— Findings could lead to targeted dietary changes to improve chronic pain

by Judy George, Senior Staff Writer, MedPage Today June 30, 2021

A diet higher in two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduced headache frequency and intensity and lowered levels of pain-related lipids in migraine patients, a randomized controlled trial showed.

Compared with people on a diet higher in linoleic acid (omega-6), people who consumed more EPA and DHA experienced 30% to 40% reductions in total headache hours per day, severe headache hours per day, and overall headache days per month, reported Christopher Ramsden, MD, of the National Institute on Aging in Baltimore, Maryland, and colleagues, in The BMJ.

High EPA and DHA diets increased circulating 17-hydroxydocosahexaenoic acid (17-HDHA), but did not affect scores on the headache impact test (HIT-6), a six-item questionnaire assessing headache impact on quality of life.

“This is the first moderate-sized controlled trial showing that targeted changes in diet can decrease chronic physical pain,” Ramsden said. “The biochemical findings support the biological plausibility of this type of approach,” he told MedPage Today.

EPA and DHA are found in fatty fish. Linoleic acid is a polyunsaturated fatty acid commonly derived from corn, soybean, and similar oils, and some nuts and seeds.

Modern industrialized diets tend to be low in EPA and DHA and high in linoleic acid. These fatty acids are precursors to oxylipins, which are involved in regulating pain and inflammation. In preclinical models, linoleic acid has been shown to increase pain.

The trial included 182 people with a baseline average of 16.3 headache days per month and 5.4 headache hours per day. Two-thirds (67%) met criteria for chronic migraine (more than 15 headache days a month). Baseline mean HIT-6 scores indicated headaches had a severe effect on quality of life. The group had a mean age of 38 and 88% were women.

Participants received meal kits that included fish, vegetables, hummus, salads, and breakfast items, and were randomly assigned to one of three diets with EPA, DHA, and linoleic acid altered as variables.

The control group had a diet with high linoleic acid levels and low levels of EPA and DHA, mimicking average U.S. intakes. Both interventional diets raised omega-3 intake: one had high EPA and DHA and high linoleic acid levels (the H3 group); the other had high EPA and DHA and low linoleic acid levels (the H3-L6 group).

Primary endpoints were the anti-nociceptive mediator 17-HDHA in blood and HIT-6 scores at week 16. Headache frequency was assessed daily with an electronic diary.

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% CI 0.2-0.9 and 0.7, 95% CI 0.4-1.1, respectively).

The diets reduced mean HIT-6 scores by 1.6 and 1.5, respectively, but were not statistically significant. A between-group minimally important difference in HIT-6 score has been estimated at 1.5 in other research.

Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day by 1.7 and 1.3, moderate-to-severe headache hours per day by 0.8 and 0.7, and headache days per month by 4.0 and 3.3, respectively. The H3-L6 diet decreased headache days per month more than the H3 diet (-2.0, 95% CI −3.2 to -0.8), suggesting additional benefit from lowering dietary linoleic acid.

Both interventional diets altered blood levels of bioactive oxylipins implicated in headache pathogenesis, but did not alter classic mediators of headache pain such as prostaglandins E2 or calcitonin gene related peptide (CGRP).

“Although this is statistically a negative study with regard to the primary clinical endpoint, there are several factors that make the overall findings clinically meaningful,” noted Rebecca Burch, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, in an accompanying editorial.

“International Headache Society guidelines and regulatory standards specify the use of headache or migraine frequency as the preferred outcome measure for trials of preventive interventions for migraine,” Burch wrote. “Interpretation of this study’s findings is therefore complex: the study was negative according to the prespecified primary outcome, but would have been positive if judged by more guideline-adherent endpoints.”

The trial results are notable for their magnitude of response, Burch added. “Clinical trials of recently approved pharmacological treatments for migraine prevention, such as monoclonal antibodies to the calcitonin gene related peptide, reported reductions of approximately 2-2.5 headache days per month in the intervention group compared with placebo,” she wrote. “The new trial suggests that a dietary intervention can be comparable or better. Dietary interventions combined with pharmacological treatments might have an additive benefit.”

Limitations of the study include using HIT-6 as the primary outcome instead of a more specific pain measure, Ramsden and colleagues acknowledged. Despite the intensive nature of the study’s interventions, participants were unable to lower dietary linoleic acid to the study’s energy target of 1.8% in the H3-L6 group. Most participants were relatively young women and results may not apply to other populations.

“There is an unmet need for safe and effective treatments for chronic pain,” Ramsden said. “The findings could open the door to new approaches for managing pain in humans, but we still know very little. With additional study, it may ultimately be possible to design better diets and integrate targeted dietary changes alongside medications to improve the lives of patients with chronic pain.”