1. Dietary modulation of nociceptive mediators and physical pain 3 October 2015 Christopher Ramsden, MD LCDR, USPHS, Clinical Investigator Section on Nutritional Neurosciences LMBB, NIAAA, National Institutes of Health Adjunct Assistant Professor UNC-Chapel Hill This presentation does not represent any policy or position of the US Federal Government. It is solely the scientific opinion of the presenter.

2. Disclosures: None

3. Outline Overview: Fatty acids and their autacoid derivatives Randomized trial: Targeted alteration of dietary n-3 and n-6 fatty acids for treatment of Chronic Daily Headache Investigation of molecular mechanisms linking endogenously-produced lipid mediators to physical pain Rationale for testing dietary modification for chronic pain Chronic pain as a public health challenge Future Directions

4. Chronic Pain as a public health challenge Institute of Medicine Report on Chronic Pain: ≈ 30% of the U.S. adults ≈ $600 billion in annual expenditures Current treatments: limited effectiveness, substantial side effects Few new classes of pain medications the past several decades

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

6. 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-6 Omega-3

7. 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 attenuates physical pain.

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

9. Development of 2 putative anti-nociceptive dietary interventions

10. 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

11. (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.

13. ‘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, Hibbeln, JR Mann JD et al., Trials 2011 bumpybrains.com Patient population

14. 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

15. 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

16. 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 mediators

17. PAIN 2013 Trial Profile

18. Characteristics of 67 patients with Chronic Daily Headache

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

20. % 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

21. Clinical effects of the H3-L6 and L6 interventions (1) Ramsden CE, Mann JD et al., Trials 2011, PAIN 2013

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

23. Diet-induced changes in anti- and pronociceptive lipid mediators

25. Associations between 12-week changes in plasma fatty acids and pain, quality of life and psychological stress Ramsden CE, Mann JD et al., J of Pain 2015

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

27. Limitations The present trial was small and should be replicated in a larger trial. Targeted fatty acids were not altered as controlled variables. The present trial cannot establish whether diet-induced biochemical alterations are possible in other tissues implicated in headache pathogenesis (e.g. trigeminal nerve, skeletal muscle). The H3-L6 intervention should also be evaluated in comparison to a control intervention providing habitual intakes of the targeted dietary fatty acids.

28. Can diet alter nociceptive mediators in key ‘pain tissues’? Rodent LA dose response trial (0.4, 5, 10 %E) Tissues (n=12) associated with: Idiopathic or poorly understood pain syndromes Pain signaling pathways (nervous system)

29. Effect of increasing dietary LA on peripheral tissues

30. Central Nervous System

31. Diet-induced changes in nociceptive mediators

32. NIH Clinical Center LC/MS/MS assay for lipid mediators of nociception

33. Future Directions Clinical efficacy Episodic Migraine (n=156) Post-traumatic Headaches (n=84) Chronic Lumbosacral Radicular Pain (n=72) PI: Kevin Carneiro Bipolar disorder (migraine) (n=84) Healthy volunteers (n=84) Elucidation of mechanisms Rodent pain behavior assays DRG and Dorsal Horn nociceptor assays LC/MS-MS nociceptive mediator assays

34. QUESTIONS

35. Acknowledgements UNC Headache Trial J. Douglas Mann Kim Faurot Beth MacIntosh Daisy Zamora Amit Ringel C. Suchindran Susan Gaylord Chanee Lynch Becky Coble David Barrow Marjorie Busby Oli Palsson Beth Fowler Carol Carr Tim McCaskill Merit McMannis Regina McCoy Gus Swenson Meg Mangan Joseph R Hibbeln John M. Davis Sharon Majchrzak-Hong Jim Loewke Ariel Feldstein Alexandros Makriyannis Jodi Wood Trevor Mori Anne Barden

36. Acknowledgements (funding) Mayday Fund* UNC NCCAM Integrative Medicine Fellowship Intramural Program of NIAAA UNC-Chapel Hill CTSA UNC NORC UNC CHAI Core John M. Davis North American Spine Society