Presentation on theme: "February 21, 2014 Doug Mann, MD, Professor of Neurology"— Presentation transcript:
1 Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine February 21, 2014Doug Mann, MD,Professor of NeurologyUniversity of North Carolina, Chapel Hill
2 OutlineSpecific AimsRationale for testing dietary modification for chronic painPreliminary studies: Basic hypotheses, Chronic Daily Headache study, results from animal studiesMolecular mechanisms linking endogenously-produced lipid mediators to physical painCurrent R01 : study design, questions.Three studies:1.) Completed – CDH funded by Mayday and forms the bases of for other studies. 2 arms2.) RO1 funded Sept 2013 and about to launch: Episodic Migraine and diet arms.3.) Post traumatic headache in soldiers, pending funding: 3 arms.Quick overview some of the relevant fatty acid biochemistry useful for understanding the presentationRandomized trial – hypothesis, design, findingsusing 45Ca2+ TRPV1 assays, transcriptomics and tissue fatty acid analyses Briefly discuss Lipidomics assay - foster collaboration among NIH pain and neuroscience investigators
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 Ongoing data analysis outcomes.2.) Starting - RO1 funded Sept Episodic Migraine (EM) and diet arms. 153 subjects.3.) Pending Review - Post traumatic headache in soldiers arms.
4 Specific Aims: R01 Migraine study Clinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine
5 Study PurposeTo 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 1To 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 2To 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 3To test our model of the proposed causal chain linking changes in n-3 and n-6 PUFAs, endovanilloid derivatives, and HA endpoints.
9 rationaleClinical 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-impactingGood abortive therapies (cost & side effects)Preventive therapies overall somewhat disappointingTiming 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.
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 biomarkersNo biochemical outcomesNo consideration of diet and ratios of omega-3 to omega-6 FA intake.Active intervention for 16 weeks196 subjects (96 intervention, 87 placebo)Strong placebo effect
16 Polyunsaturated Fats in U.S. Diets 2008 n-6 AAn-3 EPA+DHAAdditive in all kinds of food – mostly carbohydrates, starting around 1960.n-6 LA7 % of energyEstimated from Day 1 of 24-hour dietary recall interviews conducted inWhat We Eat In America, NHANES
17 US per capita consumption of vegetable oils in the 20th century kg/p/y2468101214Canola0.9YearPalmPeanutSafflowerSesameSunflower0.10.20.30.18.104.22.168.81909191919291939194919591969197919891999CoconutCornCottonseedOliveSoybeanLinoleic AcidCorn oil, cottonseed, peanut soybean, safflower,Ollive oil, macadamian nut, coconut,Blasbalg et al AJCN 2011
18 US per capita apparent consumption of n-6 LA and n-3 ALA in the 20th centuryn-6 LALA 2.2n-3 ALAALA0.35Blasbalg et al AJCN 2011
19 Overview: biochemistry of n-3 and n-6 fatty acids Quick overview some of the relevant fatty acid biochemistry useful for understanding the presentation
20 Essential Dietary Fats and their Bioactive Metabolites Omega-6Omega-3Linoleic Acidα-Linolenic Acid9-HOTrEEndoVanilloidsEicosanoidsEicosapentaenoic Acid9-HODE13-HODE18-HEPEEndoVanilloidsArachidonic AcidDocosahexaenoic AcidResolvin E1EicosanoidsEndoVanilloidsKnown as essential fats because humans lack the enzymatic machinery to synthesize de novo, therefore must get from diet.Major components of nervous system tissues and glia, immune tissues. Amounts consume influence amounts in tissues Precursor POOLS FOR ENDOGENOUS SYNTHESIS OF VARIETY OF LIPID MEDIATIORS (e.g. classical eicosanoids, also endocannabinoids, endovanilloids)Extremely Take away here – oversimplified (inflammation) – presented as if we know what is going on – extremely complex, tip of the iceberg in understandingIn general and with a few notable exceptions, lipid mediators derived from n-6 LA and AA pro-nociceptive, and those derived from n-3 EPA and DHA anti-nociceptiveDocosanoids/ ProtectinsEndoCannabinoidsProstaglandin E215-HETEEndoCannabinoidsProtectin D1Docosahexaenoyl EthanolamideSynaptamideArachidonoyl Ethanolamide
21 Diet and Physical Pain: Hypotheses Targeted changes in dietary fatty acidsalter tissue fatty acids.Alters the endogenous production ofbioactive lipid mediators(e.g. eicosanoids, endovanilloids, endocannabinoids, resolvins).Alters the neurochemical milieu in a manner that mayattenuate physical pain.
22 Rationale for targeted dietary intervention General model Mechanisms linking n-3 & n-6 fatty acids to physical painGeneral model I want to provide an overview of our proposed model linking dietary n-3 and n-6 fatty acids to pain to Help understand the rationale used to design our targeted dietary interventionAs major components of vascular, immune, myelin, glial and neuronal cell membranes, n-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with putative anti-nociceptive and pro-nociceptive properties (e.g. eicosanoids, endovanilloids, resolvins)The H3-L6 intervention increases the abundance of n-3 EPA and DHA (blue) and decreasesthe abundance of n-6 LA and AA (red) in fatty acid precursor pools, including the membranesof neurons, glia, endothelial cells, platelets, and immune cells.These changes in precursor abundance alter the concentrations of n-3 and n-6 derivedanalgesic and pro-nociceptive mediators, including E-series resolvins, D-series resolvins,maresins, prostaglandins, endovanilloids, and endocannabinoids.C. Changes in the milieu of lipid mediators alter the activities of receptors involved in painsignaling, including the vanilloid receptor (TRPV1) and several G-protein coupled receptors(e.g. E-prostanoid receptors, resolvin receptors, cannabinoid receptors).D. Increases in analgesic mediators and decreases in pro-nociceptive mediators reduce painsignaling in the trigemino-vascular system and central pain signaling pathways.
23 Preliminary studiesClinical and metabolic effects of altering omega-3 and omega-6 fatty acids in migraine
24 of dietary n-3 and n-6 fatty acids for treatment of chronic headaches: Targeted alterationof dietary n-3 and n-6 fatty acidsfor treatment of chronic headaches:a randomized trialPublished detailed study methods in the journal Trials Mayday funded trial, 2 years completed in week of Thanksgiving (2011)Discuss design and methods employed briefly here today. Present some preliminary metabolic and clinical resultsRamsden 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.Population of interest.
26 Dietary Interventions H3-L6 interventionIncrease n-3 EPA and DHAReduce n-6 LAL6 interventionMaintain low n-3 EPA and DHA intakes (typical of US)Reduce n-6 LA and n-6 AATwo active interventions that were both hypothesized to have anti-nociceptive effects – one greater than otherIntegrated method –due to ubiquity LA in food supply – most challenging aspect is to reduce LA. No previous trial reduced to less than about 4 en%, goal here is about 2 en%Laboratory analyzed foods, provided all oils and fat sources, foods for 2 meals and 2 snacks per day,Web-based intervention materialsImportantly, designed to be equally intensive and credible in terms of food provision, interactions with study dietitian and other investigators, the intensity and breadth of the dietary advice and intervention materials, You’ll see later both groups reported comparable, moderate expectation benefitMacIntosh BA, Ramsden CE et al. BJN 2012
27 ‘Chronic Daily Headache’ Patient population‘Chronic Daily Headache’Headache characteristics 15 headache days per month 4 headache hours per dayChronic migrainebumpybrains.comChronic tension-type headacheRamsden CE, Faurot K, Mann JD et al., Trials 2011
28 Methods Adults meeting Inclusions/Exclusions Provided 2 meals and two snacks per dayWe provided all oils and fatsAll provided food - biochemical analyses at NIHIntensive dietary counseling by study dietitianGuidelines for cooking, shopping, dining outBaseline phase - 4 weeks; intervention 12 weeksVisits every 2 weeks during the intervention for dietary counseling and food pick up, diary review.
29 MethodsNo 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 diaryContinue 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-nociceptiveClinical and biochemical primary endpointsMultiple secondary outcome measures
31 Overview of Trial Design H3-L6 interventionL6 interventionUSUAL CARE THROUGHOUTRandomized, parallel-group clinical trialDietitian counseling and food provision every 2 weeksPatients continued usual headache care throughout trialH3-L6 intervention
32 Clinical Outcomes Headache-related quality-of-life (HIT-6) Headache days per monthHeadache hours per dayHeadache medication usePsychological distress (BSI-18)Physical and mental function (SF-12)Dual clinical and biochemical outcomes.Clinical outcome – HIT-6 (common)HA related QOL and disabilityHA diary validated UNC HA clinic PIM previous trialsBiochemical – carefully collected processed samples – first trial to lower n-6 LA
33 Biochemical OutcomesCirculating fatty acid biosynthetic precursor pools**Erythrocytes (n-6 LA, AA; n-3 EPA, DHA)Anti- and pro-nociceptive n-3 and n-6 metabolitesEicosapentaenoic 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)Dual clinical and biochemical outcomes.Clinical outcome – HIT-6 (common)HA related QOL and disabilityHA diary validated UNC HA clinic PIM previous trialsBiochemical – carefully collected processed samples – first trial to lower n-6 LARamsden CE, Mann JD et al., Trials 2011, PAIN 2013
34 Trial Profile Assessed for eligibility Total Screened: n=211 Ineligible(n=144)EnrollmentRandomized(n=67)Allocated to H3-L6 intervention(n=33)Allocated to L6 intervention(n=34)AllocationWhat I want to show you is that (1) subjects met initial eligibility critera entered 4-6 week baseline phase – headache diary, those with >15 d, 4 hours eligible. Baseline testing battery, baseline dietary assessment, blood collection70 subjects Randomized to either (1) Low n-6 diet (average US n-3 PUFAs and all other nnutrients), Half randomized to combined Low n-6, high n-3 intervention.Discontinued intervention(n=5)Discontinued intervention(n=6)Follow-UpIntention-to-treat AnalysisHIT-6 and Headache Days(n=33)Intention-to-treat AnalysisHIT-6 and Headache Days(n=34)Analysis
35 Chronic Daily Headache Patient Characteristics Also show you in a minute that average 23 headache days per month, 10 hours per day. All subjects headache physicianMore than 70% neurology headache specialist – clearly some degree of resistance to conventional pharmacologic care
36 LA, EPA and DHA Consumption in Chronic Daily Headache Trial (g)No supplements, all through the diet.*LA intake is expressed as a percentage of daily food energy (%E).Median intakes assessed via six 24-hour dietary recalls administeredon 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 Erythrocyte fatty acid serve as a representative precursor pool here. We also have very novel data 4 plasma lipid fractions but beyond scope of presentationWE HYPOTHESIZEd THAT BOTH INTERVENTIONS WILL SHOW ANTI_NOCICEPTIVE EFFECTS, AND THAT THE H3-L6 MUCH MORE PRONOUNCED CLINICAL BENFITRamsden CE, Mann JD et al., Trials 2011, PAIN 2013
39 Headache hours per day by diet group P-diff = 0.01Great deal of metabolic results from numerous collaborations, In the Remaining time focus (zero in on) one MECHANISM of interest believe has great potential for chronic pain – TRPV1Ramsden 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 Great deal of metabolic results from numerous collaborations, In the Remaining time focus (zero in on) one MECHANISM of interest believe has great potential for chronic pain – TRPV1
42 Clinical effects of the H3-L6 and L6 interventions on SF 12 SF-12 Health relatedRamsden, Faurot, Mann et al, unpublished
43 Daily ratings of general health self-reported health*204060802.4683days since randomizationH3L6Group differencep-value = 0.03**L6* 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 Great deal of biochemical/mechanistic results from numerous collaborations, In the Remaining time focus (zero in on) one MECHANISM of interest believe has great potential for chronic pain – TRPV1
46 Since the H3-L6 intervention targets some of the same pain-related biochemical pathways as common headache medications (e.g. aspirin, valproate), shared mechanisms may help explain the reductions in medication use in the H3-L6 group.
47 Results Summary The H3-L6 intervention: Produced statistically significant, clinically relevant improvements in:Headache hours per daySevere headache daysQuality of lifePhysical functionEmotional distressProduced marked alterations in circulating n-3 and n-6 derived: EndovanilloidsEicosanoidsResolvin pathway precursors – to be analyzedEndocannabinoids** to be analyzedTargeted dietary manipulation of n-3 and n-6 fatty acids reduced headache pain and improved quality-of-life in this population with chronic headaches, and could represent a novel strategy for treating chronic pain in general. Given the promising findings of this trial, future trials evaluating clinical efficacy and elucidating biochemical mechanisms in populations with chronic pain are warranted.
48 Limitations Small trial Changes in fatty acids not independent No true control groupMediators still unclearUsed only blood tissues—unable to determine if other pertinent tissues changedAlthough there was sufficient power to detect between-group differences in the targeted biochemical and clinical outcomes,
49 Potential mechanisms responsible for pain reduction Great deal of biochemical/mechanistic results from numerous collaborations, In the Remaining time focus (zero in on) one MECHANISM of interest believe has great potential for chronic pain – TRPV1
50 Attenuation of TRPV1 hyper-activation Anti-nociceptionAttenuation of TRPV1 hyper-activationIt looks like we might have had substantial clinical benefitHowever, difficult to put pieces together b/c we have almost no data on the fatty acid composition of the eVN precursor pool in relevant tissues
52 Oxidized Linoleic Acid Metabolites are TRPV1 Agonists 9-HODE13-HODE9-oxo-ODE13-oxo-ODEName enzymes:
53 D-series resolvins and NPD1 inhibit TRPV1 activation Docosahexaenoic Acid14-hydroxy-DHA17-hydroxy-DHAName enzymes:Protectin D17 (S) Maresin 1Resolvin D2
54 Endovanilloids and the neurochemistry of pain Bear with me here….only a couple of take home points from this slide…highlight at end. Identifed by David Julius, 1997, proximal or upstream – drug target. Whether you know it or not, you are familiar with this receptor if you’ve ever eaten a hot pepper.Take home points – 1) the fatty acid composition of neuron, actually other local tissues matters.2) Improved understanding of this pathway presented opportunity for highly targeted (specific) interventions, targeted toward TRPV1 – act upstream, potential to be more selective for pain than current treatments, hopeful less side effects
55 Can diet alter endovanilloids in key ‘pain tissues’? It looks like we might have had substantial clinical benefitHowever, difficult to put pieces together b/c we have almost no data on the fatty acid composition of the eVN precursor pool in relevant tissues
56 Diet-induced changes in anti- and pro-nociceptive lipid mediators in circulation Since the H3-L6 intervention targets some of the same pain-related biochemical pathways as common headache medications (e.g. aspirin, valproate), shared mechanisms may help explain the reductions in medication use in the H3-L6 group.
57 Summary & ConclusionsTargeted dietary manipulation of n-3 and n-6 fatty acids:Reduced pain and improved quality of life in chronic headacheCould represent a novel strategy for treating chronic pain in generalFuture trials evaluating clinical efficacy and elucidating biochemical mechanisms in chronic pain are warranted
58 Future DirectionsIt looks like we might have had substantial clinical benefitHowever, difficult to put pieces together b/c we have almost no data on the fatty acid composition of the eVN precursor pool in relevant tissues
59 Ramsden, Rapoport, Yuan, Remaley NIH Clinical Center LC/MS/MS assay for lipid mediators of nociception9-HODE13-HODECOX/LOX15-LOX-1MaR114-HDoHE12-LOX15-LOXNPD117-HDoHERvD1RvD2RvD3RvD4LAPGE2COX1/25-LOX5-HETELTB415-LOX-215-HETELXA4 & LXB4TXB2AADHAEPARvE118-HEPECOX2/CYPRvE212-HETEEH9-OxoODE13-OxoODEPGD2PGF2α20-OH-LTB420-COOH-LTB45,15-DiHETE5-HEPE12-HEPE15-HEPERvD5RvD64-HDoHE7-HDoHEPGE3TXB3PGD3PGF3αCYPLXA5 & LXB55,15-DiHEPERvE312/15-LOX8-HETE9-HETE11-HETERamsden, Rapoport, Yuan, RemaleyIndicates mediators assayed for Chronic Daily Headache trial
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 A—High n-3 EPA+DHA, Low n-6 LA ARM 2: Diet B—High n-3 EPA+DHA, High n-6 LAARM 3: Diet C—Low n-3 EPA+DHA, High n-6 LA (average U.S. intake; control group)
62 Overview of Trial Design Randomization,Blood CollectionStudy End,6 wk f/u,USUAL CARE THROUGHOUTRandomized, parallel-group clinical trialDietitian counseling and food provision every 2-3 weeksPatients continue usual headache care throughout trialH3-L6 intervention
63 Fatty Acid Targets Main diet changes to achieve nutrient targets: Low n-6, high n-3Ave n-6,high n-3Ave 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)1500150Main diet changes to achieve nutrient targets:Replace all oils, spreads and salad dressings with those provided by the studyAvoid processed foods that contain oils. Replace with foods provided by the studyConsume study provided fish daily (or consume low fat meat, fish and poultry on Control)NHANES data 2009 – 2010: total fat 33%, MUFA 12%, PUFA 7.2%, SF 11%, LA 6.4%, EPA+DHA 90mgThe research kitchen will prepare special oil mixes for each for each of the diets to achieve the nutrient targets. The low n-6, high n-3 diet will consume oil that is 25% EVOO and 75% Macadamia Nut Oil and butter. The Ave n-6, high n-3 and Control diet will consume 25% EVOO and 75% corn oil as will as a butter mix that is 50% butter and 50% corn oil.The high n-3 diets will receive very high n-3 canned tuna and salmon as well as from high n-3 fish. The Control group will receive low fat fish and low fat poultry products.
64 16-Wk Diet Intervention, 6-Wk f/u Personalized nutrition counseling–9 sessionsFood provision -prepared andunprepared foodsDiet education materialsDiet websiteSeven day meal planSelf-monitoring24-hr dietary recallsbaseline, intervention, post-interventionNutrition counseling – targeted and tailored counseling. Participants meet with the registered dietitian, who is experienced in research, every 2 -3 weeks.Food provision – prepared and unprepared foods that were designed or selected to meet the fatty acid targets week supply is packed out in rolling coolers during nutrition counseling visits. Foods provided approximately 2/3rd of calorie needs.Diet education materials include research diet guidelines, food lists (allowed, limit, not allowed), how to read food labels, grocery shopping guides and dining out guide.Website includes all diet education materials and access to more than 75 recipes that fit the diet guidelines.7-day meal plan helps participants plan their meals. The meal plan is available in 3 calorie levels (2,000, 2,500 and 3,000). Participants are assigned the meal plan for weight maintenance based on 35kcals/kg.Self monitoring – a daily checklist is provided to help participants stay on track. The checklist can be completed quickly and is reviewed with the dietitian during counseling.24-hr, telephone administered, dietary recalls are conducted prior to starting the diet intervention phase and in the last 4 weeks of the diet 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 Jan 18:1-10
66 Measures-Clinical (in addition to daily diary) BaselineWk4Wk 10Wk 16Wk 22DemographicsXHeadache History/Physical ExamxHIT-6PROMIS-29 ProfileComorbid pain assessmentMIDASSatisfaction with care/dietPeriodic Assessment of Care for Headaches and Pregnancy StatusExpectation of BenefitFood Preference / DispensingBlood drawALSO SEEN AT WEEKS 2,7,13 FOR FOOD PICK-UPS, REVIEW PREFERENCES AND ADVERSE EVENTS.
68 Measures-Biochemical Endovanilloids (EPA and DHA-derived TRPV1 antagonists)17-hydroxy-DHA (Primary Outcome)-precursor to D-series resolvinsDHALC/MS/MS18-HEPE-precursor to E-series resolvinsEPAEndocannabinoids2-AGAAAEA2-DHGDHEAOEAOleic acidPEAPalmitic acidEicosanoidsPGE2LTB4TXB2Lipoxin A4Other analytesSubstance PN/AELISACalcitonin gene-related peptideCytokines (IL-1, Il-6, IL-10, TNF, MCP-1)Multiplex-ELISA
69 ReferencesRamsden 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: , 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:
70 References continuedFinkel AG, Yerry, JA, Mann JD. Dietary considerations in migraine management: Does a consistent diet improve migraine? Curr Pain Headache Rep 1: ,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: , 2013.
71 Acknowledgements UNC Program on Integrative Medicine UNC Dept of Physical Medicine and RehabilitationUNC Department of Neurology.UNC NCCAM T-32 Integrative Medicine FellowshipMayday FundUNC TraCSIntramural Program of NIAAAUNC-Chapel Hill CTSAUNC NORCUNC CHAI CoreJohn M. Davis
72 Acknowledgements Chris Ramsden Douglas Mann Kim Faurot Beth MacIntosh C. SuchindranSusan GaylordDaisy ZamoraChanee LynchAngela JohnstonBecky CobleAmit RingelDavid BarrowMarjorie BusbyOlafur PalssonBeth FowlerCarol CarrTim McCaskillMerit McMannisRegina McCoyGus SwensonMeg ManganJoseph R HibbelnSharon Majchrzak-HongJim LoewkeAriel FeldsteinAlexandros MakriyannisJodi WoodTrevor MoriAnne BardenDepartments of Physical Medicine & Rehabilitationand Neurology.