Practice Guidelines

Guidelines on Migraine: Part 5. Recommendations for Specific Prophylactic Drugs



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Am Fam Physician. 2000 Dec 1;62(11):2535-2539.

The U.S. Headache Consortium guidelines for the treatment of migraine summarize data from clinical studies of various drugs used in preventive therapy of migraine. The analysis included alpha2 agonists, anticonvulsants, antidepressants, beta blockers, calcium channel antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), serotoninergic agents, hormonal agents, feverfew, magnesium and vitamin B2 (riboflavin). Members of the consortium graded the quality of the evidence for the use of a particular drug based on the findings from clinical trials. The bulk of the analysis was based on the technical review of the treatment of migraine by the Agency for Healthcare Research and Quality (AHRQ, formerly the Agency for Health Care Policy and Research). See the accompanying table on page 2536 for a comprehensive list of specific drugs and the strength of the evidence for their use in the prophylaxis of migraine.

Summary of the Evidence for Efficacy of Drugs Used in the Prevention of Migraine

Drug (dosages tested) Quality of evidence* Scientific effect Clinical impression of effect Adverse effects Comments

Alpha2 agonists

Clonidine (0.05 to 0.225 mg per day)

B

0

0

Occasional to frequent

CNS adverse events common; overwhelming evidence demonstrates no clinical benefit for prevention of migraine.

Guanfacine (0.5 to 1 mg per day)

B

+

Unknown

Infrequent (low dose)

Limited evidence indicating superiority of 1-mg dose over 0.5-mg dose. Limited value in patients with coexistent hypertension.

Anticonvulsants

Carbamazepine (600 mgper day)

B

++

0

Occasional to frequent

Most common adverse events include vertigo, giddiness and drowsiness. Not recommended based on limited evidence of efficacy. High incidence of adverse events and methodologic concerns.

Divalproex sodium (500 to 1,500 mg per day); sodium valproate (800 to 1,500 mg per day)

A

+++

+++

Occasional to frequent

Some adverse events more than occasionally occur, including nausea, asthenia and somnolence, when higher doses are used. Other side effects include weight gain, hair loss, tremor, neural tube defects and teratogenic potential. Recommended for patients with prolonged oratypical migraine aura. Not recommended for patients with liver disease. Safety and tolerability profiles specifically in migraineurs appear similar to those in patients with other disorders.

Gabapentin (900 to 2,400 mg per day)

B

++

++

Occasional to frequent

Limited available data (two trials reported as abstracts) indicate benefit at doses ranging from 900 to 2,400 mg.

Tiagabine and topiramate (doses not given)

C

Unknown

++

Occasional

Occasional CNS adverse events with both agents; kidney stones and weight loss with topiramate; sedation could occur at doses of topiramate required to achieve efficacy.

Antidepressants

Amitriptyline (25 to 150 mg per day)

A

+++

+++

Frequent

Drowsiness, weight gain and anticholinergic adverse events are common; long-term weight gain can be troublesome. Particularly useful in patients with migraine and tension headache and in patients with depression. Risk of drug interaction between cisapride and amitriptyline. May lower seizure threshold in patients with frequent seizures.

Nortriptyline (doses not given)

C

Unknown

+++

Frequent

Better tolerated than amitriptyline

Protriptyline (doses not given)

C

Unknown

++

Frequent

Nonsedating and not as frequently associated with weight gain as other tricyclic antidepressants

Doxepin, imipramine (doses not given)

C

Unknown

+

Frequent

See prescribing information for adverse events.

Fluoxetine (20 mg every other day to 40 mg per day)

B

+

+

Occasional

Insomnia, fatigue, tremor and stomach pain are the more common adverse events. Consider use in patients with coexistent depression. SSRIs rarely interact with serotonin receptor antagonists.

Fluvoxamine, paroxetine, sertraline (doses not given)

C

Unknown

+

Occasional

See prescribing information and text above.

Phenelzine (doses not given)

C

Unknown

+++

Frequent

Requires complex management with special dietary restrictions. High potential for drug–drug interactions. May be helpful in patients with coexistent depression or when antidepressants from other classes fail.

Bupropion, mirtazapine, trazodone, venlafaxine (doses not given)

C

Unknown

+

Occasional

May be used in patients with coexistent depression or trazodone, venlafaxine anxiety.

Beta blockers

Atenolol (100 mg per day)

B

++

++

Infrequent

Adverse events include tiredness, fatigue and dizziness.

Metoprolol (50 to 300 mg per day)

B

++

+++

Infrequent

May not be accepted by active patients such as athletes. Particularly helpful in patients with coexistent anxiety or panic attacks and essential tremors (propranolol). When propranolol is used in conjunction with rizatriptan, a lower dose of rizatriptan should be given. Should not be used in patients with coexistent asthma, cardiac insufficiency or Raynaud's disease. May exacerbate depression.

Nadolol (80 to 240 mg per day)

B

+

+++

Infrequent

As above

Propranolol (40 to 240 mg

A

++

+++

Infrequent

As above

per day)

Timolol (20 to 30 mg per day)

A

+++

++

Infrequent

As above

Calcium channel antagonists

Diltiazem (doses not given)

C

Unknown

0

Occasional

Tolerability similar to others in class.

Nimodipine (60 to 120 mg per day)

B

+

+

Occasional

Abdominal discomfort common. Cost may be prohibitive.

Verapamil (240 mg per day)

B

+

+

Occasional

Constipation common. Do not use if conduction block is present. Alternative to beta blockers in athletes. Recommended in patients with coexistent stroke or for prolonged or atypical migraine aura.

NSAIDs

Aspirin (325 mg every other day, 1,300 mg per day); fenoprofen (600 to 1,800 mg per day); flurbiprofen (200 mg per day); mefenamic acid (1,500 mg per day)

B

+

+

Infrequent

Common adverse events include abdominal discomfort, gastritis and occult GI bleeding. May be useful in patients with arthritis. Consider aspirin in patients with coexistent stroke.

Aspirin + dipyridamole (975 to 1,300 mg + 75 mg per day)

B

+

Unknown

Infrequent

As above

Ibuprofen (doses not given)

C

Unknown

+

Infrequent

As above

Ketoprofen (150 mg per day)

B

++

+

Infrequent

As above

Naproxen (500 mg per day); naproxen sodium (1,100 mg per day)

B

++

++

Infrequent

As above

Serotonin antagonists

Cyproheptadine (doses not given)

C

Unknown

+

Frequent

Used in pediatric migraine. Weight gain and fatigue are common adverse events.

Ergotamine + caffeine + butalbital + belladonna alkaloids (2 capsules per day for three days before, during and two days after menses)

B

++

++

Occasional

Cafergot compound twice daily during the perimenstrual period was shown to reduce headache frequency for migraine associated with menses. Limited information available regarding adverse events associated with treatment for menses-related migraine.

Methylergonovine (methylergometrine; doses not given)

C

Unknown

+

Frequent

May be used in hormonally influenced migraine.

Methysergide (2 to 10 mg per day based on body weight)

A

+++

+++

Frequent

GI adverse events common. Serious adverse events include retroperitoneal and retropleural fibrosis, which may be associated with uninterrupted use. Triptans and ergotamines should be used with caution.

Other agents

Estradiol (1.5 mg per day for 7 days, gel)

B

++

++

Infrequent

Short-term prevention of migraine associated with menses. Adequate dose required.

Feverfew (50 to ~82 mg per day)

B

++

+

Infrequent

Mild adverse events. Withdrawal of feverfew may be associated with increased frequency of headaches.

Magnesium (400 to 600 mg per day)

B

+

+

Infrequent

Use of nonchelated formulation is associated with significant diarrhea at clinically effective doses. May be useful in patients with PMS.

Vitamin B2 (400 mg per day)

B

+++

++

Infrequent

Rare adverse events; no known interaction with other drugs.


CNS = central nervous system; SSRIs = selective serotonin reuptake inhibitors; NSAIDs = nonsteroidal anti-inflammatory drugs; GI = gastrointestinal; PMS = premenstrual syndrome.

*—Quality of the evidence is classified as follows: Grade A signifies evidence from multiple well-designed randomized clinical trials, directly relevant to the recommendation, yielded a consistent pattern of findings. Grade B signifies some evidence from randomized clinical trials supported the recommendation, but the scientific support was not optimal. For instance, few randomized trials existed, the trials that did exist were somewhat inconsistent or the trials were not directly relevant to the recommendation. An example of the last point would be the case in which trials were conducted using a study group that differed from the target group for the recommendation. Grade C signifies that the U.S. Headache Consortium achieved consensus on the recommendation in the absence of relevant randomized controlled trials.

—Scientific effect is classified as follows: 0 = the drug is ineffective or harmful; + = the effect is either not statistically or not clinically significant (i.e., less than the minimal clinically significant benefit); ++ = the effect of the drug is statistically significant and exceeds the minimal clinically significant benefit; +++ = the effect is statistically significant and far exceeds the minimal clinically significant benefit.

—Clinical impression of effect is classified as follows: 0 = ineffective, most patients have no improvement; + = somewhat effective, few people have clinically significant improvement; ++ = effective, some people have clinically significant improvement; +++ = very effective, most people have clinically significant improvement.

Adapted with permission from Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM, et al. U.S. Headache Consortium. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. Copyright © by the American Academy of Neurology.

Summary of the Evidence for Efficacy of Drugs Used in the Prevention of Migraine

View Table

Summary of the Evidence for Efficacy of Drugs Used in the Prevention of Migraine

Drug (dosages tested) Quality of evidence* Scientific effect Clinical impression of effect Adverse effects Comments

Alpha2 agonists

Clonidine (0.05 to 0.225 mg per day)

B

0

0

Occasional to frequent

CNS adverse events common; overwhelming evidence demonstrates no clinical benefit for prevention of migraine.

Guanfacine (0.5 to 1 mg per day)

B

+

Unknown

Infrequent (low dose)

Limited evidence indicating superiority of 1-mg dose over 0.5-mg dose. Limited value in patients with coexistent hypertension.

Anticonvulsants

Carbamazepine (600 mgper day)

B

++

0

Occasional to frequent

Most common adverse events include vertigo, giddiness and drowsiness. Not recommended based on limited evidence of efficacy. High incidence of adverse events and methodologic concerns.

Divalproex sodium (500 to 1,500 mg per day); sodium valproate (800 to 1,500 mg per day)

A

+++

+++

Occasional to frequent

Some adverse events more than occasionally occur, including nausea, asthenia and somnolence, when higher doses are used. Other side effects include weight gain, hair loss, tremor, neural tube defects and teratogenic potential. Recommended for patients with prolonged oratypical migraine aura. Not recommended for patients with liver disease. Safety and tolerability profiles specifically in migraineurs appear similar to those in patients with other disorders.

Gabapentin (900 to 2,400 mg per day)

B

++

++

Occasional to frequent

Limited available data (two trials reported as abstracts) indicate benefit at doses ranging from 900 to 2,400 mg.

Tiagabine and topiramate (doses not given)

C

Unknown

++

Occasional

Occasional CNS adverse events with both agents; kidney stones and weight loss with topiramate; sedation could occur at doses of topiramate required to achieve efficacy.

Antidepressants

Amitriptyline (25 to 150 mg per day)

A

+++

+++

Frequent

Drowsiness, weight gain and anticholinergic adverse events are common; long-term weight gain can be troublesome. Particularly useful in patients with migraine and tension headache and in patients with depression. Risk of drug interaction between cisapride and amitriptyline. May lower seizure threshold in patients with frequent seizures.

Nortriptyline (doses not given)

C

Unknown

+++

Frequent

Better tolerated than amitriptyline

Protriptyline (doses not given)

C

Unknown

++

Frequent

Nonsedating and not as frequently associated with weight gain as other tricyclic antidepressants

Doxepin, imipramine (doses not given)

C

Unknown

+

Frequent

See prescribing information for adverse events.

Fluoxetine (20 mg every other day to 40 mg per day)

B

+

+

Occasional

Insomnia, fatigue, tremor and stomach pain are the more common adverse events. Consider use in patients with coexistent depression. SSRIs rarely interact with serotonin receptor antagonists.

Fluvoxamine, paroxetine, sertraline (doses not given)

C

Unknown

+

Occasional

See prescribing information and text above.

Phenelzine (doses not given)

C

Unknown

+++

Frequent

Requires complex management with special dietary restrictions. High potential for drug–drug interactions. May be helpful in patients with coexistent depression or when antidepressants from other classes fail.

Bupropion, mirtazapine, trazodone, venlafaxine (doses not given)

C

Unknown

+

Occasional

May be used in patients with coexistent depression or trazodone, venlafaxine anxiety.

Beta blockers

Atenolol (100 mg per day)

B

++

++

Infrequent

Adverse events include tiredness, fatigue and dizziness.

Metoprolol (50 to 300 mg per day)

B

++

+++

Infrequent

May not be accepted by active patients such as athletes. Particularly helpful in patients with coexistent anxiety or panic attacks and essential tremors (propranolol). When propranolol is used in conjunction with rizatriptan, a lower dose of rizatriptan should be given. Should not be used in patients with coexistent asthma, cardiac insufficiency or Raynaud's disease. May exacerbate depression.

Nadolol (80 to 240 mg per day)

B

+

+++

Infrequent

As above

Propranolol (40 to 240 mg

A

++

+++

Infrequent

As above

per day)

Timolol (20 to 30 mg per day)

A

+++

++

Infrequent

As above

Calcium channel antagonists

Diltiazem (doses not given)

C

Unknown

0

Occasional

Tolerability similar to others in class.

Nimodipine (60 to 120 mg per day)

B

+

+

Occasional

Abdominal discomfort common. Cost may be prohibitive.

Verapamil (240 mg per day)

B

+

+

Occasional

Constipation common. Do not use if conduction block is present. Alternative to beta blockers in athletes. Recommended in patients with coexistent stroke or for prolonged or atypical migraine aura.

NSAIDs

Aspirin (325 mg every other day, 1,300 mg per day); fenoprofen (600 to 1,800 mg per day); flurbiprofen (200 mg per day); mefenamic acid (1,500 mg per day)

B

+

+

Infrequent

Common adverse events include abdominal discomfort, gastritis and occult GI bleeding. May be useful in patients with arthritis. Consider aspirin in patients with coexistent stroke.

Aspirin + dipyridamole (975 to 1,300 mg + 75 mg per day)

B

+

Unknown

Infrequent

As above

Ibuprofen (doses not given)

C

Unknown

+

Infrequent

As above

Ketoprofen (150 mg per day)

B

++

+

Infrequent

As above

Naproxen (500 mg per day); naproxen sodium (1,100 mg per day)

B

++

++

Infrequent

As above

Serotonin antagonists

Cyproheptadine (doses not given)

C

Unknown

+

Frequent

Used in pediatric migraine. Weight gain and fatigue are common adverse events.

Ergotamine + caffeine + butalbital + belladonna alkaloids (2 capsules per day for three days before, during and two days after menses)

B

++

++

Occasional

Cafergot compound twice daily during the perimenstrual period was shown to reduce headache frequency for migraine associated with menses. Limited information available regarding adverse events associated with treatment for menses-related migraine.

Methylergonovine (methylergometrine; doses not given)

C

Unknown

+

Frequent

May be used in hormonally influenced migraine.

Methysergide (2 to 10 mg per day based on body weight)

A

+++

+++

Frequent

GI adverse events common. Serious adverse events include retroperitoneal and retropleural fibrosis, which may be associated with uninterrupted use. Triptans and ergotamines should be used with caution.

Other agents

Estradiol (1.5 mg per day for 7 days, gel)

B

++

++

Infrequent

Short-term prevention of migraine associated with menses. Adequate dose required.

Feverfew (50 to ~82 mg per day)

B

++

+

Infrequent

Mild adverse events. Withdrawal of feverfew may be associated with increased frequency of headaches.

Magnesium (400 to 600 mg per day)

B

+

+

Infrequent

Use of nonchelated formulation is associated with significant diarrhea at clinically effective doses. May be useful in patients with PMS.

Vitamin B2 (400 mg per day)

B

+++

++

Infrequent

Rare adverse events; no known interaction with other drugs.


CNS = central nervous system; SSRIs = selective serotonin reuptake inhibitors; NSAIDs = nonsteroidal anti-inflammatory drugs; GI = gastrointestinal; PMS = premenstrual syndrome.

*—Quality of the evidence is classified as follows: Grade A signifies evidence from multiple well-designed randomized clinical trials, directly relevant to the recommendation, yielded a consistent pattern of findings. Grade B signifies some evidence from randomized clinical trials supported the recommendation, but the scientific support was not optimal. For instance, few randomized trials existed, the trials that did exist were somewhat inconsistent or the trials were not directly relevant to the recommendation. An example of the last point would be the case in which trials were conducted using a study group that differed from the target group for the recommendation. Grade C signifies that the U.S. Headache Consortium achieved consensus on the recommendation in the absence of relevant randomized controlled trials.

—Scientific effect is classified as follows: 0 = the drug is ineffective or harmful; + = the effect is either not statistically or not clinically significant (i.e., less than the minimal clinically significant benefit); ++ = the effect of the drug is statistically significant and exceeds the minimal clinically significant benefit; +++ = the effect is statistically significant and far exceeds the minimal clinically significant benefit.

—Clinical impression of effect is classified as follows: 0 = ineffective, most patients have no improvement; + = somewhat effective, few people have clinically significant improvement; ++ = effective, some people have clinically significant improvement; +++ = very effective, most people have clinically significant improvement.

Adapted with permission from Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM, et al. U.S. Headache Consortium. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. Copyright © by the American Academy of Neurology.

Summary of Evidence for Specific Drugs for Prophylaxis

The following highlights the findings from clinical studies of specific agents:

  • Alpha2 agonists—Sixteen trials of clonidine and one trial of guanfacine were reviewed and suggested that alpha2 agonists are minimally and not conclusively efficacious. Three of 11 placebo-controlled trials of clonidine showed a significant difference between placebo and treatment arms, but the magnitude of the effect was small.

  • Anticonvulsants—Strong support of the efficacy of divalproex and valproate was found in five studies of these agents. The headache consortium found that the evidence was weaker in support of the use of other anticonvulsants, such as carbamazepine, clonazepam and gabapentin.

  • Antidepressants—Clinical studies indicate that amitriptyline is the only antidepressant that has shown fairly consistent efficacy in the prevention of migraine. This agent has also been evaluated more frequently than other antidepressants. One study revealed that fluoxetine was significantly better than placebo in the prevention of migraine, but another study failed to duplicate this finding. A randomized placebo-controlled study, reported in 1998, showed that fluoxetine may be beneficial in the prevention of migraine.

  • Beta blockers—The AHRQ report on drug therapies for the prevention of migraine included analysis of 74 controlled trials of beta blockers. Propranolol was investigated in 46 studies and metoprolol in 14 studies. The consortium found consistent evidence for the efficacy of propranolol, 120 to 240 mg daily, in the prevention of migraine attacks. Studies indicate that beta blockers with intrinsic sympathomimetic activity are ineffective for preventing migraine.

  • Calcium channel antagonists—The review included 45 controlled trials of calcium channel antagonists, including 11 trials of nimodipine, five trials of nifedipine, three trials of verapamil and one trial of nicardipine. Three placebo-controlled trials of nimodipine showed no significant difference between the active agent and placebo, but two trials showed large and statistically significant differences in favor of nimodipine. In two of three placebo-controlled trials of verapamil, significant differences were found with the calcium channel blocker, but the relevance of the findings is uncertain because of high dropout rates in the two studies. In a placebo-controlled trial that included a propranolol arm, no significant differences in the effects on headache frequency were noted between verapamil and propranolol.

  • NSAIDs—The AHRQ review included 23 controlled trials of 11 different NSAIDs. A meta-analysis of five placebo-controlled trials of naproxen or naproxen sodium suggests a modest but statistically significant effect on headache index or frequency. In several studies that compared NSAIDs with propranolol and metoprolol, no differences between these agents were found.

  • Serotoninergic agents—The review included 13 controlled trials of ergot derivatives. According to the U.S. Headache Consortium, the evidence is insufficient for the efficacy of ergotamine or the combination of ergotamine, caffeine, butalbital and belladonna alkaloids (Cafergot compound) in the prevention of migraine. The guidelines also state that the usefulness of methysergide is now limited because of its association with retroperitoneal and retropleural fibrosis.

  • Hormone therapy—The review included six controlled trials on the use of estrogens and/or progestogens for the prevention of migraine. Two placebo-controlled trials of estradiol, administered premenstrually as a gel or patch, suggest that a relatively high dosage (1.5 mg per day of the gel form) may be effective in women whose migraines are associated with their menstrual cycle. Evidence does not point to a benefit in patients whose migraines are not related to the menstrual cycle.

  • Feverfew—Three trials of feverfew suggest that this herbal remedy may have an effect on migraine. One trial of a group of patients who used feverfew showed that withdrawal of the herb was followed by a statistically significant increase in headache frequency. Another study of patients who had never used feverfew revealed a statistically significant difference between the feverfew group and the placebo group. In a double-blind, randomized, crossover trial, feverfew was found to be associated with a significant reduction in pain intensity and other symptoms such as nausea, vomiting, photophobia and phonophobia.

  • Vitamins and minerals—Two studies showed benefits of magnesium over placebo, whereas a third study failed to show any benefit. In one study of high-dose (400 mg) vitamin B2 (riboflavin), a significant benefit was noted three and four months after initiation of vitamin B2 supplementation.


This is the final part of a five-part series summarizing the U.S. Headache Consortium guidelines on migraine. The first part, on the use of diagnostic imaging in nonacute headache, appeared in the October 1 issue of American Family Physician. The second part, on the general principles of drug therapy, appeared in the October 15 issue. The third part, on recommendations for specific drugs for acute treatment, appeared in the November 1 issue. The fourth part, on general principles of preventive therapy, appeared in the November 15 issue.

Funding and support for the evidence-based migraine guidelines were provided by Abbott Laboratories, AstraZeneca, Bristol Myers Squibb, Glaxo Wellcome, Merck, Pfizer, Ortho-McNeil and the American Academy of Neurology Education and Research Foundation, along with the seven participant member organizations, which include the American Academy of Family Physicians, the American Academy of Neurology, the American Headache Society, the American College of Emergency Physicians, the American College of Physicians-American Society of Internal Medicine, the American Osteopathic Association and the National Headache Foundation.


Copyright © 2000 by the American Academy of Family Physicians.
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