In general, the lipid mediators derived from the n-6 PUFA (polyunsaturated fatty acid) arachidonic acid are pro-inflammatory and pronociceptive (increase pain), while those from n-3 LC-PUFAs are less inflammatory. DHA and EPA (found in fish oil) also give rise to several compounds (resolvins, protectins and maresins) that are anti-inflammatory, pro-resolving and pain-reducing. These distinctions suggest that dietary manipulations to reduce n-6 PUFAs and increase n-3 LC-PUFAs might contribute to the effective management of pain.
This study was designed to explore this in patients with chronic daily headache. The patients were assigned to either:
diet high in n-3 LC-PUFAs (long chain poly-unsaturated fatty acids) and low in linoleic acid (n-6 fatty acid)
diet only low in linoleic acid.
The investigators examined headache-related clinical outcomes, red blood cell fatty acids and pro- and anti-nociceptive derivatives of these PUFA families. The primary outcome was headache hours per day.
Sixty-seven participants were recruited who had headaches ≥ 4 hours per day for ≥ 15 days per month for at least 3 months and a headache history of ≥ 2 years under physician headache management. Participants with headaches secondary to head or neck trauma, cranial or cervical vascular disorder, substance use or withdrawal and certain other conditions were ineligible. A neurologist classified the type of headache as chronic migraine, chronic daily headache with migraine features or chronic daily headache without migraine. Approximately 87% of participants were female, with an average age of 42 years.
After a 4-week run-in phase, participants were randomly allocated to consume either the low n-6 PUFA/high n-3 LC-PUFA diet or the low n-6 PUFA diet for 12 weeks.
The investigators calculated the total highly unsaturated fatty acids (HUFA, unsaturated fatty acids with ≥ 4 double bonds) in the red blood cells and the proportion of n-6 PUFA in the total HUFA, as well as the n-3 index, the sum of EPA and DHA. They measured anti-nociceptive mediators derived from EPA and DHA, pro-nociceptive mediators derived from linoleic and arachidonic acids.
To assess headache-related disability, participants completed the Headache Impact Test (HIT-6) at randomization and on the final day of the 12-week intervention and completed a daily headache diary for the run-in and experimental periods to determine the number of headache days. The HIT-6 test covers six categories of the effects of headache. The investigators monitored the number and type of medications used at the beginning and end of the study.
At 12 weeks, both groups had significant improvements in all clinical outcomes, but the improvements were significantly greater in those on the low n-6/high n-3 LC-PUFA diet. There were also significantly fewer patients on the low n-6/high n-3 LC-PUFA diet who used any pain-related acute or adjunctive medication at the end of the study compared with baseline.
Both groups achieved significant reductions in red blood cell n-6 HUFA score and significant increases in the omega-3 index, with changes substantially greater in the low n-6/high n-3 LC-PUFA group. It is worth noting that simply reducing the consumption of n-6 PUFAs without adding n-3 LC-PUFAs was associated with a significant increase in red blood cell EPA and DHA. Only the low n-6/high n-3 LC-PUFA group had significantly reduced red blood cell arachidonic acid levels (change, 14.3 to 12.3, P = 0.001 vs 14.2 to 13.2, NS), even though the low n-6 PUFA group reduced their dietary intake of arachidonic acid by half. This observation suggests that red blood cell concentrations of arachidonic acid are tightly regulated.
The low-n-6/high n-3 LC-PUFA diet was also associated with significant increases in the precursors of EPA- and DHA-derived resolvins, which have anti-nociceptive properties, and decreases in several pro-nociceptive eicosanoid derivatives of linoleic acid and arachidonic acid. Interestingly, the low n-6 PUFA diet was associated with lower levels of some pro-nociceptive derivative HETEs, even though their precursor levels did not change. This group also had increased anti-nociceptive precursors, which was probably related to the higher EPA and DHA levels observed in their red blood cells. The authors suggest that these changes might have resulted from reduced metabolic competition between n-6 and n-3 LC-PUFAs.
The key finding from this study was the significant marked reduction in chronic headache pain, as observed in fewer headache hours per day, fewer headache days per month and clinically improved quality of life among chronic headache patients consuming a diet low in n-6 PUFA and high in n-3 LC-PUFAs. There were modest improvements in headache pain with the low n-6 PUFA diet (Table), but none were comparable to the changes with the combined dietary PUFA alterations. The combined dietary changes were also associated with a significant reduction in the consumption of acute and chronic pain medications and red blood cell arachidonic acid concentrations. Changes in the concentrations of the PUFA-derived anti- and pro-nociceptive mediators, such as resolvins and prostaglandins suggest that these substances might contribute to the clinical improvements observed. More detailed studies could confirm and extend these observations.
These results were superior to other studies that simply supplemented with EPA and DHA without restricting n-6 fats.
This study adds to the growing body of evidence showing clinical usefulness of fish oil supplementation in the context of other dietary fatty acid intake.
Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial
Ramsden CE, Faurot KR, Zamora D, Suchindran CM, Macintosh BA, Gaylord S, Ringel A, Hibbeln JR, Feldstein AE, Mori TA, Barden A, Lynch C, Coble R, Mas E, Palsson O, Barrow DA, Mann JD.
Pain. 2013 Nov;154(11):2441-51. doi: 10.1016/j.pain.2013.07.028. Epub 2013 Jul 22.
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.