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Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial.
BMJ. 2021 06 30; 374:n1448.BMJ

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.

TRIAL REGISTRATION

ClinicalTrials.gov NCT02012790.

Authors+Show Affiliations

Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA chris.ramsden@nih.gov. Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA. Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA. Department of Psychiatry, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Metabolic and Nutrition Research Core, UNC Medical Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA.Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA.Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Cytokine Analysis Core, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.Cytokine Analysis Core, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.Department of Psychiatry, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Perioperative Medicine, NIH Clinical Center, Bethesda, MD, USA.Department of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Biostatistics, Gillings School of Global Public Health, Chapel Hill, NC, USA.Department of Physical Medicine and Rehabilitation, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Neurology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34526307

Citation

Ramsden, Christopher E., et al. "Dietary Alteration of N-3 and N-6 Fatty Acids for Headache Reduction in Adults With Migraine: Randomized Controlled Trial." BMJ (Clinical Research Ed.), vol. 374, 2021, pp. n1448.
Ramsden CE, Zamora D, Faurot KR, et al. Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial. BMJ. 2021;374:n1448.
Ramsden, C. E., Zamora, D., Faurot, K. R., MacIntosh, B., Horowitz, M., Keyes, G. S., Yuan, Z. X., Miller, V., Lynch, C., Honvoh, G., Park, J., Levy, R., Domenichiello, A. F., Johnston, A., Majchrzak-Hong, S., Hibbeln, J. R., Barrow, D. A., Loewke, J., Davis, J. M., ... Mann, J. D. (2021). Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial. BMJ (Clinical Research Ed.), 374, n1448. https://doi.org/10.1136/bmj.n1448
Ramsden CE, et al. Dietary Alteration of N-3 and N-6 Fatty Acids for Headache Reduction in Adults With Migraine: Randomized Controlled Trial. BMJ. 2021 06 30;374:n1448. PubMed PMID: 34526307.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial. AU - Ramsden,Christopher E, AU - Zamora,Daisy, AU - Faurot,Keturah R, AU - MacIntosh,Beth, AU - Horowitz,Mark, AU - Keyes,Gregory S, AU - Yuan,Zhi-Xin, AU - Miller,Vanessa, AU - Lynch,Chanee, AU - Honvoh,Gilson, AU - Park,Jinyoung, AU - Levy,Russell, AU - Domenichiello,Anthony F, AU - Johnston,Angela, AU - Majchrzak-Hong,Sharon, AU - Hibbeln,Joseph R, AU - Barrow,David A, AU - Loewke,James, AU - Davis,John M, AU - Mannes,Andrew, AU - Palsson,Olafur S, AU - Suchindran,Chirayath M, AU - Gaylord,Susan A, AU - Mann,J Douglas, Y1 - 2021/06/30/ PY - 2021/9/16/entrez PY - 2021/9/17/pubmed PY - 2021/9/23/medline SP - n1448 EP - n1448 JF - BMJ (Clinical research ed.) JO - BMJ VL - 374 N2 - 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT02012790. SN - 1756-1833 UR - https://www.unboundmedicine.com/medline/citation/34526307/Dietary_alteration_of_n_3_and_n_6_fatty_acids_for_headache_reduction_in_adults_with_migraine:_randomized_controlled_trial_ L2 - https://www.bmj.com/lookup/pmidlookup?view=long&amp;pmid=34526307 DB - PRIME DP - Unbound Medicine ER -