Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial

Abstract

Omega-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single-blinded, parallel-group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n-3 and n-6 fatty acids for treatment of chronic headaches. After a 4-week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food-based 12-week dietary interventions: a high n-3 plus low n-6 (H3-L6) intervention, or a low n-6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT-6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n-6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n-3 and n-6 derivatives. Fifty-six of 67 patients completed the intervention. Both groups achieved targeted intakes of n-3 and n-6 fatty acids. In intention-to-treat analysis, the H3-L6 intervention produced significantly greater improvement in the HIT-6 score (-7.5 vs -2.1; P<0.001) and the number of Headache Days per month (-8.8 vs -4.0; P=0.02), compared to the L6 group. The H3-L6 intervention also produced significantly greater reductions in Headache Hours per day (-4.6 vs -1.2; P=0.01) and the n-6 in HUFA score (-21.0 vs -4.0%; P<0.001), and greater increases in antinociceptive n-3 pathway markers 18-hydroxy-eicosapentaenoic acid (+118.4 vs +61.1%; P<0.001) and 17-hydroxy-docosahexaenoic acid (+170.2 vs +27.2; P<0.001). A dietary intervention increasing n-3 and reducing n-6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality-of-life in this population.

Keywords: Clinical trial; Headache; Migraine; Omega-3; Omega-6.

Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Conflict of interest statement

The authors declare that they have no competing interests. The authors alone are responsible for the content and writing of the article.

Published by Elsevier B.V.

Figures

Fig. 1

Proposed mechanisms linking targeted alterations in n-3 and n-6 fatty acids with pain reduction. This figure summarizes hypothetical mechanisms linking n-3 and n-6 fatty acids to pain reduction, including representative mediators measured in the present trial (9-HODE and Resolvin D2) as well as mediators that were not measured in this trial (Prostaglandin E2 and Resolvin E1). (A) Targeted dietary alterations increase the abundance of n-3 EPA and DHA (blue) and decrease the abundance of n-6 LA and AA (red) in fatty acid precursor pools, including the membranes of endothelial cells, platelets, immune cells, glia, myelin, and neurons. (B) These changes in precursor abundance alter the concentrations of n-3 and n-6 derived antinociceptive and pronociceptive mediators, including E- and D-series resolvins, maresins, prostaglandins, endovanilloids, and endocannabinoids. (C) Changes in the milieu of lipid mediators alter the activities of receptors involved in pain signaling, including the vanilloid receptor (TRPV1) and several G-protein coupled receptors (eg, E-prostanoid receptors, resolvin receptors, cannabinoid receptors). (D) Increases in antinociceptive mediators and decreases in pronociceptive mediators reduce pain signaling in the trigeminovascular system and central pain signaling pathways. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; LA, linoleic acid; AA, arachidonic acid; 9-HODE, 9-hydroxy-octadecadienoic acid.

Fig. 2

CONSORT trial profile.

Fig. 3

Mean daily Headache Hours by dietary intervention group. Graph depicts the average number of Headache Hours calculated for each day according to intervention group. A Loess smoothing procedure was employed to visualize trends. Participants in the 2 groups provided equivalent amounts of Headache Diary data after randomization (2145 total days of records in the L6 group and 2175 in the H3-L6 group).

Fig. 4

Change in medication use over the course of the intervention by diet group. Acute medications included vasoactive abortive medications, acute opioids, and nonsteroidal antiinflammatory drugs; Adjunctive medications included antiemetics, anxiolytics, sleep aids/hypnotics, and muscle relaxants. All changes depicted in Fig. 4 were significantly changed compared to baseline. There was no significant change in the use of Preventive medications (eg, anticonvulsants, antidepressants, vasoactive preventives, long-acting opiates) over time in either group.