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 »  Introduction
 »  Material and methods
 »  Results
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Year : 2000  |  Volume : 48  |  Issue : 3  |  Page : 223-6

A double blind controlled study of propranolol and cyproheptadine in migraine prophylaxis.

Departments of Neurosurgery, Clinical Pharmacology and Neurology, Guntur Medical College, Guntur, Andhra Pradesh, 522001, India.

Correspondence Address:
Departments of Neurosurgery, Clinical Pharmacology and Neurology, Guntur Medical College, Guntur, Andhra Pradesh, 522001, India.

  »  Abstract

Role of propranolol and cyproheptadine in the prophylaxis of migraine was studied in a controlled double blind trial. Two hundred fifty-nine patients were divided into four groups. Each group was either given a placebo, cyproheptadine, propranolol or a combination of the latter two drugs. The patients were followed for a period of three months. Significant relief in frequency, duration and severity from migranous attacks was seen in all drug treated groups over placebo. Significant correlation in response was seen in frequency, duration and severity in all the groups which received drugs. Statistically more significant relief was seen in cyproheptadine and propranolol treated group as compared to individual drug treated groups. In cyproheptadine and propranolol treated groups, the dropout rate was lower and associated symptoms were better relieved than in other groups. The study shows efficacy of combination of cyproheptadine and propranolol in migraine prophylaxis.

How to cite this article:
Rao B S, Das D G, Taraknath V R, Sarma Y. A double blind controlled study of propranolol and cyproheptadine in migraine prophylaxis. Neurol India 2000;48:223

How to cite this URL:
Rao B S, Das D G, Taraknath V R, Sarma Y. A double blind controlled study of propranolol and cyproheptadine in migraine prophylaxis. Neurol India [serial online] 2000 [cited 2021 Jul 28];48:223. Available from:

   »   Introduction Top

Migraine, as defined by the research group on headache of the World Federation of Neurology, is a familial disorder characterised by recurrent attacks of headache, widely variable in intensity, frequency and duration. Attacks are usually unilateral and are associated with anorexia, nausea and vomiting. In some cases these are preceded by, or associated with, neurological and mood disturbances. A variety of drugs have been in vogue to prevent attacks of migraine. The basic principle in management of migraine is avoiding the trigger factors, blocking the mediator and splinting the end organ. Serotonin being the main mediator and undue pulsatile vasodilation being the effect on the end organ, the present study is evolved to try cyproheptadine and beta blocker propranolol, to block the serotonin and splint the blood vessels. Earlier studies have shown the efficacy of these drugs.[1],[2] A controlled double blind study was carried out using a placebo, cyproheptadine, propranolol, and a combination of the latter two.

   »   Material and methods Top

Two hundred fifty-nine patients who attended the outpatient departments of neurology and neurosurgery were selected. The clinical examination and reasonable investigations to rule out any other cause for the headache were done. The patients who were getting two or more attacks per week were chosen for the study. These patients were explained the nature of the illness, the type of treatment, purpose of this study, and possible side effects. An informed written consent was taken and the project was cleared by the college ethical committee. The patients were divided into four groups. The first group received placebo, the second received cyproheptadine, 2 mg twice a day, the third received propranolol, 40 mg twice a day and the fourth received a combination of cyproheptadine 2 mg twice a day and propranolol 40 mg twice a day. The patients were allotted to these groups by the third investigator following the latin square design. All the patients had gone through an initial placebo phase for one week before taking the allotted drug. The drugs were administered in similar looking capsules and the patients and the clinicians were not aware of the drugs given to them. To overcome the problem of identification of different groups, all were given similar looking capsules. The patients were examined by the fourth investigator of the team independently for a period of 3 months. A record of the various details of the patients was maintained during follow up and the response to therapy was evaluated. Frequency, severity, and duration of attacks were assessed and given a score 0 to 4. The patients were explained to consider their maximum relief as '100'. In this connection, significant care was taken to explain to the patients how to assess their headache and arrive at the score. They were asked to mention the improvement in frequency, duration and severity as 100% (for total relief), 75%, 50%, 25% and 0% (no change). The score given by the patient was recorded as 4 to 0 for purpose of statistical evaluation.
Statistical significance was calculated using computerized Bartletts 'ANOVA' method.
Follow up : All the patients who took part in the clinical study were advised to discontinue the medication at the end of the study period of three months and were followed for a period of 1 year and assessed by a questionnaire at the end of one year. The patients were asked to note the incidence of relapse and use propranolol and cyproheptadine whenever a relapse occurs for a period of 2-3 weeks or till a remission is obtained.

   »   Results Top

Two hundred fifty nine patients, (174 women and 85 men) aged 16-53 years (mean 28.6 years) were recruited for the study. Two hundred four patients, (134 women and 70 men) aged 17-53 years (mean 29.7 years) completed the study. Fifty five patients dropped out of the study. Ten patients left during initial placebo phase and forty-five left during drug treatment in various groups. The number of patients in each group and dropouts during drug treatment are shown groupwise in table I.
At the end of 3 months' follow up, reduction in migraine frequency was statistically significant in all treated groups, more so in the group treated with combination of cyproheptadine and propranolol. Duration and severity were also decreased significantly in all the treated groups in comparison with placebo group, however, it was more in the group treated with both cyproheptadine and propranolol [Table II]. There was significant improvement in frequency, duration and severity between cyproheptadine and propranolol groups and between propranolol and cyproheptadine plus propranolol groups. However, there was no significance between cyproheptadine and cyproheptadine plus propranolol groups. Significant correlation was seen between decrease in frequency, duration and severity of migranous attacks in all treated groups. There were no major side effects. However, twenty five patients in all the groups suffered from minor side effects. They are distributed as follows: one patient in the placebo group, [eight] in cyproheptadine, eleven in propranolol and five in cyproheptadine and propranolol group. The common side effects experienced by the patients include drowsiness, sleep disturbance, weight gain, fatigue and dryness of mouth.
60% of the patients responded to the questionnaire sent at the end of one year. The shortest period of remission was 5 months. The relapse was seen in 15% of the patients on follow up and they responded well to the drugs advised.

   »   Discussion Top

Migraine is regarded as a hereditary paroxysmal vasoregulative instability and is characterised by episodes of intracerebral arterial constriction and extracerebral arterial dilation which occur sequentially and also concurrently. The mechanisms by which these phenomena occur remain enigmatic.
Vasomotor regulation resides within the central nervous system mediated by serotonergic natural circuits.[3] An important mechanism of this disorder could be central and peripheral modulation of synaptic serotonin.[4] Migraine is considered not only as a CNS disorder but also a systemic metabolic disorder, in which release of platelet serotonin appears to be most specific.[5] As yet no permanent cure is available for this ailment.
The drugs that have proven effective in aborting individual attacks or preventing them have been used on an empirical basis or for actions that subsequently have been shown to be unrelated to the benefits observed clinically. Various drugs used are the extracranial vasoconstrictors like ergotamine, dihydroergotamine and caffeine; serotonin antagonists like methysergide and cyproheptadine; beta adrenergic blockers like propranolol, nodolol[6] and atenolol,[7] tricyclic antidepressants like amitriptyline, monoamine oxidase inhibitor, phenelzine and vasodilator papavarine besides several other drugs like anxiolytics, prostaglandin inhibitors, stemetil, clonidine and calcium channel blockers.[8] These drugs, though having different mechanisms, depress the firing rate of serotonergic neurons within the brain stem. Propranolol appears to be a potent inhibitor of the uptake of serotonin by human platelets both invivo and in-vitro.[9],[10] The platelets may be applicable
as a model for the presynaptic nerve terminal owing to similarities in the manner in which both tissues transport, store and metabolize serotonin.[11] Sumatriptan is a new 5-HT agonist which can be administered orally or subcutaneously.[12],[13] The efficacy and tolerability of sumatriptan as nasal sprays at 10 mg and 20 mg dosage is also quite effective in the acute treatment of migraine. The more recent hypothesis is that migraine is essentially a disease of the brain characterized by a wave of excitation of neurons starting in the occiput and proceeding slowly rostrally.[14]
In the absence of identifiable and avoidable trigger factors, blocking the action of humoral mediators and splinting the vessels are the next available measures. Cyproheptadine, a serotonin and histamine antagonist and propranolol, a beta receptor blocking agent preventing vasodilation were hence chosen for this clinical study (in combination). Earlier, one of the authors (SR), in an open trial (unpublished data) found that cyproheptadine and beta blocker (propranolol) were very effective in migraine prophylaxis. They further observed that 90% of the patients with frequent attacks (almost daily or once in a few days) showed good response to this combination.
The present study revealed that combination of cyproheptadine and propranolol had definite advantage over individual drugs. Cyproheptadine alone (group II) had improved the frequency, duration and severity significantly (0.05) but dropouts (23.6%) and the (persons with) side effects were more than in the combination group (cyproheptadine and propranolol). Similarly propranolol treated group also had significantly (p=0.01 to 0.05) improved in frequency and duration but the dropouts and side effects were higher than in the combination group. The group treated with cyproheptadine and propranolol significantly improved in frequency, duration and severity. The improvement in this group was more significant (p=0.05) than that in the groups treated with inidividual drugs i.e. cyproheptadine and propranolol. This group also had less number of dropouts and the patients with side effects were less. The high dropout rate in placebo group could be because of lack of pharmacologic effect of drug. But even in placebo group, there was considerable improvement (more than 50%) in the associated symptoms. Migraine being a psychosomatic disorder and the associated symptoms being more of a psychogenic origin, this improvement in the placebo group is not unexpected. Besides the placebo group, the next higher dropout rate was seen in cyproheptadine treated group. This could be correlated with incidence of side effects which occurred in this group. In propranolol treated group, though the incidence of side effects was high, the dropout rate was lower than that of cyproheptadine group. The side effects noticed in those patients taking cyproheptadine and propranolol, singly or in combination, were their commonly known effects. No new side effects were experienced by the patients in this trial who had taken these drugs. To conclude, the combination of cyproheptadine and propranolol was effective in migraine prophylaxis, and these drugs were well tolerated when given in combination. The side effects were less when used in combination, than when they were used individually.


  »   References Top

1.TeltHansov P : Efficacy of beta blockers in migraine. A critical review. Cephalgia (Supplement)1986; 5 : 15-24.   Back to cited text no. 1    
2.Lance JW, Anthony M, Someville B : Comparative trial of serotonin antagonists in the management of migraine. BMJ 1970; 2 : 327-330.   Back to cited text no. 2    
3.Reinhard JF Jr, Liebermann JE, Schlosberg AJ et al : Serotonin neuron project to small blood vessels in the brain. Science 1974; 206 : 85-87.   Back to cited text no. 3    
4.Raskin NH, Appenzeller O : Major problems in internal medicine. Headache1980; 19 : 244.   Back to cited text no. 4    
5.Raskin NH : Pharmacology of migraine. Annu Rev Pharmacol Toxicol 1981; 21 : 463-478.   Back to cited text no. 5    
6.Sudilorsky A, Elkind AH, Lyan RE Sr et al : Comparative efficacy of nodolol and propranolol in the management of migraine. Headache 1987; 27 : 421-426.   Back to cited text no. 6    
7.Johannsson V, Nilsson LR, Widelius T et al : Atenolol in migraine prophylaxis : A double blind crossover multicentric study. Headache 1987; 27 : 372-374.   Back to cited text no. 7    
8.Herbert G, Markley MD, Cohn CD et al : Verpamil in prophylactic therapy of migraine. Neurology 1984; 34 : 973976.   Back to cited text no. 8    
9.Grobecker H, Lemmor B, Hellenbricht D et al : Inhibition by antiarrhythmic and beta sympatholytic drugs of serotonin uptake by human platelets : Experiments in vitro and in vivo. Eur J Clin Pharmacol 1973; 5 : 145-150.   Back to cited text no. 9    
10.Lingjaerdeo O : Platelet uptake and storage of serotonin. In : Serotonin in Health and Disease, Essman WB (Ed.) : Spectrum New York. 1977; 4 : 139-199.   Back to cited text no. 10    
11.Sneddon JM : Blood platelets as a model for monoamine containing neurons. Progressive Neurobiology 1973; 1 : 153-198.   Back to cited text no. 11    
12.Nappi G, Sicateri F, Bgrne M. et al : Oral sumatriptan compared with placebo in the acute treatment of migraine. J Neurol 1994; 241 : 138-144.   Back to cited text no. 12    
13.Agarwal R, Aga R, Prakash G : Headache. The National Medical Journal of India 1996; 9 : 127-129.   Back to cited text no. 13    
14.Hollister LE : Comparative efficacy of nodolol and propranolol in the management of migraine. In : Year Book of Drug Therapy, Lasagna L and Hollister LE (Ed) : Chicago Year Book Publishers, 1989: 21.   Back to cited text no. 14    


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