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.
Key Points
Migraine is among the largest causes of disability worldwide. Several oxylipins derived from n-6 fatty acids have pain promoting properties. several oxylipins derived from n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have potent antinociceptive (pain reducing) properties. 17-hydroxydocosahexaeonic acid (17-HDHA) is the pathway precursor for several families of oxylipins reported to have potent anti-pain effects in experimental models, and has been linked to lower pain scores in patients with arthritis. These oxylipins can also be derived from alpha-linolenic acid.
This study investigated the biochemical and clinical effects of two active diets (one increasing n-3 EPA+DHA alone (H3) and one with concurrent reduction in n-6 linoleic acid (H3-L6)) compared with a control diet containing average amounts (in the United States) of n-3 EPA+DHA and n-6 linoleic acid in adults with chronic and episodic migraine. It was hypothesized that both active diets would increase circulating 17-HDHA and alter other antinociceptive oxylipins in a manner that would decrease the frequency and severity of headache pain and therefore improve headache impact on quality of life. It was further hypothesized that the H3-L6 diet would produce more pronounced biochemical alterations and pain reduction compared with the H3 diet.
Overall, 182 participants were randomized to one of three diets: H3-L6 (n=61), H3 (n=61), or control (n=60); 154 of the 182 randomized participants (85%) completed ≥10 weeks of intervention, and 141 (77%) completed the 16 week intervention. The study enrolled 182 patients (88% female; average age 38 years) with migraine headaches on 5-20 days per month who were randomly assigned to one of three diets for 16 weeks. The control diet included typical levels of omega 3 and omega 6 fatty acids. One of the interventional diets kept omega 6 acid intake the same as the control, while the other lowered omega 6 acid intake. The participants to complete the headache impact test (HIT-6) – a questionnaire evaluating headache impact on quality of life. Headache frequency was also noted.
The results found a high omega 3 (H3) diet to be more beneficial in contrast to a diet that blended omega 3 and omega 6 fatty acids. The mean baseline-adjusted headache hours per day at end of study were 4.9 (95% confidence interval 4.2 to 5.6) in the control group, 3.6 (3.1 to 4.1) in the H3 group, and 3.2 (2.8 to 3.7) in the H3-L6 group. Compared with the control group, the H3 and the H3-L6 groups significantly reduced the number of total headache hours per day (−1.3, −2.1 to −0.5, and −1.7, −2.5 to −0.9, respectively) and moderate to severe headache hours per day (−0.7, −1.1 to −0.3, and −0.8, −1.2 to −0.4, respectively. Results also revealed both interventional diets increased levels of the pain-reducing oxylipin 17-hydroxydocosahexaenoic acid (17-HDHA) when compared with the control diet. HIT-6 scores improved in both interventional groups although they were not considered statistically significantly different from the control group.
Future research should include testing the H3-L6 intervention in other populations with chronic pain; and evaluating whether decreasing dietary linoleic acid to lower levels or administering the interventions for longer duration would result in greater pain reduction because turnover of polyunsaturated fatty acids in relevant tissues could take years.