Propranolol in the Prophylaxis of Migraine

SYNOPSIS
This 34-week, placebo-controlled, single crossover study with a double-blind randomized treatment sequence evaluated the effects of propranolol as a prophylactic agent in individualized doses ranging from 60–320 mg/day given to 62 patients who had common and/or classic migraine. Variables reflecting efficacy were the frequency, severity, and persistency of acute migraine attacks expressed as Headache Unit Index (HUI) and the therapeutic medication required for acute attacks during the study expressed as the Relief Medication Unit Index (RMUI). Both HUI and RMUI were significantly reduced from baseline after the six weeks of propranolol titration (p<0.0001) reflecting fewer and/or less severe headaches. During the crossover treatment periods, propranolol, in comparison with placebo, was significantly more effective in the reduction of HUI (p<0.01) and RMUI (p<0.05). Data at the end of the dose finding (titration) period were analyzed separately for patients whose final prescribed doses were 60-240 mg or 320 mg/day propranolol. Significant reductions in HUI and RMUI (p< 0.0001) were shown at this time at each dose level. At all dose levels, propranolol was well tolerated. This was the first study in which the propranolol dose for migraine extended above the usual recommended 240 mg/day, i.e., up to 320 mg/day. This higher dose was administered if the drug had been well tolerated, even if only one headache in 2 weeks occurred at lower doses. The data suggest that there is an option to prescribe propranolol at higher doses as a preventive measure, thus reducing the need for ancillary medications.     

Nifedipine Versus Propranolol for the Initial Prophylaxis of Migraine

We conducted a randomized open-labeled study of nifedipine versus propranolol for the initial prophylaxis of migraine. Propranolol was effective in 67% of patients (12/18) and well tolerated. Nifedipine was effective in only 30% of patients (6/20). The lack of overall efficacy of nifedipine was attributable to a high incidence of side effects, including an unusual symptom complex resembling erythromelalgia. These side effects led 45% (9/20) of the nifedipine patients to withdraw from the study within two weeks. By contrast, no patient (0/18) withdrew from the study within the first 2 weeks of propranolol therapy. We conclude that nifedipine is not an agent of first choice for the prophylaxis of migraine.     

苯噻啶、心得安防治偏头痛的作用机制

目的:探讨苯噻啶、心得安防治偏头痛的作用机制。方法:SD大鼠50只随机分为对照组、生理盐水(NS)组、模型组、苯噻啶组和心得安组。模型组、苯噻啶组和心得安组复制大鼠偏头痛模型,第2次造模后苯噻啶组和心得安组分别给予药物干预,第5次造模后测定颈静脉血CGRP含量和脑干及三叉神经节α-CGRP mRNA的表达量,同时观察大鼠的行为学变化。结果:大鼠行为学观察显示,与模型组相比,苯噻啶组、心得安组对硝酸甘油的耐受性增强;各组间颈静脉血CGRP含量无显著性差异(P>0.05);③苯噻啶组、心得安组大鼠脑干及三叉神经节α-CGRP mRNA表达量明显低于其他组(P<0.05)。结论:苯噻啶、心得安预防偏头痛发作可能与抑制脑干及三叉神经节α-CGRP mRNA表达有关。     

Propranolol in the Prophylaxis of Migraine - Evaluation by Spectral Analysis of Beat-to-Beat Heart Rate Fluctuations

Migraine patients seem to suffer from a continuous autonomic imbalance. Sympathetic instability, expressed by enhanced low frequency fluctuations, which exists during the headache free intervals, was observed in our previous study by spectral analysis of heart rate (HR) fluctuations. Propranolol--a beta adrenoceptor antagonist, is widely used in migraine prophylaxis. In order to specify and quantitate propranolol efficacy in migraine, spectral analysis of heart rate fluctuations was performed on 10 migraine patients before and during the treatment with propranolol. They were compared to 10 healthy control patients and 6 migraine patients who were treated for several months with propranolol and then discontinued the medication. The analysis was carried out on a 24h Holter ECG recording, which was performed for each subject during a headache free interval. Short 256 sec subtraces, taken every 30 min from the 24h ECG signal, were submitted to A/D conversion, R wave detection and computation of heart rate power spectrum. Propranolol achieved a marked effect, when comparing the power spectra of HR fluctuations in treated versus untreated migraine patients. A strong reduction (to normal level) in the low frequency HR fluctuations in the range below 0.1 Hz., was apparent in patients treated with propranolol. Subjects who had received propranolol in the past and discontinued the drug, displayed a carry-over effect of reduced fluctuations even 2-3 months after its discontinuation. It seems that the propranolol efficacy in migraine is associated with the mechanism of stabilizing the fluctuations within the frequency band related to sympathetic activity, hereby moderating the vascular instability in migraine.     

Timolol in Migraine Prophylaxis

SYNOPSIS
The literature on the use of beta-blocking drugs in migraine suggests that not all such agents are effective. A double-blind crossover study of timolol in migraine prophylaxis was undertaken with fourteen patients, in order to assess the value of this drug in particular, and also to elucidate further the reason for the varied response to different beta-blockers. Timolol significantly reduced the frequency of migraine attacks, and was preferred to placebo. This supports the contention that beta-blocking drugs without intrinsic sympathomimetic activity are effective in migraine prophylaxis.     

Prophylaxis of Migraine in Children

SYNOPSIS
About 4 percent of school children suffer from migraine. To prevent attacks it is important to inform the child, the parents and the teachers about the nature of migraine, to prescribe a sound rhythm for the child and to try to remove the attack-provoking factors. It is not always necessary to use prophylactic therapy for migraine in childhood. However, if the attacks are severe and occur three or four times a month then the use of prophylactic drugs is worthwhile. In a pilot study cyproheptadine was given to 19 children aged 6 to 16 years with good effect. Pizotifen was also tried and gave the same good result. Thirty-two school children aged 7 to 16 years were admitted to a double-blind, single crossover propranolol vs. placebo study. The result was good, and side effects of these three drugs were benign.     

Long Acting Propranolol in the Prophylaxis of Migraine. Comparison of the Daily Doses of 80 mg and 160 mg

SYNOPSIS
The efficacy of long acting propranolol in a dosage of 80 mg once daily in comparison to 160 mg once daily was assessed in the prophylactic treatment of migraine in a double-blind cross-over trial. 48 patients with classic or common migraine were included in the investigation, 6 patients withdrew, but only one because of side-effects. A four week run-in placebo period preceded the drug treatments, the duration of drug treatments was 12 weeks and there was a wash-out placebo period of 4 weeks between the treatments.
The two long acting propranolol doses, 80 mg and 160 mg once daily seemed to be equally effective. There was no difference in the antimigraineous effect. Long acting propranolol decreased both the frequency and severity of migraine attacks. Side-effects reported during the trial were mild, both doses were well tolerated. The treatment compliance during the once daily treatment was very good.     

Nadolol and Propranolol in Migraine Management

SYNOPSIS
The prophylactic effects of nadolol once daily and propranolol b.i.d. were studied in 28 patients with common or classic migraine. Following screening procedures, the subjects entered a 28- to 120-day placebo period, which was followed by a 24-week randomized, double-blind treatment period. The prophylactic effects were evaluated by frequency of migraine attacks, consumption of acute migraine-relief tablets, duration of attacks, ratings of headache and nausea severity, and duration of incapacitation. Compared to placebo, both beta blockers brought about a highly significant (p < 0.01 ) reduction in attack frequency and consumption of acute migraine-relief tablets, while no significant changes were found with regard to the other variables. No significant differences were found between the two beta blockers. The results indicate that nadolol once daily is as effective as propranolol b.i.d. in migraine management and that the main effect of beta blockers in migraine is in preventing attacks from breaking out, while the capacity for reducing the intensity or duration of unsuppressed attacks is less prominent.     

Flunarizine and Propranolol in the Treatment of Migraine

The clinical efficacy of flunarizine and of propranolol for the prevention of migraine attacks was assessed in a multicenter double-blind study lasting four months which was preceded by a single-blind placebo period of one month. For both drugs, more than half of the patients judged the effect to be good or very good. When considering the patients' daily logs, both drugs produced a significant reduction of the number of attacks. Propranolol furthermore significantly reduced the severity of attacks and the number of analgesics used during the attacks. In both groups no severe side effects were observed.     

Fluoxetine Prophylaxis of Migraine

Many patients with severe migraine remain refractory to the current treatment regimens or cannot tolerate the side effects. Since current research implicates serotonin dysregulation in migraine pathogenesis, we investigated in a double blind, placebo controlled study the prophylactic effect of the serotonergic drug fluoxetine. Sixteen subjects were randomly assigned to 8 week fluoxetine treatment and 16 to the placebo group; nine subjects in each group completed the study. Migraine headache scores were obtained for two weeks prior to commencement of treatment, and then for each successive two week period. Zung depression scores were obtained before and after completion of the study. Fluoxetine caused significant reduction in headache scores starting with weeks 3-4 of treatment; there was no significant change with placebo. Depression scores did not differ between groups before treatment, and did not significantly change with either treatment. Fluoxetine appears to be a safe and effective drug for migraine prophylaxis, and deserves further therapeutic trials with larger groups for longer periods of time.     

Migraine Headache Prophylaxis in Adolescents

Migraine headache is estimated to affect up to 28 percent of adolescents, most of whom are female. Chronic migraine in this population has been associated with reduced quality of life and academic disruption due to missed school days. Historically, migraine headache was treated episodically as it occurred. In March 2014 the U.S. Food and Drug Administration approved an existing medication, topiramate (Topamax®), for migraine prophylaxis in adolescents between the ages of 12 and 17. This is the first FDA approval of a drug for migraine prevention in this population. There are several possible adverse effects of taking topiramate, some potentially serious, so adequate education for adolescents and their families on all the potential benefits and risks is imperative.     

Current Trends in Migraine Prophylaxis

A variety of drugs from diverse pharmacological classes are in use for migraine prevention. Traditionally, they have been discovered by serendipity. Examples include β-adrenergic blockers, anticonvulsants, tricyclic antidepressants, and serotonin receptor antagonists. The mechanisms of action of migraine preventive drugs are multiple but it is postulated that they converge on two targets: (1) inhibition of cortical excitation; (2) restoring nociceptive dysmodulation. The antiepileptic drugs (e.g., topiramate, valproate, gabapentin), calcium channel blockers such as verapamil, and inhibitors of cortical spreading depression are some examples of drugs that reduce neuronal hyperexcitability. On the other hand, modulators of the serotonergic and adrenergic systems and cholinergic enhancing drugs may restore descending nociceptive inhibition and play a role in migraine prevention. To date, Level 1 evidence and clinical experience favor the use of the antidepressant amitriptyline, the anticonvulsants divalproex and topiramate, and the β-adrenergic blockers propranolol, timolol and metoprolol as first line migraine preventive drugs. The evidence for others (e.g., verapamil) is not as strong. Migraine preventive drugs have varying degrees of adverse effects, some of which could be limiting, and their efficacy should balanced with their risks of adverse effects, patients' expectations and desires, and compliance. It is hoped that future migraine preventive drugs target migraine mechanisms more specifically, which could well enhance the therapeutic index.     

Somnambulism, Migraine and Propranolol

SYNOPSIS
150 migraine patients and 150 healthy subjects without headache were questioned about previous or current somnambulism. Previous or current somnambulism was found in 21.9% of the migraine group and in 6.6% of the control group; this difference is significant (p<0.001). Of the 25 migraine patients who had childhood or adult somnambulism, 16 had common migraine and 9 had classical migraine; classical migraine is over-represented in patients with somnambulism. Three patients treated with propranolol described aggravation of current somnambulism or re-appearance of previous somnambulism with the beginning of this drug treatment.     

Atenolol for Migraine Prophylaxis

SYNOPSIS
The preventive effect of atenolol on migraine attacks was compared to placebo in a double-blind cross-over study. 24 patients with classic and/or common migraine entered the 36-week study; four subsequently dropped out. The effect of atenolol was significantly better than that of placebo. The number of headache attacks was reduced in 15 of 20 patients (r<0.05) and the values for integrated headache diminished in 19 of 20 patients (r<0.001).
Intake of ergotamine products was significantly lower in all patients using such drugs, while the consumption of common analgesics did not differ between the trial periods. No serious side effects were noted.     

Long-term Study of Propranolol in the Treatment of Migraine

SYNOPSIS
Out of 245 patients admitted to a two-month single-blind phase in a study with propranolol vs. placebo, 148 (72%) were propranolol responders. These responders were randomly assigned to propranolol or placebo for the following double-blind phase. After four weeks, they opted to either (1) remain on the assigned drug for 6 to 12 months or (2) to switch to the other drug for 6 to 12 months. In either case, they then switched drugs for a final one or two months of the study.
No tolerance was found in 80 patients who remained on propranolol for at least six months.
Resurgence of migraine was analyzed in 75 patients who took propranolol for at least six months and crossed over to placebo. Thirty-five patients (46%) continued to show the improvement achieved during propranolol therapy when it was discontinued and only 8 patients (11%) had rebound headaches. No serious complications were noted.     

Considerations on the Use of Propranolol in Complicated Migraine

SYNOPSIS
An analogy is drawn between ergotamines and propranolol treatment of complicated migraine. A case report and supportive clinical and experimental data are presented to caution against the indiscriminate use of beta blocking agents in these patients.