Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo

Abstract

Omega-3 polyunsaturated fatty acids (OPFA) have beneficial effects on inflammatory reactions and production of cytokines. They decrease the release of 5HT by platelets and possess vasorelaxant activity. This led them to be tried in the prophylactic treatment of migraine. After 4 weeks of a single-blind placebo run-in period, patients were randomized and treated in double-blind condition by placebo or OPFA 6 g a day for 16 weeks, followed by a 4-week placebo run-out period. The intention to treat population included 196 patients. Those who received all four treatment periods included 96 patients taking OPFA and 87 taking placebo. The primary efficacy analysis was the number of migraine attacks during the last 4 weeks of treatment. During this period, the mean number of attacks was 1.20 +/- 1.40 in the OPFA group and 1.26 +/- 1.11 in the placebo group (NS). The total number of attacks during the 4-month period of the study was significantly different between groups: 7.05 in the placebo group, 5.95 in the OPFA group (P = 0.036). Mean intensity, mean duration of the attacks and rescue medication use, were not significantly different between the two groups. Except for a significant difference against OPFA for eructations, the tolerance was satisfying. Despite a run-in placebo period of 1 month, a very strong placebo effect was observed in this trial: 45% reduction of the attacks between run-in and 4-month treatment period (55% in the OPFA group, P = 0.058). Finally, this large study did not confirm two previous studies based on a small number of patients.

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

“…Demonstration of adherence via dietary recalls and erythrocyte fatty acid analyses [29] is an improvement over a previous n-3 supplementation trial in migraineurs [37]. The demonstration of significant alterations in fatty acids and lipid mediators along the proposed causal chain linking diet to physical pain, with consistent directionality in both clinical and biochemical end points, is another strength of the present trial.…”

“…The only randomized controlled trial to test n-3 supplementation in a migraine population showed no clinical benefit [37], despite providing a dose of EPA + DHA comparable to our H3-L6 intervention. A possible explanation for this discrepancy is that the dietary n-6-lowering component of our H3-L6 intervention may be necessary to produce maximal clinical benefit.…”

“…A possible explanation for this discrepancy is that the dietary n-6-lowering component of our H3-L6 intervention may be necessary to produce maximal clinical benefit. Although the n-3 supplementation trial in migraineurs did not report biochemical outcomes [37], n-3 supplementation is known to increase circulating EPA + DHA and bioactive n-3 derivatives [30], and to reduce AA and bioactive AA derivatives. The H3-L6 intervention in the present trial differs from previous trials because it not only increased n-3 fatty acids, but also markedly reduced dietary n-6 LA, which competes with n-3 fatty acids for hepatic desaturation, tissue incorporation, and enzymatic conversion to bioactive derivatives [17,24,29,33,39].…”

Balancing proportions of competing omega-3 and omega-6 highly unsaturated fatty acids (HUFA) in tissue lipids

“…A 2001 study [32] reported that increased intakes of n-3 HUFA failed to give a significant difference in the number of pain attacks in the last 4 weeks of the comparative treatment period. In contrast, a 2013 report [33] used concepts mentioned in the introduction to design sufficient lowering of the competing n-6 nutrients for three months to lower the %n-6 in HUFA of erythrocytes from 78% to 74%.…”

Capillary Endothelial Na+, K+, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology

“…A reduction in polyunsaturated fatty acids (PUFAs) or increase in saturated fatty acids in membranes inhibit NKAT activity; we suggest that counteracting this inhibition with PUFA supplements may be the basis for the improved migraine symptoms reported from one open and one blinded trial, 94,95 though another double-blinded trial failed to show that PUFA supplements prevented migraine. 96 Hormonal changes, especially peri-menstrually, are known to trigger more frequent and severe migraine. We propose that 2 mechanisms from the NKAT theory may be responsible: Estrogens activate NKAT by signal transduction (Table 2); and, similar to cholesterol, estrogens influence membrane fluidity-based changes in NKAT activity.…”