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ILLUSTRATIVE CASE
A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?
Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.2 An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.3
Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).2 Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).2 However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.4
Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.5
[polldaddy:9724288]
STUDY SUMMARY
Melatonin tops amitriptyline in >50% improvement in headache frequency
This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.1 Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.
The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.
Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.
Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.
Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).
Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).
WHAT’S NEW
An effective migraine prevention alternative with minimal adverse effects
Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.
CAVEATS
Product consistency, missing study data
This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.
Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.
CHALLENGES TO IMPLEMENTATION
Challenges are negligible
There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Gonçalves AL, Martini Ferreira A, Ribeiro RT, et al. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87:1127-1132.
2. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
3. Lipton RB, Bigal ME, Diamond M, et al; The American Migraine Prevalence and Prevention Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.
4. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:754-762.
5. Alstadhaug KB, Odeh F, Salvesen R, et al. Prophylaxis of migraine with melatonin: a randomized controlled trial. Neurology. 2010;75:1527-1532.
ILLUSTRATIVE CASE
A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?
Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.2 An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.3
Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).2 Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).2 However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.4
Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.5
[polldaddy:9724288]
STUDY SUMMARY
Melatonin tops amitriptyline in >50% improvement in headache frequency
This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.1 Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.
The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.
Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.
Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.
Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).
Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).
WHAT’S NEW
An effective migraine prevention alternative with minimal adverse effects
Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.
CAVEATS
Product consistency, missing study data
This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.
Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.
CHALLENGES TO IMPLEMENTATION
Challenges are negligible
There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated over the frequency of her migraines and the debilitation they cause. She has tried prophylactic medications in the past, but stopped taking them because of the adverse effects. What do you recommend for treatment?
Daily preventive medication can be helpful for chronic migraine sufferers whose headaches have a significant impact on their lives and who have a goal of reducing headache frequency or severity, disability, and/or avoiding acute headache medication escalation.2 An estimated 38% of patients with migraines are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.3
Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many beta-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention (level A recommendation; based on ≥2 class I trials).2 Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B recommendation; based on one class I trial or 2 class II trials).2 However, adverse effects, such as somnolence, are listed as frequent with amitriptyline and occasional to frequent with topiramate.4
Researchers have investigated melatonin before. But a 2010 double-blind, crossover, randomized controlled trial (RCT) of 46 patients with 2 to 7 migraine attacks per month found no significant difference in reduction of headache frequency with extended-release melatonin 2 mg taken one hour before bed compared to placebo over an 8-week period.5
[polldaddy:9724288]
STUDY SUMMARY
Melatonin tops amitriptyline in >50% improvement in headache frequency
This RCT conducted in Brazil compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18-65 years) with chronic migraines.1 Eligible patients had a history of at least 3 migraine attacks or 4 migraine headache days per month. Patients were randomized to take identically-appearing melatonin 3 mg, amitriptyline 25 mg, or placebo nightly. The investigators appear to have concealed allocation adequately, and used double-blinding.
The primary outcome was the number of headache days per month, comparing baseline with the 4 weeks of treatment. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.
Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 days vs 4.6 days, respectively; mean difference [MD], -1.6; 95% confidence interval [CI], -2.4 to -0.9) and the amitriptyline group (6.2 days vs 5 days, respectively; MD, -1.1; 95% CI, -1.5 to -0.7) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, -1.2; 95% CI, -1.6 to -0.8) and in the amitriptyline group (4.8 vs 3.5; MD, -1.3; 95% CI, -1.7 to -0.9), when compared to placebo.
Headache duration (hours/month) at 12 weeks was reduced in both groups (amitriptyline MD, -4.4 hours; 95% CI, -5.1 to -3.9; melatonin MD, -4.8 hours; 95% CI, -5.7 to -3.9), as was the number of analgesics used (amitriptyline MD, -1; 95% CI, -1.5 to -0.5; melatonin MD, -1; 95% CI, -1.4 to -0.6) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.
Patients taking melatonin were more likely to have a >50% improvement in headache frequency compared to amitriptyline (54% vs 39%; number needed to treat [NNT]=7; P<.05); melatonin worked much better than placebo (54% vs 20%; NNT=3; P<.01).
Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16; P<.03) with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH]=5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17; P=not significant). Melatonin resulted in weight loss (mean, -0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg; P<.01).
WHAT’S NEW
An effective migraine prevention alternative with minimal adverse effects
Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers. The 3-mg dosing reduces headache frequency—both in terms of the number of migraine headache days per month and in terms of the percentage of patients with a >50% reduction in headache events—as well as headache intensity, with minimal adverse effects.
CAVEATS
Product consistency, missing study data
This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, because melatonin is available over-the-counter, the quality/actual doses may be less well regulated, and thus, there may be a lack of consistency between brands. Unlike clinical practice, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects. As a result, we are not sure of the actual lowest effective dose, or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.
Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, but the authors of the study reported using 3 different analytic techniques to estimate missing data. The primary outcome included 178 of 196 randomized patients (90.8%). For the primary endpoint, the authors treated all missing data as non-headache days. It is unclear how these missing data would affect the outcome, although an analysis like this would tend towards a null effect.
CHALLENGES TO IMPLEMENTATION
Challenges are negligible
There are really no challenges to implementing this practice changer; melatonin is readily available over-the-counter and it is affordable.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Gonçalves AL, Martini Ferreira A, Ribeiro RT, et al. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87:1127-1132.
2. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
3. Lipton RB, Bigal ME, Diamond M, et al; The American Migraine Prevalence and Prevention Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.
4. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:754-762.
5. Alstadhaug KB, Odeh F, Salvesen R, et al. Prophylaxis of migraine with melatonin: a randomized controlled trial. Neurology. 2010;75:1527-1532.
1. Gonçalves AL, Martini Ferreira A, Ribeiro RT, et al. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87:1127-1132.
2. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
3. Lipton RB, Bigal ME, Diamond M, et al; The American Migraine Prevalence and Prevention Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349.
4. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:754-762.
5. Alstadhaug KB, Odeh F, Salvesen R, et al. Prophylaxis of migraine with melatonin: a randomized controlled trial. Neurology. 2010;75:1527-1532.
Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.
PRACTICE CHANGER
Recommend nightly melatonin 3 mg to your patients with chronic migraines, as it appears to be as effective as amitriptyline in reducing headaches and causes fewer adverse effects.
STRENGTH OF RECOMMENDATION
B: Based on a single, good quality randomized controlled trial.
Gonçalves AL, Martini Ferreira A, Ribeiro RT, et al. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87:1127-1132.1
