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Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine

Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine . February 21, 2014 Doug Mann, MD, Professor of Neurology University of North Carolina, Chapel Hill. Outline. Specific Aims Rationale for testing dietary modification for chronic pain

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Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine

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  1. Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine February 21, 2014 Doug Mann, MD, Professor of Neurology University of North Carolina, Chapel Hill

  2. Outline • Specific Aims • Rationale for testing dietary modification for chronic pain • Preliminary studies: Basic hypotheses, Chronic Daily Headache study, results from animal studies • Molecular mechanisms linking endogenously-produced lipid mediators to physical pain • Current R01 : study design, questions.

  3. Studies of Diet and Chronic Pain at UNC, Program on Integrative Medicine 1.) Closed to enrollment – Chronic Daily Headache (CDH) funded by Mayday Fund 2011- 2013. Ongoing data analysis outcomes. 2.) Starting - RO1 funded Sept 2013. Episodic Migraine (EM) and diet --- 3 arms. 153 subjects. 3.) Pending Review - Post traumatic headache in soldiers --- 3 arms.

  4. Specific Aims: R01 Migraine study Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine

  5. Study Purpose To assess whether: targeted PUFA modifications designed to increase dietary n-3 EPA and DHA, with or without concurrent reduction in n-6 LA, can increase analgesic derivatives of n-3 EPA and DHA, and improve headache-related clinical outcomes.

  6. Specific Aim 1 • To assess the efficacy of the dietary interventions in inducing the predicted changes in circulating PUFA endovanilloid derivatives. • (1a) Compared to Diet C, Diet A will produce significant increases in analgesic derivatives of n-3 EPA and DHA and reductions in pro-nociceptive n-6 AA-derived and LA-derived endovanilloids. • (1b) Diet B (High n-3, High n-6 LA) will result in values for analgesic derivatives of n-3 EPA and DHA intermediate between Diet A and Diet C.

  7. Specific Aim 2 • To compare the clinical efficacy of the dietary interventions in adults with migraine. • Compared to Diet C, Diet A will produce significant improvement in: • (2a) the Headache Impact Test—a headache-specific quality of life measure, and • (2b) a significantly steeper rate of decrease in headache hours per day as compared with Diet C. • (2c) Diet B will result in changes in clinical outcomes intermediate between Diet A and Diet C.

  8. Specific Aim 3 • To test our model of the proposed causal chain linking changes in n-3 and n-6 PUFAs, endovanilloidderivatives, and HA endpoints.

  9. rationale Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine

  10. Rationale • Migraine common (16% women, 7% men) • Debilitating, painful, costly, life-impacting • Good abortive therapies (cost & side effects) • Preventive therapies overall somewhat disappointing • Timing ideal for a new strategy

  11. Rationale: food and headache • Traditional consensus with limited evidence beyond patient reports. • Neurotransmitter precursors in red wine, aged cheese, pickled foods, processed meats, other. • Allergies – gluten, dairy. • Allergy testing for specific foods. • Patient reports of specific food triggers: citrus, aspartame, caffeine, eggs, breads, other. • Elimination diet (chicken and rice) with add-backs

  12. Rationale: other potential dietary influences • Magnesiumintake as a daily supplement is effective in some with EM. No predictive elements except menses. No dietary studies. • Riboflavin as a daily supplement is effective – replicated outcomes in EM. No dietary studies. • Alpha-lipoic acid – weak clinical evidence of effectiveness in EM. No dietary studies.

  13. Migraine Co-Morbidities • Obesity --- headache (inflammation) • Crohn’s disease --- migraine • Ulcerative colitis --- migraine • Irritable bowel syndrome (Aydinlar, 2013) • Omega-6 FA consumption • Gastrointestinal symptoms • Nausea, diarrhea, cramping, bloating, pain

  14. Headache and Fatty Acids • One prior study of Omega-3 FA supplements in migraine (Pradlier, 2001) • Negative clinical, migraine-related outcomes. • Minimally affected group (average < 3 migraines/month) • No confirmation of compliance, no biomarkers • No biochemical outcomes • No consideration of diet and ratios of omega-3 to omega-6 FA intake. • Active intervention for 16 weeks • 196 subjects (96 intervention, 87 placebo) • Strong placebo effect

  15. Omega-6 Consumption 1950 to 2000

  16. Polyunsaturated Fats in U.S. Diets 2008 n-6 AA n-3 EPA+DHA n-6 LA 7 % of energy Estimated from Day 1 of 24-hour dietary recall interviews conducted in What We Eat In America, NHANES 2007-8

  17. 14 12 Soybean 10 Cottonseed Corn 8 Olive Coconut 6 4 2 kg/p/y 0 Canola 0.9 0.8 Peanut 0.7 0.6 Palm 0.5 0.4 Safflower 0.3 Sunflower 0.2 0.1 Sesame 1919 1909 1949 1959 1979 1929 1939 1969 1989 1999 Year US per capita consumption of vegetable oils in the 20th century Linoleic Acid Blasbalg et al AJCN 2011

  18. US per capita apparent consumption of n-6 LA and n-3 ALA in the 20th century n-6 LA LA 2.2 n-3 ALA ALA 0.35 Blasbalg et al AJCN 2011

  19. Overview: biochemistry of n-3 and n-6 fatty acids

  20. Essential Dietary Fats and their Bioactive Metabolites Omega-6 Omega-3 Linoleic Acid α-Linolenic Acid 9-HOTrE EndoVanilloids Eicosanoids Eicosapentaenoic Acid 18-HEPE 13-HODE 9-HODE EndoVanilloids Arachidonic Acid Docosahexaenoic Acid ResolvinE1 Eicosanoids EndoVanilloids Docosanoids/ Protectins EndoCannabinoids 15-HETE Prostaglandin E2 Protectin D1 EndoCannabinoids DocosahexaenoylEthanolamide Synaptamide ArachidonoylEthanolamide

  21. Diet and Physical Pain: Hypotheses Targeted changes in dietary fatty acids alter tissue fatty acids. Alters the endogenous production of bioactive lipid mediators (e.g. eicosanoids, endovanilloids, endocannabinoids, resolvins). Alters the neurochemical milieu in a manner that may attenuatephysical pain.

  22. Rationale for targeted dietary intervention General modelMechanisms linking n-3 & n-6 fatty acids to physical pain

  23. Preliminary studies Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine

  24. Targeted alteration of dietary n-3 and n-6 fatty acids for treatment of chronic headaches: a randomized trial Ramsden CE, Faurot K, Mann JD et al., Trials 2011, BJN 2012, PAIN 2013

  25. Chronic Daily Headache • Up to 5% of adults. Migraine - 16 and 6 % • 15 or more headache days per month. • HA for 4 hours or more per headache day. • Six months or more duration. • With or without migraine features. • Excluded “organic causes”. • Medication responses considered in the dx.

  26. Dietary Interventions • H3-L6 intervention • Increase n-3 EPA and DHA • Reduce n-6 LA • L6 intervention • Maintain low n-3 EPA and DHA intakes (typical of US) • Reduce n-6 LA and n-6 AA MacIntosh BA, Ramsden CE et al. BJN 2012

  27. ‘Chronic Daily Headache’ Patient population Headache characteristics •  15 headache days per month •  4 headache hours per day Chronic migraine bumpybrains.com Chronic tension-type headache Ramsden CE, Faurot K, Mann JD et al., Trials 2011

  28. Methods • Adults meeting Inclusions/Exclusions • Provided 2 meals and two snacks per day • We provided all oils and fats • All provided food - biochemical analyses at NIH • Intensive dietary counseling by study dietitian • Guidelines for cooking, shopping, dining out • Baseline phase - 4 weeks; intervention 12 weeks • Visits every 2 weeks during the intervention for dietary counseling and food pick up, diary review.

  29. Methods • No supplements: requested they not start on them during the study. • Not given other dietary suggestions relating to traditional consensus advice re: diet. • If they were on fish oil or PUFAs for headache, they were excluded. • Web based headache diary • Continue care with neurologist or other MD.

  30. Methods • Arm 1. Low omega-6 (L6) • Arm 2. Low omega-6, high omega-3 (L6 H3) • Both possibly anti-nociceptive • Clinical and biochemical primary endpoints • Multiple secondary outcome measures

  31. Overview of Trial Design • Randomized, parallel-group clinical trial H3-L6 intervention L6 intervention • Dietitian counseling and food provision every 2 weeks • Patients continued usual headache care throughout trial H3-L6 intervention

  32. Clinical Outcomes • Headache-related quality-of-life (HIT-6) • Headache days per month • Headache hours per day • Headache medication use • Psychological distress (BSI-18) • Physical and mental function (SF-12)

  33. Biochemical Outcomes • Circulating fatty acid biosynthetic precursor pools • **Erythrocytes (n-6 LA, AA; n-3 EPA, DHA) • Anti- and pro-nociceptive n-3 and n-6 metabolites • Eicosapentaenoicacid (e.g. 18-HEPE) • Docosahexaenoicacid (e.g. 17-HDHA) • Linoleic acid (e.g. 9- and 13-HODE and -oxoODEs) • Arachidonic acid (e.g. 5-, 8-, 9-, 11-, 12-, 15-HETE) Ramsden CE, Mann JD et al., Trials 2011, PAIN2013

  34. Trial Profile Assessed for eligibility Total Screened: n=211 Ineligible (n=144) Enrollment Randomized (n=67) Allocated to H3-L6 intervention (n=33) Allocated to L6 intervention (n=34) Allocation Discontinued intervention (n=5) Discontinued intervention (n=6) Follow-Up Intention-to-treat Analysis HIT-6 and Headache Days (n=33) Intention-to-treat Analysis HIT-6 and Headache Days (n=34) Analysis

  35. Chronic Daily Headache Patient Characteristics

  36. LA, EPA and DHA Consumption in Chronic Daily Headache Trial (g) *LA intake is expressed as a percentage of daily food energy (%E). Median intakes assessed via six 24-hour dietary recalls administered on non-consecutive days. MacIntosh BA, Ramsden CE, Mann JD et al. BJN 2012

  37. Diets altered erythrocyte fatty acid content in a manner predicted to reduce physical pain Ramsden CE, Mann JD et al., Trials 2011, PAIN2013

  38. H3-L6 intervention produced greater pain reduction Severe Headache days Headache days/ month 0 HIT-6 Headache hours/ day -10 -20 L6 H3-L6 % change (12 weeks) -30 -40 -50 Between-group comparisons p<.001 p<.02 p<.02 p<.01

  39. Headache hours per day by diet group P-diff = 0.01 Ramsden CE, Mann JD et al., Trials 2011, PAIN2013

  40. Was clinical improvement due to increased medication use?

  41. Change in medication use by diet group

  42. Clinical effects of the H3-L6 and L6 interventions on SF 12 Ramsden, Faurot, Mann et al, unpublished

  43. Daily ratings of general health H3L6 0 . 3 • Group difference • p-value = 0.03** 8 . self-reported health* 2 L6 6 . 2 4 . 2 0 20 40 60 80 days since randomization * 1= poor; 4= excellent ** Proportional odds longitudinal model, group x time interaction

  44. Clinical effects of the H3-L6 and L6 interventionson psychological distress (BSI-18) Ramsden, Faurot, Mann et al, unpublished

  45. Diet-induced changes in anti- and pro-nociceptive lipid mediators

  46. Results Summary The H3-L6 intervention: Produced statistically significant, clinically relevant improvements in: Headache hours per day Severe headache days Quality of life Physical function Emotional distress Produced marked alterations in circulating n-3 and n-6 derived: Endovanilloids Eicosanoids Resolvin pathway precursors – to be analyzed Endocannabinoids** to be analyzed

  47. Limitations • Small trial • Changes in fatty acids not independent • No true control group • Mediators still unclear • Used only blood tissues—unable to determine if other pertinent tissues changed

  48. Potential mechanisms responsible for pain reduction

  49. Attenuation of TRPV1 hyper-activation Anti-nociception

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