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NIHR Signal Common migraine prevention treatments found to be equally effective

Published on 24 September 2015

doi: 10.3310/signal-000125

This review found that the main drugs used for preventing migraine were all effective compared with placebo or dummy treatment. The results were less clear cut when comparing drugs directly against each other as there were fewer trials. This review highlights the range of drugs used to prevent migraines, reflecting the number of possible treatments available. The review’s conclusions suggest that the prescriber could be guided by individual patient characteristics, including preferences, pre-existing conditions and potential side effects. This review confirms and strengthens NICE guidance in this area.

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Why was this study needed?

Migraines affect around 15% of people in the UK, they affect all ages, but twice as many women as men. Migraine attacks last anywhere between 4 and 72 hours and symptoms like headache, visual disturbances and nausea can stop people living their normal daily life. This costs the UK economy as much as £2 billion a year in lost work. The cause of migraines is not clearly understood, although some people can identify triggers such as certain foods or stress. There are drugs to prevent migraine and those to treat symptoms. This systematic review focused on prevention.

What did this study do?

This systematic review included 179 randomised controlled trials lasting at least four weeks. Trials either compared one preventative migraine drug against another, or compared a preventative drug with a placebo (dummy pill). The trials covered 11 types of drugs (see Box 1 for more information on the range of drugs used).

The review adhered to guideline standards for conducting high-quality systematic reviews. However, the review was limited by only 51 of the 179 trials comparing one drug against another. Most trials compared one migraine drug with a placebo. This allows an indirect comparison between drugs but, with small trials, means that it is less easy to be confident in any difference or lack of difference shown. For example, in an indirect comparison people with two headaches per month might be being compared to people with a baseline headache frequency of 12 headaches per month. This limits the reliability of the findings.

What did it find?

  • Across all migraine drugs trials, people receiving treatment were twice as likely to have a 50% reduction in headaches compared to people receiving placebo. There was little difference in the effectiveness of different drugs.
  • Amitriptyline (5 placebo controlled studies) was the most effective treatment when compared with placebo for lessening the occurrence of both episodic migraine (less than 15 attacks per month) and chronic migraine (more than 15). However, amitriptyline was no more effective when directly compared with topiramate or propranolol.
  • Topiramate (12 placebo controlled trials) was more effective than placebo for episodic migraine at all doses assessed, though there was some evidence that higher doses were more effective. Two studies showed it effectively prevented chronic migraine when assessed for up to 16 weeks.
  • Propranolol (19 placebo controlled trials) was shown to be effective for episodic migraines in pooled analysis of seven studies, but two studies did not find it effective for chronic migraine.
  • People receiving preventative treatment were more likely to experience side effects – such as nausea or dry mouth – than those receiving placebo. The side effects experienced were all known side effects of these drugs. This suggests that the choice of medication should be made on an individual basis, taking into account patient characteristics – such as existing conditions – and patient preference.

What does current guidance say on this issue?

2012 NICE guidance recommends using topiramate or propranolol to prevent migraines. If these drugs are unsuitable or ineffective people can be offered acupuncture or gabapentin. For people already receiving other preventative medication, such as amitriptyline, their treatment should be continued as long as their migraines remain well-controlled. Riboflavin (vitamin B, 400 mg once a day) can reduce migraine frequency and intensity for some people, and may be suitable for those not wanting to take medication. NICE recommends that preventative treatment is reviewed after six months and that treatment decisions consider the person’s preference, other illnesses and risk of adverse events. Transcranial magnetic stimulation and botox are specialist treatments that NICE say may be considered as preventative treatments in certain circumstances.

What are the implications?

The findings of this review are in line with NICE guidance on medication for preventing migraines. The review supports the effectiveness of several drugs, including amitriptyline, though there was variable availability and quality of evidence for the different treatments. Most comparisons were against placebo, rather than to another active drug. Direct comparisons between two drugs did not demonstrate that any drug was superior to another. This suggests that when choosing which drug to prescribe, patient characteristics and potential side effect should be the main guide.

The review found evidence of a placebo effect. People given placebo experienced fewer headaches in the first 4 to 12 weeks of treatment, although by 16 weeks headaches had returned to roughly the same frequency as before. The authors recommend that all future trials that directly compare treatments also include a placebo group, to account for this placebo effect.

Citation

Jackson JL, Cogbill E, Santana-Davila R, et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PloS one. 2015;10(7):e0130733.

Bibliography

Migraine Action. Key facts about migraine. Leicester: Migraine Action; 2015.

NHS Choices. Headaches and migraines. London: NHS Choices; updated 2014.

NHS Choices. Migraine – treatment. London: NHS Choices; updated 2014.

NICE. Headaches: Diagnosis and management of headaches in young people and adults. London: National Institute for Health and Care Excellence; 2012.

NICE. Transcranial magnetic stimulation for treating and preventing migraine. London: National Institute for Health and Care Excellence; 2014.

NICE. Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. London: National Institute for Health and Care Excellence; 2012.

Why was this study needed?

Migraines affect around 15% of people in the UK, they affect all ages, but twice as many women as men. Migraine attacks last anywhere between 4 and 72 hours and symptoms like headache, visual disturbances and nausea can stop people living their normal daily life. This costs the UK economy as much as £2 billion a year in lost work. The cause of migraines is not clearly understood, although some people can identify triggers such as certain foods or stress. There are drugs to prevent migraine and those to treat symptoms. This systematic review focused on prevention.

What did this study do?

This systematic review included 179 randomised controlled trials lasting at least four weeks. Trials either compared one preventative migraine drug against another, or compared a preventative drug with a placebo (dummy pill). The trials covered 11 types of drugs (see Box 1 for more information on the range of drugs used).

The review adhered to guideline standards for conducting high-quality systematic reviews. However, the review was limited by only 51 of the 179 trials comparing one drug against another. Most trials compared one migraine drug with a placebo. This allows an indirect comparison between drugs but, with small trials, means that it is less easy to be confident in any difference or lack of difference shown. For example, in an indirect comparison people with two headaches per month might be being compared to people with a baseline headache frequency of 12 headaches per month. This limits the reliability of the findings.

What did it find?

  • Across all migraine drugs trials, people receiving treatment were twice as likely to have a 50% reduction in headaches compared to people receiving placebo. There was little difference in the effectiveness of different drugs.
  • Amitriptyline (5 placebo controlled studies) was the most effective treatment when compared with placebo for lessening the occurrence of both episodic migraine (less than 15 attacks per month) and chronic migraine (more than 15). However, amitriptyline was no more effective when directly compared with topiramate or propranolol.
  • Topiramate (12 placebo controlled trials) was more effective than placebo for episodic migraine at all doses assessed, though there was some evidence that higher doses were more effective. Two studies showed it effectively prevented chronic migraine when assessed for up to 16 weeks.
  • Propranolol (19 placebo controlled trials) was shown to be effective for episodic migraines in pooled analysis of seven studies, but two studies did not find it effective for chronic migraine.
  • People receiving preventative treatment were more likely to experience side effects – such as nausea or dry mouth – than those receiving placebo. The side effects experienced were all known side effects of these drugs. This suggests that the choice of medication should be made on an individual basis, taking into account patient characteristics – such as existing conditions – and patient preference.

What does current guidance say on this issue?

2012 NICE guidance recommends using topiramate or propranolol to prevent migraines. If these drugs are unsuitable or ineffective people can be offered acupuncture or gabapentin. For people already receiving other preventative medication, such as amitriptyline, their treatment should be continued as long as their migraines remain well-controlled. Riboflavin (vitamin B, 400 mg once a day) can reduce migraine frequency and intensity for some people, and may be suitable for those not wanting to take medication. NICE recommends that preventative treatment is reviewed after six months and that treatment decisions consider the person’s preference, other illnesses and risk of adverse events. Transcranial magnetic stimulation and botox are specialist treatments that NICE say may be considered as preventative treatments in certain circumstances.

What are the implications?

The findings of this review are in line with NICE guidance on medication for preventing migraines. The review supports the effectiveness of several drugs, including amitriptyline, though there was variable availability and quality of evidence for the different treatments. Most comparisons were against placebo, rather than to another active drug. Direct comparisons between two drugs did not demonstrate that any drug was superior to another. This suggests that when choosing which drug to prescribe, patient characteristics and potential side effect should be the main guide.

The review found evidence of a placebo effect. People given placebo experienced fewer headaches in the first 4 to 12 weeks of treatment, although by 16 weeks headaches had returned to roughly the same frequency as before. The authors recommend that all future trials that directly compare treatments also include a placebo group, to account for this placebo effect.

Citation

Jackson JL, Cogbill E, Santana-Davila R, et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PloS one. 2015;10(7):e0130733.

Bibliography

Migraine Action. Key facts about migraine. Leicester: Migraine Action; 2015.

NHS Choices. Headaches and migraines. London: NHS Choices; updated 2014.

NHS Choices. Migraine – treatment. London: NHS Choices; updated 2014.

NICE. Headaches: Diagnosis and management of headaches in young people and adults. London: National Institute for Health and Care Excellence; 2012.

NICE. Transcranial magnetic stimulation for treating and preventing migraine. London: National Institute for Health and Care Excellence; 2014.

NICE. Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. London: National Institute for Health and Care Excellence; 2012.

A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache

Published on 15 July 2015

Jackson, J. L.,Cogbill, E.,Santana-Davila, R.,Eldredge, C.,Collier, W.,Gradall, A.,Sehgal, N.,Kuester, J.

PLoS One Volume 10 , 2015

OBJECTIVE: To compare the effectiveness and side effects of migraine prophylactic medications. DESIGN: We performed a network meta-analysis. Data were extracted independently in duplicate and quality was assessed using both the JADAD and Cochrane Risk of Bias instruments. Data were pooled and network meta-analysis performed using random effects models. DATA SOURCES: PUBMED, EMBASE, Cochrane Trial Registry, bibliography of retrieved articles through 18 May 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included randomized controlled trials of adults with migraine headaches of at least 4 weeks in duration. RESULTS: Placebo controlled trials included alpha blockers (n = 9), angiotensin converting enzyme inhibitors (n = 3), angiotensin receptor blockers (n = 3), anticonvulsants (n = 32), beta-blockers (n = 39), calcium channel blockers (n = 12), flunarizine (n = 7), serotonin reuptake inhibitors (n = 6), serotonin norepinephrine reuptake inhibitors (n = 1) serotonin agonists (n = 9) and tricyclic antidepressants (n = 11). In addition there were 53 trials comparing different drugs. Drugs with at least 3 trials that were more effective than placebo for episodic migraines included amitriptyline (SMD: -1.2, 95% CI: -1.7 to -0.82), -flunarizine (-1.1 headaches/month (ha/month), 95% CI: -1.6 to -0.67), fluoxetine (SMD: -0.57, 95% CI: -0.97 to -0.17), metoprolol (-0.94 ha/month, 95% CI: -1.4 to -0.46), pizotifen (-0.43 ha/month, 95% CI: -0.6 to -0.21), propranolol (-1.3 ha/month, 95% CI: -2.0 to -0.62), topiramate (-1.1 ha/month, 95% CI: -1.9 to -0.73) and valproate (-1.5 ha/month, 95% CI: -2.1 to -0.8). Several effective drugs with less than 3 trials included: 3 ace inhibitors (enalapril, lisinopril, captopril), two angiotensin receptor blockers (candesartan, telmisartan), two anticonvulsants (lamotrigine, levetiracetam), and several beta-blockers (atenolol, bisoprolol, timolol). Network meta-analysis found amitriptyline to be better than several other medications including candesartan, fluoxetine, propranolol, topiramate and valproate and no different than atenolol, flunarizine, clomipramine or metoprolol. CONCLUSION: Several drugs good evidence supporting efficacy. There is weak evidence supporting amitriptyline's superiority over some drugs. Selection of prophylactic medication should be tailored according to patient preferences, characteristics and side effect profiles.

This review highlighted the sheer number of drugs used to prevent migraines. The drugs that have a medical licence in the UK to be used for the prevention of migraine are beta blockers such as propranolol (mainly used in the treatment of heart conditions), the anti-epilepsy drug topiramate, and pizotifen, an antihistamine and serotonin receptor antagonist.

Other drugs are sometimes used in medical practice, despite not having a licence for this use. Other drugs covered by this review included those used traditionally in the treatment of depression, other mood conditions or chronic pain: tricyclic antidepressants (TCAs, most commonly amitriptyline), selective serotonin reuptake inhibitors (SSRIs), and serotonin and norepinephrine reuptake inhibitors (SNRIs). The review also covered other drugs used in the treatment of heart and blood vessel conditions (angiotensin converting enzyme [ACE] inhibitors, calcium channel blockers, alpha blockers and angiotensin receptor blockers), and other anti-epilepsy drugs.

Expert commentary

This meta-analysis highlights some important issues for patients and researchers. Firstly, patients need to be aware that with respect to migraine prophylaxis, ‘effective’ is not synonymous with headache free – most drugs reduced the average of six headaches per month by 1 or 2 per month. Secondly, ‘new’ is not better than ‘old’ – the analysis suggests that the ‘old’ drug amitriptyline had the greatest prophylactic benefit. Finally, clinical trials need to continue longer than the usual 12 weeks – the placebo effect (a significant issue in migraine trials) does not begin to wear off until 16 weeks of treatment.

Professor Anne MacGregor, Centre for Neuroscience & Trauma, Barts and the London School of Medicine and Dentistry

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