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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.

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Presentation on theme: "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."— Presentation transcript:

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 Testa 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, endovanilloid derivatives, 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 Magnesium intake 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) Crohns 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 Estimated from Day 1 of 24-hour dietary recall interviews conducted in What We Eat In America, NHANES 2007-8 n-6 LA n-6 AA n-3 EPA+DHA 7 % of energy

17 US per capita consumption of vegetable oils in the 20 th century Blasbalg et al AJCN 2011 kg/p/y 0 2 4 6 8 10 12 14 Canola 0.9 Year Palm Peanut Safflower Sesame Sunflower 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 1909 1919 19291939 19491959 1969 1979 1989 1999 Coconut Corn Cottonseed Olive Soybean Linoleic Acid

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

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

20 Linoleic Acid 9-HODE Arachidonic Acid Prostaglandin E2 Arachidonoyl Ethanolamide 15-HETE α-Linolenic Acid 9-HOTrE Eicosapentaenoic Acid Docosahexaenoic Acid Resolvin E1 18-HEPE Docosahexaenoyl Ethanolamide Protectin D1 EndoVanilloids Eicosanoids EndoCannabinoids EndoVanilloids Docosanoids/ Protectins Synaptamide Essential Dietary Fats and their Bioactive Metabolites Eicosanoids 13-HODE EndoCannabinoids EndoVanilloids Omega-6Omega-3

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 attenuate physical pain.

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

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

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 H3-L6 intervention Dietitian counseling and food provision every 2 weeks Patients continued usual headache care throughout trial

32 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) Clinical Outcomes

33 **Erythrocytes (n-6 LA, AA; n-3 EPA, DHA) Ramsden CE, Mann JD et al., Trials 2011, PAIN 2013 Biochemical Outcomes Eicosapentaenoic acid (e.g. 18-HEPE) Docosahexaenoic acid (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) Circulating fatty acid biosynthetic precursor pools Anti- and pro-nociceptive n-3 and n-6 metabolites

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

35 Chronic Daily Headache Patient Characteristics

36 (g) MacIntosh BA, Ramsden CE, Mann JD et al. BJN 2012 LA, EPA and DHA Consumption in Chronic Daily Headache Trial *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.

37 Diets altered erythrocyte fatty acid content in a manner predicted to reduce physical pain Ramsden CE, Mann JD et al., Trials 2011, PAIN 2013

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

39 P-diff = 0.01 Headache hours per day by diet group Ramsden CE, Mann JD et al., Trials 2011, PAIN 2013

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 self-reported health* 020406080 2. 4 2. 6 2. 8 3. 0 days since randomization Daily ratings of general health Group difference p-value = 0.03** H3L6 L6L6 * 1= poor; 4= excellent ** Proportional odds longitudinal model, group x time interaction

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

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

46

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

48 Limitations Small trial Changes in fatty acids not independent No true control group Mediators still unclear Used only blood tissuesunable to determine if other pertinent tissues changed

49 Potential mechanisms responsible for pain reduction

50 Attenuation of TRPV1 hyper-activation Anti-nociception

51 TRPV1-mediated neurogenic inflammatory cascade Substance P CGRP TRPV1 Physical Pain Anxiety Alcohol Craving NK1 Recept or Physical Pain Vasodilation Tolerance Dependence Withdrawal CGRP Recept or pH Heat + - Endogenous vanilloid agonists Endogenous vanilloid agonists Endogenous vanilloid inhibitors Endogenous vanilloid inhibitors

52 Linoleic Acid 9-HODE Oxidized Linoleic Acid Metabolites are TRPV1 Agonists 13-HODE 9-oxo-ODE13-oxo-ODE

53 D-series resolvins and NPD1 inhibit TRPV1 activation Docosahexaenoic Acid Resolvin D2 Protectin D1 17-hydroxy-DHA 7 (S) Maresin 1 14-hydroxy-DHA

54 Endovanilloids and the neurochemistry of pain

55 Can diet alter endovanilloids in key pain tissues?

56 Diet-induced changes in anti- and pro-nociceptive lipid mediators in circulation

57 Summary & Conclusions Targeted dietary manipulation of n-3 and n-6 fatty acids: Reduced pain and improved quality of life in chronic headache Could represent a novel strategy for treating chronic pain in general Future trials evaluating clinical efficacy and elucidating biochemical mechanisms in chronic pain are warranted

58 Future Directions

59 8-HETE 9-HETE 11-HETE Ramsden, Rapoport, Yuan, Remaley Indicates mediators assayed for Chronic Daily Headache trial NIH Clinical Center LC/MS/MS assay for lipid mediators of nociception

60 DESIGN OF R01 TRIAL: DIET AND MIGRAINE Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine

61 Three arm trial ARM 1: Diet AHigh n-3 EPA+DHA, Low n-6 LA ARM 2: Diet BHigh n-3 EPA+DHA, High n-6 LA ARM 3: Diet CLow n-3 EPA+DHA, High n-6 LA (average U.S. intake; control group)

62 Overview of Trial Design Randomized, parallel-group clinical trial H3-L6 intervention Dietitian counseling and food provision every 2-3 weeks Patients continue usual headache care throughout trial Randomization, Blood Collection Study End, Blood Collection 6 wk f/u, Blood Collecti on

63 Fatty Acid Targets Main diet changes to achieve nutrient targets: Replace all oils, spreads and salad dressings with those provided by the study Avoid processed foods that contain oils. Replace with foods provided by the study Consume study provided fish daily (or consume low fat meat, fish and poultry on Control) FatLow n-6, high n-3 Ave n-6, high n-3 Ave n-6, Ave n- 3 (Control) Total Fat (%en)30% Monounsaturated (%en)15%12% Polyunsaturated (%en)4%7.5% Saturated Fat (%en)11% Linoleic acid (n-6) (%en)2%7.2% EPA + DHA (mg)1500 150

64 16-Wk Diet Intervention, 6-Wk f/u Personalized nutrition counseling–9 sessions Food provision -prepared and unprepared foods Diet education materials Diet website Seven day meal plan Self-monitoring 24-hr dietary recalls baseline, intervention, post-intervention Diet Methods Paper: MacIntosh BA, Ramsden CE, Raurot KR, Zamora D, Mangan M, Hibbeln JR, Mann JD. Low n-6 and low n-6 plus high n-3 diets for use in clinical research. Br J Nutr. 2013 Jan 18:1-10

65 Meal Plan Comparisons

66 Measures-Clinical (in addition to daily diary) Base line Wk 0 Wk 4 Wk 10 Wk 16 Wk 22 DemographicsX Headache History/Physical ExamXx HIT-6XXXXXX PROMIS-29 ProfileXXXXXX Comorbid pain assessmentXxxxxx MIDASXX Satisfaction with care/dietXXXXX Periodic Assessment of Care for Headaches and Pregnancy Status XXXXX Expectation of BenefitX Food Preference / DispensingXXX Blood drawXXXXX

67 Measures-Biochemical AnalyteFormulaMethod n-6 fatty acids LA18:2 n-6GC AA20:4 n-6GC DTA22:4 n-6GC DPA n-622:5 n-6GC n-3 fatty acids ALA18:3 n-3GC EPA20:5 n-3GC DPA (n-3)22:5 n-3GC DHA22:6 n-3GC Omega-3 IndexEPA + DHAGC Other fatty acids Palmitic acid16:0GC Oleic acid18:1 n-9GC Precursor Endovanilloids (LA and AA-derived TRPV1 agonists) 9-HODELALC/MS/MS 13-HODELALC/MS/MS 9-oxoODELALC/MS/MS 13-oxoODELALC/MS/MS 12-HETEAALC/MS/MS 15-HETEAALC/MS/MS

68 Measures-Biochemical Endovanilloids (EPA and DHA-derived TRPV1 antagonists) 17-hydroxy-DHA (Primary Outcome) -precursor to D-series resolvins DHALC/MS/MS 18-HEPE -precursor to E-series resolvins EPALC/MS/MS Endocannabinoids 2-AGAALC/MS/MS AEAAALC/MS/MS 2-DHGDHALC/MS/MS DHEADHALC/MS/MS OEAOleic acidLC/MS/MS PEA Palmitic acidLC/MS/MS Eicosanoids PGE2AALC/MS/MS LTB4AALC/MS/MS TXB2AALC/MS/MS Lipoxin A4AALC/MS/MS Other analytes Substance PN/AELISA Calcitonin gene-related peptideN/AELISA Cytokines (IL-1, Il-6, IL-10, TNF, MCP-1)N/AMultiplex-ELISA

69 References Ramsden CE, Mann JD, Faurot KR, Lynch C, Imam ST, MacIntosh BA, Hibbeln JR, Loewke J, Smith S, Coble R, Suchindran C and Gaylord SA. Low omega-6 vs. low omega-6 plus high omega-3 dietary intervention for Chronic Daily Headache: Protocol for a randomized clinical trial. Trials Journal 12: 97-105, 2011. MacIntosh BA, Ramsden CE, Faurot KR, Zamora D, Mangan M, Hibbeln JR, Mann JD. Low n-6 and low n-6 plus high n-3 diets for use in clinical research. Br J Nutr. 18: 1-10, 2013. Ramsden CE, Ringel A, Feldstein AE, Taha AY, Macintosh BA, Hibbeln JR, Majchrzak- Hong SF, Faurot KR, Rapoport SI, Cheon Y, Chung Y, Berk M, Mann, JD. Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essential Fatty Acids 87: 135-141. 2012.

70 References continued Finkel AG, Yerry, JA, Mann JD. Dietary considerations in migraine management: Does a consistent diet improve migraine? Curr Pain Headache Rep 1: 373-376, 2013. 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. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain, 154: 2441-51, 2013.

71 Acknowledgements UNC Program on Integrative Medicine UNC Dept of Physical Medicine and Rehabilitation UNC Department of Neurology. UNC NCCAM T-32 Integrative Medicine Fellowship Mayday Fund UNC TraCS Intramural Program of NIAAA UNC-Chapel Hill CTSA UNC NORC UNC CHAI Core John M. Davis

72 Acknowledgements Chris Ramsden Douglas Mann Kim Faurot Beth MacIntosh C. Suchindran Susan Gaylord Daisy Zamora Chanee Lynch Angela Johnston Becky Coble Amit Ringel David Barrow Marjorie Busby Olafur Palsson Beth Fowler Carol Carr Tim McCaskill Merit McMannis Regina McCoy Gus Swenson Meg Mangan Joseph R Hibbeln Sharon Majchrzak-Hong Jim Loewke Ariel Feldstein Alexandros Makriyannis Jodi Wood Trevor Mori Anne Barden Departments of Physical Medicine & Rehabilitation and Neurology.


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