Clinical & metabolic effects of altering n-3 & n-6 fatty acids in migraine (RCT)

Project: Research project


Episodic migraine is a debilitating chronic pain condition afflicting 12% of Americans. Conventional treatments rely on medications that provide limited or transient relief, target symptoms rather than the underlying causes of pain, and are associated with significant side effects and costs. It is therefore essential to investigate non-pharmacologic approaches to conventional headache treatments. Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) have been shown to regulate multiple pain-related biochemical pathways, although controlled dietary trials testing pain reduction and elucidating mechanisms of action in humans are lacking. In a pilot feasibility RCT with chronic daily headache patients, we found that targeted PUFA modifications—increased EPA+DHA with reduced linoleic acid (LA)—altered circulating endovanilloids, reducing headache frequency, headache intensity, and improved quality of life. These findings support our proposed model in which diet-induced alterations in endovanilloids modulate TRPV1 in vivo, with potential key implications for migraine and chronic pain in general; hhowever, whether a reduction in dietary LA is required to elicit the observed metabolic and clinical benefits is still unknown. The goal of this proposal is to assess whether targeted PUFA modifications designed to increase tissue n-3 EPA and DHA, with or without concurrent reduction in n-6 LA, can improve headache-related clinical outcomes. The proposed 24-week, three-arm, randomized, controlled, single-blinded trial, with 40 subjects in each group, is preceded by a 6-week baseline of usual care, followed by randomization to one of three dietary interventions: 1) a high n-3 EPA+DHA, low n-6 LA intervention (Analgesic Diet A; 2) a high n-3 EPA+DHA, high n-6 LA intervention (Analgesic Diet B); or 3) a control intervention with ‘average U.S.’ intake of all n-6 and n-3 PUFAs (Control Diet). Specific aims are: 1) To compare the clinical effects of two 18-week analgesic dietary interventions with a control diet; 2) To assess the efficacy of the dietary interventions in inducing the predicted changes in erythrocyte PUFAs; 3) To assess the efficacy of the dietary interventions in inducing the predicted changes in circulating PUFA endovanilloid derivatives; 4) To test, in an exploratory manner, our model of the proposed causal chain linking changes in n-3 and n-6 PUFAs, their endovanilloid derivatives, and headache endpoints. This proposal utilizes an innovative design and hypotheses to address current NCCAM research funding priorities, by examining clinical efficacy and underlying mechanisms of a promising dietary manipulation with potential for high impact on ameliorating a disabling, prevalent chronic pain condition, migraine.
Effective start/end date9/30/135/31/18


  • NIH National Center for Complementary and Integrative Health (NCCIH)


Linoleic Acid
Migraine Disorders
Unsaturated Fatty Acids
Fatty Acids
Chronic Pain
Omega-3 Fatty Acids
Headache Disorders
Random Allocation
Quality of Life
Costs and Cost Analysis