Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial

Abstract

Objective: To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine.

Design: Three arm, parallel group, randomized, modified double blind, controlled trial.

Setting: Ambulatory, academic medical center in the United States over 16 weeks.

Participants: 182 participants (88% women, mean age 38 years) with migraines on 5-20 days per month (67% met criteria for chronic migraine).

Interventions: Three diets designed with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid altered as controlled variables: H3 diet (n=61)-increase EPA+DHA to 1.5 g/day and maintain linoleic acid at around 7% of energy; H3-L6 diet (n=61)-increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of energy; control diet (n=60)-maintain EPA+DHA at <150 mg/day and linoleic acid at around 7% of energy. All participants received foods accounting for two thirds of daily food energy and continued usual care.

Main outcome measures: The primary endpoints (week 16) were the antinociceptive mediator 17-hydroxydocosahexaenoic acid (17-HDHA) in blood and the headache impact test (HIT-6), a six item questionnaire assessing headache impact on quality of life. Headache frequency was assessed daily with an electronic diary.

Results: In intention-to-treat analyses (n=182), the H3-L6 and H3 diets increased circulating 17-HDHA (log ng/mL) compared with the control diet (baseline-adjusted mean difference 0.6, 95% confidence interval 0.2 to 0.9; 0.7, 0.4 to 1.1, respectively). The observed improvement in HIT-6 scores in the H3-L6 and H3 groups was not statistically significant (-1.6, -4.2 to 1.0, and -1.5, -4.2 to 1.2, respectively). Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day (-1.7, -2.5 to -0.9, and -1.3, -2.1 to -0.5, respectively), moderate to severe headache hours per day (-0.8, -1.2 to -0.4, and -0.7, -1.1 to -0.3, respectively), and headache days per month (-4.0, -5.2 to -2.7, and -2.0, -3.3 to -0.7, respectively). The H3-L6 diet decreased headache days per month more than the H3 diet (-2.0, -3.2 to -0.8), suggesting additional benefit from lowering dietary linoleic acid. The H3-L6 and H3 diets altered n-3 and n-6 fatty acids and several of their nociceptive oxylipin derivatives in plasma, serum, erythrocytes or immune cells, but did not alter classic headache mediators calcitonin gene related peptide and prostaglandin E2.

Conclusions: The H3-L6 and H3 interventions altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches, but did not significantly improve quality of life.

Trial registration: ClinicalTrials.gov NCT02012790.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: the NCCIH (NIH), NIA, National Institute on Alcohol Abuse and Alcoholism, Mayday Fund, UNC Nutrition Obesity Research Center, CHAI Core, NIDDK (NIH), NC TraCS Institute, NCATS (NIH) for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years. The NIA (NIH) has claimed intellectual property related to stable analogs of oxidized lipid mediators (PCT/US2018/041086) with this manuscript’s coauthors, CER and GSK, named as inventors. All other authors declare no other relationships or activities that could appear to have influenced the submitted work.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Fig 1

Proposed mechanisms linking dietary n-6 and n-3 fatty acids and their oxylipin derivatives to headache pathogenesis. Upper left panel: modern industrialized diets tend to be low in food sources of n-3 EPA and DHA (eg, finfish and shellfish) and high in vegetable oils rich in n-6 LA; humans cannot synthesize n-3 and n-6 fatty acids de novo, and so dietary intakes affect their abundance in blood and tissues; upper middle panel: circulating blood contains pools of n-3 and n-6 fatty acids, including red blood cells which serve as a proxy for tissue fatty acids, and immune cells which can infiltrate inflamed tissues and are direct precursors to nociceptive oxylipins that can act on nerve endings; upper right panel: n-3 and n-6 fatty acids are major components of lipid membranes of tissues innervated by the trigeminal nerve, including meninges, cranial vessels, mucosal membranes, the trigeminal nerve itself, and the lipid pools in pain processing pathways (myelin, astrocytes, and central nervous system neurons); lower panel: these lipid pools serve as precursors for synthesis of oxylipins with pronociceptive and antinociceptive properties, including prostaglandins, leukotrienes, octadecanoids, resolvins, and n-3 monoepoxides. Oxylipins activate GPCRs and TRP channel receptors to regulate trigeminal nerve activation and localized release of CGRP. Oxylipins also act directly on vascular tissues to evoke vasodilation and increase vascular permeability (not shown). Four oxylipin receptors that are enriched in human trigeminal nerve are shown in the lower panel. AA=arachidonic acid; CGRP=calcitonin gene related peptide; DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid; EpOME=epoxide of linoleic acid; GPCR=G protein coupled receptor; HDHA=hydroxydocosahexaenoic acid; HETE=hydroxyeicosatetraenoic acid; HODE=hydroxyoctadecadienoic acid; LA=linoleic acid; LTB4R=leukotriene B4 receptor; TRP=transient receptor potential

Fig 2

CONSORT (consolidated standards of reporting trials) diagram

Fig 3

Effect of study diets on precursor fatty acids. Distributions of the final measure of three pools of precursor fatty acids: erythrocytes and immune cells. Boxes represent median and interquartile range. Outliers beyond whiskers are not shown. For reference, baseline median is represented by black line. To assess between group differences at final visit, an analysis of covariance was used, controlling for recruitment site. Different letters indicate P values

Fig 4

Effect of study diets on oxylipins and CGRP. Distributions of final measure of oxylipins and CGRP in plasma. Boxes represent median and interquartile range. Outliers beyond whiskers are not shown. For reference, baseline median is represented by black line. To assess between group differences at final visit, an analysis of covariance was used, controlling for recruitment site. Different letters indicate P values

Fig 5

Association of headache hours per day with precursor fatty acids and oxylipins (end of study). Each plot represents coefficients and 95% confidence intervals from linear regression model of targeted fatty acids and oxylipins on headache hours per day adjusted for the following baseline variables: age, body mass index, sex, headache hours per day, HIT-6, and chronic versus episodic migraine. Sample represents participants with data for blood measures and headache diary at end of study. AA=arachidonic acid; DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid; HDHA=docosahexaenoic acid; HETE=hydroxyeicosatetraenoic acid; HIT-6=six item headache impact test; LA=linoleic acid