Journal of. The South African Chapter of the IASP ISSN Central sensitization: Implications for the diagnosis and treatment of pain

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1 Journal of ISSN The South African Chapter of the IASP Central sensitization: Implications for the diagnosis and treatment of pain Orofacial pain Pathophysiology of postoperative pain Volume 6 Number

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3 Journal of The South African Chapter of the IASP Volume 6 Number 4 Editorial The IASP is always striving to improve knowledge concerning pain and pain therapy. One of the recent changes in their structure/curriculum was to decrease the time between World Congresses. Those of us who have been fortunate enough to attend these congresses can attest to the value of participation. Besides the normal abstract book or CD, attendees also used to receive a book titled Proceedings of the World Pain Congress. This is no longer the case. instead asked plenary speakers to prepare peer-reviewed articles review articles in which they summarise the current thoughts and evidence presented in one of their plenary lectures. These reviews will from now be published as a Special Issue of Pain. I have selected several articles that cover a range of practical topics that will be valuable to all of our members. Clifford Woolf needs no introduction to us in South Africa as he is an old Witsie hailing from Emmarentia in Johannesburg. His work on the role of central sensitization and its implications have proven the basis for much of what we do in everyday practice and the article summarises most of what we, as treating practitioners, need to know. Orofacial pain is another topic that deserves much more attention and the review by Hargreaves will subject that seems to be making the headlines is post-operative pain as it is well known that this type of pain is poorly managed. I shall try and publish as many of the review series as possible whenever the Biennial Review is receive are as practical as the Review Series and it is after all the practice of pain management that is of great concern to all of us no matter what our primary discipline may be. I wish you all well over the Festive Season and trust that you all have a good rest during the holiday season. Next year is going to be a busy one as there are many good local meetings supported by painsa including the Wits Pain Symposium, the Pretoria Pain Meeting and of course the highlight being the PAINSA Annual Congress being organized by Dr Sean Chetty and his Committee. This congress Dr. Milton Raff BSc (WITS), MBChB (Pret), FFA (SA) All correspondence to the editor should be addressed to: raffs@iafrica.com 1

4 EDITOR Dr. M Raff BSc (WITS), MBChB (Pret), FFA (SA) EDITORIAL BOARD Prof. H Meyer MBChB(Pret) MPraxMed(Pret) MFGP(SA) Prof. C L Odendaal Prof. D Mitchell BSc Hons, MSc, PhD (all University of the Witwatersrand) Dr. S Baumann BA. Mb.Ch.B.(U.C.T.), P.G.C.E.(University College of Wales), M.R.C.Psych.(London), F.C.Psych (S.A.) Mrs. P Berger BSc Physio (Wits), Acup (SA) Dr. E Frohlich MD(Tel-Aviv), DA(SA), FCA(SA), Master (Med) Pain Management (Syd) Central sensitization: Implications for the diagnosis and treatment of pain Clifford J. Woolf Orofacial pain Kenneth M. Hargreaves Pathophysiology of postoperative pain Timothy J. Brennan This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, reprinting reuse of illustrations, broad-casting, reproduction of CD- or in any other way, and storage in data banks. The use of registered names trademarks etc. in this publication does not imply, even in the absence of are exempt for the relevant laws and regulations and therefore free for general use. Product liability: the publishers cannot guarantee the accuracy of any information about the publication of medications contained in this publication. In every individual case, the user must check such information by consulting the relevant literature. PUBLISHER / MEDSPEC PUBLISHING Reni Rouncivell, Tel: (012) Fax: , Cell: , reni@medspec.co.za, Private Bag X1036, Lyttelton, South Africa 0140 ADVERTISING & RATES Sue-Anne Smook, Tel: (012) Fax: , Cell: , sueanne@medspec.co.za, Private Bag X1036, Lyttelton, South Africa 0140 Lelani Adendorff, Tel: (012) Fax: , Cell: , lelani@medspec.co.za, Private Bag X1036, Lyttelton, South Africa 0140 SUBSCRIPTIONS & ACCOUNTS Elizabeth Versteeg, Tel: , accounts@medspec.co.za FOR ADDRESS CHANGES PLEASE CONTACT: PAIN SA MEMBERS: YVONNE PYNE-JAMES, painsa@uiplay.com / NON PAIN SA MEMBERS: LINDA VANDERBERG, linda@promailhealthcare.co.za PHYSIOTHERAPY GROUP: BEVERLEY BOLTON, abcdbolt@telkomsa.net / TRADE: CALLY LAMPRECT, cally@medspec.co.za 2

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7 PAIN Ò 152 (2011) S2 S15 Review Central sensitization: Implications for the diagnosis and treatment of pain Clifford J. Woolf Program in Neurobiology and FM Kirby Neurobiology Center, Children s Hospital Boston, Department of Neurobiology, Harvard Medical School, Boston, MA, USA Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. article info abstract Article history: Received 9 August 2010 Received in revised form 24 September 2010 Accepted 24 September 2010 Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity. Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. 1. Introduction In 1983 I published a study indicating that many features of the pain hypersensitivity accompanying peripheral tissue injury or inflammation were the direct result of an augmentation of sensory signaling in the central nervous system [255]. A central amplification during angina pectoris had been postulated exactly 100 years before by W. Allen Sturge MD, who in an 1883 paper in Brain envisaged a possible central nervous system commotion... passed up from below that somehow contributed to the clinical features of ischemic cardiac pain. However, the importance of this clinical insight lay largely dormant for a century, except for one human volunteer study on secondary hyperalgesia that was recognized by the authors as suggestive of a possible central contribution to the spread of pain sensitivity [101]. What I found in a pre-clinical address: clifford.woolf@childrens.harvard.edu study on stimulus response relations in the spinal cord was that the afferent activity induced by peripheral injury triggered a long-lasting increase in the excitability of spinal cord neurons, profoundly changing the gain of the somatosensory system [255]. This central facilitation manifested as a reduction in threshold (allodynia), an increase in responsiveness and prolonged aftereffects to noxious stimuli (hyperalgesia), and a receptive field expansion that enabled input from non-injured tissue to produce pain (secondary hyperalgesia) [51, ,268,273]. I have recently reviewed the circumstances surrounding the discovery of the activity-dependent synaptic plasticity in the spinal cord that generates post-injury pain hypersensitivity [259], and that became termed central sensitization [272], as well as the current state of understanding of the cellular and molecular mechanisms responsible for this form of neuronal plasticity [147]. What I would like to specifically address in this review are the clinical implications of the phenomenon. What has central sensitization taught us about the nature and mechanisms of pain in patients, /$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi: /j.pain

8 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 S3 and what are the implications of central sensitization for pain diagnosis and therapy? Before doing this though, it is important first to understand exactly what central sensitization represents, how it has changed our general understanding of pain mechanisms, as well as reviewing the substantial data on central sensitization derived from studies on experimental pain in human volunteers. 2. What is central sensitization? Prior to the discovery of central sensitization, the prevailing view on pain processing in the central nervous system was of a largely passive neural relay that conveyed by encoded action potentials, information on the onset, duration, intensity, location and quality of peripheral noxious stimuli, much like a telephone wire, from one site to another. More specifically, the CNS pathway was seen to constitute particular anatomical connections in the spinal cord, brain stem, thalamus and cortex (the pain pathway ), linking the sensory inflow generated in high threshold primary afferents with those parts of the cortex that leads to the conscious awareness of painful sensations. The spinal gate control theory by Melzack and Wall in 1965 had highlighted that this sensory relay system could be modulated in the spinal cord by inhibitory controls [163], and considerable progress had been made by the early 1980 s in identifying such inhibitory circuits [18]. Indeed this, together with the discovery of enkephalins and endorphins [98,109], diffuse noxious inhibitory controls [150], transcutaneous nerve stimulation [224], and the rediscovery of acupuncture [25], generated a much greater emphasis at that time on endogenous inhibitory controls than on those factors that might increase excitation, and thereby produce pain hypersensitivity. However, there was one exception, which was related to the discovery of peripheral sensitization in the 1970 s [178]. Work by Iggo [28,112] and Perl [20,33,177] had identified specific high threshold sensory neurons tuned to respond only to noxious stimuli, hence their name nociceptors [265], a term first coined by Sherrington based on his studies on noxious stimulus evoked flexion reflexes. Furthermore, first Perl and then others showed that nociceptor peripheral terminals could become sensitized after injury, reducing their threshold, mainly to heat stimuli, and only within the site of injury where the terminal was exposed to inflammatory modulators, the zone of primary hyperalgesia [23,41,138,146,178]. While this phenomenon is clearly a very important contributor to inflammatory pain hypersensitivity [22], it cannot account for dynamic tactile allodynia, the temporal summation of pain, or secondary hyperalgesia. Some other explanation was needed as the neurobiological basis for these symptoms, which turned out to be increased synaptic function triggered within the CNS by nociceptive inputs [257,237,268]. The realization that synapses were subject to a form of usedependent plasticity that could increase their strength or efficacy had steadily gained ground by the early 1980 s. The phenomenon had first been described in the CNS as short lasting a post-tetanic potentiation of mono synaptic IA synaptic input to motor neurons by Lloyd in 1949 [155], one that could spread to other synapses on motor neurons [21]. This was followed by the discovery of windup in dorsal horn neurons by Mendell and Wall in 1965 [164], where repeated low frequency stimulation of a nerve at constant C-fiber strength was found to elicit a progressive increase in action potential firing over the course of the stimulus. A transformative breakthrough was the first description of long term potentiation (LTP) in the hippocampus by Bliss and Lomo in 1973, where a brief high frequency coincident input produced a persistent increase in synaptic efficacy, opening the door for an extensive and still ongoing study into the molecular mechanisms of synaptic plasticity. LTP was first recorded in the spinal cord in 1993 [182], where it represents a particular component of the general phenomenon of central sensitization [113,114,122]. In 1976 Kandel and colleagues described a sensitization of the gill withdrawal reflex in the sea snail Aplysia, which was associated with a facilitation of the synapse between sensory and motor neurons [29]. However, these data were interpreted as reflecting memory and learning rather than an invertebrate model of pain hypersensitivity, although of course the two phenomena converge in this, and in other model systems, although there are differences too [122,274]. What I found in my original study by 1983 and subsequent preclinical studies with colleagues at University College London was that a brief (10 20 s), low frequency (1 10 Hz) burst of action potentials into the CNS generated by electrical stimulation or natural activation of nociceptors increased synaptic efficacy in nociceptive neurons in the dorsal horn of the spinal cord and this lasted for tens of minutes after the end of the conditioning stimulus [50,51,230,244,245,255,256,263,264,267,272,273]. This phenomenon differed from windup, which represented a progressively increasing output during the course of a train of identical stimuli (technically called homosynaptic potentiation); central sensitization was concerned instead with the facilitation that manifested after the end of the conditioning stimuli, and that once triggered remained autonomous for some time, or only required a very low level of nociceptor input to sustain it. Furthermore, central sensitization represented a condition where input in one set of nociceptor sensory fibers (the conditioning input) amplified subsequent responses to other non-stimulated non-nociceptor or nociceptor fibers (the test input; this form of facilitation is termed heterosynaptic potentiation to distinguish it from homosynaptic potentiation where the test and conditioning input are the same) [231]. The classic form of LTP in the hippocampus is homosynaptic with changes in efficacy restricted to activated synapses, a convergent plasticity, and while this is a feature of some aspects of central sensitization [190], most of its clinically relevant attributes relate to its divergent heterosynaptic components [147]. The underlying neurobiological basis for central sensitization is that for most central circuits, the receptive field properties of neurons defined by the firing of action potentials is only the tip of the iceberg. Most of the synaptic input to neurons is subthreshold [262,263], acting subliminally either because synaptic input is too weak or membrane excitability is restrained by inhibitory inputs. Increasing synaptic strength by a presynaptic increase in an excitatory transmitter release or in the post synaptic response to the transmitter [46,100,129,130,133,151,152,154,227,231,247,264,271] or by reducing inhibition [12,103,168,180,165,208,226] or increasing membrane excitability can recruit these normal subthreshold inputs to suprathreshold action potentials, producing profound changes in functional properties [270]. More recently it has become appreciated that in addition to activity-dependent synaptic plasticity, changes in microglia, astrocytes, gap junctions, membrane excitability and gene transcription all can contribute to the maintenance of central sensitization [43,44,47,48,88,104,186,189, 205,234]. Figs. 1 and 2 summarize sensory processing under normal circumstances and the changes that result from induction of central sensitization. An important implication of these early basic science studies was the possibility that the pain we experience might not necessarily reflect the presence of a peripheral noxious stimulus. We learn from our everyday experience interfacing with the external environment to interpret pain as reflecting the presence of a peripheral damaging stimulus, and indeed this is critical to its protective function. Central sensitization introduces another dimension, one where the CNS can change, distort or amplify pain, increasing its degree, duration, and spatial extent in a manner that no longer directly reflects the specific qualities of peripheral noxious stimuli, but rather the particular functional states of circuits in the CNS. With the discovery of central sensitization, pain 6

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10 S4 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 Fig. 1. Normal sensation. The somatosensory system is organized such that the highly specialized primary sensory neurons that encode low intensity stimuli only activate those central pathways that lead to innocuous sensations, while high intensity stimuli that activate nociceptors only activate the central pathways that lead to pain and the two parallel pathways do not functionally intersect. This is mediated by the strong synaptic inputs between the particular sensory inputs and pathways and inhibitory neurons that focus activity to these dedicated circuits. Fig. 2. Central sensitization. With the induction of central sensitization in somatosensory pathways with increases in synaptic efficacy and reductions in inhibition, a central amplification occurs enhancing the pain response to noxious stimuli in amplitude, duration and spatial extent, while the strengthening of normally ineffective synapses recruits subliminal inputs such that inputs in low threshold sensory inputs can now activate the pain circuit. The two parallel sensory pathways converge. conceptually at least had become centralized instead of being exclusively peripherally driven. In this sense central sensitization represents an uncoupling of the clear stimulus response relationship that defines nociceptive pain. Nociceptive pain reflects the perception of noxious stimuli. In the absence of such potentially damaging stimuli there is no nociceptive pain. However, after the discovery of central sensitization it became clear that a noxious stimulus while sufficient was not necessary to produce pain. If the gain of neurons in the pain pathway in the CNS was increased, they could now begin to be activated by low threshold, innocuous inputs. In consequence pain could in these circumstances become the equivalent of an illusory perception, a sensation that has the exact quality of that evoked by a real noxious stimulus but which occurs in the absence of such an injurious stimulus. This does not mean that the pain is not real, just that it is not activated by noxious stimuli. Such pain can no longer be termed nociceptive, but rather reflects a state of induced pain hypersensitivity, with almost precisely the same symptom profile to that found in many clinical conditions. This raised the immediate obvious question, was central sensitization a contributor to clinical pain hypersensitivity? These notions were generally not very well received initially, particularly by physicians who believed that pain in the absence of pathology was simply due to individuals seeking work or insurance-related compensation, opioid drug seekers, and patients with psychiatric disturbances; i.e. malingerers, liars and hysterics. That a central amplification of pain might be a real neurobiological phenomenon, one that contributes to diverse clinical pain conditions, seemed to them to be unlikely, and most clinicians preferred to use loose diagnostic labels like psychosomatic or somatoform disorder to define pain conditions they did not understand. We can now 30 years later, based on data from many studies in human 8

11 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 S5 volunteers and patients, address whether central sensitization, defined operationally as an amplification of neural signaling within the CNS that elicits pain hypersensitivity, is a real phenomenon or not, and can assess its relative contribution to inflammatory, neuropathic and dysfunctional pain disorders in patients [53,258]. 3. Central sensitization in human volunteers The first clear demonstration of central sensitization in human volunteers came from a psychophysical study by LaMotte and colleagues on the secondary cutaneous hyperalgesia that is elicited by intradermal capsaicin injection (which activates the TRPV1 receptor). They found intense localized pain lasting minutes at the injection site, followed immediately by three zones of hyperalgesia; a small zone of heat hyperalgesia close to the injection site lasting 1 2 h, an intermediate zone of dynamic tactile allodynia spreading beyond the area of heat hyperalgesia and lasting several hours, and the largest zone to pinprick, way outside of the injection site, which remained present for up to 24 h [145]. The investigators then showed that the secondary mechanical hyperalgesia required sensory inflow to the CNS because local anesthesia prior to the capsaicin injection blocked it. In addition because the pain sensitivity crossed a tight band that prevented circulation in the skin, they concluded that it was not due to a local spread of the capsaicin or any peripheral inflammatory mediator. An even more direct demonstration that activity-dependent central sensitization was responsible for tactile allodynia and secondary hyperalgesia in humans came from a second study by La Motte, this time with Torebjork in 1992 [233]. They again used intradermal injection of capsaicin to induce an area of tactile allodynia that lasted for 2 h. Nerve block experiments revealed that while the capsaicin and heat pain was carried by C fibers, the mechanical allodynia was transferred to the CNS by low threshold myelinated fibers. The most elegant part of the study was their finding that electrical intraneural stimulation of single Ab mechanoreceptive fibers that elicited a non-painful tactile sensation before the capsaicin injection, began to produce pain if the fibers receptive field fell within the zone of secondary mechanical hyperalgesia. Lidocaine anesthesia of the cutaneous innervation territory of the stimulated fiber did not reverse the pain, showing that this was not peripheral in origin. They concluded that the pain evoked by stroking the skin area surrounding a painful intradermal injection of capsaicin is due to reversible changes in the central processing of mechanoreceptive input from myelinated fibres which normally evoke nonpainful tactile sensations. Another early study, this time by Koltzenburg and Torebjork, using mustard oil (which activates TRPA1) as the pain conditioning stimulus, together again with differential nerve blocks, confirmed that brush-evoked mechanical allodynia was mediated by low threshold Ab fibers that normally encode non-painful tactile sensations [140]. Unlike after capsaicin, however, the mustard oil evoked tactile allodynia required an ongoing low level input from C-nociceptors to sustain it, indicating that different sensory fibers may have different central actions, some short and others long lasting, and indeed further studies have shown differences in the duration of tactile allodynia after capsaicin and mustard oil [139], the significance of which was not appreciated a the time because it was not clear then that these irritants acted on quite different TRP receptors. That central sensitization could cause a spread of pain sensitivity across peripheral nerve territories, the neurological dogma for diagnosing a disease of the central rather than peripheral nervous system was shown by Max and colleagues using the intradermal capsaicin model in volunteers together with radial or ulnar nerve blocks to clearly identify individual nerve territory [192]. Complementing this, a study comparing skin hyperaemia induced by a skin burn injury found that the skin blood flow changes induced by the injury had disappeared by the time secondary mechanical hyperalgesia peaked, and the two were not correlated in time or space, supporting the conclusion that peripheral mechanisms do not contribute to secondary hyperalgesia [198]. Perhaps even more dramatic, was the relatively recent demonstration that intradermal capsaicin induces contralateral hyperalgesia and allodynia that are delayed in their manifestation and reduced in extent compared to the ipsilateral secondary hyperalgesia, but present in a majority of subjects [206], a form perhaps of tertiary hyperalgesia that cannot be peripheral in origin. What pain sensitivity we feel then, can be determined by the state of excitability of neurons in the CNS. Central amplification of Ad nociceptor fiber test input following a C-fiber conditioning input was shown to contribute to pinprick/ punctate secondary hyperalgesia, again using the intradermal capsaicin model [279], underscoring the different identity of the afferent signals that elicit central sensitization as a conditioning stimulus (C-fibers) from those that elicit allodynia (Fb) or hyperalgesia (Ad), a further clear manifestation of heterosynaptic facilitation. In a similar vein, another study found that pin prick hyperalgesia induced in response to intradermal capsaicin was actually mediated by capsaicin-insensitive afferents, showing that the test and conditioning inputs in this setting are quite different [87], while the secondary hyperalgesia elicited by intradermal capsaicin was shown by yet other investigators, to be restricted to mechanical stimuli, with no correlation between the magnitude of capsaicin evoked pain and the extent of punctate or tactile secondary hyperalgesia [237]. Furthermore, temporal summation to pin prick in the zone of capsaicin injection (as model of homosynaptic facilitation/windup) was mechanistically independent of the development of secondary hyperalgesia, because while the gain of the stimulus response relationship in the zone of secondary was increased that of the windup was not changed, even though the actual pain was enhanced [158]. A similar conclusion was made after a study where repeated intradermal capsaicin injections were reported to produce a progressively diminishing pain, presumably due to desensitization, while the allodynia and punctate hyperalgesia continued to increase [254]. Two more recent studies using high frequency stimulation as the conditioning input to mimic conditions that elicit LTP found that while changes in the conditioned site (homotopic site) do occur, they are accompanied by a development of pain hypersensitivity in the adjacent non-stimulated heterotopic site (reduction in threshold, pain evoked by light tactile stimuli, and exaggerated response to suprathreshold pinprick stimuli [136,240], and both sets of investigators concluded that heterosynaptic facilitation predominates in this model of central sensitization, exactly as it does for the low frequency conditioning inputs that mimic the natural firing range of nociceptors. Generalizing, it seems clear that heterosynaptic changes are a major feature of the presentation of central sensitization. Apart from changes in subjective pain measures, the consequences of central sensitization can also be detected using objective biomarkers. These include long-term changes in nociceptive withdrawal reflexes [24] and increases in cortical event related potential amplitudes [240]. Magnetic source imaging reveals an increase in the excitability of neurons in the somatosensory cortex evoked by low threshold Ab stimulation within the capsaicin-induced zone of secondary hyperalgesia [17], while magnetoencephalography detects changes in the patterns of cerebral processing [159] and functional MRI, and changes in BOLD signals in the cortex, both during secondary hyperalgesia [16]. Another MRI study found changes in the brainstem that are apparently specific to central sensitization, in addition to the changes in the primary somatosensory cortex that are related to the intensity of pain [153]. While most studies have looked at the effects of skin conditioning stimuli on skin pain sensitivity, experimental muscle pain produced by hypertonic saline injections produces long lasting 9

12 S6 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 changes in thermal sensitivity in the area of referred pain [203], while sustained nociceptive stimulation of myofascial trigger points induces a wide spread central sensitization [273,275]. Interestingly, in pre-clinical models, muscle and joint conditioning afferents have a longer lasting action in producing central sensitization than those from skin [244]. A reverse approach has shown that cutaneous capsaicin increases myofascial trigger point pressure sensitivity in segmentally related muscles [211]. Conditioning nociceptive stimuli originating in viscera, such as exposure of the lower esophagus to acid, also induces central sensitization, leading to viscerovisceral (pain hypersensitivity in the upper esophagus) and viscerosomatic hypersensitivity (allodynia on the chest wall) [193] that can be captured by esophageal evoked potentials [194], and is associated with increased temporal summation [196]. A recent study has replicated this esophageal model of central sensitization using acid and capsaicin infusions, showing also thermal and mechanical pain hypersensitivity in the rectum after the esophageal stimulation [27], indicating how widespread the effects of central sensitization are in the gastro-intestinal tract. These changes may be mechanistically related to widespread clinical pain syndromes [95]. One emerging area of considerable interest is the utility of experimental central sensitization in human volunteers to test efficacy in centrally acting drugs. Drugs with efficacy in pre-clinical models, such as NMDA receptor antagonists [271] can be tested in Phase 1b human proof of principle studies [212]. Ketamine inhibits central temporal summation [8] and secondary mechanical hyperalgesia [142] evoked by repetitive nociceptive electrical stimulation in humans as well as primary and secondary hyperalgesia after an experimental burn injury [116], visceral conditioning inputs [251,253] and topical [6] or intradermal [204] capsaicin, but not A delta mediated nociceptive pain [181]. Ketamine s action on experimental pain can be detected by fmri [210]. Similar activity is found for i.v. dextromethophan [115]. Collectively these data strongly support a role for the NMDA receptor in acute activitydependent central sensitization [147]. However, the trials also indicate the lack of therapeutic index between reducing central sensitization and inducing psychotomimetic side effects. Another class of drugs that has been extensively studied in human experimental models of central sensitization is the gabapentanoids. Oral gabapentin at doses similar to that used for chronic neuropathic pain when given to human volunteers reduced tactile allodynia and decreased mechanical secondary hyperalgesia elicited by intradermal capsaicin [92]. Even single administration of gabapentin had an antihyperalgesic effect on capsaicin-induced secondary hyperalgesia and reduced fmri signatures of central sensitization [110]. In another study gabapentin, interestingly reduced cutaneous evoked central sensitization but not muscle pain [201]. Two studies have looked at pregabalin s efficacy in experimental human central sensitization, one evoked by electrical stimuli [49] and the other by intradermal capsaicin [246]. Both of these double blind studies demonstrated efficacy for pregabalin in terms of experimental tactile allodynia and secondary hyperalgesia. These data suggest that a major component of gabapentin or pregabalin s mechanism of action is a reduction of central sensitization [238]. Many other centrally acting drugs with analgesic efficacy in patients reduce central sensitization preclinically, including duloxetine, milnacipran and lamotrigene [15,118,170] but have not been tested for this action in humans. Drugs that have failed to show efficacy in human studies of activity-dependent central sensitization are NK1 receptor antagonists [252] [49] and COX-2 inhibitors [35,49,250]. A COX-2 inhibitor does have efficacy though if the central sensitization is triggered by peripheral inflammation [225], as predicted by pre-clinical models [189]. Interestingly, while gender has been described as important for differences in nociceptive pain sensitivity, a study on the secondary hyperalgesia induced by heat and capsaicin did not reveal a gender difference [119]. Nevertheless, recent data show that pain sensitivity including secondary hyperalgesia and brush evoked allodynia is heritable, with an estimated 50% genetic contribution to the pain variance [172]. The genetic polymorphisms involved in the differential susceptibility to secondary hyperalgesia have not been comprehensively investigated, although some candidates are beginning to be identified in studies of experimental central sensitization [228]. This is an area that requires major research. The following conclusions can be made from this survey of the published studies of experimental pain hypersensitivity in human volunteers. Central sensitization is a robust phenomenon, readily induced in human volunteers in response to diverse ways of activating nociceptors (electrical stimulation, capsaicin, mustard oil, acid, heat burn, UV burn, hypertonic saline). Generally this activity-dependent plasticity manifests immediately, but its effects persist for many hours beyond the inducing conditioning stimulus, eventually returning, however, back to baseline, indicating its usual full reversibility. The phenomenon can be elicited by conditioning skin, muscle or visceral organs, and typically presents as dynamic tactile allodynia and punctate hyperalgesia but also enhanced pressure, and in some cases, thermal sensitivity, spreading from the conditioning site to neighboring non-stimulated sites, and even to very remote regions. Although there is a homosynaptic (homotopic) aspect to the phenomenon, its major manifestation is heterosynaptic (heterotopic), and for this reason and its reversibility, it is perhaps inaccurate to equate central sensitization with the LTP like phenomena in the cortex that are specifically associated with long term memory. Because central sensitization can be induced in almost all subjects and detected using subjective and objective outcome measures and is sensitive to pharmacological interventions, it is a useful tool for determining the activity of drugs on centrally driven pain hypersensitivity. Globally, the data obtained in human volunteer studies demonstrate that induction of use-dependent central facilitation in nociceptive central pathways increases pain sensitivity and may, therefore, contribute to clinical pain syndromes. Experimental studies in human volunteers are necessarily restricted to use non-injurious conditioning inputs, and therefore are limited to studying only the activity-dependent components of pain hypersensitivity elicited by sensory inputs, and not those transcription-dependent and structural changes that manifest after inflammation or nerve injury, which may have different mechanisms, time courses and presentations [53,97,121,123,160,171, 189,229,242,261,269]. The limited experience with more severe human experimental injury indicates that central sensitization also contributes to the late hyperalgesia present in this model [58,176]. 4. Central sensitization and the clinical pain phenotype What features of the clinical phenotype may be contributed to, or generated exclusively by central sensitization? While the human experimental studies reviewed above indicate that if a patient has dynamic tactile allodynia, secondary punctuate/pressure hyperalgesia, temporal summation and sensory aftereffects, central sensitization may well be involved. Any sensory experience greater in amplitude, duration and spatial extent than that would be expected from a defined peripheral input under normal circumstances qualifies as potentially reflecting a central amplification due to increased excitation or reduced inhibition. These changes could include a reduction in threshold, exaggerated response to a noxious stimulus, pain after the end of a stimulus, and a spread of sensitivity to normal tissue. However, because we cannot directly measure sensory inflow, and because peripheral changes can contribute to sensory amplification, as with peripheral sensitization, pain hypersensitivity by itself is not enough to make an 10

13 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 S7 irrefutable diagnosis of central sensitization. A further complication is that because peripheral input commonly is the trigger of central sensitization, a reduction in pain sensitivity produced by targeting a peripheral trigger with a local anesthetic does not exclude central amplification, but may rather indicate a role of peripheral input in maintaining it [140]. Nevertheless, there are some features of patient s symptoms which are more likely to indicate central rather than peripheral contribution to pain hypersensitivity. These include pain mediated by low threshold Ab fibers (determined by nerve block or electrical stimulation), a spread of pain sensitivity to areas with no demonstrable pathology, aftersensations, enhances temporal summation, and the maintenance of pain by low frequency stimuli that normally do not evoke any ongoing pain. To assess how central sensitization may present in patients, we need a detailed phenotyping of different patient cohorts to capture exactly what changes in sensitivity occur, where and when [9,11,55,86,93,188,197]. Ideally this should be combined with objective measures of central activity, such as fmri, so that clear diagnostic criteria for determining the presence of central sensitization in patients can be established. The utility of diagnostic criteria for the presence of central sensitization would not only be insight into the pathophysiological mechanisms responsible for producing pain but more so in defining potential treatment strategies. If a particular patient s pain is primarily the result of abnormal activity in nociceptors, as in patients with primary erythromelalgia [74], the optimal therapy required is likely to be different from a patient whose tactile allodynia and secondary hyperalgesia are entirely maintained by central sensitization due to changes in synaptic efficacy in the spinal cord. This is the rationale for a mechanism-based approach to the diagnosis and treatment of pain [258,266]. Indeed response to a trial treatment, such as to the NMDA receptor antagonist ketamine, can itself be a potential diagnostic for the presence central sensitization. 5. To which clinical syndromes does central sensitization contribute? Given the caveats about the lack of absolute diagnostic criteria for identifying the presence of central sensitization in patients, a fairly large number of studies have nevertheless putatively identified this phenomenon as contributing to patients pain phenotype. I will briefly review these, based on disease Rheumatoid arthritis (RA) Patients with RA, the prototypic inflammatory joint disease, have extra-articular tenderness which is correlated with the extent of joint disease [141] but whether this is the result of peripheral or central sensitization has not been studied. A study on juvenile chronic arthritis reported enhanced sensitivity to noxious stimuli both at joints and in remote areas in patients with and without active disease, suggesting the possibility that the disease when active sets up a state of autonomous central sensitization [107] Osteoarthritis (OA) This degenerative joint disease with characteristic destruction of cartilage and alteration in bone is a very common cause of chronic pain, particularly in the elderly. The degree of pain does not always correlate with the extent of joint damage or presence of active inflammation raising the possibility that there may be a central component to the pain [26]. Supporting this is the enhanced degree and duration of pain and secondary hyperalgesia evoked by intramuscular injection of hypertonic saline in patients with OA compared to controls [13]. Patients with high pre-operative pain and a low pain threshold have a higher risk of persistent pain after total knee replacement for OA, which was interpreted as reflecting central sensitization [157]. Another study on 62 patients showed that pain of central neural origin (widespread reduced pressure pain thresholds) negatively impacted on knee functional capacity [117]. OA patients have a lower pain threshold and have punctate hyperalgesia in areas of referred pain, which is associated with greater activation in the brainstem as detected by fmri, representing a possible biomarker for central changes [99]. The centrally acting amine uptake inhibitor duloxetine which reduces central sensitization in pre-clinical models [15,124] significantly reduced pain more than placebo in an RCT in 231 patients with knee OA pain [45], indicating that drugs that target central sensitization are efficacious in this patient population. In a recent phenotyping study in 48 patients with painful knee OA and 24 age matched controls, the patients had reduced pressure pain thresholds both at the joint and in remote areas, and increased temporal summation. While the degree of sensitization correlated with the pain, it did not correlate with radiological findings, leading to the conclusion that central sensitization is an important contributor to knee OA pain [7]. Collectively, these data intriguingly suggest that the pain of OA, a peripheral pathology, has an important central component, and this is clearly deserving more study to understand its extent, mechanism and therapeutic implications Temporomandibular disorders (TMD) Unlike OA, the pathophysiology of this syndrome is much less well understood. However, TMD has been found to be associated with an increase in generalized pain sensitivity after isometric contraction of the orofacial muscles [166], and widespread bilateral mechanical [78] and thermal [175] pain sensitivity are reported in women with myofascial TMD compared to age matched controls, which was interpreted as suggesting widespread central sensitization. In addition, a greater referred pain is elicited from the more frequent trigger points that are found in these patients, than in controls [77]. As for other types of facial pain, mechanical allodynia is a major feature of periradicular inflammation (periradicular periodontitis) with reduced threshold also in contralateral non inflamed teeth, reflecting central sensitization [132]. After a third molar extraction evidence for central sensitization could be detected for at least a week (enhanced response to repetitive intraoral pinprick and electrical stimulation, aftersensations and extraoral hyperalgesia) [126] Fibromyalgia (FM) One of the first suggestions that fibromyalgia patients may have generalized central sensitization came from a psychophysical study that identified widespread reduction in thermal and mechanical pain thresholds, as well as greater cerebral laser evoked potentials [90], a finding replicated soon after [156]. Another early small study using ketamine, showed an NMDA-dependent component to fibromyalgia and suggested that tender points may represent secondary hyperalgesia due to central sensitization [209]. Supporting this, Arendt-Nielson and colleagues found in small study that fibromyalgia patients had lower pressure thresholds and increased temporal summation to muscle stimulation, and that intramuscular hypertonic saline injections provoked a longer lasting and more widespread pain. In a related study, they found that the referred pain, temporal summation, muscular hyperalgesia and muscle pain in fibromyalgia patients were all attenuated by ketamine [96]. In 2001, Staud and Price begun a series of studies on fibromyalgia, first showing temporal summation and after sensations of the pain elicited by repetitive cutaneous thermal stimuli and repetitive mechanical stimuli to muscles 11

14 S8 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 [221]. In a second study they found that temporal summation occurred at substantially lower forces and at a lower frequency of stimulation in fibromyalgia patients than in control subjects, and that painful after sensations were greater in amplitude and more prolonged [215]. The enhanced experimental pain in fibromyalgia patients was shown to contribute to the variance of the clinical pain [220]. These investigators then showed that the maintenance of experimentally induced pain in fibromyalgia patients requires significantly less frequent stimulation than in normal controls, and concluded that this heightened sensitivity to very low frequency inputs contributes to the persistent pain in these patients [218]. A later study showed that the temporal summation of pain and its maintenance was widespread, and could be equally elicited from hands or feet, leading to the conclusion that central sensitization in these patients was generalized across the neuraxis [219]. In an fmri study they then found a stimulus and frequency dependent activation in several brain regions in fibromyalgia patients and controls, including ipsilateral and contralateral thalamus, medial thalamus, S1, bilateral S2, mid- and posterior insula, rostral and mid-anterior cingulate cortex. The stimulus temperatures necessary to evoke equivalent levels of brain activity were, however, significantly less in fibromyalgia patients, suggesting that the enhanced neural mechanisms in fibromyalgia are not the result of selective enhancement at cortical levels [216]. The Staud and Price group then designed experiments to see if peripheral sensitization may contribute to the enhanced temporal summation of thermal pain in fibromyalgia patients and concluded that it does not, based on thermal thresholds [214]. Recently they have found using local anesthetic injections though, that peripheral input from muscle appears to be important in maintaining central sensitization in FM patients [217]. This would mean that fibromyalgia may have both peripheral and central contributions, whose extent may vary from patient to patient. Certainly muscle afferents seem to have a potent capacity in pre-clinical [244] and experimental human studies [275] to induce central sensitization. A quantitative sensory testing study in 85 fibromyalgia patients and 40 matched controls found that the patients had altered heat and cold thresholds and a reduced tolerance for pain, as well as a reduced nociceptive reflex threshold, a measure of central excitability [65]. The latter finding was sufficiently different from controls that the authors suggest it could be used as a diagnostic measure of central sensitization, identifying patients for whom centrally acting drugs may be particularly beneficial. Other studies have confirmed the increased generalized sensitivity in FM patients to pressure and thermal stimuli [94,173,179] and to electrical stimulation of skin and muscle, with enhanced cortical evoked potentials [66]. The data overall seem to support a major role for central sensitization in the generation of the symptoms of FM, and the success of centrally acting treatments, such as pregabalin or duloxetine in treating these conditions, may reflect a reduction in central sensitization in these patients Miscellaneous musculoskeletal disorders Chronic neck pain resulting from whiplash is associated with lowered pain thresholds in uninjured tissue [57,222]. Injection of local anesthetic into myofascial trigger points in these patients results in an immediate increase in range of motion and elevation in pressure pain thresholds, which was felt to reflect dynamic maintenance of central sensitization by afferent triggers [85]. Patients with shoulder impingement syndrome also show widespread muscle sensitivity and an increased number of trigger points [105]. A widespread (bilateral) mechanical pain hypersensitivity is observed in patients with unilateral epicondylalgia (tennis elbow) interpreted as indicating central sensitization, possibly induced by a peripheral trigger [75]. Similar generalized deep tissue hyperalgesia can also be demonstrated in patients with chronic radiating low back pain with intervertebral disc herniation [173]. Collectively these data indicate that diverse musculoskeletal disorders are characterized by a spread of pain sensitivity to deep uninjured tissue and that low level peripheral inputs may maintain this Headache The first intimation that headaches have an important component mediated by central sensitization came from a study of spontaneous tension-type headaches which found that even in the absence of headache pericranial muscle tenderness was increased in patients compared to control subjects. During headache, muscle tenderness increased and thermal pain threshold decreased in the temporal region, but remained normal in the hand which was interpreted as an indication that segmental central sensitization contributed to pain in frequent sufferers of tension-type headache [120]. This was then followed by the observation by Bernstein and colleagues that cutaneous allodynia developed in 79% of patients during migraine attacks in, and sometimes beyond the area of referred pain [36,37]. This finding has been repeated in several studies since then [52,161,135,207]. While cephalic and extracephalic allodynia are well described, spontaneous body pain and allodynia have also been reported as preceding migraine attacks [56]. Laser evoked cutaneous pain thresholds are reduced during migraine attacks and cortical evoked potentials increased [62]. No change in heat pain thresholds are found in chronic tension-type headache, but there is pericranial tenderness [63,80] and hyperalgesia of neck shoulder muscles [81]. Nociceptive input from muscles has been suggested to contribute to the induction of central sensitization in tension-type headache [79], much as has been suggested for FM. In patients with cluster headaches the nociceptive flexion reflex threshold is reduced on the symptomatic side [191]. In a population study on primary headaches in 523 patients, evidence for pain hypersensitivity was found in those with tension type pain, with a greater disturbance in individuals with chronic or more frequent headaches, implying that central sensitization may contribute to the chronification of headache [30], something that is supported by epidemiological data [31]. In a longitudinal prospective study on whether increased pain sensitivity is a cause or an effect, a study in 100 individuals found that subjects had normal thresholds prior to the development of headache, but this decreased in those who then developed chronic tension-type headache, suggesting that the pain hypersensitivity is a consequence of frequent tension-type headaches, and not a predictor or risk factor [32], a finding interpreted as a showing that central sensitization plays a role in the chronification of tension-type headaches. Interestingly, a study in patients with either chronic migraine and chronic tension-type headache found in both cohorts reduced threshold for pressure, pinprick, blink, and the nociceptive flexion reflex, as well as higher windup ratios [83], possibly reflecting a common role for central sensitization in the chronification of different types of headache Neuropathic pain The first demonstration of a likely contribution of central sensitization to neuropathic pain came from a study by Campbell and colleagues, who showed that an ischemic conduction block of large myelinated fibers specifically reduced dynamic tactile allodynia [42], a finding that was soon replicated [140]. Since then careful phenotyping studies of conditions like carpal tunnel syndrome have revealed enhanced bilateral sensitivity and an extraterritorial spread of symptoms in patients with unilateral or single nerve entrapment, supporting a contribution of central sensitization [61,76,82,278]. Furthermore, ketamine reduces established periph- 12

15 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 S9 eral neuropathic pain [125] and chronic phantom limb pain [73] indicating that ongoing activity- and NMDA receptor-dependent synaptic plasticity may contribute to maintain neuropathic pain. That tricyclic antidepressants, dual uptake inhibitors and calcium channel alpha(2)-delta ligands, all centrally acting drugs that normalize enhanced neural activity, are the current first line treatments for neuropathic pain [72], reinforces the importance of the central component of the pain and its suitability as a target for treatment Complex regional pain syndrome (CRPS) A prominent feature of chronic CRPS1 is tactile hyperesthesia and pressure hyperalgesia [241], which can be registered as enhanced S1 activation by a neuromagnetometer [243]. There is also thermal hyperalgesia in acute CRPS1 patients, which on the side ipsilateral to the diseased limb, may have a peripheral component due to ongoing aseptic inflammation, but the presence of contralateral hypersensitivity in the absence of any inflammatory changes points to an involvement of the CNS [108]. In a small randomized placebo controlled trial intravenous ketamine reduced CRPS pain [200] Post-surgical pain This is a very heterogenous group comprising acute postoperative pain and persistent pain of multiple causes, including surgically induced neuropathic pain [1,131]. In the acute phase, incisional pain is associated with a secondary punctate hyperalgesia that is ketamine sensitive [223], with no spread in thermal sensitivity [143] indicating induction of central sensitization. Considerable controversy exists over whether pre-emptive treatment targeting central sensitization is superior to postoperative treatment in treating either the acute postoperative pain or its transition to chronic pain [4,5,54,60,68,70,71,128,149,102,236,260]. Surprisingly, because of numerous technical problems related to the design, conduct and interpretation of such studies, this turns out to be a difficult issue to resolve [134,167]. This is not the place to review the full literature on pre-emptive analgesia, however my personal take on the available data is that there appears to be a small signal for pre- vs. postoperative analgesic treatment in some settings, but it is likely not generally clinically relevant. It seems clearly important though that patients have full analgesia established on recovery from a general anesthetic or adequate regional anesthesia during surgery, and this can be maintained until surgical healing is well advanced [19,14,277]. The treatment plan for controlling postoperative pain can potentially include drugs with action on central sensitization such as ketamine [184], pregabalin [34,162], gabapentin [202] and duloxetine [106], which in the limited number of trials currently available show some efficacy, but more RCT are required to assess their utility in treating acute postoperative pain or in reducing the risk of developing chronic pain [59] Visceral pain hypersensitivity syndromes Pain hypersensitivity is a feature of several common disorders of the gastro-intestinal tract including irritable bowel syndrome, non-cardiac chest pain and chronic pancreatitis that all appear to have a central sensitization component. A majority of IBS patients have both rectal and somatic hypersensitivity [249]. Repetitive sigmoid stimulation in patients with IBS induces rectal hyperalgesia and viscerosomatic referral [169]. Local rectal anesthesia reduces rectal and somatic pain in irritable bowel syndrome patients, supporting the possibility that visceral hyperalgesia and secondary cutaneous hyperalgesia in irritable bowel syndrome are the results of central sensitization dynamically maintained by input from the GIT. Patients with non-cardiac chest pain have esophageal hypersensitivity [195], with a reduced tolerance to repeated distension, increased size of referred pain and a greater propensity to show secondary hyperalgesia after acid infusion in their lower esophagus [69], all interpreted as reflecting the consequence of central sensitization. Chronic pancreatitis is associated with generalized deep pressure hyperalgesia [39,174] and patients display greater degree and spatial extent secondary hyperalgesia elicited by repetitive experimental stimulation, suggesting enhanced central sensitization [67] that is reduced by a thorascopic splanchnic denervation [38], which may reflect that visceral input from the pancreas maintains the central sensitization. In the urological tract, pain hypersensitivity is a feature of interstitial cystitis, chronic prostatitis, endometriosis, and vulvodynia, conditions whose pathophysiology and etiology are however, poorly understood. Although central sensitization has been hypothesized to contribute [137], not much data are available and few studies have been performed. Men with chronic prostatitis have though heightened pain sensitivity in the perineum [239,276], while women with vulvodynia have an enhanced post capsaicin allodynia and secondary hyperalgesia compared to controls [84] Co-morbidity of pain conditions characterized by pain hypersensitivity Pain can be defined as nociceptive when it is generated by noxious stimuli, inflammatory when produced by tissue injury and/or immune cell activation, and neuropathic, when it is due to a lesion of the nervous system. What about pain conditions though, where there is no noxious stimulus, inflammation or damage to the nervous system? There are several common syndromes that present with pain hypersensitivity but no clear etiological factor, i.e. considered unexplained and which might actually reflect not only peripheral pathology but also a primary dysfunction of the nervous system. These include fibromyalgia, tension-type headache, temporomandibular joint disease and irritable bowel syndrome, all of which may have a specific contribution to their phenotype by central sensitization, as detailed above. If a heightened sensitivity of the CNS or an increased propensity to develop central sensitization is a common feature of these syndromes, one would expect that there may be increased co-occurrence or comorbidity of the different conditions. It is also possible that an enhanced capacity to produce or maintain central sensitization is the primary defect in some of these syndromes. In a study on almost 4000 twins for comorbidity of chronic fatigue, low back pain, irritable bowel syndrome, chronic tension-type headache, temporomandibular joint disease, major depression, panic attacks and post-traumatic stress disorder, associations were found that far exceeded those expected by chance, and the conclusion was that these conditions share a common etiology [199]. Another large epidemiological study on 44,000 individuals including twins for comorbidity with chronic widespread pain found co-occurrence with chronic fatigue, joint pain, depressive symptoms, and irritable bowel syndrome, leading to the conclusion that associations between chronic widespread pain and its comorbidities may include genetic factors [127]. Yet another study on 2299 subjects for four unexplained syndromes; chronic wide spread pain, chronic orofacial pain, irritable bowel and chronic fatigue again found that the occurrence of multiple syndromes was greater than expected by chance [2]. These epidemiological findings strongly suggest that there may be a common mechanistic basis for these diverse conditions, and that may have a hereditary component. Smaller studies have found comorbidity between fibromyalgia and the following conditions: migraine in females but not males [111], primary headache [64], chronic fatigue symptom [89], 13

16 S10 C.J. Woolf / PAIN Ò 152 (2011) S2 S15 systemic lupus erythematosus [213], irritable bowel syndrome [144], rheumatoid arthritis [183], the premenstrual syndrome [3], chronic urticaria [235] and cervical myofascial pain syndrome [40]. Comorbidity has been shown also for back pain and temporomandibular disorders [248], migraine and temporomandibular disorders [91], irritable bowel syndrome and functional dyspepsia, fibromyalgia and chronic pelvic pain [185], and finally between migraine and irritable bowel syndrome, chronic fatigue and fibromyalgia [232]. There is also an overlap between urological disorders like chronic pelvic pain, interstitial cystitis, painful bladder syndrome, chronic prostatitis and vulvodynia with fibromyalgia, chronic fatigue, temporomandibular disorders and irritable bowel syndrome [187], and more specifically between vulvodynia, fibromyalgia and irritable bowel syndrome [10]. The overwhelming conclusion from these diverse epidemiological studies is that chronic pain hypersensitivity in the absence of inflammation or nerve damage results in apparently phenotypically different syndromes depending on the tissue/organs affected. However, the overall similarity of the sensitivity changes may reflect a common contribution of central sensitization, and this may account for the unexpectedly high comorbid rate of the apparently different syndromes. To test if there are indeed central sensitization syndromes, we will need a clear set of diagnostic criteria and biomarkers for the phenomenon. If this hypothesis is correct, the implications may be that treatment strategies targeted at normalizing hyperexcitability in the CNS may have a shared efficacy for the different manifestations of the central sensitization syndrome. 6. Conclusions Clinical pain is not simply the consequence of a switching on of the pain system in the periphery by a particular pathology, but instead reflects to a substantial extent, the state of excitability of central nociceptive circuits. The induction of activity-dependent increases in synaptic function in these circuits triggered and maintained by dynamic nociceptor inputs, shifts the sensitivity of the pain system such that normally innocuous inputs can activate it and the perceptual responses to noxious inputs are exaggerated, prolonged and spread widely. These sensory changes represent the manifestation of central sensitization, and extensive experimental medicine and clinical investigations over the past twenty years have revealed it to be an important component of the pain hypersensitivity present many patients. While considerable progress has been made in teasing out the cellular and molecular mechanism responsible [148], much remains still to be learned, particularly which genetic and environmental contributors increase the risk of developing central sensitization in particular systems, exactly what triggers and sustains the phenomenon, and what is responsible in some individuals for its persistence. Nevertheless, the identification of the contribution of central sensitization to many unexplained clinical pain conditions has both provided a mechanistic explanation, and offered a therapeutic target. Conflict of interest There is no conflict of interest. Acknowledgements Supported by research funds from the NIH. I thank all my colleagues whose work has over the past 25 years contributed to the study of central sensitization but particularly Alban Latremoliere for his careful reading of the MS and Christian von Hehn for making the two figures. 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22 PAIN Ò 152 (2011) S25 S32 Review Orofacial pain Kenneth M. Hargreaves Departments of Endodontics, Pharmacology, Physiology and Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. 1. Introduction Pain in the oral and craniofacial system represents a major medical and social problem. Indeed, a U.S. Surgeon General s report on orofacial health concludes that,...oral health means much more than healthy teeth. It means being free of chronic oral-facial pain conditions... [172]. Community-based surveys indicate that many subjects commonly report pain in the orofacial region, with estimates of >39 million, or 22% of Americans older than 18 years of age, in the United States alone [108]. Other population-based surveys conducted in the United Kingdom [111,112], Germany [91], or regional pain care centers in the United States [54] report similar occurrence rates [135]. Importantly, chronic widespread body pain, patient sex and age, and psychosocial factors appear to serve as risk factors for chronic orofacial pain [1,2,92,99,138]. In addition to its high degree of prevalence, the reported intensities of various orofacial pain conditions are similar to that observed with many spinal pain disorders (Fig. 1). Moreover, orofacial pain is derived from many unique target tissues, such as the meninges, cornea, tooth pulp, oral/ nasal mucosa, and temporomandibular joint (Fig. 2), and thus has several unique physiologic characteristics compared with the spinal nociceptive system [23]. Given these considerations, it is not surprising that accurate diagnosis and effective management of orofacial pain conditions represents a significant health care problem. Publications in the field of orofacial pain demonstrate a steady increase over the last several decades (Fig. 3). This is a complex literature; a recent bibliometric analysis of orofacial pain articles published in indicated that 975 articles on orofacial pain were published in 275 journals from authors representing 54 countries [142]. Thus, orofacial pain disorders represent a complex constellation of conditions with an equally diverse literature base. Accordingly, this review will focus on a summary of major research foci on orofacial pain without attempting to provide a comprehensive review of the entire literature. 2. Physiologic studies on trigeminal pain Several reviews are available that document the historical development of physiologic research on the trigeminal nociceptive Address: Department of Endodontics, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel.: ; fax: address: Hargreaves@uthscsa.edu system [33,53,114,120,149]. More recent studies have characterized differences in electrophysiological [82], anatomical [10], or pharmacological [42,80] properties of trigeminal afferents innervating distinct target tissues. Collectively, many of these studies provide support for the hypothesis that target tissue interactions with trigeminal neuron terminals, via either soluble factors such as neurotrophins [48], or by integrin binding to extracellular matrix molecules [22,25], regulate the expression or trafficking of neuronal proteins, including ion channels and receptors [90,139] or second messenger signaling pathways [25]. Thus, the presence of unique target tissues innervated by trigeminal afferent fibers likely contributes to differences in the responsiveness of these neurons. A recent review characterizes differences between the trigeminal and spinal afferent systems under basal conditions [23]. Table 1 illustrates differences between the trigeminal and spinal systems after various forms of injury. Collectively, these studies indicate that the trigeminal system has many unique features that may contribute to distinct response patterns to tissue injury. The hypothesis of peripheral regulation of neuronal phenotype has been expanded by the recognition that estradiol selectively alters gene transcription in trigeminal neurons with increased expression of neuropeptides, such as prolactin, that are capable of sensitizing neuronal responses to capsaicin or noxious heat [49]. Additional studies have demonstrated that trigeminal peptidergic neurons undergo morphological changes ( sprouting ) in response to injury-induced inflammation in target tissues [33]. In contrast, there is a lack of sympathetic fiber sprouting in trigeminal ganglion cells, unlike the well-recognized occurrence in the spinal system [19,29,63]. Thus, an emerging body of evidence reveals the dynamic and specific responsiveness of the trigeminal system to either injury of its various target tissues or to the presence of certain gonadal steroids. Other studies have employed cultured trigeminal ganglia (TG) to evaluate cellular mechanisms of neuronal activation. For example, cannabinoids activate a calcineurin pathway leading to the rapid dephosphorylation and desensitization of transient receptor potential cation channel, subfamily V, member 1 (TRPV1), thereby contributing to an ionotropic mechanism for peripheral cannabinoid antinociception [4,5,89,133]. Moreover, accumulating evidence indicates a functional cross-desensitization between TRPV1 and TRP subfamily A, member 1 (TRPA1) on trigeminal neurons, possibly via formation of a heteromer [4,6,146,147]. Additional studies have used cultured TG to demonstrate that opioid receptors are /$36.00 Ó 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi: /j.pain

23 S26 K.M. Hargreaves / PAIN Ò 152 (2011) S25 S32 Fig. 1. Comparison of pain intensity among spinal and orofacial pain disorders using the McGill Total Rank Pain Index (PRI[T]). The PRI(T) is an ordinal scale consisting of the sum of the ranks of words in each of the 20 sub-categories on the McGill Pain Questionnaire and ranges from 0 to 78. Data taken from: [14,35,71,73,116,117,150,164,176,183,184]. Cornea Nasal/oral Mucosa Dental Pulp Meninges TMJ TSNC expressed on sensory neurons but are not coupled to inhibitory signaling pathways under basal experimental conditions. Instead, pretreatment with arachidonic acid or with agonists to receptors coupled to Gaq signaling pathways (eg, bradykinin, trypsin) is required to induce the rapid development of a functional competence for opioid receptor signaling to Gai pathways leading to inhibition of neuronal activities [24,25,60,131,132]. These cellular findings are consistent with the observation that opioids have little efficacy for peripheral antinociception under basal conditions, but rapidly gain functional competence following injection of inflammatory mediators [145] or the development of inflammation. Recent studies have employed cultured trigeminal neurons to identify endogenous TRPV1 agonists [130,134]. Heating of isolated superfused peripheral tissue to a noxious temperature range leads to the release of oxidized linoleic acid metabolites (OLAMs), including 9- and 13-hydroxyoctadecadienoic acid (HODE). The administration of synthetic 9- and 13-HODE (and their oxoode metabolites) selectively activates TRPV1, leading to inward currents, increased accumulation of intracellular calcium, and triggering exocytosis of neuropeptides from TG neurons and thermal allodynia. These effects are blocked by TRPV1 antagonists and are Vg Vp Vo Vtr Vi Vc Fig. 2. Unique target tissues innervated by the trigeminal sensory system. Taken from Bereiter et al. [23], with permission. observed only in trigeminal neurons from wild-type mice but not TRPV1 knockouts [130]. Moreover, the intracellular delivery of compounds that block OLAM formation (eg, nordihydroguaiaretic acid) or a combination of anti-9- and anti-13-hode antibodies both significantly inhibit heat-evoked activation of trigeminal neurons. Collectively, these findings strongly implicate the OLAMs as a family of endogenous TRPV1 agonists. Interestingly, the pronounced effect of TRPV1 antagonists for blocking heat hyperalgesia in inflammation as well as mechanical allodynia (after intrathecal administration) has led to the hypothesis that an endogenous TRPV1 system might be activated under conditions of tissue injury. In support of this hypothesis, the administration of anti-olam antibodies produces a peripherally mediated thermal antinociception and a centrally mediated blockade of mechanical allodynia in the complete Freund s model of inflammation [130,134]. Thus, the OLAM system appears to contribute to acute heat detection by TRPV1 and to regulate more persistent conditions such as inflammatory pain. Future research directions may include preclinical studies focusing on mechanisms underlying differences between trigeminal and spinal pain conditions, mechanisms of sex-dependent differences in pain transduction and processing, and on the biological basis and pharmacological regulation of acute and chronic orofacial pain conditions. Many of these studies would be promoted by the development of standardized preclinical pain models and assessment methods. In addition to research on the biological mechanisms of nociceptive transmission, numerous clinical studies have described strong psychosocial/disability components to orofacial pain. Indeed, some diagnostic classification schemes differentiate the dimension of tissue contributions from psychosocial/disability factors [55] contributing to orofacial pain disorders. These studies demonstrate that the orofacial pain patient is confronted with a complex, multidimensional disorder that is best managed with appropriate treatment for all underlying factors [2,46,56,61,85,97,154]. 3. Studies on trigeminal inflammatory disorders Many translational studies have evaluated acute inflammatory injury to the trigeminal system. The dental impaction pain model has been developed as a standard clinical method for evaluating many analgesic drugs [43,45,115]. Other investigators have used this model of acute inflammatory pain to evaluate preemptive anesthesia [66,68], activation of endogenous opioid analgesic systems [70,78,104,105], local release of inflammatory mediators as collected by implanted microdialysis probes [50,67,77,162], other physiologic mechanisms [76], or the association of genetic polymorphisms with postoperative pain [95,96,98]. This clinical model has several notable advantages, including participation of relatively healthy subjects not taking concurrent drugs, standardized surgical procedures leading to reduced variance, and relatively large numbers of potential participants. Collectively, these studies on patients undergoing surgical dental extractions have contributed greatly to evaluation of analgesics, anesthetics, and anxiolytics, as well as basic biological research on human subjects. Other studies have focused on chronic inflammation of the oral and craniofacial region. Clinical studies on irreversible pulpitis in teeth ( toothache ) have demonstrated that this condition of bacterial-induced inflammation/necrosis is associated with significant changes in expression of ion channels [8,16,83,110,178,182], receptors [106], and neuropeptides [32,33]. Moreover, inflammation of a single tooth in patients appears sufficient to trigger central sensitization [59,94,127,151]. Animal studies on inflammation in the trigeminal region have demonstrated target-site-dependent differences in sensitization/activation [62,79,175] as well as sex-dependent differences in neuronal activities [20,126,168]. 21

24 K.M. Hargreaves / PAIN Ò 152 (2011) S25 S32 S27 Fig. 3. Rates of articles published on orofacial pain. Data were acquired from a PubMed search (August 2010) using the search criteria of: (orofacial or trigeminal or temporomandibular or dental or tooth) and (pain or headache or hyperalgesia or allodynia or nociceptor or nociceptive). Future research directions on trigeminal inflammatory disorders may include preclinical and translational clinical studies focusing on mechanisms underlying the development and maintenance of inflammatory hyperalgesia/allodynia. Importantly, the clinical condition of pulpitis results in a very restricted pain locus (often within a tissue volume of <200 ul), intense pain reports [73], and dynamic neuronal and immunoplasticity. Thus, the pulpitis pain model is important not only from the perspective of high prevalence [108] and health care disparity [174], but also serves as a useful model for translational research [27]. 4. Studies on trigeminal neuropathic disorders The orofacial region has unique neuropathic pain disorders not seen in the spinal system, including trigeminal neuralgia and glossopharyngeal neuralgia [15]. Numerous clinical reports document these and other orofacial neuropathic or neuritic/neuralgic pain conditions and their responsiveness to surgical or pharmacological treatments [15,38,118,124,129,168,184]. Several etiologic factors appear to contribute to the development of neuropathic pain disorders. Proposed mechanisms include injury/compression to the trigeminal nerve, inflammatory insult (possibly including glial contributions), or infection with herpes virus [3,15,17,40,124, 125,177]. However, not all injuries to the trigeminal nerve lead to neuropathic pain disorders; indeed, the incidence of neuropathic pain after injury to orofacial structures is relatively low after dental treatment [34,109,137], facial trauma [17], orthognathic surgery [39], tooth extraction [26,36,143,173], or placement of dental implants [72]. This apparent resistance of the trigeminal system to development of neuropathic conditions is an interesting clinical observation that should prompt preclinical research comparing trigeminal to spinal afferent systems for susceptibility to neuropathic pain disorders. It is interesting that the trigeminal system appears programmed for periodic loss of innervated structures during postnatal development, with the shedding of 20 deciduous teeth per person, with minimal development of neuropathic pain conditions. Several risk factors for trigeminal neuralgia have been found, including multiple sclerosis [44,140] and hypertension [93]. Additional studies have reported changes in the expression of ion channels (eg, NaV1.3, 1.7, 1.8, TRPA1) in surgical biopsies collected from patients suffering from neuropathic orofacial pain [119,153]. Animal models of trigeminal neuropathic pain have been developed and include chronic constriction injury of the infraorbital nerve as well as transaction of the inferior alveolar nerve [3,177]. Interestingly, both preclinical and clinical studies have implicated constriction of peripheral nerves as an etiologic mechanism for inducing neuropathic pain via alteration in primary afferent functions [81], although certain cortical changes have been reported as well [28]. This has led to the development of clinical surgical decompression procedures to treat patients with trigeminal neuralgia [166,167]. Several preclinical studies have implicated ion channels and endothelin receptors as well as glial mechanisms in contributing to the development of these models of neuropathic pain conditions [11,40,81,125]. 5. Studies on chronic trigeminal myofascial and joint pain The diagnosis and management of many chronic orofacial pain conditions has been greatly hampered by confusion in determining etiologies from the temporomandibular joint versus myofascial sources. This has led to clinical studies difficult to interpret and diagnostic classifications that did not have a strong biological basis due to the lack of differentiation between joint and muscle contributions to the patient s pain condition. Clinical studies on myofascial pain or temporomandibular dysfunction (TMD) were considerably improved by the development of the Research Diagnostic Criteria [55,56], which highlighted the need for developing standardized diagnostic methods and definitions. Considerable evidence has been published demonstrating that patient sex/gender and exposure to sex steroids serve as risk factors for developing chronic orofacial pain conditions [61,65, ]. However, this is not observed in all studies, and other risk factors such as chronic widespread body pain, a prior history of physical abuse, or health anxiety have also been reported to be associated with the development of chronic orofacial pain disorders [1,55,61,92,100,107]. The reasons why some but not all studies detect sex/gender as a significant risk factor for orofacial pain disorders is not clear, but may be due to differences in patient populations, case definitions, or experimental approaches. Related preclinical studies have demonstrated that trigeminal neurons express estrogen receptors and undergo dramatic changes in gene expression [9,21,49] or firing rates [62] following exposure to estradiol. Other clinical studies have focused on synovial fluid levels of inflammatory mediators to test for other possible biological mechanisms [31,160] or have evaluated the role of peripheral glutamate receptors in triggering myofascial pain [7,12]. A very interesting approach is the application of genetics to patients with TMD. A haplotype of the catechol-o-methyltransferase gene in patients is associated with reduced responsiveness to experimental pain and to reduced risk for TMD [47]. Moreover, a mechanistic hypothesis for the protective effect of this haplotype has been advanced [121], and TMD patients with this catechol-o-methyltransferase haplotype respond with increased analgesia from drugs such as propranolol [169]. 6. Studies on other orofacial pain conditions Many other orofacial pain disorders also have been evaluated. The trigeminal autonomic cephalgias include cluster headache, 22

25 S28 K.M. Hargreaves / PAIN Ò 152 (2011) S25 S32 Table 1 Comparison of the trigeminal and spinal afferent systems after injury. Marker Injury model Comparison Authors Galanin Axotomy TG DRG for upregulation Arvidsson et al. [13]; Zhang et al. [185] NPY Axotomy TG DRG for upregulation Arvidsson et al. [13]; Zhang et al. [185] Sympathetic fiber sprouting into ganglion and basket formation Axotomy or CCI TG: No DRG: Yes Bongenhielm et al. [29]; Benoliel et al. [19] Sympathetic fiber sprouting into NGF infusion icv X 14d DRG > TG Nauta et al. [122] ganglion SNS/PN3 = NaV1.8 Axotomy TG: Downregulation followed by Bongenhielm et al. [30] normalization DRG: Persistent downregulation Ankyrin(G) Axotomy TG: Persistent downregulation Bongenhielm et al. [30] Ectopic firing of afferents Axotomy TG < DRG Tal and Devor[165] Augmented excitability Axotomy TG DRG Tal and Devor [165]; Zhang et al. [186]; Cherkas et al. [37] Frequency and rhythmicity of Tight ligation of infraorbital vs sciatic DRG had significantly greater Tal and Devor [165] spontaneous discharges nerves spontaneous discharge rate than TG neurons for both myelinated and unmyelinated fibers. DRG afferents had rhythmic discharge rates (not seen with TG) Satellite glial cells Axotomy TG DRG for upregulation of GFPA, proliferation Woodham et al. [181]; Stephenson et al. [158]; Cherkas et al. [37] NOS Axotomy TG DRG for upregulation Hokfelt et al. [84] P2X3 & ATF-3 expression Partial axotomy TG DRG Tsuzuki et al. [171] GM3 ganglioside. Knockout GM2/GD2 and the GD3 Facial wounding > Rest of the body Inoue et al. [87] synthase gene With peripheral nerve degeneration Peripheral chromatolysis LiCl TG DRG Levine et al. (2004) Sensory neuropathy with neuronal degeneration Sjogren s Syndrome TG DRG Malinow et al. [113] Infectivity of contralateral ganglia HSV polypeptide ICP4 (VP175) expression in ganglia Viral replication and degradation of host cells, mrna Herpes simplex virus-1 (HSV) infection Herpes simplex virus-1 (HSV) infection Herpes simplex virus-1 (HSV) infection 70% of TG contralateral to side of HSV Thackray et al. [170] injection produced infections after inoculation, whereas only 10% of contralateral DRG produced infections. TG DRG Pepose et al. [136] TG DRG with wild-type HSV more virulent in both ganglia than HSV mutants lacking virion host shutoff (vhs) protein Smith et al. [156] Infectivity of ganglia Simian varicella virus (SVV) TG DRG White et al. [179] Substance P in ganglia Streptozotocin-diabetes TG had 26% reduction (P < 0.01), but Robinson et al. [144] DRG = 11% non-significant reduction Substance P in ganglia mf rat (mutilated foot; an autosomal DRG < TG Scaravilli [148] recessive sensory neuropathy with reduced pain responsiveness Caspase-3 mediated neuronal Knockout of Rb (retinoblastoma TG DRG for protection from Simpson et al. [152] apoptosis tumor suppressor protein) apoptosis in double knockout of Rb and caspase-3 compared to single Rb knockout Number of neurons in ganglia TRKa knockout TG DRG for extensive neuronal loss Smeyne et al. [155] Reactivation of virus HSV mutant with gamma 34.5 gene TG > resistant to reactivation than Spivack et al. [157] deletion DRG Wide-spread numbness and pain 4 12 d after antibiotic treatment Acute sensory neuronopathy syndrome in humans TG DRG Sterman et al. [159] Pain Trigeminal neuralgia in humans TG: Yes (max/mand divisions > ophthalmic) DRG: No equivalent Spontaneous behavior Formalin OVX females exhibited significantly greater increase in formalin hyperalgesia after orofacial injection (upper lip) compared to hind paw injection. Result is consistent with hypothesis of a difference in sex steroid regulation of nociception between TG and DRG systems Jannetta [88]; Sweet [161]; Wilkins [180]; Goya et al. [69]; Hamlyn [74,75]; Tacconi and Miles [163] Pajot et al. [128] SNS, sensory neuron specific; PN3, peripheral nerve sodium channel type 3; NOS, nitric oxide synthase; P2X3, purinoceptor 3; ICP4, infected cell protein 4; TG, trigeminal ganglia; DRG, dorsal root ganglia; NPY, neuropeptide Y; CCI, chronic constriction injury; NGF, nerve growth factor; NOA, ATF-3, activating transcription factor 3; OVX, ovariectomized. paroxysmal hemicrania, and unilateral neuralgiform headaches [41]. This collection of pain disorders is characterized by unilateral head pain in association with autonomic features such as tearing and conjunctival involvement, and considerable research has shed light on pain referral patterns and issues related to proper diagnosis and treatment [18,51,58,64,86]. Most cases of trigeminal auto- 23

26 K.M. Hargreaves / PAIN Ò 152 (2011) S25 S32 S29 nomic cephalgia reflect primary headaches, although rare cases may be associated with pituitary tumors [41]. Pain is a major aspect of oral cancer [57] and often represents the initial symptom that prompts patients to seek health providers. Pain due to oral cancer may be due to soluble factors released from tumor cells, a localized inflammatory response to the tumor, or even nerve entrapment. Several recent studies have implicated the endothelin system and proteases (eg, PAR-2 receptor activation) in mediating mechanical allodynia experimental models of oral cancer pain [52,141]. Burning mouth syndrome is a rare disorder, commonly characterized by spontaneous burning pain and mechanical allodynia. Although idiopathic, it has many features of neuropathic pain and has been reported to be associated with altered peripheral expression of voltage-gated sodium channels [16]. 7. Discussion Orofacial pain disorders comprise a major and expensive component of health care and collectively have a high prevalence rate, a large range in pain intensity with a commensurate, often devastating impact on quality of life [149]. Although there are many common aspects of pain transduction and processing between the trigeminal and spinal systems, there are numerous examples of unique features in the peripheral and central components of the trigeminal pain system. Accordingly, ongoing basic and clinical research focused on acute and chronic orofacial pain conditions is required to understand the unique features of this pain system and to develop and evaluate better ways to treat patients with orofacial pain. A major barrier for improved patient care and translational research is the lack of validated diagnostic criteria. Although efforts have been made to classify TMD patients with the Research Diagnostic Criteria for TMD, headache patients with the International Headache Society criteria, and orofacial pain with the American Academy of Orofacial Pain standards, clinical research indicates that each of these 3 methods is incomplete for comprehensive diagnosis of orofacial pain patients [18]. Thus, further research is critically required to establish a comprehensive, sensitive, and specific diagnostic classification scheme for all orofacial pain patients. This would provide a critical contribution to practitioners and foster the development of a powerful dataset for clinical research. In addition, recent studies have incorporated quality-of-life indices, which provide important additional information on clinical outcomes [123]. 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30 PAIN Ò 152 (2011) S33 S40 Review Pathophysiology of postoperative pain Timothy J. Brennan Departments of Anesthesia and Pharmacology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. 1. Introduction 1.1. Clinical perspective Acute postoperative pain remains a significant medical problem. Patients undergoing outpatient ambulatory surgery have clinically significant postoperative pain, even when administration of oral opioids and nonopioid adjuncts are optimized [1]. Regional analgesic techniques improve pain control, except their use is limited to a minority of all surgical patients [8,31]. For those patients undergoing major surgical procedures, ongoing pain or pain at rest, and pain during activities are important clinical symptoms. Pain at rest is usually moderate; the average visual analogue pain scale (VAS) score is 3 to 4 of 10 during the first 2 to 3 days after surgery [24]. These pain scores occur even when parenteral treatments are administered. Usually, pain at rest resolves within the first week after surgery (see schematic, Fig. 1). Pain with activities, such as coughing or walking, is severe during the first 2 to 3 days; the average VAS score can be as great as 7 to 8. Pain with activities is moderate or severe for many days and even weeks later. Functional capability is limited during this period as well; thus, pain can be moderate, and the activities such as ability to cough or walking distance to evoke this pain are reduced [16,36]. Greater opioid dosing to further reduce pain is limited by side effects such as nausea, vomiting, ileus, respiratory depression, and sedation [8]. Clinically, our goal is to advance simple, safe, effective therapies that will greatly reduce postoperative pain. In the last 10 to 15 years, gabapentinoids and cyclooxygenase-2 inhibitors have undergone extensive trials, and regional anesthesia is advancing in acceptance [9]. In general, we have had difficulty making major improvements in the overall treatment of clinical postoperative pain for the majority of patients Scientific perspective Currently, we recognize that the etiology and treatment of pain produced by surgery is different than other clinical pain conditions such as rheumatoid arthritis, fibromyalgia, or acute herpes zoster Address: Department of Anesthesia, 200 Hawkins Drive, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. Tel.: ; fax: address: tim-brennan@uiowa.edu [6,23]. Many pain models may be useful for mechanistic studies but less valuable for developing novel targets to treat particular clinical pain conditions. To advance our treatment of acute postoperative pain, we must recognize that many preclinical pain models, such as antigen-specific inflammation or receptor-specific chemical stimuli (ie, formalin or capsaicin), do not necessarily translate well to incisional pain mechanisms [15,44,46,47]. Theoretically, if the etiology and pathophysiology of the clinical condition are mimicked by the experimental model, analgesic target discovery may be improved. A second goal for preclinical rodent pain research is to make the end points for nociceptive testing have proximate translatability to clinical pain and analgesia [34]. Others have suggested that plasma levels of drugs for antinociception in animals and plasma concentrations for analgesia in human subjects be compared to improve the translatability of the models and the behavior in rodents [34]. Limitations of pain models and behaviors may be one of several factors contributing to our limited success in developing new treatments for acute postoperative pain [20,32]. Because there has been considerable debate regarding the clinical utility of rodent pain models, we and others undertook studies on the etiology of nociception caused by incisions [2,12,21,26, 28,39]. Perhaps improving our understanding of the mechanisms for postoperative pain could increase the chances of developing new treatments for patients. It is our hope that research on incisional pain mechanisms and relating these preclinical results to patient symptoms has advanced our understanding of animal pain models; incision-induced, painrelated behaviors in animal models; and postoperative pain mechanisms in patients. The long-term goal of postoperative pain research and acute incisional pain studies is for patients to undergo painless or nearly painless surgery. 2. Preclincal studies 2.1. Rat plantar incision Several years ago, it was noted that few studies used incisions to understand mechanisms of pain caused by surgery. At the time of our model development, many pain behaviors used hind paw injections into the glabrous skin and nociception was measured using behaviors associated with hind paw withdrawal [14]. We undertook experiments using hind paw incision to use similar /$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi: /j.pain

31 VAS S34 T.J. Brennan / PAIN Ò 152 (2011) S33 S cough 1-minute scoring period over 1 hour. Guarding is increased after incision and gradually returns towards preincision values over the next 2 to 3 days. The rapid resolution of guarding pain after plantar incision, although a robust mechanical and heat hyperalgesia are still evident, suggests different mechanisms. We were interested in the relationship of guarding behavior to spontaneous activity (SA) in nociceptive pathways and postoperative pain in patients. If SA in part signals nonevoked, guarding pain in nociceptors and dorsal horn neurons, both measures, guarding and SA, may be in part translatable to pain at rest in patients after surgery. 0 behaviors and to compare these responses to other models [5]. Other preclinical surgical models were developed. For plantar incision, we use general anesthesia. The hind paw is sterilized, and the glabrous skin is incised usually through the skin and underlying plantar fascia, which are in close apposition in vivo (Fig. 2A D). After incising to the fascia, an underlying flexor digitorum brevis muscle is encountered. This muscle contracts the lateral 4 digits of the hind paw. This underlying flexor muscle is elevated, divided, and retracted. Then the skin overlying the muscle is closed with sutures. The rat is allowed to recover from general anesthesia, and pain behaviors can be tested as early as 1 hour after incision. In patients who undergo surgical procedures that access deep tissues, skin is incised and underlying muscles are divided and retracted so that inflamed organs or cancerous tumors can be removed. Therefore, the somatic injury after plantar incision has some similarities to the somatic injury of some patients undergoing surgery Evoked pain behaviors A variety of pain-related, nociceptive behaviors can be measured after plantar incision [45]. Reduced heat withdrawal latency is greatest the day of incision and sustained for approximately 5 days, and is completely resolved by 7 to 10 days after the procedure. Withdrawal threshold to punctate monofilament application adjacent to the incision for mechanical testing is also markedly decreased, and this response is sustained for 5 to 10 days. Both primary mechanical hyperalgesia and primary heat hyperalgesia are present in patients after surgery [22,37]. Finally, other pain behaviors have been measured. These include Randall-Selitto mechanical withdrawal threshold [40], weight bearing [40], and secondary mechanical withdrawal threshold [45] Guarding Pre Op Days After Surgery Fig. 1. Schematic of postoperative pain after major surgery in patients with optimized parenteral opioid analgesia. Top line is pain with cough; bottom line is pain at rest. VAS, visual analogue scale. Immediately after plantar incision, there is a small amount of spontaneous pain behavior, such as licking of the incised hind paw. This usually resolves 30 minutes to 1 hour after emergence from anesthesia [5]. We have observed that rats guard the incised hind paw early in the postoperative period. We have measured nonevoked pain behavior using a cumulative pain score that examines the position in which both paws are placed on a plastic mesh floor. A cumulative pain score is obtained depending on the position in which the paw is observed during the majority of the rest 3. In vivo neurophysiology experiments 3.1. Spontaneous activity in nociceptive pathways after incision A key to translational pain research is to identity sensitized nociceptors and dorsal horn neurons that encode enhanced nociception so that targets transmitting these amplified signals can be evaluated for therapeutic potential. Ongoing activity or SA, one aspect of sensitization, is a stimulus-independent measurement of sensitization [23,33,35]. We have undertaken a series of electrophysiological studies in rats that had undergone plantar incision 1 day earlier and examined primary afferent and dorsal horn neuron activity and compared SA with unincised, sham-operated animals. Most studies in our laboratory include not only measurements of ongoing SA, but also heat, mechanical, and in some cases chemical sensitivity. SA is perhaps the most robust form of sensitization produced in postinjury states because no stimulus is required [19]. This review focuses on the generation of or an increase in the magnitude of SA of nociceptors and dorsal horn neurons produced by incisions. One day after plantar incision, guarding behavior is usually significantly elevated [5]. We compared the SA of primary afferent nociceptors from rats that had undergone plantar incision [29], which included incisions in skin, fascia, and muscle 1 day earlier than those that had undergone sham operation (Fig. 3). The nociceptors studied from the incision group innervated, at least in part, the area of the incision. Thirty-nine afferent fibers were recorded in the sham-operated group, and 28 fibers were recorded in the plantar incision group on postoperative day 1. In the incision group, 11 of 28 nociceptors had SA; the average frequency was approximately 17 imp/s. In this study, the majority of spontaneously active Ad and C-fiber activity was >15 imp/s after incision. In the sham group, no afferents were spontaneously active. The origin of the SA was the incised tissue because local anesthetic infiltrated into the receptive field of the nociceptor in the hind paw eliminated the activity [29]. It was surprising that the rate of SA was quite high in some nociceptive fibers. We performed the corresponding experiment, but this time recording dorsal horn neurons [43]. We measured behavior in rats that had undergone skin, fascia, and muscle incision on postoperative day 1 and compared the behavior with that of rats that underwent a sham operation (Fig. 4). The mean guarding pain scores were 15 and 0 in the incised and sham-operated groups, respectively. Rats then underwent electrophysiology experiments, recordings of single dorsal horn neuron activity under general anesthesia. These dorsal horn neurons received input from afferent fibers innervating the glabrous skin of the hind paw and had a mechanoreceptive field that again included at least part of the area of the incision. SA was identified in 9 of 27 neurons in the control group and 16 of 26 neurons in the incision group. The average dorsal horn SA in the incised rats was 19 imp/s, and was 10 imp/s in the sham-operated group. In this series, both the proportion of neurons with SA and the magnitude of SA were greater in the 29

32 T.J. Brennan / PAIN Ò 152 (2011) S33 S40 S35 neurons from the incised group. Bupivacaine injection into the skin and deep tissue of the hind paw reduced the level of SA in the incised group to the same level of that in the sham-operated group [43]. Bupivacaine did not affect the magnitude of SA in the sham group. In summary, although SA is intrinsic to some dorsal horn neurons, the proportion of neurons with SA and the amount of SA were both increased 1 day after incision. Altogether, increased spinal dorsal horn neuron activity remained largely dependent on ongoing primary afferent input on postoperative day 1 when guarding behavior was evident. The SA was quite high in dorsal horn neurons and in agreement with the magnitude of activity in primary afferent nociceptors in similar groups of animals (Fig. 3) Tissues contributing to guarding pain and SA of nociceptive pathways Three previous studies identified cutaneous nociceptors and examined SA before and after skin injury using scalpel blades or Fig. 2. Photographs of the different stages of the rat plantar incision. (A) A 1-cm longitudinal incision is made through the skin and fascia starting 0.5 cm from the proximal edge of the heel and extending toward the distal aspect of the paw. (B and C) The underlying flexor muscle is elevated and also incised longitudinally. The muscle is split and dissected longitudinally. (D) After hemostasis, the wound is apposed with 2 mattress sutures of 5 0 nylon. 30

33 S36 T.J. Brennan / PAIN Ò 152 (2011) S33 S40 A B Activity (volts) ms C D percentage of afferents (%) /39 * 11/28 mean rate (imp/s) * control incision control incision (n=11) Fig. 3. Spontaneous activity in nociceptors 1 day after plantar incision [29]. (A) Schematic of in vivo recording from nociceptors from rats that underwent hind paw incision. (B) Example of spontaneous action potentials recorded from a nociceptor in a rat that underwent plantar incision. (C) Percentage of nociceptors with spontaneous activity in the control group that underwent a sham operation and group that underwent skin, fascia, and muscle incision [29,42]. (D) Mean rate of spontaneous activity of nociceptors that underwent skin, fascia and muscle incision [29,42]. needles. In 2 separate studies, investigators used needles to penetrate the receptive fields of both A-delta and C-fiber nociceptors recorded from cutaneous nerves in the cat [3,7]. Activation during needle penetrations occurred; however, no sustained SA was generated after the injury. Finally, Hamalainen et al. [13] recorded afferent fibers from the tibial nerve innervating the hind paw of the rat. Activity was generated during incision and other forms of sensitization were evident, yet no nociceptors developed ongoing, sustained SA after incision. It was surprising that nociceptors could not be activated immediately after incision because dorsal horn neurons generate some sustained SA during and after the same incisions [30,38,46]. Dorsal horn neurons receive convergent input from a variety of tissues, whereas nociceptors innervate specific tissues. Perhaps by selecting cutaneous nociceptors and incising their receptive fields, these cutaneous nociceptors did not generate SA after incision. We hypothesized that deep tissue incision that included fascia and muscle would generate SA in nociceptive pathways and produce unprovoked guarding pain, but a skin-only incision would not. We undertook a series of experiments incising skin only, skin, fascia and muscle (deep tissue), or sham (no operation) surgery. Guarding behavior was measured in separate groups of rats after sham, skin, or skin plus deep tissue incision 1 day later. A fourth group was studied 7 days after skin plus deep tissue incision, when pain behaviors generally resolve. These same groups then underwent in vivo recording of single-fiber nociceptors innervating the area of the incision (Fig. 5A C). Compared with the sham control group, skin incision induced a small amount of guarding on the day of incision only, whereas skin plus deep tissue incision caused guarding for 5 days after incision and this behavior completely resolved on postoperative day 7 [41,42]. On postoperative day 1, skin incision (18%) produced a similar prevalence of SA in nociceptors as the sham-operated group (13%), whereas skin plus deep tissue incision generated a greater prevalence of SA in nociceptors (61%); the rate of SA also tended to be greater after skin plus deep tissue incision (10 ± 3 imp/s) versus the control group (6 ± 6) and skin incision group (6 ± 3 imp/s). Seven days after skin plus deep tissue incision, when pain behaviors had resolved, the prevalence of SA (14%) and the amount of SA (0.3 ± 0.1) were similar to that in the sham group [42]. Incision of skin was not sufficient to produce guarding pain behavior, but incision that included skin fascia and muscle was sufficient. In addition, skin incision was sufficient to produce the typical reduced heat withdrawal latency and reduced mechanical withdrawal threshold on postoperative day 1 [41,42]. A comparable series of experiments in 4 similar groups of rats was undertaken, except in these 4 groups (Fig. 5D F), dorsal horn neurons were recorded on postoperative day 1 [41]. Pain behaviors again showed the importance of deep muscle incision on the generation of guarding, but normal heat and mechanical responses after skin-only incision. On postoperative day 1, skin incision (53%) produced a similar prevalence of SA in dorsal horn neurons as in the sham-operated group (36%), whereas skin plus deep tissue incision generated a greater prevalence of SA in dorsal horn neurons (78%); the rate of SA also tended to be greater after skin plus deep tissue incision (14 ± 3 imp/s) versus the control group (6 ± 2) and skin incision group (9 ± 2 imp/s). Seven days after skin plus deep tissue incision, when pain behaviors had resolved, the prevalence of SA (30%) and the amount of SA (6 ± 2) were similar to that in the sham group. Bupivacaine infiltration into the incision 31

34 T.J. Brennan / PAIN Ò 152 (2011) S33 S40 S37 A B 1.5 Activity (volts) C D E cumulative pain score *** percentage of neurons (%) /27 * 16/26 mean rate (imp/s) * control (n=17) incision (n=17) control incision control (n=9) incision (n=16) Fig. 4. Spontaneous activity in dorsal horn neurons 1 day after plantar incision [43]. (A) Schematic of dorsal horn neuron recording. (B) Example of spontaneous action potentials recorded from dorsal horn neuron in a rat that underwent plantar incision. Reproduced from PAIN 144: with permission of the International Association for the Study of Pain Ò (IASP Ò ). The figure may not be reproduced for any other purpose without permission. (C) Guarding pain score in rats that underwent a sham (control) operation and a group that underwent skin, fascia, and muscle incision. (D) Percentage of dorsal horn neurons with spontaneous activity in the control group and group that underwent skin, fascia, and muscle incision. (E) Mean rate of spontaneous activity of dorsal horn neurons in the control and incision groups. C and D adapted with permission [43, p. 823 and 824]. A B C percentage of afferents (%) /23 ** 4/22 * 14/23 ** 3/22 mean rate (imps/s) control skin skin+deep POD1 skin+deep POD7 control (n=3) skin (n=4) POD1 skin+deep (n=14) skin+deep (n=3) POD7 D E percentage of neurons (%) ** *** 25/32 16/30 10/28 10/34 control skin skin+deep skin+deep POD1 POD7 F mean rate (imps/s) control (n=10) skin (n=16) POD1 skin+deep (n=25) skin+deep (n=10) POD7 Fig. 5. Spontaneous activity in nociceptors and dorsal horn neurons. (A C) Nociceptor recordings in rats that underwent a sham (control) operation; a skin incision; a skin, fascia, and muscle incision; and a group 7 days after skin, fascia, and muscle incision. Percentage of nociceptors with spontaneous activity (B) and average spontaneous activity (C). B and C reprinted with permission [42]. (D F) Dorsal horn neuron recordings in rats that underwent a sham (control) operation; a skin incision; a skin, fascia, and muscle incision; and a group 7 days after skin, fascia, and muscle incision. Percentage of dorsal horn neurons with spontaneous activity (E) and average spontaneous activity (F). E and F adapted and reprinted with permission [41]. E and F have been reproduced with permission from the International Association for the Study of Pain Ò (IASP Ò ). The figure may not be reproduced for any other purpose without permission. 32

35 S38 T.J. Brennan / PAIN Ò 152 (2011) S33 S40 decreased SA in the skin plus deep tissue incision group to the same level as in the sham-operated rats on postoperative day 1 [41]. These data showed that incised deep tissue rather than skin had a central role in the genesis of guarding behavior and SA in nociceptors and nociceptive transmitting dorsal horn neurons (Fig. 6). Nociceptor and dorsal horn SA was associated with guarding behavior after incision. Decreased heat withdrawal latency and decreased mechanical withdrawal threshold occurred with skin incision only. 4. Human studies 4.1. Forearm incision Data from human studies support these preclinical incisional pain studies [17,18]. First, when an incision was made in the forearms of human volunteers, pain diminished soon after the blade had been pulled out from the skin; spontaneous pain rapidly decreased and resolved within 30 minutes after incision. However, mechanical hyperalgesia was evident. The hyperalgesia was similar in magnitude and duration to the mechanical withdrawal thresholds in rats after plantar incision. Thus, forearm incision in volunteers has similarities to skin incision of the rat hind paw Clinical studies In support of this concept, 2 surgical approaches for a unilateral total hip arthroplasty, a minimally invasive approach and a conventional approach, were recently compared [11]. Both approaches used the same length of skin incision, 20 cm. The minimally invasive approach preserved the underlying muscles, whereas muscles were incised and divided in the conventional approach. The minimally invasive approach resulted in significantly less postoperative pain and opioid consumption than the conventional approach. In a complimentary study [27], 2 groups of patients underwent total hip arthroplasty with the same amount of deep tissue dissection through different lengths of skin incision (10 vs 20 cm). There was no difference in postoperative pain between groups when the same degree of deep tissue injury occurred. Together, these postoperative pain studies indicate that reducing the amount of deep tissue injury decreases pain at rest and opioid consumption, whereas varying the magnitude of the skin incision did not affect pain at rest or opioid use. 5. Implications for animal models, clinical disease states, and drug discovery In preclinical behavioral studies, there has been a significant emphasis on exaggerated withdrawal responses in models of pathologic pain states. This began with testing changes in heat withdrawal latency and subsequently punctate mechanical withdrawal thresholds. Both heat hyperalgesia [22] and decreased mechanical pain threshold [37] occur in surgical patients. Because there has been increasing awareness of the limitations of these evoked behavioral responses, the applicability of cutaneous hyperalgesia to patient postoperative pain symptoms may be limited. Fig. 6. Schematic for the development guarding pain and SA in the nociceptive pathways after plantar incision. (A) An incision in the skin only (epidermis and dermis layer) induces minimal SA in nociceptors and dorsal horn neurons, which receive predominately cutaneous input. (B) An incision including skin and deep tissue (fascia and muscle layer) results in sustained SA in muscle-innervating primary afferents and the dorsal horn neurons receiving input from muscle. Reprinted with permission [42]. 33

36 T.J. Brennan / PAIN Ò 152 (2011) S33 S40 S39 The implications of our data are the following. Clinical studies with local anesthetic infiltration and nerve blockade indicate that preincision analgesia has little clinical benefit compared with administration of analgesic drugs later after surgery [25]. Basic science data indicate that early after surgery, primary afferent activation and peripheral sensitization are profound when patient s postoperative pain is greatest [29,41 43]. Central sensitization occurs early in the postoperative period, but its precise role in clinical acute pain is not clear [10]. Central sensitization likely contributes to referred pain and secondary hyperalgesia; perhaps it is related to chronic posttraumatic pain [4]. There is profound primary afferent and dorsal horn neuron activation 1 day after plantar incision [29,42]. Despite evidence that some nociceptors have ongoing activity P20 imp/s, no obvious licking, biting, or scratching of the hind paw is evident 1 day after plantar incision. These data suggest that behaviors resulting from ongoing activity in nociceptive pathways may be modest and difficult to detect behaviorally, but may represent very clinically significant acute pain. The demonstration of high ongoing activity in dorsal horn neurons and primary afferent fibers suggests that these neurophysiology experiments may detect activation of the nociceptive system when spontaneous nociceptive behaviors are limited. Using evoked stimuli to test the effect of an analgesic drug could fail to capture drugs effective against ongoing activity in nociceptive pathways, a correlate to human pain at rest. Thus, a useful analgesic drug may be overlooked when only evoked responses are tested. Tests that utilize mechanical and heat stimuli may largely evaluate cutaneous sensitivity after incision. This may apply to other models as well. Skin injury and skin testing may have limited clinical relevance and may in part have contributed to the limited discovery of new analgesic drugs. The skin is certainly an important model system, but clinical pathophysiologic relevance may be limited for postoperative patients. 6. Conclusions Clinical studies indicate that improvements in postoperative pain control will advance perioperative medicine. Models for pain and nociception continue to be refined and evaluated. For postoperative models, the behavioral responses after incision and neurophysiologic studies on activities of primary afferent and dorsal horn neurons indicate that different tissues have unique responses to incision. These studies hopefully will improve our understanding of incisional pain mechanisms and the behavioral aspects of activation and sensitization of nociceptive pathways. Conflict of interest statement The author has no conflict of interest to declare. 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37 S40 T.J. Brennan / PAIN Ò 152 (2011) S33 S40 [33] Reeh PW, Bayer J, Kocher L, Handwerker HO. Sensitization of nociceptive cutaneous nerve fibers from the rat s tail by noxious mechanical stimulation. Exp Brain Res 1987;65: [34] Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I, Mogil JS, Stohr T. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards. Pain 2008;139: [35] Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 1995;15: [36] Singelyn FJ, Deyaert M, Joris D, Pendeville E, Gouverneur JM. Effects of intravenous patient-controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg 1998;87: [37] Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997;41: [38] Vandermeulen EP, Brennan TJ. Alterations in ascending dorsal horn neurons by a surgical incision in the rat foot. Anesthesiology 2000;93: [39] Weber J, Loram L, Mitchell B, Themistocleous A. A model of incisional pain: the effects of dermal tail incision on pain behaviours of Sprague Dawley rats. J Neurosci Methods 2005;145: [40] Whiteside GT, Harrison J, Boulet J, Mark L, Pearson M, Gottshall S, Walker K. Pharmacological characterisation of a rat model of incisional pain. Br J Pharmacol 2004;141: [41] Xu J, Brennan TJ. Comparison of skin incision vs. skin plus deep tissue incision on ongoing pain and spontaneous activity in dorsal horn neurons. Pain 2009;144: [42] Xu J, Brennan TJ. Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision. Anesthesiology 2010;112: [43] Xu J, Richebe P, Brennan TJ. Separate groups of dorsal horn neurons transmit spontaneous activity and mechanosensitivity one day after plantar incision. Eur J Pain 2009;13: [44] Zahn PK, Brennan TJ. Lack of effect of intrathecally administered N-methyl-Daspartate receptor antagonists in a rat model for postoperative pain. Anesthesiology 1998;88: [45] Zahn PK, Brennan TJ. Primary and secondary hyperalgesia in a rat model for human postoperative pain. Anesthesiology 1999;90: [46] Zahn PK, Pogatzki-Zahn EM, Brennan TJ. Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 2005;114: [47] Zahn PK, Subieta A, Park SS, Brennan TJ. Effect of blockade of nerve growth factor and tumor necrosis factor on pain behaviors after plantar incision. J Pain 2004;5:

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