An effective migraine prevention alternative with minimal adverse effects Melatonin is an accessible and affordable option for preventing migraine headaches in chronic sufferers

Langner, Shannon

Lyon, Corey

Stevermer, James J.

University of Missouri: MOspace

320 THE JOURNAL OF FAMILY PRACTICE  |   MAY 2017  |   VOL 66, NO 5Priority Updates from the Research Literature from the Family Physicians Inquiries NetworkPURLs®Corey Lyon, DO;  Shannon Langner, MD University of Colorado Family Medicine Residency, DenverD E P U T Y  E D I T O RJames J. Stevermer, MD, MSPHDepartment of Family and Community Medicine, University of Missouri-Columbia Consider melatonin for migraine prevention This affordable, over-the-counter hormone is as effective as amitriptyline, causes fewer adverse effects, and may have a surprising added benefit. PRACTICE CHANGERRecommend 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 RECOMMENDATIONB: Based on a single, good quality random-ized controlled trial.Gonçalves AL, Martini Ferreira A, Ribeiro RT, et al. Randomised clini-cal trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87:1127-1132.1ILLUSTRATIVE CASEA 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 debilita-tion 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 suffer-ers whose headaches have a signifi-cant 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 candi-dates 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 recom-mended for migraine prevention (level A recommendation; based on ≥2 class I tri-als).2 Medications such as antidepressants (amitriptyline, venlafaxine) and other beta-blockers (atenolol, nadolol) are probably effective and can be considered (level B rec-ommendation; 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 fre-quent with topiramate.4Researchers have investigated melato-nin before. But a 2010 double-blind, cross-over, 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.5STUDY SUMMARYMelatonin tops amitriptyline in >50% improvement in headache frequencyThis RCT conducted in Brazil compared the effectiveness of melatonin to amitripty-line and placebo for migraine prevention in Do you ever prescribe melatonin for the prevention of migraines in chronic migraine sufferers?n  Yesn  NoINSTANT  POLLjfponline.com321JFPONLINE.COM VOL 66, NO 5  |  MAY 2017  |  THE JOURNAL OF FAMILY PRACTICECONTINUED196 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 pla-cebo 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 base-line 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 melato-nin 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 amitripty-line 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 (ami-triptyline 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 signifi-cant difference between the melatonin and amitriptyline groups for these outcomes. Patients taking melatonin were more likely to have a >50% improvement in head-ache frequency compared to amitripty-line (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 amitrip-tyline 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 NEWAn effective migraine prevention alternative with minimal adverse effectsMelatonin is an accessible and afford-able option for preventing migraine head-aches 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. CAVEATSProduct consistency, missing study dataThis 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 clini-cal 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 con-tinued 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 out-come 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 miss-ing data would affect the outcome, although an analysis like this would tend towards a null effect. An estimated  38% of patients with migraines are appropriate  candidates  for prophylactic therapy,  but only 3% to 13% are taking preventive  medications.322 THE JOURNAL OF FAMILY PRACTICE  |   MAY 2017  |   VOL 66, NO 5PURLs®CHALLENGES TO IMPLEMENTATIONChallenges are negligibleThere are really no challenges to imple-menting this practice changer; melatonin is readily available over-the-counter and it is affordable.                      JFPACKNOWLEDGEMENTThe 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 responsi-bility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved. References  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 guide-line update: pharmacologic treatment for episodic migraine pre-vention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Head-ache Society. Neurology. 2012;78:1337-1345. 3.   Lipton RB, Bigal ME, Diamond M, et al; The American Migraine Prevalence and Prevention Advisory Group. Migraine preva-lence, disease burden, and the need for preventive therapy. Neu-rology. 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 mi-graine with melatonin: a randomized controlled trial. Neurology. 2010;75:1527-1532.This supplement is sponsored by Primary Care Education Consortium and Primary Care Metabolic Group and is supported by funding from Janssen Pharmaceuticals, Inc.To read the supplement, visit the Education Center section on The Journal of Family Practice website:A SUPPLEMENT TO THE JOURNAL OF FAMILY PRACTICE Elements for Success in Managing Type 2 Diabetes With SGLT-2 InhibitorsONLINE NOW!Eden M. Miller, DOExecutive Director and Co-founder, Diabetes NationHigh Lakes Health CareSt. Charles HospitalBend, Oregon▼▼This supplement highlights the role of the kidney and the beneﬁ ts of SGLT-2 inhibitors in individualizing treatment for type 2 diabetes.MDEDGE.COM/JFP/EDUCATION-CENTER/LATESTPCEC_SGLT-2 AD 0217.indd   1 2/17/17   10:15 AM

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