The U.S. Headache Consortium Guidelines and the AHCPR Technical Review included 17 controlled trials of a2 agonists for the prevention of migraine: 16 of clonidine () and one of guanfacine. The evidence from these trials suggests that a2 agonists are minimally, and not conclusively, efficacious. Of the 11 placebo-controlled trials of clonidine, 3 found a significant difference in favor of the active agent, but the magnitude of the effect was small. Two comparative trials comparing clonidine with the β-blockers metoprolol and propranolol yielded mixed results. Two comparative trials showed no significant differences among clonidine, practolol, and pindolol. One trial each found no significant differences between clonidine and pizotifen, or between clonidine and carbamazepine.
Clonidine’s most commonly reported AEs were drowsiness and tiredness. In studies comparing clonidine with β-blockers, AEs occurred at similar rates for both interventions.
Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists
Schrader et al. conducted a double-blind, placebo-controlled, crossover study of lisinopril, an angiotensin-converting enzyme inhibitor, in migraine prophylaxis. The treatment period was 12 weeks, with one 10 mg lisinopril tablet once daily for one week, then two 10 mg lisinopril tablets once daily for 11 weeks, followed by a two-week washout period. The second treatment period consisted of one placebo tablet, once daily for one week, and then two placebo tablets for 11 weeks. Hours with headache, days with headache, days with migraine, and headache severity index were significantly reduced by 20% (95% confidence interval 5-36%), 17% (95% confidence interval 5-30%), 21% (95% confidence interval 9-34%), and 20% (95% confidence interval 3-37%), respectively, with lisinopril compared with placebo. Days with migraine were reduced by at least 50% in 14 participants for active treatment versus placebo and in 17 patients for active treatment versus run-in period. Days with migraine were fewer by at least 50% in 14 participants for active treatment versus placebo. Intention to treat analysis of data from 55 patients supported the differences in favor of lisinopril for the primary end points.
Tronvik et al. performed a randomized, double-blind, placebo-controlled crossover study of candesartan, an angiotensin II receptor blocker, in migraine prevention. Sixty patients aged 18 to 65 years with two to six migraine attacks per month were recruited. A placebo run-in period of four weeks was followed by two 12-week treatment periods separated by four weeks of placebo washout. Thirty patients were randomly assigned to receive one 16mg candesartan cilexetil tablet daily in the first treatment period, followed by one placebo tablet daily in the second period. The remaining 30 patients received placebo followed by candesartan. In a period of 12 weeks, the mean number of days with headache was 18.5 with placebo versus 13.6 with candesartan (p = 0.001) in the intention-to-treat analysis (n =W). The number of candesartan responders (reduction of 50% or greater com-pared with placebo) was 18 of 57 (31.6%) for days with headache and 23 of 57 (40.4%) for days with migraine. AEs were similar in the two periods. In this study, the angiotensin II receptor blocker candesartan was effective, with a tolerability profile comparable with that of placebo.
O’Neill and Mann and Masel et al. found that aspirin (ASA) (650 mg/day) decreased headache frequency. Two major multicenter trials, however, proved the efficacy of ASA in the prophylaxis of migraine. In 1988, “The British Physician Trial” showed that a daily dose of 500 mg ASA reduced the frequency of migraine by an average of 30%. In a double-blind trial of low-dose ASA (325 mg every other day) in 22,071 U.S. maie physicians (Physician Health Study), Buring et al. found a 20% reduction in headache frequency. Although this is statistically significant, it may not be clinically significant. In a small open trial, Baldratti et al. compared the efficacy of ASA (13.5mg/kg) with propranolol (1.8mg/kg). In this trial, both drugs were equally effective and reduced the frequency, duration, and intensity of attacks to the same extent. In a double-blind crossover trial, ASA (500 mg daily) was statistically less effective than 200 mg propranolol daily. High-dose ASA use may lead to overuse and the development of rebound headaches, although, in practice, ASA is usually implicated with other compounds in combination analgesies. ASA in low doses is indicated for the prophylaxis of myocardial infarction and transient ischemie attacks. We would use ASA only in patients who had prolonged or nonvisual aura.
Nonsteroidal Anti-inflammatory Drugs
Some NSAIDs may be effective in migraine prophylaxis. These include sodium naproxen, fenoprofen, ketoprofen, and tolfenamic acid. Some headache disorders (paroxysmal hemicrania and hemicrania continua) are defined by their responsiveness to indomethacin. Although NSAIDs are effective, they must be used with caution because of their gastrointestinal and renal function AEs.
Botulinum Toxin Type A (Botox®)
Silberstein et al. evaluated the safety and efficacy of pericranial botulinum toxin type A injections as prophylactic treatment of chronic moderate-to-severe migraine. One hundred twenty-three patients who had chronic International Headache Society (IHS)-defined migraine and a history of two to eight moderate-to-severe migraine attacks during a one-month baseline were randomized to treatment with either 0, 25, or 75 U of botulinum toxin type A injected symmetrically into glabellar, frontalis, and temporalis muscles. Diaries were kept for three months postinjection. At 12 centers, 41, 42, and 40 patients were randomized to 0, 25, and 75 U botulinum toxin type A treatment groups and had baseline frequencies of migraine of 4.41, 4.45, and 3.95 attacks per month, respectively. The 25 U botulinum toxin type A treatment group fared significantly better than the placebo group by the following measures: reduction in mean frequency of moderate-to-severe migraines during days 31 to 60, incidence of 50% reduction in mild-to-severe migraines at days 61 to 90, and improvement by patient global assessment for days 31 to 60 postinjection. The 75 U botulinum toxin type A treatment group was significantly better than the placebo group on patient global assessment for days 31 to 60, but not other parameters. Botulinum toxin type A treatment was well tolerated, but high-dose botulinum toxin type A showed significantly more treatment-related AEs than placebo. No serious treatment-related AEs were reported. Pericranial injection of botulinum toxin type A (25 U) showed significant differences compared with vehicle-induced type in reducing migraine frequency and associated symptoms during the 90 days following injection. Further studies are currently underway.
Substance P Antagonist (Lanepitant)
Goldstein et al. studied lanepitant, a potent nonpeptide neurokinin-1 receptor antagonist that inhibits neurogenic durai inflammation in migraine prevention. Patients with IHS migraine, with and without aura, were enrolled in a 12-week, double-blind, parallel-design study comparing the effect of 200 mg q.d. lanepitant (n = 42) and placebo (n = 42) on migraine frequency. The primary outcome measure was response rate, i.e., the proportion of patients with a 50% reduction in days of headache. The end point response rate for lanepitant-treated patients (41.0%) was not statistically significantly (p = 0.W) greater than that for placebo-treated patients (22.0%).
Leukotriene Receptor Antagonist (Montelukast)
A previous, small, open-label study of migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used to treat asthma. Brandes et al. evaluated the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Over the three months of treatment, there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (p = 0.304). Montelukast 20 mg was not an effective prophylactic for prevention of migraine.
Medicinal Herbs, Vitamins, and Minerais ()
According to a national survey, between 1990 and 1997, the use of herbal medicinal products by the generai U.S. population increased by a staggering 480%.
Feverfew (Tanacetum parthenium), a medicinal herb, has traditionally been used for fever, women’s ailments, inflammatory conditions, psoriasis, toothache, insect bites, rheumatism, asthma, and stomachache. During the last decades, it has also been used for migraine prophylaxis. Five trials were conducted; two that were reported in the AHCPR and three that were conducted after the report was published. One trial was conducted in a self-selected group of feverfew users and showed that withdrawing feverfew led to a statistically significant increase in headache frequency. A pilot study of 17 migraineurs who ate fresh feverfew leaves daily was undertaken at the City of London Migraine Clinic. Patients were given capsules of freeze-dried feverfew or placebo. Those receiving placebo had a tripling in the frequency of migraine attacks. Patients on placebo reported increased nervousness, tension headaches, insomnia, or joint stiffness constituting a “post-feverfew syndrome” (perhaps another example of rebound).
The other, more conventional, trial was conducted in a larger group of migraineurs, most of whom (71%) had never used feverfew. This trial reported a smaller difference between feverfew and the control treatment than did the other trial, but still found the difference to be statistically significant in favor of feverfew (p < 0.W). Three trials were not included in the AHCPR report. One was a double-blind, randomized crossover trial that tested the efficacy of feverfew compared with placebo, and reported that treatment with feverfew was associated with a significant reduction in pain intensity and nonheadache symptoms (nausea, vomiting, photo-phobia, and phonophobia). The other trial reported no significant differences between feverfew, given as an alcoholic extract, and placebo in reducing the migraine frequency. Pfaffenrath et al. found no difference between several doses of a new feverfew extract and placebo except in a small subset of patients with more than four migraine attacks a month. Thus, only three of five studies were positive. The better quality studies were negative. Feverfew may be effective in the prevention of migraine.
Pittler and Ernst conducted a new systematic review of the evidence from rigorous clinical trials of feverfew’s efficacy in migraine prevention, updating their older systematic review. The same five trials, quoted above, met the inclusion criteria. In total, 343 patients participated in the included studies. Three trials were crossover trials, whereas two used a parallel-group design. Two studies were withdrawal studies, and three were treatment studies. Three trials administered dried, powdered feverfew extract, one used an alcoholic feverfew extract, and another used a C02 extract.
While the two studies with the highest methodological quality showed no beneficiai events, three others were in favor of feverfew. Among the four trials with an acceptable sample size, two studies reported feverfew to be superior to placebo, while two did not. The frequency of migraine was reduced by feverfew in two trials, while two reported no such effect. Results from these trials were mixed and did not convincingly establish that feverfew is efficacious in preventing migraine. Only mild and transient AEs were reported in the included trials.
Feverfew’s AEs include mouth ulceration and a more widespread oral inflammation associated with loss of taste. Feverfew’s mechanism of action is uncertain. It is rich in sesquiterpene lactones, especially parthenolide, which may be a nonspecific NE, 5-HT, bradykinin, prostaglandin, and acetylcholine antagonist. The biologie variation in the sesquiterpene lactone content and the long-term safety and effectiveness of feverfew are of concern.
The sesquiterpene lactone parthenolide has been suggested as the main active component of feverfew. This hypothesis was supported by in vitro experiments that emphasized its biological activity. These studies have demonstrated that the plant has inhibitory effects on platelet aggregation and release of serotonin from blood platelets and leukocytes. One trial that used feverfew extract with a standardized and constant concentration of parthenolides to treat migraine did not show any beneficiai effect. Thus, the clinical effectiveness of feverfew for migraine prevention has not been established beyond reasonable doubt. More clinical trials are needed, both on a larger scale and with various feverfew extracts, including parthenolide-free sesquiterpene lactone chemotypes. At present, the identity of the principle active constituent(s) of feverfew remains unclear. It has recently been suggested that feverfew is a nuclear factor kappa B antagonist.
Petasites. Petasites hybridus root (butterbur) is a perennial shrub whose extracts have been used for therapeutic purposes in traditional medicine for centuries. Lipton et al. conducted a randomized, double-blind, placebo-controlled trial of Petasites’ efficacy in migraine prophylaxis. Two hundred forty-five eligible IHS migraine patients were randomized to one of three arms: petasites extract 50 mg b.i.d., petasites extract 75 mg b.i.d., or placebo b.i.d. Over the four months of treatment, migraine attack frequency was reduced by 26% for placebo, 48% for petasites extract 75 mg b.i.d. (p = 0.0012 vs. placebo), and 36% for petasites extract 50 mg b.i.d. (p = 0.127 vs. placebo). The most frequently reported AE was mild gastrointestinal events, predominantly burping. This study demonstrates that a standardized petasites extract, 75 mg b.i.d., is more effective than placebo and is well tolerated as a preventive therapy for migraine.
Diener et al. performed an independent reanalysis of a randomized, placebo-controlled, parallel-group study on the efficacy and tolerability of a special butterbur root extract (Petadolex®) for the prophylaxis of migraine. To follow regulatory requirements, an independent reanalysis of the original data was performed. Following a four-week baseline phase, 33 patients were randomized to treatment with two 25 mg capsules of butterbur twice a day and 27 to placebo. The mean monthly attack frequency decreased from 3.4 at baseline to 1.8 after three months (p = 0.W) in the active group and from 2.9 to 2.6 in the placebo group (n.s.). The responder rate (improvement of migraine frequency by more than 50%) was 45%o in the active group and 15% in the placebo group. Butterbur was well tolerated and may be effective in the prophylaxis of migraine.
Riboflavin. A mitochondrial dysfunction resulting in impaired oxygen metabolism may play a role in migraine pathogenesis. Riboflavin (vitamin BW) is the precursor of flavin mononucleotide and flavin adenine dinucleotide, which are required for the activity of flavoenzymes involved in the electron transport chain. Given to patients with MELAS or mitochondrial myopathies on the assumption that large doses might augment activity of mitochondrial complexes I and II, riboflavin improved clinical as well as biochemical parameters.
Based on the results of an open trial in migraine, a placebo-controlled, double-blind trial of high dose of vitamin B2 (400 mg) was performed and showed significant benefit. Schoenen et al. compared riboflavin (400 mg) with placebo in migraineurs in a randomized trial of three months’ duration. Riboflavin was significantly superior to placebo in reducing attack frequency (p = 0.005), headache days (p = 0.012), and migraine index (p = 0.012). The proportion of patients who improved by at least 50% in headache days, i.e., “responders,” was 15% for placebo and 59% for riboflavin (p = 0.002), and the number-needed-to-treat for effectiveness was 2.3. Only three AEs occurred: two in the riboflavin group (diarrhea and polyuria) and one in the placebo group (abdominal cramps). None was serious.
Coenzyme Q. Rozen et al. assessed the efficacy of coenzyme Q10 as a preventive treatment for migraine headaches in an open-label trial. Thirty-two patients with a history of episodic migraine, with or without aura, were treated with coenzyme Qi0 at a dose of 150 mg/day. Thirty-one of 32 patients completed the study; 61.3% of patients had a greater than 50% reduction in number of days with migraine headache. There were no side effects noted with coenzyme Q10. From this open-label investigation, coenzyme Qio appears to be a good migraine preventive. Sandor et al. performed a double-blind, placebo-controlled trial of coenzyme Q10 (100 mg TID) in 42 patients for three months. The 50%-responder rate was 47.6% for coenzyme Qi0 and 14.3% for placebo.
Magnesium supplementation was effective in one of two trials. One study enrolled 81 patients who had IHS migraine. Patients received 600 mg (24mmol) of oral magnesium (trimagnesium dicitrate) or placebo daily for 12 weeks. In the weeks 9 to 12, the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared with the baseline (p < 0.05). The number of days with migraine and symptomatic drug consumption also decreased significantly in the magnesium group. AEs were diarrhea (18.6%) and gastric irritation (4.7%).
In another multicenter, prospective, randomized, double-blind, placebo-controlled study, 20mmol magnesium-L-aspartate-hydrochloride trihydrate given in divided doses was evaluated. An interim analysis was performed with 69 patients (64 women, 5 men). Of these, 35 had received magnesium and 34, placebo. There were 10 responders in each group (28.6% magnesium and 29.4% placebo). There was no benent from magnesium compared with placebo in the number of migraine days or migraine attacks.
The studies differed in the amount of magnesium (24 mmol vs. 20 mmol) and in the sait (dicitrate vs. aspartate). Those differences may produce differences in bioavailability and efficacy and account for the reported difference.