Do Omega-6 and Trans Fatty Acids Play a Role in Complex Regional Pain Syndrome? A Pilot Study

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Do Omega-6 and Trans Fatty Acids Play a Role in Complex Regional Pain Syndrome? A Pilot Study
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  Do Omega-6 and  Trans  Fatty Acids Play aRole in Complex Regional Pain Syndrome? A Pilot Study  pme_882 1115..1125 Christopher Ramsden, MD,* Christine Gagnon,PhD,* Joseph Graciosa, BS, † Keturah Faurot,MPH, ‡ Robert David, PhD, § J. Alexander Bralley,PhD, § and R. Norman Harden, MD* *Rehabilitation Institute of Chicago, Department ofPhysical Medicine and Rehabilitation, NorthwesternUniversity Feinberg School of Medicine, Chicago,Illinois; † Rehabilitation Institute of Chicago, NorthwesternUniversity Feinberg School of Medicine, Chicago,Illinois; ‡ Department of Physical Medicine and Rehabilitation,Program on Integrative Medicine, University of NorthCarolina Chapel Hill School of Medicine, Chapel Hill,North Carolina; § Metametrix Clinical Laboratory, Atlanta, Georgia, USA Reprint requests to:  Christopher Ramsden, MD,National Institutes of Health, MSC 2088 31 CenterDrive Rm. 1B58, Bethesda, MD 20892, USA. Tel:919-381-7630; Fax: 301-443-6076; E-mail:chris.ramsden@nih.gov.  Abstract Objectives. Thestudyaimstocomparetheomega-6(n-6) and omega-3 (n-3) highly unsaturated fattyacids (HUFA), and  trans   fatty acid ( trans   FA) statusof Complex Regional Pain Syndrome (CRPS)patients to pain-free controls.Design. Case control study.Setting. The setting was at a multidisciplinary reha-bilitation center.Patients. Twenty patients that met the Budapestresearch diagnostic criteria for CRPS and 15 pain-free control subjects were included in this study.Outcome Measures. Fasting plasma fatty acidswere collected from all participants. In CRPSpatients, pain was assessed using the McGillPainQuestionnaire—ShortForm.Inaddition,resultsfrom the perceived disability (Pain Disability Index),pain-related anxiety (Pain Anxiety Symptom ScaleShort Form), depression (Center for Epidemio-logic Studies Depression Scale Short Form), andquality of life (Short Form-36 [SF-36]) wereevaluated.Results. Compared with controls, CRPS patientsdemonstrated elevated concentrations of n-6 HUFAand  trans   FA. No differences in n-3 HUFAconcentra-tions were observed. Plasma concentrations of then-6 HUFA docosatetraenoic acid were inversely cor-related with the “vitality” section of the SF-36.  Trans  FA concentrations positively correlated with pain-related disability and anxiety.Conclusion. These pilot data suggest that elevatedn-6 HUFA and  trans   FA may play a role in CRPSpathogenesis. These findings should be replicated,and more research is needed to explore the clinicalsignificance of low n-6 and  trans   FA diets with orwithout concurrent n-3 HUFA supplementation, forthe management of CRPS.Key Words. CRPS; Omega-6; Omega-3; Trans FattyAcids; Arachidonic Acid; Chronic Pain Introduction Complex Regional Pain Syndrome (CRPS) is a disablingneurological disorder that follows injury to peripheralnerves or their soft tissue innervations [1]. The mostprominent feature of CRPS is refractory persistent pain,usually in a distal limb. Pain is typically accompanied byvasomotor and sudomotor changes, edema, trophicchanges, and impaired motor function [1]. While theunderlying biologic mechanisms are not fully known,accumulating evidence suggests that sustained immuneactivation may participate in the development and per-petuation of CRPS [2–4]. Further evidence indicates thatCRPS is characterized by major changes in the structureand function of the central nervous system [5,6]. Thesederangements may distort pain processing in a mannerthat is manifest as chronic hyperalgesia and allodynia[5,6]. Despite advances in our understanding of CRPSpathophysiology, patients often do not obtain satisfactoryor lasting relief from conventional therapies, which relyheavily on pharmacologic agents. The interdisciplinarystandard of care is often unavailable to patients for a Pain Medicine 2010; 11: 1115–1125Wiley Periodicals, Inc. 1115  variety of reasons, prominently funding or access [7]. Thus, lack of effective or accessible treatment optionsmakes CRPS a challenging condition for patients andclinicians; novel prevention and treatment strategies areurgently needed.Recently, dietary and supplemental fatty acids havereceived considerable attention as risk modifiers for a widerange of chronic medical conditions, including immune [8]and neuropsychiatric disorders [9,10]. Because these bio-active acids influence several of the putative mechanismsinvolved in pain processing, dietary choices may play arole in CRPS prevention and management. Omega-6 and Omega-3 Fatty Acids and Pain Processing Omega-6 (n-6) and omega-3 (n-3) 20- and 22-carbon highly unsaturated fatty acids (HUFA) with threeor more double bonds are fundamental structural com-ponents of neuronal, glial, myelin, and immune cellmembrane phospholipids [11,12]. Here, they influencea host of biochemical processes that are involved inchronic pain, including: 1) ion channel activity and neu-ronal membrane excitability [13,14]; 2) monoamineneurotransmission [15], and 3) immune/inflammatoryresponses [12].Because humans lack the enzymatic machinery to syn-thesize n-6 or n-3 acids de novo, the n-6 and n-3 HUFA composition of blood and tissue membranes are largelydetermined by dietary supplies of n-6 and n-3 HUFA and their respective 18-carbon n-6 and n-3 precursors[16]. The n-6 and n-3 HUFA have different, and some-times opposite, impacts on key biochemical processesinvolved in pain processing. In general, n-6 HUFA andtheir oxidized metabolites promote [17,18], and n-3HUFA antagonize (or minimally influence) [19,20], meta-bolic processes that facilitate hyperalgesia. Thus, n-6and n-3 fatty acids may play conflicting roles in thedevelopment or maintenance of CRPS and other patho-logical pain states.Previous reports have indicated that supplementaldoses of the two principle n-3 HUFA eicosapentae-noic acid (EPA; 20:5 n-3) and docosahexaenoic acid(DHA; 22:6 n-3), have moderate analgesic or nonsteroi-dal anti-inflammatory drug (NSAID)-sparing effects ininflammatory arthritis [8], dysmenorrhea [21], and chronicmusculoskeletal pain [22,23]. Beneficial effects of n-3HUFA were generally attributed to competition withthe n-6 HUFA arachidonic acid (AA; 20:4 n-6), andensuing reduction of hyperalgesic AA-derived eicosa-noids. However, n-6 and n-3 HUFA are pleiotropicmolecules that may also influence pain signaling bymodulating the functions of synaptic and axonal ionchannels [13], serving as substrates for mediatorsactively involved in inflammatory resolution [24], and byacting as potent ligands for nuclear receptors thatmodulate gene expression [25]. Trans  Fatty Acids Like n-6 and n-3 HUFA,  trans  fatty acids ( trans  FA) pro-duced by industrial hydrogenation [26], deodorization [27],and/or frying [28] of vegetable oils, can alter nervoustissue and immune tissue structure and function. Forexample, moderate quantities of dietary  trans  FA increased nervous tissue accretion of n-6 HUFA [29], andaltered brain monoamine neurotransmitter concentrationsin rats [29] and pigs [30]. In humans,  trans  FA intake isassociated with elevated circulating pro-inflammatorycytokines [31], which have previously been implicated inperipheral and central pain sensitization [32,33]. Thus,plausible biologic mechanisms exist whereby  trans  FA may alter the development and maintenance of pathologi-cal pain, as well as common pain-related comorbiditiessuch as depression [34], anxiety [35], and catastrophizing[36]. To our knowledge, however, the relationship between trans  FA and chronic pain has not been previouslyinvestigated.Because n-6, n-3 HUFA, and  trans  FA are readily modifi-able through dietary changes, and high n-6 and  trans  FA,and/or low n-3 HUFA may be risk factors for the develop-ment of chronic pain, a more thorough understanding of the roles of dietary fatty acids in chronic pain may lead tonew treatments for these conditions. The demonstrationof baseline differences in the n-6 HUFA, n-3 HUFA, and/or trans  FA status between chronic pain patients and con-trols may have important implications for future therapeu-tic intervention trials. Objectives  The major objective of this pilot study was to investigatethe potential relationships between plasma concentrationsof n-6 HUFA, n-3 HUFA, and  trans  FA and persistent pain,with CRPS selected as a paradigm of chronic pain. Ourprincipal hypothesis was that, compared with thosewithout pain, CRPS patients would have lower concen-trations of fatty acids with purported analgesic properties(n-3 HUFA), and higher concentrations of fatty acids withpossible hyperalgesic properties (n-6 HUFA and  trans  FA). A secondary hypothesis was that n-6 HUFA and  trans  FA would be positively correlated, and n-3 HUFA would beinversely correlated, with self-reported measures of painseverity, disability, anxiety and depressive symptoms inCRPS patients. Materials and Methods Patients and Controls Patients with chronic CRPS were recruited from an out-patient chronic pain center, inpatient hospital, and otheroutpatient clinics affiliated with an urban academic reha-bilitation hospital. Individuals at least 18 years of age whosatisfied the Budapest research diagnostic criteria forCRPS [1] were invited to participate in the study. Controlswere recruited via advertising in the same outpatient andinpatient settings. Individuals at least 18 years of age 1116 Ramsden et al.  without active pain were invited to participate in the study.Pregnant women and those regularly consuming fatty acidsupplements were excluded from both groups. The Insti-tutional Review Board approved the study protocol, andall subjects provided written consent prior to the study.  Assessments Potential participants were evaluated during a singlemorning visit that included a review of eligibility andexclusion criteria. CRPS patients who met the eligibilitycriteria were enrolled in the study, underwent a focusedhistory and physical exam, provided a fasting bloodsample, and completed a self-report measures question-naire battery that included: the McGill Pain QuestionnaireShort Form (MPQ-SF) [37], the Pain Disability Index (PDI)[38], the Pain Anxiety Symptom Scale Short Form(PASS-20) [39], the Center for Epidemiologic StudiesDepression Scale Short Form (CESD-10) [40], and theShort Form-36 Health Survey (SF-36) [41]. Control sub- jects completed a visual analog scale (VAS) to confirmlack of pain, which was defined as  < 5 mm on the100-mm scale. Those who met all eligibility criteria pro-vided a fasting blood sample. All study visits took placein the outpatient clinics. Blood Collection and Analytic Methods Fasting whole blood samples were collected intolavender-top EDTA glass tubes. Samples were centrifugedimmediately, and plasma was pipetted into a transfer tubeand stored in a  - 70°C freezer until ready for analysis.Plasma fatty acids were determined using gaschromatography-mass spectrometry GC/MS in SIM mode(Metametrix Clinical Laboratory). Total fatty acids wereesterified using direct transesterification with an acetylchloride methanol : iso-octane mixture. The fatty acidmethyl esters (FAME) were then separated by GC using anHP-23  Cis/Trans  FAME capillary column. The sample fattyacids were identified and quantified against a standardmixture of known fatty acids using an HP 5793 MS [42].Plasma fatty acid measurements were reported in micro-molar(umol/L)concentrations,andalsowereconvertedtopercent of total fatty acids by weight (%TFA) for quantita-tive and qualitative analysis, respectively. Data Analysis Individual fatty acids of interest were measured. Theseincluded the n-3 HUFA EPA (20:5n-3), docosapentaenoicacid (DPA; 22:5n-3), and DHA (22:6n-3), and the n-6HUFA dihomo-gamma-linolenic acid (DGLA; 20:3n-6), AA (20:4n-6), and docosatetraenoic acid (DTA; 22:4n-6), aswell as total 18-carbon  trans  FA. Ratios and percentagesof interest were also calculated. These included the ratioof n-6 AA divided by n-3 EPA, and the percentage of n-6HUFA in total HUFA ( %n6 in HUFA  ). HUFAs were consid-ered to be fatty acids if they were at least 20 carbons inlength with three or more double bonds. The equation forcalculation of %  n6 in HUFA  was: (20:3n-6  +  20:4n-6  +  22:4n-6)/(20:5n-3  +  22:5n-3  +  22:6n-3  +  20:3n-6  + 20:4n-6  +  22:4n-6)  ¥  100. Because of our small samplesize and the non-normal distributions for some fatty aciddata, we used the Wilcoxon rank sum test, a test of medians, to compare the individual fatty acids by casestatus (CRPS vs control). Spearman’s rank correlationcoefficients were used to examine the associations of theindividual fatty acids with scores obtained via self-reportedoutcome measures (MPQ-SF, PDI, PASS-20, CES-D-10,SF-36). A student’s  t  -test was used to examine the com-parability of demographic data for the two groups. Allsignificance levels were set at .05 with no correction formultiple comparisons. All statistics were completed withStata statistical software, release 11 (College Station, TX,USA). Results Demographics  Thirty-five participants, 20 with CRPS and 15 controlswere enrolled in the study (Table 1). Of those with CRPS,80% were female. Their ages ranged from 23 to 65 with Table 1  Characteristics of the study population, Complex Regional Pain Syndrome (CRPS) patients andhealthy controls, Chicago, 2007–2008 CharacteristicCRPS (N  =  20) Non-CRPS (N  =  15)Mean (SD) Mean (SD)Age in years 44 (13) 36 (13)Duration of CRPS in months 96.1 (113.0) Not applicableGenderMale 4 (20) 2 (13)Female 16 (80) 13 (87)EthnicityCaucasian, non-Hispanic 17 (85.0) 12 (80.0)Non-White 2 (10.0) 3 (20)Missing 1 0 1117 Omega-6 and Trans Fatty Acids in CRPS  an average age of 44 (standard deviation [SD]  =  13). Theduration of CRPS ranged from 7 to 479, with an averageof 96 months (SD  =  113). Eighty-seven percent of controlswere female. Their ages ranged from 24 to 67, with anaverage age of 36 (SD  =  13) (Table 1). There were nosignificant differences in gender, age, or ethnicity betweengroups (all  P  ’s  >  0.05). Comparison of Fatty Acid Data by Group  The median concentration of total n-6 HUFA was signifi-cantly higher in CRPS patients than controls (698.2 vs602.5 umol/L;  P   <  0.01, Table 2). Median concentrationsof individual n-6 HUFA were also higher in CRPS patientsthan controls, as follows: DGLA (157.5 vs 107.0, P   <  0.01); AA (536.8 vs 478.7,  P   =  0.10); DTA (26.6 vs19.7,  P   <  0.01). There were no significant differences inmedian concentrations of total n-3 HUFA, EPA, DPA, orDHA between CRPS patients and controls (all  P  ’s  >  0.05). The median concentration of total 18-carbon  trans  FA wasalso significantly higher in CRPS patients vs controls (67.8vs 48.5;  P   <  0.01). The median total fatty acid concentra-tion was significantly higher in CRPS patients than con-trols (11262.3 vs 9335.9;  P   0.01). Plasma triglycerideconcentrations were not measured directly, but all fourmajor components of triglycerides (saturated fatty acids,4554.3 vs 3707.3,  P   <  0.01; monounsaturated fatty acids,2781.3 vs 1860.8,  P   <  0.01; n-6 linoleic acid, 2038.5 vs1739.1,  P   =  0.07; and n-3 alpha-linolenic acid, 54.4 vs35.1,  P   =  0.01), were higher in CRPS patients than con-trols (Table 2, and Appendix 1). When fatty acids wereexpressed qualitatively as a %TFA (Table 3), median con-centrations of total n-3 HUFA were significantly lower inCRPS patients vs controls (3.55 vs 4.42;  P   =  0.03). Therewere no statistically significant differences in n-6 HUFA or trans  FA between patients and controls (all  P  ’s  >  0.05). Ratios and Percentages of Interest   The mean %  n-6 in HUFA  was 72.2% in the CRPS patientsvs 69.2% in controls ( P   =  0.11, Table 3). No significantdifferences were seen for AA to EPA ratios (16.4 vs 14.7, P   =  0.42). Relationships among Fatty Acids and Outcome Data in CRPS Patients On Spearman correlation analysis, CRPS subjects withhigher n-6 DTA tended to have lower vitality scores on theSF-36 (  r   =  –0.50,  P   =  0.03). There were no other signifi-cant correlations between other n-6 HUFA, n-3 HUFA, ortotal HUFA and measures of pain severity, depressivesymptoms, anxiety, or general health (all  P  ’s  >  0.05).CRPS subjects with higher total 18-carbon  trans  FA tended to have higher pain-related anxiety (PASS-20;  r   =  0.56;  P   =  0.03) and pain-related disability (PDI;  r   =  0.63;  P   =  0.02). No other significant correlationsbetween  trans  FA and the other measures were present(all  P  ’s  >  0.05). Discussion  This study showed that plasma concentrations of both n-6HUFA and  trans  FA are significantly higher in CRPSpatients than in pain-free controls (Table 2). To our knowl-edge, this is the first demonstration of elevated n-6 HUFA or  trans  FA in CRPS. Contrary to our expectations,elevated n-6 HUFA concentrations in CRPS patients werenot accompanied by predicted deficits in n-3 HUFA concentrations.Median plasma concentrations of total n-6 HUFA, DGLA,and DTA, were significantly higher in CRPS patients thancontrols (Table 2). Median n-6 AA concentrations werealso higher in CRPS patients, but the difference did notreach statistical significance ( P   =  0.10). Interestingly, themaximum value observed for AA in the 15 control partici-pants was  < 550 umol/L, while 9 of 20 CRPS patients(45%) had AA concentrations above 550 umol/L.Several plausible biologic mechanisms exist whereby theoverabundance of n-6 HUFA observed in our studycould predispose to both hyperalgesia and commonpain-related psychological comorbidities. First, n-6 AA isthe precursor to 2-series prostanoids, 4-series leukot-rienes, and other potent mediators of pain and inflam-mation [17,18]. As part of the inflammatory milieuproduced by activated immune cells and glial cells, these AA-derived eicosanoids amplify and perpetuate theinflammatory response by recruiting and activating otherimmune cells [43], sensitizing nerve endings, and lower-ing pain thresholds [17,18]. Recently, peripheral AA-derived prostanoids have been shown to relayinflammatory signals and to induce long-term synapticplasticity throughout the neural axis [44–46]. Hyperalge-sia in response to peripheral inflammation is in partdependent upon supraspinal AA signaling [47,48].Second, as a major component of excitable membranes, AA modulates virtually all known ion channels, blockingsome and activating others [13,49]. Animal evidencesuggests that AA interacts with and augmentsglutamate-induced N-methyl-D-aspartate receptor acti-vation [50], a key metabolic component of central sen-sitization [51]. Moreover, researchers have uncoveredbiochemical cross-talk between glutamate-induced exci-totoxicity and neuroinflammation involving AA signaling[52]. Finally, accumulating evidence indicates that HUFA influence monoamine neurotransmission [15], perhapsvia altering membrane function and scaffolding formonoamine neurotransmitter receptors or transporters[53–55]. Indeed, high blood and tissue levels of n-6HUFA, high n-6 HUFA to n-3 HUFA ratios, and elevatedn-6 AA metabolism have been linked to major depres-sive disorder [56], refractory depression [57], and neu-roticism [58], three conditions characterized bydysfunctional monoaminergic neurotransmission [59]. Thus, three neurobiological derangements observed incentral pain sensitization (neuronal hyperexcitability, dys-functional monoamine neurotransmission, and neuro-inflammation) converge at the level of supraspinal AA metabolism. 1118 Ramsden et al.         T     a       b       l     e       2 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      <     0 .    0    1    1    8   :    3   n  -    3    (    A    L    A    )    5    4 .    4    3    7 .    9 ,    6    5 .    5    3    5 .    1    2    7 .    7 ,    4    8 .    9    1    5 .    3    2 .    4 ,    2    8 .    5    0 .    0    1    T   o    t   a    l    M    U    F    A    2 ,    7    8    1 .    3    2 ,    2    8    3 .    9 ,    3 ,    4    4    6 .    4    1 ,    8    6    0 .    8    1 ,    6    2    3 .    6 ,    2 ,    3    1    1 .    7    8    5    3 .    6    4    3    5 .    8 ,    1 ,    3    3    9 .    3       <     0 .    0    1    T   o    t   a    l    S    F    A    4 ,    5    5    4 .    3    3 ,    8    3    6 .    9 ,    5 ,    2    3    9 .    8    3 ,    7    0    7 .    3    3 ,    2    6    1 .    7 ,    4 ,    1    6    5 .    5    8    4    4 .    2    3    2    1 .    1 ,    1 ,    5    3    8 .    9       <     0 .    0    1    1    8    C    t   r   a   n   s    F    A    6    7 .    8    5    4 .    7 ,    9    6 .    8    4    8 .    5    3    9 .    0 ,    5    4 .    3    2    0 .    7    7 .    2 ,    4    3 .    1       <     0 .    0    1    T   o    t   a    l    F   a    t    t   y    A   c    i    d   s    1    1 ,    2    6    2 .    3    1    0 ,    4    2    8 .    0 ,    1    3 ,    0    4    7 .    6    9 ,    3    3    5 .    9    8 ,    1    6    6 .    8 ,    1    0 ,    3    3    4 .    8    2 ,    2    2    4 .    0    1 ,    0    0    5 .    5 ,    3 ,    6    5    5 .    6       <     0 .    0    1     *    T    h   e    H   o    d   g   e   s  –    L   e    h   m   a   n   n    t   e   s    t   w   a   s   u   s   e    d    t   o   p   r   o   v    i    d   e    t    h   e    d    i    f    f   e   r   e   n   c   e    b   e    t   w   e   e   n    t    h   e   m   e    d    i   a   n   s   w    i    t    h   c   o   n    fi    d   e   n   c   e    i   n    t   e   r   v   a    l   s .     †       P    v   a    l   u   e   s   a   r   e    b   a   s   e    d   o   n    t    h   e    W    i    l   c   o   x   o   n   r   a   n    k  -   s   u   m    t   e   s    t .    H    U    F    A     =     h    i   g    h    l   y   u   n   s   a    t   u   r   a    t   e    d    f   a    t    t   y   a   c    i    d   ;    D    G    L    A     =     d    i    h   o   m   o  -   g   a   m   m   a  -    l    i   n   o    l   e   n    i   c   a   c    i    d   ;    A    A     =    a   r   a   c    h    i    d   o   n    i   c   a   c    i    d   ;    D    T    A     =     d   o   c   o   s   a    t   e    t   r   a   e   n   o    i   c   a   c    i    d ,    E    P    A     =    e    i   c   o   s   a   p   e   n    t   a   e   n   o    i   c   a   c    i    d   ;    D    P    A     =     d   o   c   o   s   a   p   e   n    t   a   e   n   o    i   c   a   c    i    d   ;    D    H    A     =     d   o   c   o   s   a    h   e   x   a   e   n   o    i   c   a   c    i    d   ;    L    A     =     l    i   n   o    l   e    i   c   a   c    i    d   ;    G    L    A     =    g   a   m   m   a  -    l    i   n   o    l   e   n    i   c   a   c    i    d   ;    A    L    A     =    a    l   p    h   a  -    l    i   n   o    l   e   n    i   c   a   c    i    d   ;    M    U    F    A     =    m   o   n   o  -   u   n   s   a    t   u   r   a    t   e    d    f   a    t    t   y   a   c    i    d   s   ;    S    F    A     =    s   a    t   u   r   a    t   e    d    f   a    t    t   y   a   c    i    d   s . 1119 Omega-6 and Trans Fatty Acids in CRPS
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