Advertisement

Psychophysical and Electrophysiological Evidence for Enhanced Pain Facilitation and Unaltered Pain Inhibition in Acute Low Back Pain Patients

      Highlights

      • Pain inhibition and facilitation were assessed in acute low back patients.
      • Mechanisms were assessed using psychophysical and electrophysiological tests.
      • Patients presented enhanced pain facilitation but no difference in pain inhibition.

      Abstract

      The aim of this case-control study was to examine differences in neural correlates of pain facilitatory and inhibitory mechanisms between acute low back pain (LBP) patients and healthy individuals. Pressure pain tolerance, electrical pain detection thresholds, pain ratings to repetitive suprathreshold electrical stimulation (SES) and conditioned pain modulation (CPM) were assessed in 18 patients with acute LBP and 18 healthy control participants. Furthermore, event-related potentials (ERPs) in response to repetitive SES were obtained from high-density electroencephalography. Results showed that the LBP group presented lower pressure pain tolerance and higher pain ratings to SES compared with the control group. Both groups displayed effective CPM, with no differences in CPM magnitude between groups. Both groups presented similar reductions in ERP amplitudes during CPM, but ERP responses to repetitive SES were significantly larger in the LBP group. In conclusion, acute LBP patients presented enhanced pain facilitatory mechanisms, whereas no significant changes in pain inhibitory mechanisms were observed. These results provide new insight into the central mechanisms underlying acute LBP.

      Perspective

      This article present evidence that acute LBP patients show enhanced pain facilitation and unaltered pain inhibition compared with pain-free volunteers. These results provide new insight into the central mechanisms underlying acute LBP.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Albu S.
        • Gómez-Soriano J.
        • Avila-Martin G.
        • Taylor J.
        Deficient conditioned pain modulation after spinal cord injury correlates with clinical spontaneous pain measures.
        Pain. 2015; 156: 260-272
        • Andersson G.B.
        Epidemiological features of chronic low-back pain.
        Lancet. 1999; 354: 581-585
        • Arendt-Nielsen L.
        Central sensitization in humans: Assessment and pharmacology.
        in: Schaible H.G. Pain Control. Springer-Verlag, Berlin, Heidelberg2015: 79-102
        • Arendt-Nielsen L.
        • Egsgaard L.L.
        • Petersen K.K.
        • Eskehave T.N.
        • Graven- Nielsen T.
        • Hoeck H.C.
        • Simonsen O.
        A mechanism-based pain sensitivity index to characterize knee osteoarthritis patients with different disease stages and pain levels.
        Eur J Pain. 2015; 19: 1406-1417
        • Arendt-Nielsen L.
        • Gotliebsen K.
        Segmental inhibition of laser-evoked brain potentials by ipsi- and contralaterally applied cold pressor pain.
        Eur J Appl Physiol Occup Physiol. 1992; 64: 56-61
        • Banic B.
        • Petersen-Felix S.
        • Andersen O.K.
        • Radanov B.P.
        • Villiger M.P.
        • Arendt-Nielsen L.
        • Curatolo M.
        Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia.
        Pain. 2004; 107: 7-15
        • Beck A.
        • Steer R.
        • Brown G.
        Manual for the Beck Depression Inventory.
        2nd ed. Psychological Corp, San Antonio, TX1996
        • Biurrun Manresa J.A.
        • Neziri A.Y.
        • Curatolo M.
        • Arendt-Nielsen L.
        • Andersen O.K.
        Reflex receptive fields are enlarged in patients with musculoskeletal low back and neck pain.
        Pain. 2013; 154: 1318-1324
        • Brock C.
        • Olesen S.S.
        • Valeriani M.
        • Arendt-Nielsen L.
        • Drewes A.M.
        Brain activity in rectosigmoid pain: Unravelling conditioning pain modulatory pathways.
        Clin Neurophysiol. 2012; 123: 829-837
        • Brunia C.H.
        • van Boxtel G.J.
        • Böcker K.B.
        Negative slow waves as indices of anticipation: the Bereitschaftspotential, the contingent negative variation, and the stimulus-preceding negativity.
        in: Kappenman E.S. Luck S.J. The Oxford Handbook of Event-Related Potential Components, Online ed. Oxford University Press, Oxford, UK2012
        • Buchgreitz L.
        • Egsgaard L.L.
        • Jensen R.
        • Arendt-Nielsen L.
        • Bendtsen L.
        Abnormal pain processing in chronic tension-type headache: A high-density EEG brain mapping study.
        Brain. 2008; 131: 3232-3238
        • Cassidy J.D.
        • Côté P.
        • Carroll L.J.
        • Kristman V.
        Incidence and course of low back pain episodes in the general population.
        Spine (Phila Pa 1976). 2005; 30: 2817-2823
        • Chen A.C.
        • Shimojo M.
        • Svensson P.
        • Arendt-Nielsen L.
        Brain dynamics of scalp evoked potentials and current source densities to repetitive (5-pulse train) painful stimulation of skin and muscle: Central correlate of temporal summation.
        Brain Topogr. 2000; 13: 59-72
        • Cook A.J.
        • Woolf C.J.
        • Wall P.D.
        • McMahon S.B.
        Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input.
        Nature. 1987; 325: 151-153
        • Crombez G.
        • Van Damme S.
        • Eccleston C.
        Hypervigilance to pain: An experimental and clinical analysis.
        Pain. 2005; 116: 4-7
        • Curatolo M.
        • Möller M.
        • Ashraf A.
        • Neziri A.Y.
        • Streitberger K.
        • Andersen O.K.
        • Arendt-Nielsen L.
        • Müller M.
        Pain hypersensitivity and spinal nociceptive hypersensitivity in chronic pain: Prevalence and associated factors.
        Pain. 2015; 156: 2373-2382
        • Delorme A.
        • Makeig S.
        EEGLAB: An open source toolbox for analysis of single-trial EEG dynamics including independent component analysis.
        J Neurosci Methods. 2004; 134: 9-21
        • De Tommaso M.
        • Sardaro M.
        • Pecoraro C.
        • Di Fruscolo O.
        • Serpino C.
        • Lamberti P.
        • Livrea P.
        Effects of the remote C fibres stimulation induced by capsaicin on the blink reflex in chronic migraine.
        Cephalalgia. 2007; 27: 881-890
        • Dubner R.
        • Basbaum A.I.
        Spinal dorsal horn plasticity following tissue or nerve injury.
        in: Wall P.D. Melzack R. Textbook of Pain. Churchill Livingstone, Edinburgh1994: 225-241
        • Fallon N.
        • Li X.
        • Chiu Y.
        • Nurmikko T.
        • Stancak A.
        Altered cortical processing of observed pain in patients with fibromyalgia syndrome.
        J Pain. 2015; 16: 717-726
        • Fallon N.
        • Li X.
        • Stancak A.
        Pain catastrophising affects cortical responses to viewing pain in others.
        PLoS One. 2015; 10: 1-19
        • Fardo F.
        • Allen M.
        • Jegind E.M.
        • Angrilli A.
        • Roepstorff A.
        Neurocognitive evidence for mental imagery-driven hypoalgesic and hyperalgesic pain regulation.
        Neuroimage. 2015; 120: 350-361
        • Fields H.L.
        State-dependent opioid control of pain.
        Nat Rev Neurosci. 2004; 5: 565-575
        • Flor H.
        • Diers M.
        • Birbaumer N.
        Peripheral and electrocortical responses to painful and non-painful stimulation in chronic pain patients, tension headache patients and healthy controls.
        Neurosci Lett. 2004; 361: 147-150
        • Fujii-Abe K.
        • Oono Y.
        • Motohashi K.
        • Fukayama H.
        • Umino M.
        Heterotopic CO2 laser stimulation inhibits tooth-related somatosensory evoked potentials.
        Pain Med. 2010; 11: 825-833
        • Fujii K.
        • Motohashi K.
        • Umino M.
        Heterotopic ischemic pain attenuates somatosensory evoked potentials induced by electrical tooth stimulation: Diffuse noxious inhibitory controls in the trigeminal nerve territory.
        Eur J Pain. 2006; 10: 495-504
        • Fusco B.M.
        • Colantoni O.
        • Giacovazzo M.
        Alteration of central excitation circuits in chronic headache and analgesic misuse.
        Headache. 1997; 37: 486-491
        • Goffaux P.
        • de Souza J.B.
        • Potvin S.
        • Marchand S.
        Pain relief through expectation supersedes descending inhibitory deficits in fibromyalgia patients.
        Pain. 2009; 145: 18-23
        • Goffaux P.
        • Redmond W.J.
        • Rainville P.
        • Marchand S.
        Descending analgesia - When the spine echoes what the brain expects.
        Pain. 2007; 130: 137-143
        • Graven-Nielsen T.
        • Aspegren Kendall S.
        • Henriksson K.G.
        • Bengtsson M.
        • Sörensen J.
        • Johnson A.
        • Gerdle B.
        • Arendt-Nielsen L.
        Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients.
        Pain. 2000; 85: 483-491
        • Haggman S.P.
        • Sharpe L.A.
        • Nicholas M.K.
        • Refshauge K.M.
        Attentional biases toward sensory pain words in acute and chronic pain patients.
        J Pain. 2010; 11: 1136-1145
        • Heinricher M.M.
        • Tavares I.
        • Leith J.L.
        • Lumb B.M.
        Descending control of nociception: Specificity, recruitment and plasticity.
        Brain Res Rev. 2009; 60: 214-225
        • Hestbaek L.
        • Leboeuf-Yde C.
        • Manniche C.
        Low back pain: What is the long-term course? A review of studies of general patient populations.
        Eur Spine J. 2003; 12: 149-165
        • Iannetti G.D.
        • Hughes N.P.
        • Lee M.C.
        • Mouraux A.
        Determinants of laser-evoked EEG responses: Pain perception or stimulus saliency?.
        J Neurophysiol. 2008; 100: 815-828
        • Julien N.
        • Goffaux P.
        • Arsenault P.
        • Marchand S.
        Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition.
        Pain. 2005; 114: 295-302
        • Jung T.P.
        • Makeig S.
        • Humphries C.
        • Lee T.W.
        • Mckeown M.J.
        • Iragui V.
        • Sejnowski T.J.
        Removing electroencephalographic artifacts by blind source separation.
        Psychophysiology. 2000; 37: 163-178
        • Klyne D.M.
        • Schmid A.B.
        • Moseley G.L.
        • Sterling M.
        • Hodges P.W.
        Effect of types and anatomic arrangement of painful stimuli on conditioned pain modulation.
        J Pain. 2015; 16: 176-185
        • Kunz M.
        • Mohammadian P.
        • Renner B.
        • Roscher S.
        • Kobal G.
        • Lautenbacher S.
        Chemo-somatosensory evoked potentials: A sensitive tool to assess conditioned pain modulation?.
        Somatosens Mot Res. 2014; 31: 100-110
        • Ladouceur A.
        • Tessier J.
        • Provencher B.
        • Rainville P.
        • Piché M.
        Top-down attentional modulation of analgesia induced by heterotopic noxious counterstimulation.
        Pain. 2012; 153: 1755-1762
        • Landau R.
        • Kraft J.C.
        • Flint L.Y.
        • Carvalho B.
        • Richebé P.
        • Cardoso M.
        • Lavand’homme P.
        • Granot M.
        • Yarnitsky D.
        • Cahana A.
        An experimental paradigm for the prediction of post-operative pain (PPOP).
        J Vis Exp. 2010; 35: 1671
        • Latremoliere A.
        • Woolf C.J.
        Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
        J Pain. 2009; 10: 895-926
        • Laux L.
        • Glanzmann P.
        • Schaffner P.
        • Spielberger C.D.
        State-Trait-Angstinventar (STAI).
        Hogrefe Verlag, Göttingen1981
        • Lee T.W.
        • Girolami M.
        • Sejnowski T.J.
        Independent component analysis using an extended infomax algorithm for mixed subgaussian and supergaussian sources.
        Neural Comput. 1999; 11: 417-441
        • Legrain V.
        • Guérit J.M.
        • Bruyer R.
        • Plaghki L.
        Attentional modulation of the nociceptive processing into the human brain: Selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials.
        Pain. 2002; 99: 21-39
        • Legrain V.
        • Mancini F.
        • Sambo C.F.
        • Torta D.M.
        • Ronga I.
        • Valentini E.
        Cognitive aspects of nociception and pain. Bridging neurophysiology with cognitive psychology.
        Clin Neurophysiol. 2012; 42: 325-336
        • Lewis G.N.
        • Rice D.A.
        • McNair P.J.
        Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis.
        J Pain. 2012; 13: 936-944
        • Maris E.
        • Oostenveld R.
        Nonparametric statistical testing of EEG- and MEG-data.
        J Neurosci Methods. 2007; 164: 177-190
        • Millan M.J.
        Descending control of pain.
        Prog Neurobiol. 2002; 66: 355-474
        • Mlekusch S.
        • Neziri A.Y.
        • Limacher A.
        • Jüni P.
        • Arendt-Nielsen L.
        • Curatolo M.
        Conditioned pain modulation in patients with acute and chronic low back pain.
        Clin J Pain. 2016; 32: 116-121
        • Mlekusch S.
        • Schliessbach J.
        • Cámara R.J.
        • Arendt-Nielsen L.
        • Jüni P.
        • Curatolo M.
        Do central hypersensitivity and altered pain modulation predict the course of chronic low back and neck pain?.
        Clin J Pain. 2013; 29: 673-680
        • Moont R.
        • Crispel Y.
        • Lev R.
        • Pud D.
        • Yarnitsky D.
        Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study.
        Pain. 2011; 152: 1469-1477
        • Moont R.
        • Pud D.
        • Sprecher E.
        • Sharvit G.
        • Yarnitsky D.
        “Pain inhibits pain” mechanisms: Is pain modulation simply due to distraction?.
        Pain. 2010; 150: 113-120
        • Mouraux A.
        • Iannetti G.D.
        Nociceptive laser-evoked brain potentials do not reflect nociceptive-specific neural activity.
        J Neurophysiol. 2009; 101: 3258-3269
        • Nasri-Heir C.
        • Khan J.
        • Benoliel R.
        • Feng C.
        • Yarnitsky D.
        • Kuo F.
        • Hirschberg C.
        • Hartwell G.
        • Huang C.Y.
        • Heir G.
        • Korczeniewska O.
        • Diehl S.R.
        • Eliav E.
        Altered pain modulation in patients with persistent postendodontic pain.
        Pain. 2015; 156: 2032-2041
        • Neziri A.Y.
        • Haesler S.
        • Petersen-Felix S.
        • Müller M.
        • Arendt-Nielsen L.
        • Manresa J.B.
        • Andersen O.K.
        • Curatolo M.
        Generalized expansion of nociceptive reflex receptive fields in chronic pain patients.
        Pain. 2010; 151: 798-805
        • Niesters M.
        • Proto P.L.
        • Aarts L.
        • Sarton E.Y.
        • Drewes A.M.
        • Dahan A.
        Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.
        Br J Anaesth. 2014; 113: 148-156
        • Nir R.R.
        • Yarnitsky D.
        • Honigman L.
        • Granot M.
        Cognitive manipulation targeted at decreasing the conditioning pain perception reduces the efficacy of conditioned pain modulation.
        Pain. 2012; 153: 170-176
        • Olesen S.S.
        • Brock C.
        • Krarup A.L.
        • Funch-Jensen P.
        • Arendt-Nielsen L.
        • Wilder-Smith O.H.
        • Drewes A.M.
        Descending inhibitory pain modulation is impaired in patients with chronic pancreatitis.
        Clin Gastroenterol Hepatol. 2010; 8: 724-730
        • O’Neill S.
        • Manniche C.
        • Graven-Nielsen T.
        • Arendt-Nielsen L.
        Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.
        Eur J Pain. 2007; 11: 415-420
        • Oono Y.
        • Fujii K.
        • Motohashi K.
        • Umino M.
        Diffuse noxious inhibitory controls triggered by heterotopic CO2 laser conditioning stimulation decreased the SEP amplitudes induced by electrical tooth stimulation with different intensity at an equally inhibitory rate.
        Pain. 2008; 136: 356-365
        • Pickering G.
        • Pereira B.
        • Dufour E.
        • Soule S.
        • Dubray C.
        Impaired modulation of pain in patients with postherpetic neuralgia.
        Pain Res Manag. 2014; 19: e19-e23
        • Pud D.
        • Granovsky Y.
        • Yarnitsky D.
        The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans.
        Pain. 2009; 144: 16-19
        • Quante M.
        • Hille S.
        • Schofer M.D.
        • Lorenz J.
        • Hauck M.
        Noxious counterirritation in patients with advanced osteoarthritis of the knee reduces MCC but not SII pain generators: A combined use of MEG and EEG.
        J Pain Res. 2008; 1: 1-8
        • Rhudy J.L.
        • Martin S.L.
        • Terry E.L.
        • France C.R.
        • Bartley E.J.
        • DelVentura J.L.
        • Kerr K.L.
        Pain catastrophizing is related to temporal summation of pain but not temporal summation of the nociceptive flexion reflex.
        Pain. 2011; 152: 794-801
        • Romaniello A.
        • Arendt-Nielsen L.
        • Cruccu G.
        • Svensson P.
        Modulation of trigeminal laser evoked potentials and laser silent periods by homotopical experimental pain.
        Pain. 2002; 98: 217-228
        • Ronga I.
        • Valentini E.
        • Mouraux A.
        • Iannetti G.D.
        Novelty is not enough: laser-evoked potentials are determined by stimulus saliency, not absolute novelty.
        J Neurophysiol. 2013; 44: 692-701
        • Rosenstiel A.K.
        • Keefe F.J.
        The use of coping strategies in chronic low back pain patients: Relationship to patient characteristics and current adjustment.
        Pain. 1983; 17: 33-44
        • Rustamov N.
        • Tessier J.
        • Provencher B.
        • Lehmann A.
        • Piché M.
        Inhibitory effects of heterotopic noxious counter-stimulation on perception and brain activity related to Aβ-fiber activation.
        Eur J Neurosci. 2016; 44: 1771-1778
        • Seminowicz D.A.
        • Davis K.D.
        Interactions of pain intensity and cognitive load: The brain stays on task.
        Cereb Cortex. 2007; 17: 1412-1422
        • Skou S.T.
        • Graven-Nielsen T.
        • Rasmussen S.
        • Simonsen O.H.
        • Laursen M.B.
        • Arendt-Nielsen L.
        Facilitation of pain sensitization in knee osteoarthritis and persistent post-operative pain: A cross-sectional study.
        Eur J Pain. 2014; 18: 1024-1031
        • Staud R.
        Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.
        Expert Rev Neurother. 2012; 12: 577-585
        • Staud R.
        • Cannon R.C.
        • Mauderli A.P.
        • Robinson M.E.
        • Price D.D.
        • Vierck C.J.
        Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome.
        Pain. 2003; 102: 87-95
        • Staud R.
        • Robinson M.E.
        • Vierck C.J.
        • Price D.D.
        • Vierck Jr., C.J.
        • Price D.D.
        Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients.
        Pain. 2003; 101: 167-174
        • Terry E.L.
        • Kerr K.L.
        • Delventura J.L.
        • Rhudy J.L.
        Anxiety sensitivity does not enhance pain signaling at the spinal level.
        Clin J Pain. 2012; 28: 505-510
        • Tommaso M.
        • Difruscolo O.
        • Sardaro M.
        • Libro G.
        • Pecoraro C.
        • Serpino C.
        • Lamberti P.
        • Livrea P.
        Effects of remote cutaneous pain on trigeminal laser-evoked potentials in migraine patients.
        J Headache Pain. 2007; 8: 167-174
        • Torta D.M.
        • Churyukanov M.V.
        • Plaghki L.
        • Mouraux A.
        The effect of heterotopic noxious conditioning stimulation on Adelta-, C- and Abeta-fibre brain responses in humans.
        Eur J Neurosci. 2015; 42: 2707-2715
        • Treede R.D.
        • Kunde V.
        Middle-latency somatosensory evoked potentials after stimulation of the radial and median nerves: Component structure and scalp topography.
        J Clin Neurophysiol. 1995; 12: 291-301
        • Valentini E.
        The role of perceptual expectation on repetition suppression: A quest to dissect the differential contribution of probability of occurrence and event predictability.
        Front Hum Neurosci. 2011; 5: 567-576
        • Valentini E.
        • Torta D.M.
        • Mouraux A.
        • Iannetti G.D.
        Dishabituation of laser-evoked EEG responses: Dissecting the effect of certain and uncertain changes in stimulus modality.
        J Cogn Neurosci. 2011; 23: 2822-2837
        • Valeriani M.
        • Le Pera D.
        • Restuccia D.
        • De Armas L.
        • Maiese T.
        • Tonali P.
        • Vigevano F.
        • Arendt-Nielsen L.
        Segmental inhibition of cutaneous heat sensation and of laser-evoked potentials by experimental muscle pain.
        Neuroscience. 2005; 136: 301-309
        • Van Damme S.
        • Legrain V.
        • Vogt J.
        • Crombez G.
        Keeping pain in mind: A motivational account of attention to pain.
        Neurosci Biobehav Rev. 2010; 34: 204-213
        • van den Broeke E.N.
        • Mouraux A.
        High-frequency electrical stimulation of the human skin induces heterotopical mechanical hyperalgesia, heat hyperalgesia, and enhanced responses to nonnociceptive vibrotactile input.
        J Neurophysiol. 2014; 111: 1564-1573
        • Van Den Broeke E.N.
        • Van Rijn C.M.
        • Manresa J.A.
        • Andersen O.K.
        • Arendt-Nielsen L.
        • Wilder-Smith O.H.
        Neurophysiological correlates of nociceptive heterosynaptic long-term potentiation in humans.
        J Neurophysiol. 2010; 103: 2107-2113
        • Wang A.L.
        • Mouraux A.
        • Liang M.
        • Iannetti G.D.
        Stimulus novelty, and not neural refractoriness, explains the repetition suppression of laser-evoked potentials.
        J Neurophysiol. 2010; 104: 2116-2124
        • Watanabe I.
        • Svensson P.
        • Arendt-Nielsen L.
        Influence of segmental and extra-segmental conditioning, stimuli on cortical potentials evoked by painful electrical stimulation.
        Somatosens Mot Res. 1999; 16: 243-250
        • Woolf C.J.
        Central sensitization: Implications for the diagnosis and treatment of pain.
        Pain. 2011; 152: S2-S15
        • Yarnitsky D.
        Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states.
        Curr Opin Anaesthesiol. 2010; 23: 611-615
        • Yarnitsky D.
        • Arendt-Nielsen L.
        • Bouhassira D.
        • Edwards R.R.
        • Fillingim R.B.
        • Granot M.
        • Hansson P.
        • Lautenbacher S.
        • Marchand S.
        • Wilder-Smith O.
        Recommendations on terminology and practice of psychophysical DNIC testing.
        Eur J Pain. 2010; 14: 339
        • Yarnitsky D.
        • Crispel Y.
        • Eisenberg E.
        • Granovsky Y.
        • Ben-Nun A.
        • Sprecher E.
        • Best L.A.
        • Granot M.
        Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk.
        Pain. 2008; 138: 22-28

      CHORUS Manuscript

      View Open Manuscript