Conditioned Pain Modulation in Populations With Chronic Pain: A Systematic Review and Meta-Analysis

Published:September 14, 2012DOI:


      A systematic literature review and meta-analysis were undertaken to determine if conditioned pain modulation is dysfunctional in populations with chronic pain. Studies that used a standardized protocol to evaluate conditioned pain modulation in a chronic pain population and in a healthy control population were selected and reviewed. Thirty studies were included in the final review, encompassing data from 778 patients and 664 control participants. Across all studies there was a large effect size of .78, reflecting reduced conditioned pain modulation in the patient group. Analysis of moderator variables indicated a significant influence of participant gender and age on the effect size. Methodological moderator variables of type of outcome measure, type of test stimulus, type of conditioning stimulus, and the level of conditioning stimulus pain were not significant. A risk of bias assessment indicated that poor blinding of assessors and a lack of control of confounding variables were common. It is concluded that conditioned pain modulation is impaired in populations with chronic pain. Future studies should ensure adequate matching of participant age and gender between patient and control groups, blinding of the assessors obtaining the outcome measures, and more rigorous control for variables known to influence the level of modulation.


      This review compared the efficacy of conditioned pain modulation between chronic pain and healthy populations. The finding of impaired modulation in the chronic pain groups highlights the dysfunction of endogenous pain modulatory mechanisms in this population.

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        • Arendt-Nielsen L.
        • Nie H.
        • Laursen M.B.
        • Laursen B.S.
        • Madeleine P.
        • Simonsen O.H.
        • Graven-Nielsen T.
        Sensitization in patients with painful knee osteoarthritis.
        Pain. 2010; 149: 573-581
        • Bouhassira D.
        • Villanueva L.
        • Bing Z.
        • Le Bars D.
        Involvement of the subnucleus reticularis dorsalis in diffuse noxious inhibitory controls in the rat.
        Brain Res. 1992; 595: 353-357
        • Cathcart S.
        • Winefield A.H.
        • Lushington K.
        • Rolan P.
        Noxious inhibition of temporal summation is impaired in chronic tension-type headache.
        Headache. 2010; 50: 403-412
        • Cohen J.
        A power primer.
        Psychol Bull. 1992; 112: 155-159
        • de Souza J.B.
        • Potvin S.
        • Goffaux P.
        • Charest J.
        • Marchand S.
        The deficit of pain inhibition in fibromyalgia is more pronounced in patients with comorbid depressive symptoms.
        Clin J Pain. 2009; 25: 123-127
        • 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
        • Desbois C.
        • Le Bars D.
        • Villanueva L.
        Organization of cortical projections to the medullary subnucleus reticularis dorsalis: A retrograde and anterograde tracing study in the rat.
        J Comp Neurol. 1999; 410: 178-196
        • Drummond P.D.
        • Knudsen L.
        Central pain modulation and scalp tenderness in frequent episodic tension-type headache.
        Headache. 2011; 51: 375-383
        • Edwards R.R.
        Individual differences in endogenous pain modulation as a risk factor for chronic pain.
        Neurology. 2005; 65: 437-443
        • Edwards R.R.
        • Fillingim R.B.
        • Ness T.J.
        Age-related differences in endogenous pain modulation: A comparison of diffuse noxious inhibitory controls in healthy older and younger adults.
        Pain. 2003; 101: 155-165
        • Edwards R.R.
        • Grace E.
        • Peterson S.
        • Klick B.
        • Haythornthwaite J.A.
        • Smith M.T.
        Sleep continuity and architecture: Associations with pain inhibitory proceses in patients with temporomandibular joint disorder.
        Eur J Pain. 2009; 13: 1043-1047
        • France C.R.
        • Suchowiecki S.
        A comparison of diffuse noxious inhibitory controls in men and women.
        Pain. 1999; 81: 77-84
        • 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
        • Goodin B.R.
        • McGuire L.
        • Allshouse M.
        • Stapleton L.
        • Haythornthwaite J.A.
        • Burns N.
        • Mayes L.A.
        • Edwards R.R.
        Associations between catastrophizing and endogenous pain-inhibitory processes: Sex differences.
        J Pain. 2009; 10: 180-190
        • Heymen S.
        • Maixner W.
        • Whitehead W.E.
        • Klatzkin R.R.
        • Mechlin B.
        • Light K.C.
        Central processing of noxious somatic stimuli in patients with irritable bowel syndrome compared with healthy controls.
        Clin J Pain. 2010; 26: 104-109
        • Johannesson U.
        • de Boussard C.N.
        • Brodda Jansen G.
        • Bohm-Starke N.
        Evidence of diffuse noxious inhibitory controls (DNIC) elicited by cold noxious stimulation in patients with provoked vestibulodynia.
        Pain. 2007; 130: 31-39
        • Kashima K.
        • Rahman O.I.F.
        • Sakoda S.
        • Shiba R.
        Increased pain sensitivity of the upper extremities of TMD patients with myalgia to experimentally-evoked noxious stimulation: Possibility of worsened endogenous opioid systems.
        Cranio. 1999; 17: 241-246
        • King C.D.
        • Wong F.
        • Currie T.
        • Mauderli A.P.
        • Fillingim R.B.
        • Riley III, J.L.
        Deficiency in endogenous modulation of prolonged heat pain in patients with Irritable Bowel Syndrome and Temporomandibular Disorder.
        Pain. 2009; 143: 172-178
        • Knudsen L.
        • Petersen G.L.
        • Nørskov K.N.
        • Vase L.
        • Finnerup N.
        • Jensen T.S.
        • Svensson P.
        Review of neuroimaging studies related to pain modulation.
        Scand J Pain. 2011; 2: 108-120
        • Kosek E.
        • Hansson P.
        Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects.
        Pain. 1997; 70: 41-51
        • Kosek E.
        • Ordeberg G.
        Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief.
        Pain. 2000; 88: 69-78
        • Larivière M.
        • Goffaux P.
        • Marchand S.
        • Julien N.
        Changes in pain perception and descending inhibitory controls start at middle age in healthy adults.
        Clin J Pain. 2007; 23: 506-510
        • Lautenbacher S.
        • Rollman G.B.
        Possible deficiencies of pain modulation in fibromyalgia.
        Clin J Pain. 1997; 13: 189-196
        • Le Bars D.
        The whole body receptive field of dorsal horn multireceptive neurones.
        Brain Res Brain Res Rev. 2002; 40: 29-44
        • Le Bars D.
        • Dickenson A.H.
        • Besson J.M.
        Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.
        Pain. 1979; 6: 283-304
        • Leffler A.S.
        • Hansson P.
        • Kosek E.
        Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia.
        Eur J Pain. 2002; 6: 149-159
        • Leffler A.S.
        • Kosek E.
        • Lerndal T.
        • Nordmark B.
        • Hansson P.
        Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis.
        Eur J Pain. 2002; 6: 161-176
        • Leonard G.
        • Goffaux P.
        • Mathieu D.
        • Blanchard J.
        • Kenny B.
        • Marchand S.
        Evidence of descending inhibition deficits in atypical but not classical trigeminal neuralgia.
        Pain. 2009; 147: 217-223
        • Miyazaki T.
        • Wang X.
        • Inui K.
        • Domino E.F.
        • Kakigi R.
        The effect of smoking on pain-related evoked potentials.
        Brain Res. 2010; 1313: 185-191
        • 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
        • Motl R.W.
        • O'Connor P.J.
        • Dishman R.K.
        Effect of caffeine on perceptions of leg muscle pain during moderate intensity cycling exercise.
        J Pain. 2003; 4: 316-321
        • Mylius V.
        • Engau I.
        • Teepker M.
        • Stiasny-Kolster K.
        • Schepelmann K.
        • Oertel W.H.
        • Lautenbacher S.
        • Moller J.C.
        Pain sensitivity and descending inhibition of pain in Parkinson's disease.
        J Neurol Neurosurg Psychiatry. 2009; 80: 24-28
        • Normand E.
        • Potvin S.
        • Gaumond I.
        • Cloutier G.
        • Corbin J.F.
        • Marchand S.
        Pain inhibition is deficient in chronic widespread pain but normal in major depressive disorder.
        J Clin Psychiatry. 2011; 72: 219-224
        • 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
        • Perrotta A.
        • Serrao M.
        • Sandrini G.
        • Burstein R.
        • Sances G.
        • Rossi P.
        • Bartolo M.
        • Pierelli F.
        • Nappi G.
        Sensitisation of spinal cord pain processing in medication overuse headache involves supraspinal pain control.
        Cephalalgia. 2010; 30: 272-284
        • Piché M.
        • Arsenault M.
        • Poitras P.
        • Rainville P.
        • Bouin M.
        Widespread hypersensitivity is related to altered pain inhibition processes in irritable bowel syndrome.
        Pain. 2010; 148: 49-58
        • Piché M.
        • Bouin M.
        • Arsenault M.
        • Poitras P.
        • Rainville P.
        Decreased pain inhibition in irritable bowel syndrome depends on altered descending modulation and higher-order brain processes.
        Neuroscience. 2011; 195: 166-175
        • Pielsticker A.
        • Haag G.
        • Zaudig M.
        • Lautenbacher S.
        Impairment of pain inhibition in chronic tension-type headache.
        Pain. 2005; 118: 215-223
        • Popescu A.
        • Leresche L.
        • Truelove E.L.
        • Drangsholt M.T.
        Gender differences in pain modulation by diffuse noxious inhibitory controls: A systematic review.
        Pain. 2010; 150: 309-318
        • Potvin S.
        • Larouche A.
        • Normand E.
        • de Souza J.B.
        • Gaumond I.
        • Grignon S.
        • Marchand S.
        DRD3 Ser9Gly polymorphism is related to thermal pain perception and modulation in chronic widespread pain patients and healthy controls.
        J Pain. 2009; 10: 969-975
        • Potvin S.
        • Larouche A.
        • Normand E.
        • de Souza J.B.
        • Gaumond I.
        • Marchand S.
        • Grignon S.
        No relationship between the ins del polymorphism of the serotonin transporter promoter and pain perception in fibromyalgia patients and healthy controls.
        Eur J Pain. 2010; 14: 742-746
        • 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
        • Quiton R.L.
        • Greenspan J.D.
        Sex differences in endogenous pain modulation by distracting and painful conditioning stimulation.
        Pain. 2007; 132: S134-S149
        • Roosink M.
        • Renzenbrink G.J.
        • Buitenweg J.R.
        • van Dongen R.T.
        • Geurts A.C.
        • Ijzerman M.J.
        Somatosensory symptoms and signs and conditioned pain modulation in chronic post-stroke shoulder pain.
        J Pain. 2011; 12: 476-485
        • Sandrini G.
        • Rossi P.
        • Milanov I.
        • Serrao M.
        • Cecchini A.P.
        • Nappi G.
        Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients.
        Cephalalgia. 2006; 26: 782-789
        • Sandrini G.
        • Serrao M.
        • Rossi P.
        • Romaniello A.
        • Cruccu G.
        • Willer J.
        The lower limb flexion reflex in humans.
        Prog Neurobiol. 2005; 77: 353-395
        • Smith M.T.
        • Edwards R.R.
        • McCann U.D.
        • Haythornthwaite J.A.
        The effects of sleep deprivation on pain inhibition and spontaneous pain in women.
        Sleep. 2007; 30: 494-505
        • Song G.H.
        • Venkatraman V.
        • Ho K.Y.
        • Chee M.W.L.
        • Yeoh K.G.
        • Wilder-Smith C.H.
        Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls.
        Pain. 2006; 126: 79-90
        • Sprenger C.
        • Bingel U.
        • Büchel C.
        Treating pain with pain: Supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation.
        Pain. 2011; 152: 428-439
        • Staud R.
        • Robinson M.E.
        • 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
        • Tousignant-Laflamme Y.
        • Marchand S.
        Excitatory and inhibitory pain mechanisms during the menstrual cycle in healthy women.
        Pain. 2009; 146: 47-55
        • Tuveson B.
        • Leffler A.-S.
        • Hansson P.
        Heterotopic noxious conditioning stimulation (HNCS) reduced the intensity of spontaneous pain, but not of allodynia in painful peripheral neuropathy.
        Eur J Pain. 2007; 11: 452-462
        • Tuveson B.
        • Leffler A.-S.
        • Hansson P.
        Influence of heterotopic noxious conditioning stimulation on spontaneous pain and dynamic mechanical allodynia in central post-stroke pain patients.
        Pain. 2009; 143: 84-91
        • van Wijk G.
        • Veldhuijzen D.S.
        Perspective on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes.
        J Pain. 2010; 11: 408-419
        • Villanueva L.
        • Bouhassira D.
        • Le Bars D.
        The medullary subnucleus reticularis dorsalis (SRD) as a key link in both the transmission and modulation of pain signals.
        Pain. 1996; 67: 231-240
        • Wilder-Smith C.H.
        • Robert-Yap J.
        Abnormal endogenous pain modulation and somatic and visceral hypersensitivity in female patients with irritable bowel syndrome.
        World J Gastroenterol. 2007; 13: 3699-3704
        • Wilder-Smith C.H.
        • Schindler D.
        • Lovblad K.
        • Redmond S.M.
        • Nirkko A.
        Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls.
        Gut. 2004; 53: 1595-1601
        • 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