Migraine Prophylaxis with Salmon Calcitonin: a Cross-over Double-blind,Placebo-controlled Study

Carlo Gennari, M.D.,* M. Silvio Chierichetti, M.D.,** Stefano Gonnelli, M.D.,* Claudio Vibelli, B.sc.,** MarioMontagnani, M.D.* and Marco Piolini, M.D.**

*Institute of Medical Semeiotic, University of Siena, Siena, Italy.

**Medical Department, Sandoz Prodotti Farmaceutici S.p.A., Milano, Italy.

Reprint requests to: Prof. Carlo Gennari, Instituto di Semeiotica Medica, Universita' di Siena, 1-53100 Seina,Italy.

Accepted for Publication: June 10, 1985

SYNOPSIS

Ten women with histories of migraine attacks and with diagnosis of classic or common migraineconcluded a double-blind, placebo controlled, cross-over study to assess the effectiveness of syntheticsalmon calcitonin 100 MRC U. i.m. a day in preventing migraine attacks. After a two-month run-in phase thewomen were randomly allocated to one of the following two-month sequences: placebo-calcitonin orcalcitonin-placebo. The patients filled in every day a standard card with number, duration and severity ofattacks. The mean migraine frequency per month on calcitonin was 3.7±0.7 (s.e.m.) and on placebo 7.7±1.3(r<0.01). The ratio of total score of headache intensity to the number of days of observation on calcitoninwas 0.18±0.03 and on placebo was 0.30±0.04 (r<0.01). It is concluded that calcitonin is effective forprophylactic treatment of migraine and should be useful when other first-choice treatments arecontraindicated.

(Headache 26:13-16, 1986)

INTRODUCTION

The pathogenesis of migraine is not yet fully understood. There is evidence that cerebral blood flow is reduced inthe prodromal phase of migraine and increases during the headache phase.1-3

Many studies have been devoted to characterization of the triggering factors associated with vasospasm. Severalfactors have been claimed to trigger the initial decrease in cerebral blood flow, including noradrenaline,5-hydroxytryptamine, histamine and prostaglandins.4-6 Whatever the factors that trigger the vascular phenomena ofmigraine, the mechanism of vasocontriction and vasodilation of cerebral arteries are certainly implicated.

Recently, it has been stressed that calcium ion concentration in vascular smooth muscle is an important factor inpromoting vasoconstriction and that a decrease in intracellular calcium ion concentration is probably the mostimportant element in promoting vasodilation.7 Calcium influx is the main contributor to the increase in intracellularcalcium ion concentration that leads to contraction and serves as a trigger for the release of calcium fromsarcolemmal storage sites and from sarcoplasmic reticulum.8

Since contraction of vascular smooth muscle depends on transmembrane calcium flux, agents which counteractcalcium influx into vascular smooth muscle cell might be useful for preventing the initial spasm of cerebral arteriesand in fact, calcium-channel blockers have been found to be effective for prophylaxis of migraine.9-12

Calcitonin is a calcium-regulating hormone secreted in man by the C-cells of the thyroid gland. The best knownpharmacologic effect of calcitonin is to lower plasma calcium by inhibiting osteoclastic bone resorption. Thishormone has also been identified in many extrathyroidal sites in man and its widespread distribution has suggestedthat calcitonin has not only its classical endocrine effects but also local regulatory paracrine effects.13,14 It has beenhypothesized that calcitonin is a neurotransmitter and that its primary effect is inhibition of some cell functions.Target cells other than those in bone have not been systematically identified. There are some indications that theseextraskeletal effects of calcitonin may occur through modifying the flux of calcium across the membranes andwithin cell compartments.15

Some studies have promoted evidence that the primary action of calcitonin is to shift calcium outside the cellsbefore it produces the characteristic decrease in extracellular calcium.16,17

In addition, it has been clearly demonstrated that calcitonin increases calcium accumulation by the mitochondria ofseveral types of cells,18 thus decreasing cytosol calcium. Probably, calcitonin inhibits some cellular functions bylowering the calcium level in the cytosol. Thoracic and facial flush are frequent clinical observations duringcalcitonin treatment implying that the hormone produces peripheral vasodilation.19 Recently, it has beendemonstrated that calcitonin decreases basal and stimulated calcium influx in aortic tissue, thus decreasing thecytoplasmic calcium which is necessary for the contraction

of the vascular smooth muscle.20 One can therefore hypothesize that calcitonin may be effective in blockingthe migraine cascade, probably by preventing the initial cerebral vasospasm. We have conducted aplacebo-controlled, double-blind, cross-over trial to assess the effectiveness of calcitonin in preventingmigraine attacks.

PATIENTS AND METHODS

Twenty women with histories of at least two migraine attacks per month and with diagnoses of classic orcommon migraine, fulfilled the criteria of the "Ad Hoc Committee Classification of Headache".21 They enteredthe study after their informed consent was obtained, to be evaluated monthly for six consecutive months. Acareful physical, neurological and laboratory evaluation of the clinical picture of each patient was madebefore the study. Criteria for exclusion were severe hepatic, renal or cardiac dysfunction, pregnancy orlactation. The patients entered a two-month run-in period in which the number and the intensity of themigraine attacks were recorded. During this period they were allowed to take only symptomatic drugs(analgesics, ergot derivatives). At the end of the run-in period, the patients were randomly allocated to one ofthe following sequences of treatments: synthetic salmon calcitonin (sCT) - placebo (PL) or PL-sCT. Eachtreatment lasted two months, with a wash-out of five days between. One ampoule of sCT (100 I.U.) or PL,identical in appearance, was given i.m. every day.

No other prophylactic drugs were allowed during the study. Symptomatic drugs could be taken freely.Patients were asked to fill in every day a standard card with number, duration and severity of attacks and theamount of symptomatic drugs used. Headache severity was scored from I to 3,12 with 1 representing mildheadache episodes, without nausea, vomiting or interference with normal life and mild analgesicconsumption; 2 moderate unilateral headache with nausea; and 3 severe unilateral headache with vomitingand considerable interference with normal life.

The number of migraine attacks per month (migraine frequency) and the Headache Unit Index (HUI), i.e. thetotal score of headache severity divided by the total number of days observed,12 recorded in the twotreatment-phases, were analyzed statistically by a model for change-over design.22

The overall run-in and treatment values in each group were compared with the two-tailed paired t test.

RESULTS

Twenty women entered the study. Eight dropped out during the initial period, either because they did not fitthe selection criteria (2 patients with fewer than two migraine attacks per month) or did not cooperate (6patients). Ten patients, aged between 19 and 65 years (mean 37±5 s.e.m.), completed the study. Two morepatients were dropped, one during the initial PL and one during the initial sCT period, because they were notavailable for follow up.

The initial values for HUI and migraine frequency for the 5 patients who received sCT and PL in that orderwere similar to the initial values for the 5 patients who received them in the reverse order.

The slight decrease (3%) in migraine frequency at the end of the run-in period was not statistically significant(Fig. 1, left side). The migraine frequency

per month on PL was 7.7±1.3 (mean±s.e.m.) and on sCT 3.7±0.7 (between treatments: F=27.9; (r< 0.01). The average decrease duringsCT treatment was 54%.

No difference could be seen between those treated with sCT or PL first or second (between periods: F<I; NS), suggesting there were nocarry-over or rebound phenomena. Only one patient had about the same migraine frequency during PL and sCT periods. The meannumber of migraines during the first month was a little higher than during the second month on either sCT (4.1 vs 3.1) or PL (8.6 vs7.0).

The decrease (2%) in HUI during the run-in period was not statistically significant (Fig. 1 ). The mean HUI was 0.3±0.04 on PL and0.18±0.03 on sCT (between treatments: F=11.3; (r<0.01), with no difference according to which treatment was given first. The averagefall during sCT treatment was 43%, only one patient complained of worsening of symptoms during sCT treatment. The HUI measuredduring the first month did not differ statistically from the HUI of the second month in either group.

Except for mild and transient episodes of facial flushing and gastrointestinal disturbances, also observed in some cases during PL, therewere no major side effects during sCT treatment. No patients dropped out of the study because of adverse reactions.

DISCUSSION

The treatment of migraine is substantially based on symptomatic and preventive therapy.

Many medications have been and are very popular for symptomatic treatment of migraine, such as ergotamine tartrate, nonsteroidalanalgesics, alone or in combination, sympathicomimetic agents and meperidine. Meperidine, ergotamine and antiemetics are oftennecessary to control an acute attack.23 Steroid therapy may dramatically improve a prolonged attack that has not been aborted by thoseagents.24

Preventive therapy should be considered when: (1) the frequency of migraines exceeds the safety limits for symptomatics, (2) whenthere are medical contraindications to the use of symptomatic drugs, (3) when migraine attacks occur at regular intervals of time orunder the same set of circumstances. Various nonspecific medical and surgical procedures have been tried and recommended fordecreasing the frequency of attacks.

Methysergide is effective, but can cause retroperitoneal fibrosis and should not be used for periods longer than 3 months, with a restperiod in between;25 it is also contraindicated in pregnancy and in occlusive vascular disease.

Since some studies have suggested that there is a link between prostaglandins and migraine,26 drugs that inhibit prostaglandinsynthetase, such as indomethacin, have been employed in migraine.5 However, their use has been limited by their well-knownside-effects on the gastrointestinal tract. Propranolol or other beta-blockers have also been found to be effective27,28 but have somecontraindications (congestive heart failure, insulin-dependent diabetes, asthma) and may also have such side effects as depression,hypotension and exercise intolerance.

Antidepressants,29 cyproheptadine alone and in combination,30 and many other drugs from clonidine31 to monoamine oxidase inhibitors,32

serotonin precursors33 and platelet aggregation antagonists,34 have been tested or suggested for the prevention of migraine.

Calcium-channel blocking agents, such as flunarizine, nimodipine, nifedipine and verapamil, are effective in preventing migraine,9,12,35 buttheir clinical use is limited by their side-effects and by the long time needed for measurable therapeutic effects to occur,

The results of this double-blind, placebo-controlled, crossover study show that salmon calcitonin (100 I.U. given i.m. every day for twomonths) is highly effective for prophylactic treatment of migraine with the reservations that a small number of patients were studied andthat it must be given intramuscularly every day. On the other hand, salmon calcitonin has practically no contraindications.

The mechanism by which calcitonin prevents migraine attacks remains to be elucidated. Probably, it inhibits the vasospasm of cerebralarteries in the prodromic phase of migraine, by lowering the calcium level in the cytosol of the vascular smooth muscle cells. If ourresults can be confirmed by other studies, this drugs should be useful for those patients for whom other treatments are contraindicatedor potentially dangerous.

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