Do we need a third mechanistic descriptor for chronic pain states? : PAIN

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Topical Review

Do we need a third mechanistic descriptor for chronic pain states?

Kosek, Evaa,*; Cohen, Miltonb; Baron, Ralfc; Gebhart, Gerald F.d; Mico, Juan-Antonioe; Rice, Andrew S.C.f; Rief, Winfriedg; Sluka, A. Kathleenh

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PAIN 157(7):p 1382-1386, July 2016. | DOI: 10.1097/j.pain.0000000000000507

1. Introduction

The redefinition of neuropathic pain,23 which specifically excludes the concept of “dysfunction,” has left a large group of patients without a valid pathophysiological descriptor for their experience of pain. This group comprises people who have neither obvious activation of nociceptors nor neuropathy (defined as disease or damage of the somatosensory system) but in whom clinical and psychophysical findings suggest altered nociceptive function. Typical such patient groups include those labelled as having fibromyalgia, complex regional pain syndrome (CRPS) type 1, other instances of “musculoskeletal” pain (such as “nonspecific” chronic low-back pain), and “functional” visceral pain disorders (such as irritable bowel syndrome, bladder pain syndrome). The aim of this topical review was to propose, for debate, a third mechanistic descriptor intended for chronic pain characterized by altered nociceptive function.

1.1. Historical review

Before developing any argument for a third descriptor to accommodate these patients, it is worthwhile reviewing the history of pain terminology. Traditionally, pain mechanisms have been divided into “nociceptive” and “neuropathic” categories. See Table 1 for the historical overview of these definitions.

Table 1.:
Historical overview of mechanistic pain terminology.

1.2. Implications of the changed definition of “neuropathic pain”

In the 2005 iteration, “nociceptive” pain was the norm, the “default” or common sense experience of injury = damage ≤pain, familiar to humans. But it evolved that any pain that was not “nociceptive” might be termed “neuropathic” because the latter descriptor included “dysfunction,” which was taken to include any inferred change in nociceptive function. Although it has always been possible to invoke another category, such as “unknown” or “idiopathic,” that strategy runs a poor third to the other 2, as there is no implication of a putative mechanism.

The 2011 redefinition of neuropathic pain makes biological and etymological sense. The note that accompanies this definition is stringent: Neuropathic pain is a clinical description (and not a diagnosis), which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. This robust definition is not being challenged.

However, the note that accompanies the 2011 redefinition of nociceptive pain—pain that arises from actual or threatened damage to nonneural tissue and is due to activation of nociceptors—states: This termis designed to contrast with neuropathic pain. The term is used to describe pain occurring with a normally functioning somatosensory nervous system to contrast with the abnormal function seen in neuropathic pain (emphasis added). This perpetuates the “nociceptive–neuropathic” dichotomy as above, except that now the “default” position is neuropathic pain, so that any pain condition that is not characterized by damage to neuronal tissue may attract the term “nociceptive.” This is not only counterintuitive, as surely “a normally functioning somatosensory nervous system” should be taken as the basis for any contrast, but also it fails to accommodate a large group of patients in whom “activation of nociceptors” cannot be confidently established.

2. Proposals

This situation requires clarification. The proposals put forward here, as presented in Table 2, include:

  • (1) Assertion of nociceptive pain
  • (2) Confirmation of definition of neuropathic pain, but not as default
  • (3) Need for a third descriptor.

Table 2.:
Proposed taxonomy for the classification of pain compared with the existing IASP taxonomy from 2011 (, changes highlighted.

2.1. Assertion of nociceptive pain

“Nociceptive pain” is the most common human experience of pain. Therefore, we propose that the current IASP 2011 definition of nociceptive pain be used, but that the note be shortened to: “The term is used to describe pain occurring with a normally functioning somatosensory nervous system.” Nociceptive pain should not be defined as the alternative to neuropathic pain. This common-sense biological position presumes that the tissue was “normal” before the noxious stimulus and that the somatosensory apparatus is also “normal.”

2.2. Confirmation of definition of neuropathic pain, but not as default

The new definition of neuropathic pain does not require amendment. However, because it is not as common as nociceptive pain and it does not reflect the usual experience of pain, it should not be the default descriptor.

2.3. Need for a third descriptor

Even with these points of clarification, the situation of only 2 descriptors will remain unsatisfactory for those patients in whom “activation of nociceptors” cannot be confidently demonstrated or assumed and who also do not meet the definition of “definite” or “probable” neuropathic pain. Appending “possible” neuropathic pain leaves them in taxonomic limbo.

In the current state of knowledge, there are reasons to infer that altered nociceptive function does occur in patients experiencing pain in a regional (or more widespread) distribution, unassociated with frank signs of neuropathy but characterized by hypersensitivity in apparently normal tissues. The similarity of such findings to those in frank neural injury or disease suggests that common mechanism(s) may be relevant. A reasonable inference from the presence of these findings is that there has occurred a change in nociceptive processing, probably in the central nervous system. The latter is supported by the findings of demonstrated changes in cerebral activation,16,19,38,39,45 connectivity,4,14,20,25,33,37,41,50 and even in specific cerebral structures1,5,18,22,24,31,36,44 in certain clinical pain states, when also adjusted for depression or anxiety.5,18,21,22,36 However, in these pain conditions, there is no consistent evidence of a lesion or disease of the somatosensory system as a primary cause of the pain, thus disqualifying the pain from attracting the neuropathic descriptor.

2.4. Proposal for a third descriptor

It is proposed that a new term be introduced to describe pain states characterized by clinical and psychophysical findings that suggest altered nociception, despite there being no clear evidence of actual or threatened tissue damage causing the activation of nociceptors or evidence for disease or lesion of the somatosensory system causing the chronic pain.

The candidate adjectives for this third descriptor include:

  • (1) “Nociplastic,” from “nociceptive plasticity,” to reflect change in function of nociceptive pathways.
  • (2) “Algopathic,” from “algos” (Greek for pain) plus “pathic” (from Greek “patheia” for suffering), paraphrased as “a pathological perception/sensation of pain not generated by injury.”
  • (3) “Nocipathic,” from “nociceptive pathology,” to denote a pathological (ie, not “normal”) state of nociception.

The term is intended for clinical usage and is neither a diagnosis nor a synonym for “central sensitization of nociception,” which is a neurophysiological concept. It may well be that the phenomenon of hypersensitivity occurring in ostensibly normal, uninjured tissue without evidence of neuropathy leads to a clinical inference that sensitization may be the underlying mechanism, so that the term is used as a descriptor for that situation. Such reasoning is no different from the phenomenon of observable tissue damage leading to the inference of activation of nociceptors and applying the term “nociceptive pain,” or from the phenomenon of signs of neuropathy leading to the inference of disease or damage of neural structures and applying the term “neuropathic pain.”

3. Discussion

3.1. Do we need a third mechanistic descriptor?

The present IASP terminology does not reflect the current understanding that chronic pain is not necessarily a symptom but can result from altered nociceptive function and thus constitute a condition in itself. Consequently, the pain of some large patient groups suffering from altered nociceptive function is currently classified as “pain of unknown origin.” An argument in favour of continuing to use the current nondescriptors “unknown” or “idiopathic” relies on confusion that might arise out of challenges in defining a new descriptor. However, the inability of the current IASP pain terminology to harmonize with current concepts has resulted in the use of other nondefined descriptors such as “dysfunctional”40 or “pathological”35 pain, which not only give no insight into possible mechanisms but also carry implications that may stigmatize patients.9,10

The use of a third mechanistic descriptor in clinical practice has the potential to confer validity on the patient's experience of pain and to facilitate communication between patients, clinicians, and other stakeholders. Clinicians would be encouraged to screen for signs of altered nociceptive function, thus improving diagnosis and treatment, as patients suffering from altered nociceptive function typically respond better to centrally than peripherally targeted therapies. The term would also facilitate research efforts, by identifying altered nociceptive function as an important area for mechanistic studies, establishment of treatment guidelines and development of new treatment strategies.

3.2. When should the descriptor be used and when not?

The descriptor is primarily intended for patients suffering from chronic pain conditions characterized by evidence of altered nociceptive processing, such as those currently labelled as fibromyalgia,22 CRPS,47 nonspecific chronic low-back pain,16 irritable bowel syndrome,39 and other “functional” visceral pain disorders.8,48 In addition, patients suffering initially from nociceptive pain, such as osteoarthritis, may develop alterations in nociceptive processing manifested as altered descending pain inhibition3,28 accompanied by spread of hypersensitivity.2,17,29 These patients would then be considered to have a combination of nociceptive and “nociplastic/algopathic/nocipathic” contributors to their pain. The new descriptor is intended to distinguish patients suffering from conditions where altered nociception has been documented from those where the pain mechanisms are still truly unknown. Therefore, the new descriptor does not apply to patients reporting pain without hypersensitivity. As such, it is neither a synonym for idiopathic pain or pain of unknown origin nor a label awarded by exclusion.

3.3. Problems regarding validity and use of the new descriptor

Opponents of a new descriptor may argue that mechanisms implicit in the terms “nociceptive” and “neuropathic” are proven, in contrast to the inference of functional changes in the nervous system, which as yet cannot be confirmed. A nociceptive focus may be visualized by radiology or reflected in some laboratory findings. It is argued that neuropathy can be identified by quantitative sensory testing, nerve conduction studies, intra-epidermal nerve fiber density assessments, or by imaging of the central nervous system.

However, despite the fact that pathology can be documented for nociceptive and neuropathic pain, the relationship between that pathology and pain mechanisms remains elusive. The latter is illustrated by the low concordance between the degree of tissue damage/inflammation and pain11 or by the low proportion of people with peripheral nerve injury who develop chronic neuropathic pain.32 Although it is true that no specific structural pathology underlying “nociplastic/algopathic/nocipathic” pain has been found, altered nociceptive processing has been documented by quantitative sensory testing,7,15,27,42,47,48 sensory evoked potentials,12,13,34 and functional magnetic resonance imaging.16,19,38,48 Importantly, these functional changes have in many instances been related to pain severity.1,31,41,43 Therefore, while acknowledging these limitations in the current and the proposed pain terminology, there remains a rationale for using the new descriptor to distinguish patients with altered nociception from patients with pain of unknown origin.

One unresolved situation is when a patient with nociceptive pain could be classified as also having “nociplastic/algopathic/nocipathic” pain. Clinicians are faced with a continuum of signs of hypersensitivity in patients with chronic pain. Individual differences in sensitivity to stimuli are marked even in healthy subjects26,30 and no clinically useful method to quantify nociceptor activation exists. Although tests of descending pain inhibition could be used clinically,6 the validity and reliability of these tests in a clinical setting remain to be established.49

Therefore, nociceptive and “nociplastic/algopathic/nocipathic” pain should not be regarded as exclusive categorical labels but rather, pragmatically, as concurrent possible mechanistic contributors to the patient's pain. This would be similar to the concurrence of nociceptive and neuropathic contributors in other situations.

3.4. Is future progress in pain research likely to affect the use of the descriptors?

These mechanistic terms are descriptors of putative contributors to the experience of pain, not diagnoses; they are placeholders for current concepts and not “set in concrete.” As our knowledge of pain mechanisms advances, so should pain terminology change.

3.5. Concluding remarks

This topical review suggests introducing a third mechanistic pain descriptor to be used in patients with clinically determined altered nociception. If the suggestion is well received, the next step will be to define a set of clinically useful positive classification criteria. The term is mechanistic and thus complementary to, but not synonymous with, the proposed ICD-11 diagnostic term “primary pain.”46 By writing this article, the authors hope to open up a fruitful debate regarding modernization of mechanistic pain terminology.

Conflict of interest statement

E. Kosek has received consultancy and speaker fees in the past 36 months from Eli Lilly and Company and Orion and has ongoing research collaborations with Eli Lilly and Company and AbbVie. M. Cohen has received consultancy fees from Mundipharma and Pfizer for preparation and presentation of educational material. R. Baron has received grants/research support from Pfizer, Genzyme, Grünenthal, and Mundipharma. He is a member of the EU Project No 633491: DOLOR-isk. A member of the IMI “Europain” collaboration and industry members of this are: AstraZeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal, Eli Lilly, and Boehringer Ingelheim. German Federal Ministry of Education and Research (BMBF): Member of the ERA_NET NEU-RON/IM-PAIN Project. German Research Network on Neuropathic Pain, NoPain system biology. German Research Foundation (DFG). He has received speaking fees from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharmaceuticals, Bayer Schering, MSD, and bioCSL. He has been a consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Novartis, Bristol-Myers Squibb, Biogenidec, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Glenmark Pharmaceuticals, and bioCSL. G. F. Gebhart, J. -A. Mico, and A. S.C. Rice have nothing to declare. W. Rief has received consultancy fees from Heel and speaker's fees from Bayer. K. Sluka has been Consultant for DJO, Inc, and Bayer, Inc, received research funding from Medtronic, Inc and royalties from IASP Press.


The authors are members of the Terminology Task Force of the International Association for the Study of Pain, which gave logistical support to perform this work.

E. Kosek and M. Cohen contributed equally.

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[1]. Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, Gitelman DR. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 2004;24:10410–5.
[2]. Aranda-Villalobos P, Fernández-de-Las-Peñas C, Navarro-Espigares JL, Hernández-Torres E, Villalobos M, Arendt-Nielsen L, Arroyo-Morales M. Normalization of widespread pressure pain hypersensitivity after total hip replacement in patients with hip osteoarthritis is associated with clinical and functional improvements. Arthritis Rheum 2013;65:1262–70.
[3]. Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T. Sensitization in patients with painful knee osteoarthritis. PAIN 2010;149:573–81.
[4]. Baliki MN, Mansour AR, Baria AT, Apkarian AV. Functional reorganization of the default mode network across chronic pain conditions. PLoS One 2014;9:e106133.
[5]. Barad M, Ueno T, Younger J, Chatterjee N, Mackey S. Complex regional pain syndrome is associated with structural abnormalities in pain-related regions of the human brain. J Pain 2014;15:197–203.
[6]. Biurrun Manresa JA, Fritsche R, Vuilleumier PH, Oehler C, Mørch CD, Arendt-Nielsen L, Andersen OK, Curatolo M. Is the conditioned pain modulation paradigm reliable? A test-retest assessment using the nociceptive withdrawal reflex. PLoS One 2014;9:e100241.
[7]. Blumenstiel K, Gerhardt A, Rolke R, Bieber C, Tesarz J, Friederich HC, Eich W, Treede RD. Quantitative sensory testing profiles in chronic back pain are distinct from those in fibromyalgia. Clin J Pain 2011;27:682–90.
[8]. Clemens JQ. Male and female pelvic pain disorders—Is it all in their heads? J Urol 2008;179:813–14.
[9]. Cohen M, Quintner J, Buchanan D, Nielsen A, Guy L. Stigmatization of patients with chronic pain: the “dark side” of empathy. Pain Med 2011;12:1637–43.
[10]. Cohen ML, Quintner J, Buchanan D. Is chronic pain a disease? Pain Med 2013;14:1284–8.
[11]. Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet 2005;365:965–73.
[12]. Diers M, Koeppe C, Diesch E, Stolle AM, Hölzl R, Schiltenwolf M, van Ackern K, Flor H. Central processing of acute muscle pain in chronic low back pain patients: an EEG mapping study. J Clin Neurophysiol 2007;24:76–83.
[13]. Diers M, Koeppe C, Yilmaz P, Thieme K, Markela-Lerenc J, Schiltenwolf M, van Ackern K, Flor H. Pain ratings and somatosensory evoked responses to repetitive intramuscular and intracutaneous stimulation in fibromyalgia syndrome. J Clin Neurophysiol 2008;25:153–60.
[14]. Flodin P, Martinsen S, Löfgren M, Bileviciute-Ljungar I, Kosek E, Fransson P. Fibromyalgia is associated with decreased connectivity between pain- and sensorimotor brain areas. Brain Connect 2014;4:587–94.
[15]. Gierthmühlen J, Maier C, Baron R, Tölle T, Treede R, Birbaumer N, Huge V, Koroschetz J, Krumova EK, Lauchart M, Maihöfner C, Richter H, Westermann A; German Research Network on Neuropathic Pain (DFNS) study group. Sensory signs in complex regional pain syndrome and peripheral nerve injury. PAIN 2012;153:765–74.
[16]. Giesecke T, Gracely RH, Grant MAB, Nachemson N, Petzke F, Williams DA, Clauw DJ. Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum 2004;50:613–23.
[17]. Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL. Normalisation of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum 2012;64:2907–16.
[18]. Ivo R, Nicklas A, Dargel J, Sobottke R, Delank KS, Eysel P, Weber B. Brain structural and psychometric alterations in chronic low back pain. Eur Spine J 2013;22:1958–64.
[19]. Jensen KB, Kosek E, Petzke F, Carville S, Fransson P, Marcus H, Williams SC, Choy E, Giesecke T, Mainguy Y, Gracely R, Ingvar M. Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain. PAIN 2009;144:95–100.
[20]. Jensen KB, Loitoile R, Kosek E, Petzke F, Carville S, Fransson P, Marcus H, Williams SCR, Choy E, Mainguy Y, Vitton O, Gracely RH, Gollub R, Ingvar M, Kong J. Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network. Mol Pain 2012;8:32.
[21]. Jensen KB, Petzke F, Carville S, Fransson P, Marcus H, Williams SC, Choy E, Mainguy Y, Gracely R, Ingvar M, Kosek E. Anxiety and depressive symptoms in fibromyalgia are related to poor perception of health but not to pain sensitivity or cerebral processing of pain. Arthritis Rheum 2010;62:3488–95.
[22]. Jensen KB, Srinivasan P, Spaeth R, Tan Y, Kosek E, Petzke F, Carville S, Fransson P, Marcus H, Williams S, Choy E, Vitton O, Gracely R, Ingvar M, Kong J. Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia pain. Arthritis Rheum 2013;65:3293–303.
[23]. Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, Rice AS, Treede RD. A new definition of neuropathic pain. PAIN 2011;152:2204–5.
[24]. Kairys A, Schmidt-Wilcke T, Puiu T, Ichesco E, Labus J, Martucci K, Farmer MA, Ness TJ, Deutsch G, Mayer EA, Mackey S, Apkarian AV, Maravilla K, Clauw DJ, Harris RE. Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome. J Urol 2015;193:131–7.
[25]. Kilpatrick L, Kutch J, Tillisch K, Naliboff B, Labus J, Jiang Z, Farmer MA, Apkarian AV, Mackey S, Martucci KT, Clauw DJ, Harris RE, Deutsch G, Ness TJ, Yang CC, Maravilla K, Mullins C, Mayer EA. Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome. J Urol 2014;192:947–55.
[26]. Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. PAIN 1996;68:375–83.
[27]. Kosek E, Ekholm J, Nordemar R. A comparison of pressure pain thresholds in different tissues and body regions. Long-term reliability of pressure algometry in healthy volunteers. Scand J Rehabil Med 1993;25:117–24.
[28]. 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.
[29]. Kosek E, Ordeberg G. Abnormalities of somatosensory perception in patients with painful osteoarthritis normalize following successful treatment. Eur J Pain 2000;4:229–38.
[30]. Krøigård T, Sothynathan I, Sindrup S. Intraindividual Variability and Long-Term Changes of Thermal Quantitative Sensory Testing. J Clin Neurophysiol 2015;32:352–6.
[31]. Kuchinad A, Schweinhardt P, Seminowicz D, Wood P, Chizh B, Bushnell M. Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J Neurosci 2007;27:4004–7.
[32]. Landerholm S, Ekblom A, Hansson P. Somatosensory function in patients with and without pain after traumatic peripheral nerve injury. Eur J Pain 2010;14:847–53.
[33]. Loggia ML, Kim J, Gollub RL, Vangel MG, Kirsch I, Kong J, Wasan AD, Napadow V. Default mode network connectivity encodes clinical pain: an arterial spin labeling study. PAIN 2013;154:24–33.
[34]. Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalography Clin Neurophysiol 1996;100:165–8.
[35]. Luo C, Kuner T, Kuner R. Synaptic plasticity in pathological pain. Trends Neurosci 2014;37:343–55.
[36]. Lutz J, Jäger L, Quervain D, Krauseneck T, Padberg F, Wichnalek M, Beyer A, Stahl R, Zirngibl B, Morhard D, Reiser M, Schelling G. White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-tensor and volumetric imaging study. Arthritis Rheum 2008;58:3960–9.
[37]. Ma X, Li S, Tian J, Jiang G, Wen H, Wang T, Fang J, Zhan W, Xu Y. Altered brain spontaneous activity and connectivity network in irritable bowel syndrome patients: a resting-state fMRI study. Clin Neurophysiol 2015;126:1190–7.
[38]. Maihöfner C, Forster C, Birklein F, Neundörfer B, Handwerker H. Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study. PAIN 2005;114:93–103.
[39]. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000;118:842–8.
[40]. Nagakura Y. Challenges in drug discovery for overcoming 'dysfunctional pain': an emerging category of chronic pain. Expert Opin Drug Discov 2015;9:1–3.
[41]. Napadow V, LaCount L, Park K, As-Sanie S, Clauw D, Harris R. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010;62:2545–55.
[42]. Puta C, Schulz B, Schoeler S, Magerl W, Gabriel B, Gabriel HH, Miltner WH, Weiss T. Somatosensory abnormalities for painful and innocuous stimuli at the back and at a site distinct from the region of pain in chronic back pain patients. PLoS One 2013;8:e58885.
[43]. Schmidt-Wilcke T, Kairys A, Ichesco E, Fernandez-Sanchez M, Barjola P, Heitzeg M, Harris RE, Clauw DJ, Glass J, Williams DA. Changes in clinical pain in fibromyalgia patients correlate with changes in brain activation in the cingulate cortex in a response inhibition task. Pain Med 2014;15:1346–58.
[44]. Seminowicz D, Labus J, Bueller J, Tillisch K, Naliboff B, Bushnell M, Mayer EA. Regional gray matter density changes in brains of patients with irritable bowel syndrome. Gastroenterology 2010;139:48–57.
[45]. Silverman D, Munakata J, Ennes H, Mandelkern M, Hoh C, Mayer E. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997;112:64–72.
[46]. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JW, Wang SJ. A classification of chronic pain for ICD-11. PAIN 2015;156:1003–6.
[47]. van Rooijen DE, Marinus J, van Hilten JJ. Muscle hyperalgesia is widespread in patients with complex regional pain syndrome. PAIN 2013;154:2745–9.
[48]. Wilder-Smith C. The balancing act: endogenous modulation of pain in functional gastrointestinal disorders. Gut 2011;60:1589–99.
[49]. Yarnitsky D, Granot M, Granovsky Y. Pain modulation profile and pain therapy: between pro- and antinociception. PAIN 2014;155:663–5.
[50]. Yu R, Gollub RL, Spaeth R, Napadow V, Wasan A, Kong J. Disrupted functional connectivity of the periaqueductal gray in chronic low back pain. Neuroimage Clin 2014;23:100–8.

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