European Multicenter Trial of Nimodipine in the Prophylaxis of Common Migraine (Migraine Without Aura)

SYNOPSIS
This double blind, randomized study of the calcium antagonist Nimodipine 40 mg t.i.d. vs placebo in the prophylaxis of common migraine (migraine without aura) included 192 patients. Patients with 2–8 migraine days/4 weeks, age 18–60, who had no other types of recurring headaches except up to 6 interval headaches/4 weeks were included. The study was carried out at 11 European centers. After a 4 week run-in period, patients were randomly allocated to Nimodipine or placebo for 12 weeks (parallel groups). There were 19 drop-outs, 12 on Nimodipine and 7 on placebo, A gradual and marked improvement was seen both with Nimodipine and with placebo amounting to approximately 60% during the last 4 weeks. Statistical analysis on all included patients (intention to treat) revealed no difference between Nimodipine and placebo for migraine days (P = 0.69) or migraine index (p = 0.91). In patients "valid for analysis of efficacy" there were also no significant differences. Due to a very marked placebo effect and use of the parallel groups design, the present trial was not very powerful despite the large number of patients and a satisfactory compliance. We cannot rule out that Nimodipine might have up to 30% effect on a single main outcome parameter, but the uniform lack of response in all tested parameters makes this unlikely. Therefore Nimodipine probably has only a small or no effect in common migraine (migraine without aura).     

Nimodipine versus Flunarizine in Common Migraine: A Controlled Pilot Trial

SYNOPSIS
The effects of Nimodipine and Flunarizine, both calcium-antagonist drugs, in the prevention of common migraine were investigated in a double-blind randomized parallel study. Five patients of the 30 included in the study dropped out because of adverse reactions. Two were treated with Nimodipine and three with Flunarizine. Our results suggest a similar efficacy for both drugs, although Nimodipine seems to have a shorter latency of effect. Nimodipine is a useful new agent for common migraine prevention.     

A Placebo-Controlled Crossover Trial Using Trazodone in Pediatric Migraine

SYNOPSIS
An 8-month, double-blind, placebo-controlled cross-over trial was carried out on the use of trazodone in pediatric migraine prophylaxis. It involved 40 patients aged 7 to 18 years old and suffering from migraine without aura, randomly divided into 2 groups.
After a 4-week run-in period, Group A received oral trazodone (1 mg/kg a day divided into 3 doses) for 12 weeks, while Group B received a placebo. After a further 4-week washout period, Group A was given the placebo and Group B was treated with trazodone for a further 12 weeks. The trial was completed by 35 patients, the number of drop-outs being comparable in the two groups.
During the first treatment period, both the frequency and the duration of the migraine episodes were significantly reduced in both groups. During the second, a significant further improvement in both parameters was only observed in Group B. No side-effects were observed at any time. Our results showed that, like other antidepressants, trazodone is a valid prophylactic agent for juvenile migraine.     

Flunarizine Versus Metoprolol in Migraine Prophylaxis: A Double-Blind, Randomized Parallel Group Study of Efficacy and Tolerability

The prophylactic effect of flunarizine and metoprolol was studied in a multi-center randomized, double-blind trial of 149 patients with migraine with or without aura. After a 4-week placebo run-in period, patients were randomly allocated to treatment with flunarizine 10 mg daily or metoprolol 200 mg daily for 16 weeks (parallel group design). Both drugs reduced the number of migraine days per month by 37% (95% confidence interval 21-53%) compared with the placebo run-in period. All efficacy parameters were significantly reduced by both drugs and no significant difference was found between the two drugs at any time of the treatment period. However, calculation of the 95% confidence limits showed that each drug may have a superiority of more than 100% on a single main effect parameter. The most common adverse experiences were day-time sedation (both drugs) and weight gain (flunarizine). Depression was the most serious side-effect occurring in 8% on flunarizine and 3% on metoprolol. We conclude that both drugs are effective in the prevention of migraine attacks but a higher number of dropouts occurred on flunarizine because of depression or weight gain.     

Migraine variants

The term "migrant variant" is not used in the headache classification of the International Headache Society (IHS), but it includes those forms of migraine that are not typical of migraine with or without aura. Headaches that do not quite fulfill all of the IHS criteria are termed "migrainous disorder." Migraine associated with auras arising from unusual sites includes basilar migraine, retinal migraine, and ophthalmoplegic migraine. Two of the chromosomal sites for hemiplegic migraine have been identified. Migraine aura may occur without headache and an aura may be prolonged. Migrainous infarct has occurred when the aura lasts more than 1 week or imaging studies are positive and other etiologies have been ruled out. If the migraine attack is prolonged beyond 3 days the term "status migrainousus" is applied.     

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.     

Classic migraine: Effective prophylaxis with metoprolol

Metoprolol slow-release tablets (Durules®), 200 mg, given once daily in the morning were compared with placebo in the prophylaxis of classic migraine. The trial comprised eight Scandinavian neurologic centres and was designed as a double-blind cross-over study with 4 weeks' run-in, four weeks washout, and 8 weeks of either treatment. Seventy-seven patients with two to eight migraine attacks per month were entered in the trial, and 73 completed it. A total of 1119 attacks with aura symptoms and 374 without were recorded. Metoprolol was significantly better than placebo with regard to the total frequency of attacks (1.8 versus 2.5 attacks/4 weeks), mean duration of attacks (6.0 versus 8.0 h/attack), mean global rating, and consumption of analgesics per attack: Similar differences could be shown for attacks with aura symptoms alone, except for the duration of attacks. Metoprolol is the first drug for which a prophylactic effect in classic migraine has been convincingly demonstrated.     

Contingent Negative Variation in Migraine

The Contingent Negative Variation (CNV) is an event-related slow potential. It was recorded in healthy volunteers (n = 8) and in patients suffering from migraine without (n = 12) or with (n = 5) aura, during one (CNV1) and three second (CNV3) foreperiods in a forewarned reaction time task. CNV1 was recorded at the vertex while CNV3 was recorded at multiple electrode sites to assess topographical differences. Seven out of twelve migraine patients without aura had increased CNV1 amplitudes. CNV3 amplitudes were increased as well, but only at electrode positions C3 and C4 and not at Fz. CNV3, which allows for analysis of both an early and a late CNV component, could improve the discrimination of migraine without aura beyond that of CNV1. In migraine with aura all CNV parameters were at control levels, confirming previous results. The data obtained are discussed in terms of arousal, activation and stress and the "biobehavioral model of migraine" (Welch, 1986).     

Blood Pressure Changes in Migraine Patients before,during and after Migraine Attacks

Migraine attacks are characterized by headaches associated with neurological, gastrointestinal, and autonomic symptoms. A relationship between migraine and hypertension or hypotension is controversial. In this study, we aimed to determine if blood pressure changes were related to migraine attacks. From the outpatient clinic of our neurology department, 62 normotensive migraine patients with and without aura were chosen for study in accordance with the International Headache Society 2004 criteria. A questionnaire including general and specific questions was given to the patients to be filled out during 6 consequent migraine attacks. The patients received a fully automatic digital brachial upper arm sphygmomanometer (Omron M 4‐1) to measure the changes in their blood pressure during attacks. The patients were asked to record their blood pressure changes 3 times: (1) just before or very early, (2) during (when headache peaks), and (3) 1 hour after the attack. Twenty‐three of the 62 patients (57 women, 5 men) had migraine with aura (22 women and 1 man), and 39 of them did not have aura (35 women and 4 men). There was no statistically significant difference between systolic and diastolic values obtained before or very early, during the peak level, and 1 hour after the end of the attacks (P > 0.05). Although diastolic hypotensive values were not different statistically between groups, when all the patients were considered, diastolic hypotensive values were detected in a considerable number of patients (a total of 115 measurements). In this normotensive migrainous population, we observed that diastolic hypotension before or very early, during, and after migraine attack was the most significant result (5.1%). Although it was not statistically significant, the total number of hypotensive values was remarkable.     

Efficacy of nimodipine in the prophylaxis of migraine

The efficacy of nimodipine in the prophylaxis of migraine was assessed in a double-blind, placebo-controlled, cross-over study carried out on 33 patients, 20 of whom suffered from classic and 13 from common migraine. Four patients dropped out, but not as a result of the side effects of the drug. The duration of drug treatment was 8 weeks. The dosage used was 30 mg four times daily. Nimodipine proved to be better than placebo, the number of migraine attacks and severity of headache showing a significant reduction. The drug was well tolerated and no marked side effects were noted. The results suggest that nimodipine is a useful new prophylactic drug for migraine, but further studies are needed before its final value can be evaluated.     

Migraine Warnings

SYNOPSIS
The early prodromal phase of a migraine attack, poorly documented yet conceivably relevant to the pathogenesisof the attack, was studied in 149 patients, mainly female, with classic or common migraine who were aware ofthese prodromal phenomena. On a questionnaire a variety of prodromes, nearly all well reproduceable, werereported. Day-before and day-of-attack symptoms were noticed by 79% and 88% of the patients, respectively. Inthe other 12–21% signs were mainly observed by the partner. Some prodromes invoked the "cause orconsequence?" question as to certain trigger factors. Others bore rather striking similarities to the classic aura, sothat evolutive symptoms seemed to merge with the early part of the migraine attack. The incidence, or at least theawareness of prodromes was correlated with the occurrence of some factors aggravating the headache and withpost-attack symptoms, was higher in women, in patients with long-standing disease and frequent attacks, inpatients who had other types of headaches as well, and in classic migraine sufferers.     

Migraine with aura versus migraine without aura: pain intensity and associated symptom intensities after placebo

OBJECTIVE: To compare the intensity of pain and associated symptoms after placebo administration in patients with migraine with aura and migraine without aura. BACKGROUND: Studies that evaluate drugs used in the acute treatment of migraine ideally should include a placebo arm. The International Headache Society also recommends stratification according to age and sex but not by the presence versus absence of aura. METHODS: The study was conducted as part of a placebo controlled randomized survey comparing four active drugs against placebo in the acute treatment of migraine. Patients were blinded as to treatment received. Placebo consisted of 10 mL of normal saline (0.9%) intravenously. Pain intensity was evaluated by a 10-point analogical-verbal scale. Nausea, photophobia, and phonophobia were evaluated by a four-point analogical-verbal scale. For statistical analysis, unpaired t-test with Welch correction was used. RESULTS: After placebo administration, reduction of symptom intensity (pain, nausea, photophobia, and phonophobia) in patients with migraine without aura was significantly greater than that observed in patients with migraine with aura. CONCLUSIONS: Our findings suggest that studies comparing placebo against an active drug should use stratification according to the presence versus absence of aura.     

Prospective Analysis of Factors Related to Migraine Aura - The PAMINA Study

Objectives.- The aim of this study was to examine factors increasing and decreasing the risk of occurrence of migraine aura and of headache and migraine not associated with aura (HoA, MoA) prospectively by means of a daily diary. Methods.- Of 327 patients with migraine completing a comprehensive diary up to 90 days, we selected all patients who recorded at least 1 episode of migraine aura. To find risk indicators and triggers of aura, HoA, and MoA, we analyzed 56 variables and calculated univariate and multivariate generalized linear mixed models. Results.- Fifty-four patients recorded a total of 4562 patient days including 354 days with migraine aura. In the multivariate analysis, the risk of aura was statistically significantly increased by smoking, menstruation, and hunger, and it was decreased by holidays and days off. The risk of HoA and/or MoA was increased during menstruation, by psychic tension, tiredness, and odors, and it was decreased by smoking. Conclusion.- Menstruation is the most prominent factor increasing the risk of aura as well as that of HoA and MoA. Smoking shows the most striking difference increasing the risk of aura, but decreasing the risk of HoA and MoA.     

Chronic Naloxone Administration, a Potential Treatment for Migraine, Enhances Morphine-Induced Miosis

The degree and duration of miosis, induced by low doses of parenteral morphine (65 mcg/Kg i.m.) before and after ten days of naloxone treatment, were evaluated in eleven volunteers affected by migraine without aura. Morphine induced miosis was significantly more intense and persistent after chronic naloxone treatment than before the drug was administered. In another group of seven volunteers suffering from migraine without aura, no differences between morphine-induced miosis, prior to and after a ten-day treatment with placebo, were observed. In addition, a third group of fifty-four subjects, suffering from migraine without aura, underwent three-month naloxone treatment (150 mcg/Kg/i.m./day). All subjects included in the third group, were partially or totally refractory to conventional therapy. Pupillopharmacological results indicate that the benefit gained from chronic administration of the opiate antagonist may be related to some type of naloxone-induced supersensitivity of the opioid receptor population.     

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.     

Acephalgic Migraine

SYNOPSIS
Acephalgic migraine is a term used interchangeably with the term migraine equivalents. These terms by definition refer to any migrainous phenomena that may occur in the absence of a migraine headache.¹ Perhaps 20% of migraineurs may experience acephalgic attacks of migraine at one time or another. The idea that various symptoms can occur in the absence of any headache has been noted for hundreds of years, but very little has been written about this condition recently. Some people do not believe the symptoms that are often classified as migraine equivalents are in actuality part of the migraine syndrome. Because there is as yet no specific test for migraine, there is no proof that these various symptoms are due to the same neurovascular dysfunction we know as migraine. The diagnosis of migraine is based only on the patient's history and the exclusion of other diagnoses. It is not unusual for a headache patient to see several headache "specialists" and be given different diagnoses.
Some prefer the term "migraine accompaniments" for neurological or visual symptoms occurring with or without a headache.² The aura of the classic migraine attack may linger into the painful phase and thus "accompany" rather than just precede the headache. At times, symptoms typical of the aura may occur and may not be followed by a headache (acephalgic migraine). The term "complicated migraine"should probably be reserved for those neural and/or visual symptoms that outlast the headache by at least 24 hours and should not be used when referring to symptoms of shorter duration which may accompany the headache or which occur in the absence of migraine headache. Although non-visual migraine equivalents are not nearly as common as visual symptoms, it is important to recognize the fact that migraine may account for almost any recurrent, transient, episodic organ dysfunction.     

Clonazepam (Rivotril) in Migraine Prophylaxis

SYNOPSIS
A double-blind cross-over study with clonazepam (Rivotril) 0.5 mg b.i.d. versus placebo was carried out in 38 migraine patients. After a pre–test period of 4 weeks, Rivotril 1 mg per day and placebo were given during a 4 week period each, in a randomized fashion; thereafter Rivotril 2 mg per day was given for 4 weeks in a semi-blind fashion.
With regard to headache days, the results for both I and 2 mg Rivotril differed significantly (p<0.05) from the pre–test status, whereas with regard to the headache index, only the result for 2 mg differed significantly from pre-test results. When the placebo results (and not the pre–test results) were used, no significant difference was found with either 1 or 2 mg Rivotril.
More than half the patients complained of some drowsiness on Rivotril medication, particularly in the initial phase. Eighteen patients continued with Rivotril medication on a long–term basis in an open trial with some beneficial effect and less side–effects.     

Beta-blockers and migraine. Efficacy of time-release propranolol versus placebo

The efficacy and safety of long-acting propranolol (LA.P) 160 mg once-daily in the prophylactic treatment of migraine were tested against placebo in a multicentric, double-blind, randomized study comparing the two groups in a parallel manner over a treatment period of 12 weeks, and following a 4 week-placebo run-in period. Fifty-five out of the 74 patients who entered the trial included at the end of the run-in period. Forty-one patients completed the study. Out of the 14 patients who withdrew from the study, none discontinued because of side-effects. The statistical analysis was done according to the "intention to treat" principle. LA.P was significantly more efficient than placebo in reducing the frequency of migraine attacks (p = 0.01 by variance analysis). LA.P reduced the average number of monthly crises by 48% on day 84. There was a slight but significant reduction of the systolic blood pressure and heart rate in the erect position. There was no significant difference between LA.P and placebo regarding either the number of complaints or the number of side-effects elicited out of an 17 item questionnaire. None of the observed side effects led to a withdrawal of treatment.     

Clonidine Prophylaxis of Childhood Migraine and Other Vascular Headache

SYNOPSISFifty-seven children, ages 0–15 years, with migraine or other vascular headaches were treated with clonidine (28) and placebo (29). A double-blind technique without crossover was used for two months. The mean daily dose was 1.2 mgkg body weight during the first month, and 2.1 mgkg during the second month. Mean total follow-up period was 7.9 months. Headaches were completely abolished during treatment in one-third of patients in both placebo and clonidine groups. Fifty-seven percent of children on clonidine and 42 percent of those on placebo were greatly improved. This difference is not statistically significant. Cases with visual aura or positive family history for migraine or both, responded statistically better to clonidine than to placebo. Improved response was noted with increased dose of clonidine. Two patients had side effects which interfered with daily activities and one discontinued treatment because of nausea and vomiting.     

Magnesium in the prophylaxis of migraine-a double-blind, placebo-controlled study

The migraine prophylactic effect of 10 mmol magnesium twice-daily has been evaluated in a multicentre, prospective, randomized, double-blind, placebo-controlled study. Patients with two to six migraine attacks per month without aura, and history of migraine of at least 2 years, were included. A 4-week baseline period without medication was followed by 12 weeks of treatment with magnesium or placebo. The primary efficacy end-point was a reduction of at least 50% in intensity or duration of migraine attacks in hours at the end of the 12 weeks of treatment compared to baseline. With a calculated total sample size of 150 patients, an interim analysis was planned after completing treatment of at least 60 patients, which in fact was performed with 69 patients (64F, 5M), aged 18–64 years. Of these, 35 had received magnesium and 34 placebo. The number of responders was 1 in each group (28.6% under magnesium and 29.4% under placebo). As determined in the study protocol, this was a major reason to discontinue the trial. With regard to the number of migraine days or migraine attacks there was no benefit with magnesium compared to placebo. There were no centre-specific differences, and the final assessments of treatment efficacy by the doctor and patient were largely equivocal. With respect to tolerability and safety, 45.7% of patients in the magnesium group reported primarily mild adverse' events like soft stool and diarrhoea in contrast to 23.5% in the placebo group.