Specific Migraine-Preventive Agents

By | January 31, 2015

β-Adrenergic Blockers

β-blockers, the most widely used class of drugs in prophylactic migraine treatment, are approximately 50% effective in producing a greater than 50% reduction in attack frequency. Rabkin et al. serendipitously discovered propranolol’s effectiveness in headache treatment in patients who were being treated for angina.

The Agency for Healthcare Policy and Research (AHCPR) Technical Report and the U.S. Headache Consortium analyzed 74 controlled trials of β-blockers for migraine prevention. Evidence consistently showed propranolol to be effective for migraine prevention with a daily dose of 120 to 240 mg. No absolute correlation has been found between propranolol’s dose and its clinical efficacy. One meta-analysis revealed that, on average, propranolol yielded a 44% reduction in migraine activity compared with a 14% reduction with placebo. Overall, one out of six patients discontinued propranolol treatment.

Linde and Rossnagel in a Cochrane analysis included randomized and quasi-randomized clinical trials of at least four weeks’ duration, comparing the clinical effects of propranolol with placebo or another drug in adult migraineurs. A total of 58 trials with 5072 participants met the inclusion criteria. Overall, the 26 placebo-controlled trials showed clear short-term effects of propranolol over placebo. The 47 comparisons with calcium antagonists, other beta-blockers, and a variety of other drugs did not yield any clear-cut differences. Propranolol was more effective than placebo in the short-term interval treatment of migraine.

One trial comparing propranolol and amitriptyline suggested that propranolol is more efficacious in patients with migraine alone, and amitriptyline has a superior effect on patients with the phenotypes of migraine and tension-type headache. Four trials comparing metoprolol with placebo had mixed results. Metoprolol was similar to propranolol, flunarizine, and pizotifen. Timolol, atenolol, and nadolol are also likely to be beneficiai based on comparisons with placebo or with propranolol.

β-Blockers with intrinsic sympathomimetic activity (acebutolol, alprenolol, oxprenolol, and pindolol) are not effective for migraine prevention. The only factor that correlates with the efficacy of β-blockers is the absence of partial agonist activity.

Mechanism of Action

The mechanism of action of β-blockers is not certain, but it appears that their antimigraine effect is due to inhibition of β1-mediated mechanisms. β-Blockade inhibits norepinephrine (NE) release by blocking prejunctional β-receptors. In addition, it results in a delayed reduction in tyrosine hydroxylase activity, the rate-limiting step in NE synthesis, in the superior cervical ganglia. In the rat brainstem, a delayed reduction of the locus ceruleus neuron-firing rate has been demonstrated after propranolol administration. This could explain the delay in the prophylactic effect of the β-blocker.

The action of β-blockers is probably central and could be mediated by (i) inhibiting central β-receptors interfering with the vigilance-enhancing adrenergic pathway, (ii) interaction with 5-HT receptors (but not ail β-blockers bind to the 5-HT receptors), and (iii) cross-modulation of the serotonin System. Propranolol inhibits nitric oxide (NO) production by blocking inducible NO synthase. Propranolol also inhibits kainate-induced currents and is synergistic with TV-methyl D-aspartate blockers, which reduce neuronal activity and has membrane-stabilizing properties.

Schoenen et al. have shown that contingent negative variation (CNV), an event-related slow negative scalp potential, is significantly increased and its habituation reduced in patients with untreated migraine without aura. CNV normalizes after treatment with β-blockers, which is consistent with central adrenergic hyperactivity in migraine. Migraineurs who have elevated CNV scores have a much better response to β-blocker therapy (80% effective) than migraineurs who have a low or normal score (22% effective), suggesting that the CNV may predict the response to β-blocker treatment. Migraineurs exhibit an enhanced, centrally mediated secretion of epinephrine after exposure to light; this returns to normal after treatment with propranolol.

All β-blockers can produce behavioral adverse events (AEs), such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression, memory disturbance, and hallucinations, indicating that they ail affect the central nervous System (CNS). AEs most commonly reported in clinical trials with β-blockers were fatigue, depression, nausea, dizziness, and insomnia. These symptoms appear to be fairly well tolerated and were seldom the cause of premature withdrawal from trials. Common AEs include gastrointestinal complaints and decreased exercise tolerance. Less common are orthostatic hypotension, significant bradycardia, impotence, and aggravation of intrinsic muscle disease. Propranolol has been reported to have an adverse effect on the fetus. Congestive heart failure, asthma, and insulin-dependent diabetes are contraindications to the use of nonselective β-blockers. β-Blockers are not absolutely contraindicated in migraine with aura unless a clear stroke risk is present. Whether this includes prolonged aura is uncertain. The reported adverse reactions to propranolol may be either coincidental or idiosyncratic, but the actual risk is uncertain.

Some authors have commented on continued improvement and lack of rebound after discontinuing propranolol. Others have found no carry-over effects. However, it seems more reasonable to slowly taper β-blockers, because stopping them abruptly can cause increased headache and the withdrawal symptoms of tachycardia and tremulousness.

Clinical Use

Propranolol [approved by the Food and Drug Administration (FDA) for migraine] is a nonselective β-blocker with a half-life of four to six hours. It is also available in a long-acting formulation. The therapeutically effective dose ranges from 40 to 400 mg/day, with no correlation between propranolol and 4-hydroxypropranolol plasma levels and headache relief. The short-acting form can be given three to four times a day, although we recommend twice a day, and the long-acting form, once or twice a day. Propranolol should be started at a dose of 40 mg/day in divided doses and slowly increased to tolerance. An advantage of the regular propranolol is its greater dosing flexibility. The dose in children is 1 to 2mg/kg/day (Table β-Blockers and Antidepressants in the Preventive Treatment of Migraine).

Nadolol is a nonselective β-blocker with a long half-life. It is less lipid soluble than propranolol and has fewer CNS side effects. The dose ranges from 20 to 160 mg/day, given once daily or in split doses. Some authorities prefer it to propranolol because it has fewer side effects.

Table β-Blockers and Antidepressants in the Preventive Treatment of Migraine

Agent Daily dose (mg) Comment
Atenolol 50-200 Can be used q.d. / Less side effects than propranolol
Metoprolol 100-200 Short-acting form must be used b.i.d. / The long-acting form must be used q.d.
Nadolol 20-160 Can be used q.d. / Less side effects than propranolol
Propranolol 40-400 The short-acting form should be used b.i.d. or t.i.d. / The long-acting form can be used q.d. or b.i.d. / 1-2mg/kg in children
Timolol 20-60 The dose should be divided / Short half-life
Tertiary amines
Amitriptyline 10-400 Starting dose of 10 mg at bedtimebedtime
Doxepin 10-300 Starting dose of 10 mg at
Secondary amines
Nortriptyline 10-150 Starting dose of 10-25mg at bedtime / If insomnia present, must be given early in the morning
Protriptyline  5-60 Starting dose of 10-25mg at bedtime
Selective serotonin reuptake inhibitors
Fluoxetine tablets  10-80 Evidence in the treatment of migraine is controversial
Sertraline tablets  25-100 Some may worsen the migraine pattern
Paroxetine tablets  10-30 May be used as an adjuvant in the treatment of migraine and severe depression
Venlafaxine tablets  37.5-225
Mirtazapine tablets  15-45
Monoamine oxidase inhibitors
Phenelzine 30-90 Strict diet considerations

Timolol (approved by the FDA for migraine) is a nonselective β-blocker with a short half-life. The dose ranges from 20 to 60 mg/day in divided doses.

Atenolol is a selective β1-blocker with fewer side effects than propranolol. The dose ranges from 50 to 200 mg/day once daily.

Metoprolol is a selective β1-blocker with a short half-life. The dose ranges from 100 to 200 mg/day in divided doses. The long-acting preparation may be given once a day.

Specific Migraine-Preventive Agents: Antidepressants

Specific Migraine-Preventive Agents: Calcium-Channel Antagonists

Specific Migraine-Preventive Agents: Anticonvulsants

Specific Migraine-Preventive Agents: Serotonin Antagonists

Specific Migraine-Preventive Agents: Other Drugs