateral, especially inchildren)

Always unilateral (supraorbital and/or temporal)

Frequency

Episodic (<15 days/mo) orchronic (≥15 days /mo)

Episodic (variable) Episodic headaches last 7 days to 1 y, separated bypain-free periods lasting ≥14 daysChronic: attacks occur for more than 1 y or withheadache-free intervals <14 days

Duration 30 min to 7 days 4–72 h 15–180 min

Aggravatedby physicalactivity

No Yes No

Associatedsymptoms

No nausea/vomiting(anorexia may occur) andno photophobia andphonophobia (or 1 but notthe other may occur)

Either nausea and/orvomiting or photophobiaand phonophobia; mayoccur with or without aura(usually visual)

At least 1 of the following (on same side as headache):lacrimation, conjunctival injection, nasal congestion,rhinorrhea, miosis, ptosis, forehead/facial sweating,eyelid edema (mild or no photo/phonophobia, novomiting)

Figure 1 - Assessment and Management of Patients with Headache



Drug-induced Headache11 , 15

Table 2 lists drugs that commonly cause headache as a side effect.

Table 2: Drugs Associated with Headache15 , 16 , 17 , 18

Drugs associated with intracranial hypertension a

Antibiotics: minocycline, tetracycline, trimethoprim-sulfamethoxazoleCorticosteroidsOther: cimetidine, isotretinoin, tamoxifen

Drugs with headache as a side effect a

ACEIs: e.g., captoprilBeta-blockers: e.g., atenolol, propranolol (also used for migraine prophylaxis)Calcium channel blockers: nifedipineOther antihypertensives: hydralazine, methyldopaH2 antagonists: e.g., cimetidine, ranitidine

Nitrates: e.g., nitroglycerinNSAIDs: diclofenac, indomethacin (also used to treat certain types of headache)Oral contraceptives and HRT (in some patients predisposed to migraine)SSRIs: e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertralineOther: caffeine (especially caffeine withdrawal), cyclosporine, danazol, latanoprost ophthalmic drops, metronidazole

a. Most common drug-related causes (not exhaustive).

Abbreviations: ACEIs=angiotensin converting enzyme inhibitors; HRT=hormone replacement therapy; NSAIDs=nonsteroidal anti-inflammatory drugs; SSRIs=selective serotonin reuptake inhibitors

Red Flags for Serious Headache7 , 10 , 11

Severe/abrupt onset (“worst headache ever”)Onset in middle age or older (>40 years)Neurologic signs: stiff neck, focal signs, reduced consciousnessSystemic signs: appears ill, fever, nausea/vomiting (not explained by migraine or systemic illness)Significant change in pattern of headaches: increased frequency and/or progressive severityNocturnal occurrence or on awakening in morning; if patient consistently has headache on awakening or is awakened by aheadache, there is a possibility of a brain tumor; however, migraines sometimes occur on awakeningOnset with exercise or sexual activity (may be benign or serious)

Medication Overuse Headache

Medication overuse headache (MOH) is an under-recognized condition that may occur in migraine or tension-type headachesufferers. Recognition and treatment of MOH may lead to long-term improvement in headache relief and quality of life for manypatients. Frequent use of analgesics on ≥15 days per month for ≥3 months can lead to MOH (headache present on ≥15 days permonth) or chronic daily headaches in migraine/tension-type headache sufferers. MOH occurs in association with analgesics such asacetaminophen, ASA or NSAIDs alone (much less likely to occur with NSAIDs) but is more common with combination productscontaining barbiturates, caffeine and/or opioids. In general, analgesics should be used <15 days per month for primary headachedisorders, such as migraine or tension-type headache, to prevent the development of MOH. Frequent use of ergotamine or triptanmedications (>10 days per month) can also result in MOH. Analgesic overuse headache tends to resemble tension-type headaches



medications (>10 days per month) can also result in MOH. Analgesic overuse headache tends to resemble tension-type headaches

(migraine headaches can also be superimposed) whereas triptan overuse manifests as increased frequency of migraine.19 , 20 ,

21 , 22 , 23 , 24

Treatment of MOH involves completely discontinuing the implicated drug(s), relieving withdrawal symptoms, treating recurrentheadaches with migraine-specific medications (adhering to limitations in frequency of use) and initiating prophylactic therapy (e.g.,tricyclic antidepressants, divalproex sodium, topiramate). Patients taking high doses of barbiturate-containing analgesics shouldnot abruptly discontinue them, since seizures may occur on withdrawal. Ideally, patients should be referred to aneurologist/headache specialist. Community pharmacists can play a key role in preventing and managing MOH by monitoring useof both prescription and nonprescription medications, counseling on appropriate use of antimigraine medications and providing

support to patients withdrawing from medications.19 , 20 , 21 , 22 , 23 , 24

Prevention

Migraine attacks and other headaches are often triggered by 1 or more factors (Table 3).

Table 3: Migraine Triggers13 , 16

Type of Triggera Examples

Foods and beverages that contain nitrites, monosodiumglutamate (MSG), aspartame or neurotransmitter precursors(e.g., tyramine, tyrosine, phenylalanine)

Aged cheeses, cured meats (e.g., hot dogs, bacon), chocolate,alcoholic beverages (especially red wine), caffeine-containingbeverages.Missed or delayed meals can also trigger migraine.

Environmental Weather changes (barometric pressure changes),bright/flickering lights, loud noise, strong odours (e.g.,perfume), cigarette smoke, travel across time zones.

Chemical Benzene, insecticides, perfumes or other strong odours.

Hormonal Menstruation, pregnancy (especially in first trimester),perimenopause.

Drugs See Table 2.

Other Sleep-wake cycle alterations, stress/anxiety (or let-down fromstress), intense activity/physical exertion, sexual activity.

a. Most common triggers are listed (not an exhaustive list).

Identification and avoidance of triggers in individuals are important in migraine prevention. Lifestyle changes such as maintainingregular sleeping and eating schedules, reducing stress and limiting caffeine intake (sudden decrease in consumption may lead tocaffeine withdrawal headache; caffeine may help alleviate headache in some migraine sufferers) may reduce the frequency of

headaches, particularly migraine.16 Drugs implicated in triggering headache or migraine (see Table 2) should be discontinued on atrial basis if feasible.

Triggers vary among individual patients. It is not necessary for patients to avoid all potential triggers. Migraine headaches may beprecipitated in some individuals by ingestion of foods containing nitrites, monosodium glutamate or aspartame, or foods containinga high content of neurotransmitter precursors (e.g., tyramine, tyrosine, phenylalanine). Maintaining a diary of food intake may

help identify migraine triggers ingested within 24 hours prior to an attack.16

Nonpharmacologic therapies such as relaxation therapy, biofeedback and cognitive-behavioural therapy may also be helpful in

preventing migraine headaches in some individuals.16 For drugs used in the prevention of migraine, see Pharmacologic Therapy.

Nonpharmacologic Therapy

Patient education is very important in the management of headache. Provide patients with an explanation of their headachedisorder. Reassure them (once the diagnosis has been confirmed by a physician in some cases) that they do not have a seriousunderlying cause for headaches (e.g., brain tumor). Use printed materials to reinforce verbal information. Establish realistic goalsand expectations of treatment; explain benefits and limitations of various treatment options in collaboration with the patient’s

physician. Patients may also benefit from referral to self-help groups.7 , 16 , 25

During a migraine attack, simple measures such as resting in a dark, quiet room and applying a cold cloth/ice pack to the headare helpful, although not evidence-based. Sleep often alleviates migraine headaches. There is evidence that some biobehaviouralmeasures such as biofeedback, relaxation therapy, cognitive-behavioural therapy and acupuncture may help prevent migraine insome individuals. Controversial measures include chiropractic and other physical therapies, transcutaneous electrical stimulation,

hypnosis, occipital or supraorbital nerve blockade and homeopathic remedies.16 , 25

Pharmacologic Therapy

Acute/Symptomatic

Nonprescription Therapy

Mild tension-type headache may not require treatment. Simple analgesics (e.g., ASA, acetaminophen) or NSAIDs (e.g.,

ibuprofen) will often alleviate tension-type headaches.2 , 7



ibuprofen) will often alleviate tension-type headaches.2 , 7

Mild to moderate migraine attacks may also respond to simple analgesics or NSAIDs (e.g., ibuprofen, naproxen sodium)administered in adequate doses. However, many migraine sufferers rely on nonprescription medications to the exclusion of

prescription medications, and do not achieve adequate pain relief.32 , 33 , 34 , 35 , 36 Most published trials of nonprescriptionagents in migraine have systematically excluded patients with more severe attacks. Patients who encounter significant disabilityduring 50% or more of their attacks and/or vomiting in more than 20% of attacks are poor candidates for exclusivenonprescription therapy, and should seek help from their physician. Patients who fail to obtain acceptable relief after an adequatetrial of a nonprescription agent should also be referred to their physician. Pharmacists are well positioned to identify patients who

may benefit from nonprescription therapy or who should be referred to a physician for appropriate therapy.26 Moderate to severeattacks of migraine often require the use of prescription medications.

See Table 4 for nonprescription analgesics.

Table 4: Nonprescription Analgesics for Acute Therapy of Tension-type and Migraine Headaches

For product selection, consult the tables in Products for Minor Ailments. Analgesic Products: Internal Analgesics

and Antipyretics.

Class Drug Dose AdverseEffects

DrugInteractions

Use inPregnancy Comments

SimpleAnalgesics

acetaminophen

Adult: 1000mg Q4H × 2doses PRN (doNOT exceed 4g/day)Pediatric:10–15mg/kg/doseQ4H × 2doses PRN

Potentialliver (andrarelykidney)dysfunctionwith chronicuse of highdoses orwith acuteoverdose.

Warfarin:increased riskof bleeding(more likelywith doses>1.3 g/day ×>1 wk but canoccur withshorter termuse).

Relatively safeduring alltrimesters;considered to beanalgesic of firstchoice duringpregnancy.26 , 27

Limit use to <15 days/monthto avoid medication-overuseheadache. Limited evidence forefficacy. Effective in childhoodmigraine.8 In adults, it is

considered to be less effectivethan ASA or NSAIDs.6

1 g dose shown to be effectivefor migraine, although patientswith severe migraine were

excluded.28

NSAIDs ASA Adult:975–1000 mgQ4H × 2doses PRNPediatric(≥12 y): 500–650 mg singledose

GI upset,ulceration orbleed.

Warfarin (↑bleeding risk).

Relatively safe inintermittent dosesduring first andsecond trimesters;avoid use in thirdtrimester (may beassociated withprolonged gestationand labour,prematurenarrowing of ductusarteriosus,persistentpulmonaryhypertension of thenewborn).29

Use <15 days/month to avoidmedication overuse headache.Good evidence for efficacy.Should not be used inpresence of viral illness orfever in children (due topossibility of Reye’ssyndrome). Avoid enteric-coated preparations as thisdelays onset. A meta-analysisof 3 trials concluded thateffervescent ASA 1000 mg wasas effective as sumatriptan 50mg for acute migraineattacks.30

NSAIDs ibuprofen Adult:200–400 mgQ6H × 2doses PRNPediatric: 5–10mg/kg/doseup to 4 timesdaily


Warfarin (↑bleeding risk).

Relatively safe inintermittent dosesduring first andsecond trimesters;avoid use in thirdtrimester (may beassociated withprolonged gestationand labour,prematurenarrowing of ductusarteriosus,persistentpulmonaryhypertension of thenewborn).29

Use <15 days/month to avoidanalgesic overuse headache.Good evidence for efficacy. Ameta-analysis concluded thatibuprofen at doses of 200 mgor 400 mg is effective inrendering patients pain-free at2 h; however, photophobia andphonophobia improved onlywith the 400 mg dose.31 Some

patients may require higher(prescription strength) doses.

NSAIDs naproxensodium

Adult:220 mg Q8-12H × 2 dosesPRN


Relatively safe inintermittent dosesduring first andsecond trimesters;avoid use in thirdtrimester (may beassociated withprolonged gestationand labour,prematurenarrowing of ductusarteriosus,persistent

Use <15 days/month to avoidmedication overuse headache.Good evidence for efficacy.Some patients may requirehigher (prescription strength)doses.



persistentpulmonaryhypertension of thenewborn).29

OpioidCombi-nations

codeine (8 mg withASA oracetaminophenplus caffeine)

Adult: 1–2tablets Q4HPRNPediatric(adolescentsonly): 1–2tablets up toQID

GI upset,ulceration orbleed. ASAandPotentialliver (andrarelykidney)dysfunctionwith chronicuse of highdoses orwith acuteoverdose.Codeine:sedation,constipation,dependence,tolerance.

Additivesedation withother CNSdepressants(e.g., alcohol);CYP 2D6inhibitors (e.g.,amiodarone,cimetidine,fluoxetine,moclobemide,paroxetine,quinidine) mayantagonizeanalgesic effectof codeine.

See also ASA andacetaminophen.Codeine has anincreased incidenceof congenitalanomalies includingcleft palate andinguinal hernias.

Use <10 days/month to avoidmedication overuse headache.Overuse of caffeine can lead towithdrawal headache.

Prescription Therapy

For more information on prescription therapy, see Therapeutic Choices, Neurologic Disorders: Headache in Adults and Therapeutic

Choices, Neurologic Disorders: Headache in Children.

There are many prescription medications available for the treatment of acute migraine attacks.6 , 7 , 37 Triptans or 5-HT1B/1Dreceptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan)

are considered to be the most efficacious agents for acute migraine treatment.37 They alleviate not only headache pain but alsoassociated migraine symptoms (nausea/vomiting, photophobia/phonophobia). The triptans are available in various deliverysystems: subcutaneous injection (sumatriptan), oral tablets (all), orally disintegrating tablets (rizatriptan, zolmitriptan) and

intranasal (sumatriptan, zolmitriptan).38 Dihydroergotamine (DHE) in nasal or injection form is also useful for migraine.6

Evidence suggests that oral ergot preparations (e.g., ergotamine tartrate) have limited efficacy and excessive side effects.6 , 39

In contrast, DHE has proven efficacy.6 , 40 Various parenteral agents are used for treatment of severe migraine in the emergencyroom; for example, DHE with an antiemetic, chlorpromazine, prochlorperazine, ketorolac, metoclopramide,

dexamethasone or opioids (not considered first-line therapy).6

It has been shown that an NSAID (e.g., naproxen sodium) combined with a triptan (e.g., sumatriptan) has better efficacy

compared to monotherapy with either agent, and reduces headache recurrence.41 , 42 In the U.S., a single-tablet formulation ofsumatriptan 85 mg and naproxen sodium 500 mg is available (not currently available in Canada).

Overuse of analgesics by migraine sufferers (3 or more days per week for several months), particularly combination productscontaining caffeine ± codeine ± barbiturates (e.g., butalbital), may lead to chronic headaches (see Medication OveruseHeadache).

Adjunctive drugs for the management of nausea/vomiting associated with migraine include dimenhydrinate and prescription

drugs such as domperidone, metoclopramide and prochlorperazine.6

The treatment of acute attacks of cluster headache requires the use of oxygen or prescription medications that have a rapid onsetof action (e.g., subcutaneous sumatriptan or DHE, intranasal zolmitriptan). Nonprescription medications are not effective for

cluster headache.5

Prophylactic Therapy

Consider prophylactic therapy for migraine in the following circumstances:6 , 7 , 56

Three or more severe attacks per month that fail to respond adequately to acute/symptomatic therapiesSevere attacks (any number) that significantly impair normal activity or patient’s quality of lifeOptimal acute therapies have failed, are contraindicated or have produced serious side effectsFrequent attacks resulting in potential overuse of acute therapies, which may lead to medication overuse headache

The goal of migraine prophylaxis is to reduce the frequency and severity of migraine attacks. In general, only 1 preventive agentis used at a time (in resistant cases, neurologists sometimes prescribe combinations). Medications should be started at a low doseand titrated upward to a maximally effective and tolerable dose. A trial period of 2–3 months is needed to assess the efficacy ofmost prophylactic medications. Prophylactic agents may be continued for several months (sometimes years) and then withdrawngradually to prevent rebound headaches. Selection of prophylactic therapy should take into consideration concurrent medicalconditions and/or contraindications (e.g., beta-blockers are contraindicated in patients with asthma). Patients should keep a diary

to monitor their response to therapy.6

Nonprescription Prophylactic Therapy

Feverfew (Tanacetum parthenium) is a popular herbal remedy that has been advocated for use in migraine prevention. Theactive constituent of feverfew is not presently known (parthenolide has been suggested as the active component). A systematic



active constituent of feverfew is not presently known (parthenolide has been suggested as the active component). A systematicreview evaluated the evidence for the clinical effectiveness of feverfew using data from 5 randomized, double-blind, placebo-controlled trials. Several methodologic problems, such as small sample size, were identified in the trials. Although feverfew wasfavoured over placebo in the majority of trials (most were of poor quality), it was concluded that the clinical effectiveness of

feverfew in the prevention of migraine has not been established beyond a reasonable doubt.44 A randomized, double-blind,multicentre trial (14 patients) of a special CO2 extract of feverfew failed to show a migraine prophylactic effect compared to

placebo.45 Another randomized, double-blind, placebo-controlled, multicentre trial (170 patients) showed that a CO2 extract of

feverfew in a dose of 6.25 mg 3 times daily significantly reduced migraine frequency compared to placebo, and showed a

favourable benefit-risk ratio.46 Evidence to date and clinical experience suggest that at best, feverfew has minimal effect onmigraine frequency. Adverse effects associated with feverfew are generally mild and reversible. Mouth ulceration and GIsymptoms have been reported most frequently. There are also anecdotal reports of contact dermatitis. A “post-feverfewsyndrome” (rebound of migraine symptoms, anxiety, insomnia, muscle and joint stiffness) has been reported by long-timeconsumers following abrupt discontinuation. Feverfew should be avoided in pregnancy as it may stimulate uterine contractions and

lead to miscarriage or premature labour.44 , 47

Butterbur (Petasites hybridus extract), in a dose of 75 mg twice daily, has been shown to be significantly more effective thanplacebo in a randomized, controlled three-arm trial (butterbur 50 mg twice daily or 75 mg twice daily or placebo) in 245 patientswith migraine (butterbur 50 mg twice daily was not significantly more effective than placebo). The proportion of patients with≥50% reduction in attack frequency after 4 months was 68% in the butterbur 75 mg arm versus 49% for the placebo arm.Butterbur was well tolerated; the most frequently reported adverse events included mild gastrointestinal events (primarilyburping). Patients should be cautioned against consuming any part of the Petasites plant other than specific products commercially

prepared, in which the plant carcinogens have been removed.48 A previous, smaller, single-centre study showed that butterbur

(50 mg twice daily) was more effective than placebo in reducing headache frequency in migraine patients.49

Coenzyme Q10 (300 mg/day) was found to be well tolerated and superior to placebo for migraine prophylaxis in a randomized,

controlled trial of 42 migraine patients.50 Further large-scale studies are needed to determine the efficacy of coenzyme Q10 inmigraine prophylaxis.

Magnesium deficiency has been suspected to play a role in the pathogenesis of migraine. Prophylactic oral magnesiumsupplementation has been shown to be effective in 2 double-blind studies, but ineffective in another in which lack of response may

have been due to poor absorption of magnesium from the preparation.51 , 52 , 53 In 1 of the studies demonstrating the efficacyof magnesium, patients received 600 mg (24 mmol) of magnesium daily in the form of trimagnesium dicitrate (not available in

Canada; an alternative may be magnesium citrate).51 More definitive, large-scale studies are needed to assess the role ofmagnesium in migraine prophylaxis.

Riboflavin (vitamin B2) was investigated for migraine prophylaxis in 1 randomized, double-blind, placebo-controlled trial in 55

migraine patients.54 Riboflavin was administered in a dose of 400 mg per day for 3 months. The proportion of patients who had atleast a 50% reduction in frequency of attacks was 50% for the riboflavin group versus 15% for the placebo group. The exactmechanism of action is not known but may be related to its effects on mitochondrial energy metabolism (mitochondrialdysfunction, resulting in impaired oxygen metabolism, may play a role in migraine pathogenesis). Only minor adverse effectswere reported in the riboflavin group (1 case of diarrhea and 1 case of polyuria). Riboflavin can also cause a yellow discoloration

of the urine (not clinically significant).54 A randomized, double-blind study evaluated the efficacy of riboflavin (200 mg daily)versus placebo in 48 children with migraine. The results suggested that riboflavin is not effective in preventing migraine in children

(high placebo response rate was seen).55 Further large-scale studies and comparative studies are needed to determine theefficacy of riboflavin in migraine prophylaxis.

See Table 5 for nonprescription products for prophylaxis of migraine headaches.

Table 5: Nonprescription Products for Prophylaxis of Migraine Headaches43

For product selection, consult the tables in Products for Minor Ailments. Herbal and Natural Health Products:

Single Entity Products; Vitamin Products: Single Entity Vitamins and Minerals

Class Drug Dose Adverse Effects Drug

Interactions Use in

Pregnancy Comments

NaturalHealth Products

feverfew Adult: 1–2 tabletsof standardizedfeverfew driedleaf powder 125mg per day,containing at least0.2% parthenolide(e.g., Tanacet)

Mouth ulceration (primarily ifchewing fresh leaves), GIsymptoms, nervousness,headache, insomnia,dizziness, joint stiffness,tiredness, palpitations, skinrash, weight gain, menstrualchanges; “post-feverfewsyndrome” following abruptdiscontinuation in long-termusers (e.g., headache,anxiety, insomnia, muscleand joint stiffness).

Nonedocumented;potentialinteraction withanticoagulants,antiplatelet drugs,thrombolytics(feverfew mayinhibit plateletaggregation);feverfew mayinhibit CYP 3A4,1A2, 2C19, 2C9(not reported inhumans to date).

Should beavoided.Maystimulateuterinecontractionsand causemiscarriageorprematurelabour.

Conflictingevidence forefficacy.44 , 45 ,

46 , 47 Lack of

long-term safetydata (studieslasted up to 4mo). Avoid use ifprevious contactdermatitis fromplants in theAsteraceaefamily, includingaster, chamomile,ragweed,chrysanthemum,sunflower, tansy,yarrow.


butterbur (Petasiteshybridusroot

Adult: 75 mg BIDPediatric: norecommendations;some evidence for

Generally well tolerated; mildgastrointestinal events(mainly burping).

No significantinteractions.

Insufficientdata.Preparationscontaining

Good evidence forefficacy inadults.48 , 49

Caution patients



rootextract);standardizedto contain aminimum of15%petasins(e.g.,

Petadolex –Weber &Weber,GmbH & Co,Germany)

some evidence forsafe use inchildren 6–17 yfor up to 4 mo

containinghepatotoxicalkaloidmight beteratogenicandhepatotoxic.

Caution patientsagainstconsuming anypart of Petasitesplant in any formother thancommerciallypreparedproducts, in whichplant carcinogensand hepatotoxicalkaloids havebeen removed.


coenzymeQ10

Adult: 300mg/day in 3divided dosesPediatric: norecommendations;some evidence ofefficacy in childrenwho have lowlevels ofcoenzyme Q10

Generally well tolerated; GIeffects (<1%; minimized bygiving in divided doses 2 or 3times daily).

May have additiveblood pressurelowering effectswhen used withantihypertensiveagents.May reduceanticoagulanteffects of warfarin(monitor patientsclosely).

May lower efficacyofchemotherapeuticagents (e.g.doxorubicin;preliminaryevidence).

Insufficientdata.

One small trialshowing efficacyin adults.50

May take up to 3mo for significantbenefit.

Minerals

magnesium Adult: 300 mg (elementalmagnesium) BID Pediatric: norecommendations;some evidence ofefficacy in children

Generally well tolerated;diarrhea, GI upset.

May decreaseabsorption ofbisphosphonates(e.g., alendronate,risedronate),tetracylines orquinoloneantibiotics (e.g.,ciprofloxacin,levofloxacin,moxifloxacin);separate doses byat least 2 h.

Consideredreasonablysafe.

Conflictingevidence forefficacy.51 , 52 ,

53

Some magnesiumsalts are poorlyabsorbed;suggest citratesalt.

Vitamins

riboflavin Adult: 400mg/dayPediatric:Insufficientevidence ofefficacy

Generally well tolerated;yellow discoloration of urine(benign).

No significantinteractions.

Safety ofhigh-dosetherapy notshown to besafe but notconsideredteratogenic.

One small trial inadults showingefficacy.54

Lack of efficacy inpediatric migraine

prophylaxis.55

Prescription Prophylactic Therapy

For more information prescription prophylactic therapy, see Therapeutic Choices, Neurologic Disorders: Headache in Adults and

Therapeutic Choices, Neurologic Disorders: Headache in Children.

Prescription medications used for migraine prophylaxis include beta-blockers without intrinsic sympathomimetic activity (e.g.,propranolol, nadolol, metoprolol), tricyclic antidepressants (e.g., amitriptyline, nortriptyline), calcium channel blockers (e.g.,flunarizine, verapamil), serotonin (5-HT2) receptor antagonists (e.g., pizotifen), valproic acid/divalproex sodium, topiramate and

NSAIDs (e.g., naproxen sodium 550 mg twice daily for 1 week per month for menstrual migraine prophylaxis).6 , 7 Clinical trials

are ongoing with several other promising agents such as gabapentin and botulinum toxin.7

For cluster headache, prophylactic medications (verapamil, lithium carbonate or valproic acid) are started at the onset of thecluster period, in conjunction with corticosteroids (e.g., prednisone 60–80 mg per day for 2–3 days, followed by 10 mg decrementsevery 2–3 days) or ergotamine derivatives (daily for 2–3 weeks, not used within 24 hours of a triptan). Preventive medications

are continued for the duration of the cluster period.5

Monitoring of Therapy

Acute Therapy



Ideally medications should relieve headaches (no pain or mild pain), as well as associated nausea/vomiting andphotophobia/phonophobia, within about 2 hours. Patients should report any significant adverse effects to their physician orpharmacist (see Table 4 for side effects and drug interactions of nonprescription medications).

Prophylactic Therapy

Migraine prophylactic medications should be tried for at least 2 months to determine efficacy. A “good” response is considered to

be a 50% reduction in the frequency of migraine attacks. Patients should record attacks in a migraine diary.4 Patients shouldreport any adverse effects to their physician or pharmacist (see Table 5 for side effects associated with nonprescriptionprophylactic medications).

Resource Tips

Canada: Headache Network Canada. Available from: www.headachenetwork.ca (bilingual—English and French).

Ontario: Help for Headaches. Available from: www.headache-help.org.

U.S.: American Committee for Headache Education, American Headache Society. Available from: www.achenet.org.

Suggested Readings

Goadsby PJ, Lipton RB, Ferrari MD. Migraine–current understanding and treatment. N Engl J Med 2002;346:257-70.

Purdy RA. Headache in adults. In: Repchinsky C, editor. Therapeutic choices. 6th ed. Ottawa: Canadian Pharmacists Association;2011. p. 199–216.

Smith TR, Stoneman J. Medication overuse headache from antimigraine therapy: clinical features, pathogenesis and management.Drugs 2004;64:2503-14.

Worthington I. Current migraine therapies: an overview. Pharm Pract 2004:1-7.

References

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3. Goadsby PJ, Lipton RB, Ferrari MD. Migraine–current understanding and treatment. N Engl J Med 2002;346:257-70.

4. Silberstein SD. Migraine. Lancet 2004;363:381-91.

5. Ekbom K, Hardebo JE. Cluster headache: aetiology, diagnosis and management. Drugs 2002:62:61-9.

6. Pryse-Phillips WE, Dodick DW, Edmeads JG et al. Guidelines for the diagnosis and management of migraine in clinical

practice. Canadian Headache Society. CMAJ 1997;156:1273-87.

7. Purdy RA. Headache in adults. In: Repchinsky C, editor. Therapeutic choices. 6th ed. Ottawa: Canadian Pharmacists

Association; 2011. p. 199–216.

8. Whiting S. Headache in children. In: Repchinsky C, editor. Therapeutic choices. 6th ed. Ottawa: Canadian Pharmacists

Association; 2011. p. 217-28.

9. Worthington I. Pediatric migraine. Pharm Prac 1999;15:48-57.

10. Dodick D. Headache as a symptom of ominous disease. What are the warning signals? Postgrad Med 1997;101:46-50, 55-6,

62-4.

11. Clinch CR. Evaluation of acute headaches in adults. Am Fam Physician 2001;63:685-92.

12. Campbell JK, Sakai F. Diagnosis and differential diagnosis. In: Olesen J, Tfelt-Hansen P, Welch KMA, editors. The headaches.

2nd ed. Philadelphia: Lippincott William & Wilkins; 2000. p. 359-63.

13. Worthington I. Current migraine therapies: an overview. Pharm Pract 2004:1-7.

14. Cady RK, Dodick DW, Levine HL et al. Sinus headache: a neurology, otolaryngology, allergy, and primary care consensus

on diagnosis and treatment. Mayo Clin Proc 2005;80:908-16.

15. Silberstein SD. Drug-induced headache. Neurol Clin 1998;16:107-23.

16. Pryse-Phillips WE, Dodick DW, Edmeads JG et al. Guidelines for the nonpharmacologic management of migraine in clinical

practice. Canadian Headache Society. CMAJ 1998;159:47-54.

17. Askmark H, Lundberg PO, Olsson S. Drug-related headache. Headache 1989;29:441-4.

18. Weston BC. Migraine headache associated with latanoprost. Arch Ophthalmol 2001;119:300-1.

19. Smith TR, Stoneman J. Medication overuse headache from antimigraine therapy: clinical features, pathogenesis and

management. Drugs 2004;64:2503-14.

20. Dowson AJ, Dodick DW, Limmroth V. Medication overuse headache in patients with primary headache disorders:

epidemiology, management and pathogenesis. CNS Drugs 2005;19:483-97.

21. Turner CJ, Pryse-Phillips W. Pilot study to improve health outcomes for medication-induced headache sufferers. Can J Clin

Pharmacol 1999;6:113-7.

22. Limmroth V, Katsarava Z. Medication overuse headache. Curr Opin Neurol 2004;17:301-6.

23. Dodick D. Freitag F. Evidence-based understanding of medication-overuse headache: clinical implications. Headache

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24. Grazzi L, Andrasik F. Medication-overuse headache: description, treatment, and relapse prevention. Curr Pain Headache Rep

2006;10:71-7.

25. Li Y, Liang F, Yang X et al. Acupuncture for treating acute attacks of migraine: a randomized controlled trial. Headache

2009;49:805-16.

26. Wenzel RG, Sarvis CA, Krause ML. Over-the-counter drugs for acute migraine attacks: literature review and

recommendations. Pharmacotherapy 2003;23:494-505.

27. Menon R, Bushnell CD. Headache and pregnancy. Neurologist 2008;14:108-19.

28. Lipton RB, Baggish JS, Stewart WF et al. Efficacy and safety of acetaminophen in the treatment of migraine: results of a

randomized, double-blind, placebo-controlled, population-based study. Arch Intern Med 2000;160:3486-92.

29. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed.

Baltimore: Lippincott Williams & Wilkins; 2008.

30. Lampl C, Voelker M, Diener HC. Efficacy and safety of 1,000 mg effervescent aspirin: individual patient data meta-analysis

of three trials in migraine headache and migraine accompanying symptoms. J Neurol 2007;254:705-12.

31. Suthisisang C, Poolsup N, Kittikulsuth W et al. Efficacy of low-dose ibuprofen in acute migraine treatment: systematic review

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32. Rapoport AM. Emerging nonspecific migraine therapies: targets and unmet needs. Headache 1999:39:S27-34.

33. Sheftell FD. Role and impact of over-the-counter medications in the management of headache. Neurol Clin 1997;15:187-98.

34. Lipton RB, Stewart WF, Goadsby PJ. Headache-related disability in the management of migraine. Neurology 2001;56:S1-3.

35. Edmeads J, Findlay H, Tugwell P et al. Impact of migraine and tension-type headache on life-style, consulting behaviour, and

medication use: a Canadian population survey. Can J Neurol Sci 1993;20:131-7.

36. Lipton RB, Stewart WF. Acute migraine therapy: do doctors understand what patients with migraine want from therapy?

Headache 1999;39:S20-266.

37. Gawel MJ, Worthington I, Maggisano A. A systematic review of the use of triptans in acute migraine. Can J Neurol Sci

2001;28:30-41.

38. Worthington I. Delivery systems for acute migraine medications. Can Fam Physician 2001;47:322-9.

39. Tfelt-Hansen P, Saxena PR, Dahlof C et al. Ergotamine in the acute treatment of migraine: a review and European

consensus. Brain 2000;123:9-18.

40. Saper JR, Silberstein S. Pharmacology of dihydroergotamine and evidence for efficacy and safety in migraine. Headache

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41. Brandes JL, Kudrow D, Stark SR et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA

2007;297:1443-54.

42. Smith TR, Sunshine A, Stark SR et al. Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache

2005;45:983-91.

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44. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia

1998;18:704-8.

45. Pfaffenrath V, Diener HC, Fischer M et al. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine

prophylaxis–a double-blind, multicentre, randomized, placebo-controlled dose-response study. Cephalalgia 2002;22:523-32.

46. Diener HC, Pfaffenrath V, Schnitker J et al. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine

prevention–a randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia 2005;25:1031-41.

47. Chavez ML, Chavez PI. Feverfew. Hosp Pharm 1999;34:436-61.

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51. Mauskop A, Altura BM. Magnesium for migraine: rationale for use and therapeutic potential. CNS Drugs 1998;9:185-90.

52. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-

centre, placebo-controlled and double-blind randomized study. Cephalalgia 1996;16:257-63.

53. Pfaffenrath V, Wessely P, Meyer C et al. Magnesium in the prophylaxis of migraine–a double-blind, placebo-controlled study.

Cephalalgia 1996;16:436-40.

54. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled

trial. Neurology 1998;50:466-70.

55. MacLennan SC, Wade FM, Forrest KM et al. High-dose riboflavin for migraine prophylaxis in children: a double-blind,

randomized, placebo-controlled trial. J Child Neurol 2008;23:1300-4.

56. Tflet-Hansen P, Welch KMA. General principles of pharmacological treatment of migraine. In: Olesen J, Tfelt-Hansen P,

Welch KMA, editors. The headaches. 2nd ed. Philadelphia: Lippincott William & Wilkins; 2000. p. 385-9.

Headache — What You Need to Know

Headache is very common. Some headaches go away after a short time, or with a nonprescription pain reliever. Other headaches(migraines) may be more severe and may need treatment prescribed by your doctor. Most headaches are not caused by serioushealth problems.

What should you do about headaches?



What should you do about headaches?

Tension-type headaches

The most common type of headache is called a “tension-type headache.” This kind of headache may be caused by manythings, not only tension. You may get this kind of headache if you have a cold or the flu.The pain is usually mild to moderate. It may be on both sides of the head or across the forehead. It often feels like there istightness or pressure in your head and sometimes in the shoulders and back of the neck.The pain usually goes away on its own. Nonprescription pain relievers such as ASA, acetaminophen, ibuprofen or naproxensodium might help. If you have this kind of headache often (more than 15 times in 1 month), see your doctor.

Migraine headaches

Migraine headaches are also fairly common. More women than men have migraine headaches. They also tend to run infamilies. Children can get migraines as well as adults.Migraine headaches usually occur on 1 side of the head. Some people, especially children, feel pain on both sides of the head.The pain is usually moderate to severe and throbbing. Physical activity tends to make the pain worse.A person may have other symptoms in addition to the pain. For example:

nausea or vomiting, or bothsensitivity to light and sounda visual sensation (called an aura) that sometimes occurs just before the headache (for example, flashes or bursts oflight, zig-zag lines, dark spots surrounded by light).

What triggers migraine headaches?

Many things can trigger a migraine headache. Triggers are different for each person. Keeping a diary about your headaches mayhelp you figure out what causes them. Some common triggers are:

Food (such as aged cheeses, cured meats, chocolate, red wine)Caffeine (from coffee, cola drinks, etc.—having too much or suddenly reducing the amount you normally have)Hormones (in women—at the time of your monthly menstrual period or during menopause)Chemicals (such as MSG in foods)Environment (changes in weather, bright lights, loud noises, strong odours, cigarette smoke)Other factors (such as anxiety/stress, too much or too little sleep, not eating regularly)

How can you treat a migraine?

Prevention

Avoid foods and other things that may trigger a migraine.Some people find that biofeedback, relaxation, acupuncture and cognitive-behavioural therapy help to prevent migraineheadaches.

Mild Migraine Headaches

Lying down in a dark, quiet room and applying a cold cloth or ice pack to the head may be helpful. Sleep will also help.Nonprescription pain relievers such as ASA, acetaminophen, ibuprofen or naproxen sodium might help.

It is important not to use pain relievers more than 15 days per month. If you use them more often, you may begin to getmore frequent or daily headaches from the medication (called “medication-overuse headache”).See your doctor if you have headaches every day or almost every day. The doctor may suggest that you stop taking painrelievers for a while. If your headaches are severe, the doctor will usually prescribe other medication.

Moderate or Severe Migraine Headache

See your doctor. You may need a prescription medication.You may need medication to treat nausea. A nonprescription medication is dimenhydrinate (Gravol). Your doctor may alsoprescribe other medication.Go to the emergency room if the migraine isn’t relieved by medication or you have severe vomiting.Your doctor may prescribe medication that you take daily to prevent migraines if you have them often, if they are severe, orif they last a long time.Some people have found that certain vitamins or herbal remedies help prevent migraines. Talk to a doctor or pharmacistbefore taking any preventive medication.

Other Headaches

There are many other less common types of headache. See your doctor to find out what is causing your headache. Many peoplewho think they have “sinus” headaches are actually suffering from migraine or another type of headache. Sinus headaches onlyoccur if a sinus infection is present.

Severe, New or Unusual Headaches

Some headaches may be the first sign of a more serious health problem. Go to the emergency room if:

You suddenly have a severe headache that is worse than any you have had before.You have symptoms such as fever, stiff neck, drowsiness, confusion, seizures or a general feeling of weakness, as well as aheadache.



headache.

See your doctor as soon as possible if:

You experience a new or unusual type of headache.There is a change in your usual headache pattern (for example, headaches happen more often or become severe).You start to have headaches in middle age or later (age 40 or over).

For more information on migraine headaches:

American Headache Society. Available from: www.achenet.org.

Headache Network Canada. Available from: www.headachenetwork.ca.

Minor Ailments. © Canadian Pharmacists Association, 2012. All rights reserved.

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