Clinical question

How effective and acceptable are various dosages of EPA/DHA compared with current pharmacological interventions for migraine prevention?

Key points

Despite the conclusion of this article, there is still only preliminary evidence of the benefit of supplemental omega-3 fatty acids for migraine. The authors of the review looked at relatively few, mostly small (N~50) omega-3 trials, and concluded that:

• High-dosage EPA/DHA (>1.5 grams/day) significantly reduces migraine frequency and severity compared with placebo.
• High-dose omega-3 fatty acids were associated with the greatest improvement in the frequency of migraine days among all pharmacologic interventions, followed by valproate and topiramate.
• EPA/DHA had favorable acceptability rates, which were comparable to those of other pharmacologic treatments.
• Combination treatments (EPA/DHA + amitriptyline) also demonstrated high response rates without increasing adverse event frequencies.

Author’s conclusions

“This study provides compelling evidence that high-dosage EPA/DHA supplementation can be considered a first-choice treatment for migraine prophylaxis because this treatment displayed the highest efficacy and highest acceptability of all studied treatments.”

Relevance

Migraine affects more than 40 million Americans, and, while a host of preventive medications exist, studies have shown that long-term compliance can be less than 50%, especially among people with chronic migraine.^1,2,3 Even with the introduction of CGRP modulators, which promise better compliance, issues regarding access to this medication continue to demand additional patient-friendly prevention options. Although omega-3 fatty acids have shown potential in the setting of migraine due to their neuro–anti-inflammatory actions, previous trials on supplements have had methodological limitations, which have limited consistent findings.^4,5 Currently, we know that an increased intake of omega-3 fatty acids through the diet with a concomitant decrease in omega-6 fatty acids has strong evidence in the prevention of migraine based on the work of NIH researcher Chris Ramsden as published in The BMJ.⁶

Details of the trial

Setting: A comprehensive network meta-analysis evaluating randomized controlled trials (RCTs) of medications and various dosages of omega-3 fatty acids for migraine prevention. A total of 6616 individuals from 40 RCTs (but only 4 for omega-3 fatty acids, 1 for amitriptyline + omega-3 fatty acids, and 35 for prescription treatment). Participants were predominantly female (78.9%), with a mean age of 35 years, and had episodic or chronic migraine.

In total, 78 articles were considered for full-text review, of which 38 were excluded for various reasons including non-oral treatments and use in acute treatment.

The few omega-3 trials were categorized into low-, medium-, and high-dose EPA/DHA levels:

• EPA+ DHA <900 mg/day,
• 900 to 1500 mg/day, and
• 1500 mg/day or higher

Preventive drugs evaluated were: Topiramate, valproate, propranolol, timolol, amitriptyline, venlafaxine, lisinopril, frovatriptan, and candesartan.

Treatments: High, medium, and low dosages of EPA/DHA were compared with FDA-approved or guideline-recommended migraine prophylactic medications.

Endpoints: Primary outcomes included changes in migraine frequency and acceptability (dropout rates). Secondary outcomes included response rates, changes in migraine severity, rate of rescue medication usage, and incidence of adverse events.

Limitations: Unfortunately, numerous limitations in this analysis make its stated conclusions not ready for prime time, including:

• The analysis did not include common preventatives, including botulinum toxin or CGRP antibodies. The authors did state that the analysis would focus on oral medications; nonetheless, if you are making claims about first-line therapies, these medications need to be considered.
• Oddly, it mentioned frovatriptan as one of the preventatives in the methodologies; however, this medication is a member of the triptan family used for the acute treatment of migraines. This is likely a mistake in the manuscript.
• The conclusions regarding omega-3 fatty acids are based on only 5 trials, which are then further subdivided in the conclusion into four categories (three doses of omega-3 fatty acids and one for omega-3 fatty acid combined with amitriptyline). In addition, these trials were small (4 with Ns of 25–50) with the largest older trial (N ~200) being nonsignificant potentially due to the use of olive oil as a placebo.
• These smaller omega-3 fatty acid trials likely suffer from being underpowered as the authors point out: “similarly, the main findings regarding the efficacy of EPA/DHA in migraine prophylaxis primarily came from the few RCTs using EPA/DHA products…. Therefore, clinicians should avoid overinterpretation of the findings in the present NMA and apply them in a relatively conservative way.” Unfortunately many readers will only read the abstract, which had a much less conservative tone, stating that there is “compelling evidence” and that “high dosage EPA/DHA supplementation can be considered a first-choice treatment for migraine prophylaxis.”
• There was no mention of omega-6–to–omega-3 fatty acid ratios as well as the importance of the make-up of the omega-3 (EPA vs DHA) fatty acids having an impact, which is likely related to the smaller number of trials.

Incorporation into practice

Omega-3 fatty acids are an intriguing potential for the prevention of migraines. At this point, the evidence is strongest for an increase in dietary omega-3 fatty acids with a concomitant reduction in omega-6 fatty acids, which can be achieved through a reduction in the intake of packaged foods that use omega-6 fatty acid as a preservative as well as a switch to less omega-6–predominant cooking oils, such as extra virgin olive oil. The choice of dietary omega-3 fatty acid should be based on sustainable and low-toxin sources with sites like the Monterey Bay Aquarium’s Seafood Watch to help with the choice.

At this point, supplemental omega-3 fatty acids have relatively preliminary evidence for preventing migraines and need additional evidence to support their use. Meanwhile, the strongest use case for supplemental omega-3 fatty acids is for individuals on other preventive drugs such as amitriptyline and those who may not consume omega-3 fatty acids in their diet and who wish to turn to dietary supplementation. Similar to dietary omega-3 fatty acids, testing sources like USP, NSF, and ConsumerLab should be referenced to confirm the safety testing of the supplement being considered.

Remaining questions: Future supplemental omega-3 fatty acid trials should optimally examine factors including:

• Background dietary omega-3 fatty acid intake and pre– and post–omega-3 and –omega-6 fatty acid levels to determine whether these factors affect potential benefit
• The dose–response of varying omega-3 fatty acid dosages and the formulation make-up of subconstituents such as EPA, DHA, DPA, and resolvins
• Verification of the safety of the intervention to confirm the lack of heavy metal toxicity
• Evaluation of the long-term benefits and safety, especially across diverse patient populations, including those with different migraine types and comorbidities

References

1. Martin VT, Feoktistov A, Solomon GD. A Rational Approach to Migraine Diagnosis and Management in Primary Care. Ann Med. 2021;53(1):1969-1980. https://doi.org/10.1080/07853890.2021.1995626
2. Puledda F, Goadsby PJ. An Update on Non‐Pharmacological Neuromodulation for the Acute and Preventive Treatment of Migraine. Headache. 2017;57(4):685-691. https://doi.org/10.1111/head.13069
3. Hepp Z, Dodick DW, Varon SF, et al. Adherence to Oral Migraine-Preventive Medications Among Patients With Chronic Migraine. Cephalalgia. 2015;35(6):478-488. https://doi.org/10.1177/0333102414547138
4. Abdolahi M, Jafarieh A, Sarraf P, et al. The Neuromodulatory Effects of Omega-3 Fatty Acids and Nano-Curcumin on the COX-2/iNOS Network in Migraines: a Clinical Trial Study From Gene Expression to Clinical Symptoms. Endocr Metab Immune Disord Drug Targets. 2019;19(6):874-884. https://doi.org/10.2174/1871530319666190212170140
5. Maghsoumi-Norouzabad L, Mansoori A, Abed R, et al. Effects of Omega-3 Fatty Acids on the Frequency, Severity, and Duration of Migraine Attacks: a Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutr Neurosci. 2018;21(9):614-623. https://doi.org/10.1080/1028415x.2017.1344371
6. Ramsden CE, Zamora D, Faurot KR, et al. Dietary Alteration of n-3 and n-6 Fatty acids for Headache Reduction in Adults With Migraine: Randomized Controlled Trial. BMJ. 2021;374:n1448. https://doi.org/10.1136/bmj.n1448

Abstract

Migraine is a highly prevalent neurologic disorder with prevalence rates ranging from 9% to 18% worldwide. Current pharmacologic prophylactic strategies for migraine have limited efficacy and acceptability, with relatively low response rates of 40% to 50% and limited safety profiles. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered promising therapeutic agents for migraine prophylaxis. The aim of this network meta-analysis (NMA) was to compare the efficacy and acceptability of various dosages of EPA/DHA and other current Food and Drug Administration-approved or guideline-recommended prophylactic pharmacologic interventions for migraine. Randomized controlled trials (RCTs) were eligible for inclusion if they enrolled participants with a diagnosis of either episodic or chronic migraine. All NMA procedures were conducted under the frequentist model. The primary outcomes assessed were 1) changes in migraine frequency and 2) acceptability (i.e., dropout for any reason). Secondary outcomes included response rates, changes in migraine severity, changes in the frequency of using rescue medications, and frequency of any adverse events. Forty RCTs were included (N = 6616; mean age = 35.0 y; 78.9% women). Our analysis showed that supplementation with high dosage EPA/DHA yields the highest decrease in migraine frequency [standardized mean difference (SMD): -1.36; 95% confidence interval (CI): -2.32, -0.39 compared with placebo] and the largest decrease in migraine severity (SMD: -2.23; 95% CI: -3.17, -1.30 compared with placebo) in all studied interventions. Furthermore, supplementation with high dosage EPA/DHA showed the most favorable acceptability rates (odds ratio: 1.00; 95% CI: 0.06, 17.41 compared with placebo) of all examined prophylactic treatments. This study provides compelling evidence that high dosage EPA/DHA supplementation can be considered a first-choice treatment of migraine prophylaxis because this treatment displayed the highest efficacy and highest acceptability of all studied treatments. This study was registered in PROSPERO as CRD42022319577.

Journal Abstract