Ò
PAIN 155 (2014) 2444–2445
www.elsevier.com/locate/pain
Commentary
Conditioned pain modulation and offset analgesia: Different avenues to inhibit pain The ability of the body to modulate sensory information has been a focus of a number of studies over the past several years. Experimentally, pain modulation can be assessed by a number of methods including conditioned pain modulation (CPM) and offset analgesia (OA) as highlighted in the current study by NahmanAverbuch et al. [15]. CPM is frequently demonstrated through the reductions of a primary painful stimulus (ie, focal heat) by a second remote conditioning stimulus (ie, cold water immersion [6,9,17,22,23]). In contrast, OA is demonstrated by using a prolonged thermal pulse in which a slight reduction in the thermode temperature (ie, 1°C) is associated with a transient (10 s) reduction in pain intensity [7,15,16,18,29,30]. Although only a small number of studies have evaluated CPM and OA in the same cohort [8,17,18,20], the combined use of these inhibitory models may provide a glimpse into different characteristics underlying an individual’s inhibitory phenotype, which could have implications for future experimental and clinical research. The study by Nahman-Averbuch et al. [15] was designed to investigate differences between the psychophysical and neural correlates of CPM and OA. Using the same thermal stimulation paradigm (ie, 30 s prolonged pulse at 49°C applied to the leg), the studies demonstrated reductions in the subjective ratings of heat pain during both concurrent immersion of the contralateral foot into moderately painful cold water bath (CPM induction) and following a 1°C temperature drop (OA induction)—observations that are in agreement with those of previous studies [6,7,9,10,15,16,23,30]. However, the magnitude of inhibition observed in the 2 models did not correlate suggesting different mechanisms underlying inhibition. Confirming the psychophysical data, fMRI assessment of each paradigm demonstrated differences in cortical and subcortical activity. In general, widespread deactivations were observed in a number of classical pain-related areas during CPM, which was contrasted by activation in a number of areas including the brain stem region associated with the periaqueductal gray (PAG) during the OA paradigm. Based on the current study, differences in the modulation of pain are dependent on the spatial (CPM) and temporal (OA) presentation of nociceptive information, which in turn results in a differential pattern of neurobiological activity in areas involved in pain perception and modulation. More importantly, the study adds to the discussion about the methods and implications of different
q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2014.07.008
inhibitory mechanisms (CPM vs OA) and within different inhibitory paradigms (variations of CPM). What does the current study tell us about pain modulation? The findings of the study suggest that experimental manipulations, which result in comparable magnitudes of subjective inhibition, may be a consequence of different neurobiological mechanisms. This concept is neither surprising nor unexpected, but the current study demonstrates the complexity of nervous system in regulating sensory information through multiple neurological structures and neurotransmitters depending on the presentation of the stimulus. Interestingly, the authors comment that inhibition during CPM appears to be due to spinal inhibition rather than descending modulation. CPM reflects the psychophysical representation [28] of the previously described phenomenon termed diffuse noxious inhibitory control, referring to observations by Le Bars and colleagues in which activity within the lower aspect of the brain stem suppresses activity within the spinal cord [11,12], which can be indirectly modulated by activity within the PAG [2] and the rostral ventromedial medulla [1]. In contrast, OA is associated with increased activity within the PAG and rostral ventromedial medulla [4,29], although a peripheral component may also exist [16]. Thus, CPM represents a subjective response to a range of possible mechanisms, which may include the originally proposed spino-bulbo-spinal loop described by Le Bars and colleagues, a spinal-mediated mechanism proposed by Nahman-Averbuch et al. [15], as well as brain stem, and/or higher-order cortical regions reported in recent imaging studies (ie, PAG, Anterior Cingulate Cortex [22,24]). Thus, depending on the presentation of the testing and conditioning stimuli, different mechanisms may be engaged. In addition, CPM and OA paradigms can differ in terms of the underlying neurotransmitter system. Based on experiments with pharmacological manipulations, CPM appears to be sensitive to opioids [9,21,26] and the N-methyl-D-aspartate (NMDA) receptor antagonism [18], a finding that contrasts with OA, which appears to be resistant to these manipulations [14,19,18]. Recently, similar differences were observed with tapentadol [20], a dual l-opioid receptor agonist and norepinephrine reuptake inhibitor. Several weeks of treatment restored the inhibitory capacity assessed by CPM in patients with diabetic polyneuropathy but not affect OA, suggesting differential neuromodulatory tone underlying each paradigm.
http://dx.doi.org/10.1016/j.pain.2014.08.017 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Ò
Commentary / PAIN 155 (2014) 2444–2445
What are the clinical implications of multiple pain modulatory mechanisms? The current study also has clinical implications for the evaluation of pain modulation models. Although a reduced capacity to inhibit pain during CPM is commonly observed in clinical pain populations (for review, see [27]), only 1 study has reported a reduction in OA in neuropathic pain patients [19]. Thus, it is unclear whether a reduction in OA is also observed in other pain cohorts, or if one or both methods exhibit comparable inhibitory deficits. Considering recent evidence that the efficiency of CPM [5,13] and other modulatory mechanisms [25] appears to be intact in patients, the evaluation of multiple paradigms may provide additional information about the inhibitory phenotype of the participant [3]. For example, a proportion of patients may have an intact descending pain system as assessed by CPM, but they may fail to engage neurological mechanisms underlying OA. While balancing the burden to the participant, studies could incorporate a multiple step evaluation of several inhibitory paradigms, which could include incorporating assessments of both CPM and OA paradigms within a testing protocol. The use of CPM and OA may indicate a selective or widespread dysfunction of inhibitory mechanism, and imaging will assist in this investigation. In sum, the study by Nahman-Averbuch et al. [15] adds to the current literature regarding the neurobiological mechanisms involved in pain inhibition. In order to understand these mechanisms better, additional research is needed to determine if methodological factors including variations of testing paradigms including CPM (ie, different conditioning stimuli, temporal and spatial presentation of stimuli) alter these neurological profiles in addition to how these mechanisms differ in individuals with chronic pain. I anticipate that the current study will encourage additional investigation into the neurobiological mechanisms underlying inhibition. Conflict of interest The author is aware of no conflicts of interest regarding this commentary. References [1] Bouhassira D, Chitour D, Villanueva L, Le Bars D. Morphine and diffuse noxious inhibitory controls in the rat: effects of lesions of the rostral ventromedial medulla. Eur J Pharmacol 1993;232:207–15. [2] Bouhassira D, Villanueva L, Le Bars D. Effects of systemic morphine on diffuse noxious inhibitory controls: role of the periaqueductal grey. Eur J Pharmacol 1992;216:149–56. [3] Cruz-Almeida Y, Fillingim RB. Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Med 2014;15:61–72. [4] Derbyshire SW, Osborn J. Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla. Neuroimage 2009;47:1002–6. [5] Garrett PH, Sarlani E, Grace EG, Greenspan JD. Chronic temporomandibular disorders are not necessarily associated with a compromised endogenous analgesic system. J Orofac Pain 2013;27:142–50. [6] Goodin BR, Kronfli T, King CD, Glover TL, Sibille K, Fillingim RB. Testing the relation between dispositional optimism and conditioned pain modulation: does ethnicity matter? J Behav Med 2013;36:165–74. [7] Grill JD, Coghill RC. Transient analgesia evoked by noxious stimulus offset. J Neurophysiol 2002;87:2205–8.
2445
[8] Honigman L, Yarnitsky D, Sprecher E, Weissman-Fogel I. Psychophysical testing of spatial and temporal dimensions of endogenous analgesia: conditioned pain modulation and offset analgesia. Exp Brain Res 2013;228: 493–501. [9] King CD, Goodin B, Kindler LL, Caudle RM, Edwards RR, Gravenstein N, Riley 3rd JL, Fillingim RB. Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing. J Behav Med 2013;36:315–27. [10] King CD, Wong F, Currie T, Mauderli AP, Fillingim RB, Riley 3rd JL. Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder. PAINÒ 2009;143:172–8. [11] Le Bars D. The whole body receptive field of dorsal horn multireceptive neurones. Brain Res Brain Res Rev 2002;40:29–44. [12] Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. PAINÒ 1979;6: 283–304. [13] Martel MO, Wasan AD, Edwards RR. Sex differences in the stability of conditioned pain modulation (CPM) among patients with chronic pain. Pain Med 2013;14:1757–68. [14] Martucci KT, Eisenach JC, Tong C, Coghill RC. Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information. PAINÒ 2012;153:1232–43. [15] Nahman-Averbuch H, Martucci KT, Granovsky Y, Weissman-Fogel I, Yarnitsky D, Coghill RC. Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information. PAINÒ 2014;155:2491–501. [16] Naugle KM, Cruz-Almeida Y, Fillingim RB, Riley 3rd JL. Offset analgesia is reduced in older adults. PAINÒ 2013;154:2381–7. [17] Naugle KM, Riley 3rd JL. Self-reported physical activity predicts pain inhibitory and facilitatory function. Med Sci Sports Exerc 2014;46:622–9. [18] Niesters M, Dahan A, Swartjes M, Noppers I, Fillingim RB, Aarts L, Sarton EY. Effect of ketamine on endogenous pain modulation in healthy volunteers. PAINÒ 2011;152:656–63. [19] Niesters M, Hoitsma E, Sarton E, Aarts L, Dahan A. Offset analgesia in neuropathic pain patients and effect of treatment with morphine and ketamine. Anesthesiology 2011;115:1063–71. [20] Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth 2014;113:148–56. [21] Pertovaara A, Kemppainen P, Johansson G, Karonen SL. Ischemic pain nonsegmentally produces a predominant reduction of pain and thermal sensitivity in man—a selective role for endogenous opioids. Brain Res 1982;251:83–92. [22] Piche M, Arsenault M, Rainville P. Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci 2009;29:14236–46. [23] Riley 3rd JL, King CD, Wong F, Fillingim RB, Mauderli AP. Lack of endogenous modulation and reduced decay of prolonged heat pain in older adults. PAINÒ 2010;150:153–60. [24] Sprenger C, Bingel U, Buchel C. Treating pain with pain: supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation. PAINÒ 2011;152:428–39. [25] Staud R, Robinson ME, Goldman CT, Price DD. Attenuation of experimental pain by vibro-tactile stimulation in patients with chronic local or widespread musculoskeletal pain. Eur J Pain 2011;15:836–42. [26] Willer JC, Le Bars D, De Broucker T. Diffuse noxious inhibitory controls in man: involvement of an opioidergic link. Eur J Pharmacol 1990;182:347–55. [27] Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 2010;23:611–5. [28] Yarnitsky D, Arendt-Nielsen L, Bouhassira D, Edwards RR, Fillingim RB, Granot M, Hansson P, Lautenbacher S, Marchand S, Wilder-Smith O. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 2010;14:339. [29] Yelle MD, Oshiro Y, Kraft RA, Coghill RC. Temporal filtering of nociceptive information by dynamic activation of endogenous pain modulatory systems. J Neurosci 2009;29:10264–71. [30] Yelle MD, Rogers JM, Coghill RC. Offset analgesia: a temporal contrast mechanism for nociceptive information. PAINÒ 2008;134:174–86.
Christopher D. King University of Florida Pain Research and Intervention Center of Excellence (PRICE), Gainesville, FL 32610, USA E-mail address: [email protected]fl.edu
PAIN 155 (2014) 2444–2445
www.elsevier.com/locate/pain
Commentary
Conditioned pain modulation and offset analgesia: Different avenues to inhibit pain The ability of the body to modulate sensory information has been a focus of a number of studies over the past several years. Experimentally, pain modulation can be assessed by a number of methods including conditioned pain modulation (CPM) and offset analgesia (OA) as highlighted in the current study by NahmanAverbuch et al. [15]. CPM is frequently demonstrated through the reductions of a primary painful stimulus (ie, focal heat) by a second remote conditioning stimulus (ie, cold water immersion [6,9,17,22,23]). In contrast, OA is demonstrated by using a prolonged thermal pulse in which a slight reduction in the thermode temperature (ie, 1°C) is associated with a transient (10 s) reduction in pain intensity [7,15,16,18,29,30]. Although only a small number of studies have evaluated CPM and OA in the same cohort [8,17,18,20], the combined use of these inhibitory models may provide a glimpse into different characteristics underlying an individual’s inhibitory phenotype, which could have implications for future experimental and clinical research. The study by Nahman-Averbuch et al. [15] was designed to investigate differences between the psychophysical and neural correlates of CPM and OA. Using the same thermal stimulation paradigm (ie, 30 s prolonged pulse at 49°C applied to the leg), the studies demonstrated reductions in the subjective ratings of heat pain during both concurrent immersion of the contralateral foot into moderately painful cold water bath (CPM induction) and following a 1°C temperature drop (OA induction)—observations that are in agreement with those of previous studies [6,7,9,10,15,16,23,30]. However, the magnitude of inhibition observed in the 2 models did not correlate suggesting different mechanisms underlying inhibition. Confirming the psychophysical data, fMRI assessment of each paradigm demonstrated differences in cortical and subcortical activity. In general, widespread deactivations were observed in a number of classical pain-related areas during CPM, which was contrasted by activation in a number of areas including the brain stem region associated with the periaqueductal gray (PAG) during the OA paradigm. Based on the current study, differences in the modulation of pain are dependent on the spatial (CPM) and temporal (OA) presentation of nociceptive information, which in turn results in a differential pattern of neurobiological activity in areas involved in pain perception and modulation. More importantly, the study adds to the discussion about the methods and implications of different
q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2014.07.008
inhibitory mechanisms (CPM vs OA) and within different inhibitory paradigms (variations of CPM). What does the current study tell us about pain modulation? The findings of the study suggest that experimental manipulations, which result in comparable magnitudes of subjective inhibition, may be a consequence of different neurobiological mechanisms. This concept is neither surprising nor unexpected, but the current study demonstrates the complexity of nervous system in regulating sensory information through multiple neurological structures and neurotransmitters depending on the presentation of the stimulus. Interestingly, the authors comment that inhibition during CPM appears to be due to spinal inhibition rather than descending modulation. CPM reflects the psychophysical representation [28] of the previously described phenomenon termed diffuse noxious inhibitory control, referring to observations by Le Bars and colleagues in which activity within the lower aspect of the brain stem suppresses activity within the spinal cord [11,12], which can be indirectly modulated by activity within the PAG [2] and the rostral ventromedial medulla [1]. In contrast, OA is associated with increased activity within the PAG and rostral ventromedial medulla [4,29], although a peripheral component may also exist [16]. Thus, CPM represents a subjective response to a range of possible mechanisms, which may include the originally proposed spino-bulbo-spinal loop described by Le Bars and colleagues, a spinal-mediated mechanism proposed by Nahman-Averbuch et al. [15], as well as brain stem, and/or higher-order cortical regions reported in recent imaging studies (ie, PAG, Anterior Cingulate Cortex [22,24]). Thus, depending on the presentation of the testing and conditioning stimuli, different mechanisms may be engaged. In addition, CPM and OA paradigms can differ in terms of the underlying neurotransmitter system. Based on experiments with pharmacological manipulations, CPM appears to be sensitive to opioids [9,21,26] and the N-methyl-D-aspartate (NMDA) receptor antagonism [18], a finding that contrasts with OA, which appears to be resistant to these manipulations [14,19,18]. Recently, similar differences were observed with tapentadol [20], a dual l-opioid receptor agonist and norepinephrine reuptake inhibitor. Several weeks of treatment restored the inhibitory capacity assessed by CPM in patients with diabetic polyneuropathy but not affect OA, suggesting differential neuromodulatory tone underlying each paradigm.
http://dx.doi.org/10.1016/j.pain.2014.08.017 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Ò
Commentary / PAIN 155 (2014) 2444–2445
What are the clinical implications of multiple pain modulatory mechanisms? The current study also has clinical implications for the evaluation of pain modulation models. Although a reduced capacity to inhibit pain during CPM is commonly observed in clinical pain populations (for review, see [27]), only 1 study has reported a reduction in OA in neuropathic pain patients [19]. Thus, it is unclear whether a reduction in OA is also observed in other pain cohorts, or if one or both methods exhibit comparable inhibitory deficits. Considering recent evidence that the efficiency of CPM [5,13] and other modulatory mechanisms [25] appears to be intact in patients, the evaluation of multiple paradigms may provide additional information about the inhibitory phenotype of the participant [3]. For example, a proportion of patients may have an intact descending pain system as assessed by CPM, but they may fail to engage neurological mechanisms underlying OA. While balancing the burden to the participant, studies could incorporate a multiple step evaluation of several inhibitory paradigms, which could include incorporating assessments of both CPM and OA paradigms within a testing protocol. The use of CPM and OA may indicate a selective or widespread dysfunction of inhibitory mechanism, and imaging will assist in this investigation. In sum, the study by Nahman-Averbuch et al. [15] adds to the current literature regarding the neurobiological mechanisms involved in pain inhibition. In order to understand these mechanisms better, additional research is needed to determine if methodological factors including variations of testing paradigms including CPM (ie, different conditioning stimuli, temporal and spatial presentation of stimuli) alter these neurological profiles in addition to how these mechanisms differ in individuals with chronic pain. I anticipate that the current study will encourage additional investigation into the neurobiological mechanisms underlying inhibition. Conflict of interest The author is aware of no conflicts of interest regarding this commentary. References [1] Bouhassira D, Chitour D, Villanueva L, Le Bars D. Morphine and diffuse noxious inhibitory controls in the rat: effects of lesions of the rostral ventromedial medulla. Eur J Pharmacol 1993;232:207–15. [2] Bouhassira D, Villanueva L, Le Bars D. Effects of systemic morphine on diffuse noxious inhibitory controls: role of the periaqueductal grey. Eur J Pharmacol 1992;216:149–56. [3] Cruz-Almeida Y, Fillingim RB. Can quantitative sensory testing move us closer to mechanism-based pain management? Pain Med 2014;15:61–72. [4] Derbyshire SW, Osborn J. Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla. Neuroimage 2009;47:1002–6. [5] Garrett PH, Sarlani E, Grace EG, Greenspan JD. Chronic temporomandibular disorders are not necessarily associated with a compromised endogenous analgesic system. J Orofac Pain 2013;27:142–50. [6] Goodin BR, Kronfli T, King CD, Glover TL, Sibille K, Fillingim RB. Testing the relation between dispositional optimism and conditioned pain modulation: does ethnicity matter? J Behav Med 2013;36:165–74. [7] Grill JD, Coghill RC. Transient analgesia evoked by noxious stimulus offset. J Neurophysiol 2002;87:2205–8.
2445
[8] Honigman L, Yarnitsky D, Sprecher E, Weissman-Fogel I. Psychophysical testing of spatial and temporal dimensions of endogenous analgesia: conditioned pain modulation and offset analgesia. Exp Brain Res 2013;228: 493–501. [9] King CD, Goodin B, Kindler LL, Caudle RM, Edwards RR, Gravenstein N, Riley 3rd JL, Fillingim RB. Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing. J Behav Med 2013;36:315–27. [10] King CD, Wong F, Currie T, Mauderli AP, Fillingim RB, Riley 3rd JL. Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder. PAINÒ 2009;143:172–8. [11] Le Bars D. The whole body receptive field of dorsal horn multireceptive neurones. Brain Res Brain Res Rev 2002;40:29–44. [12] Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. PAINÒ 1979;6: 283–304. [13] Martel MO, Wasan AD, Edwards RR. Sex differences in the stability of conditioned pain modulation (CPM) among patients with chronic pain. Pain Med 2013;14:1757–68. [14] Martucci KT, Eisenach JC, Tong C, Coghill RC. Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information. PAINÒ 2012;153:1232–43. [15] Nahman-Averbuch H, Martucci KT, Granovsky Y, Weissman-Fogel I, Yarnitsky D, Coghill RC. Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information. PAINÒ 2014;155:2491–501. [16] Naugle KM, Cruz-Almeida Y, Fillingim RB, Riley 3rd JL. Offset analgesia is reduced in older adults. PAINÒ 2013;154:2381–7. [17] Naugle KM, Riley 3rd JL. Self-reported physical activity predicts pain inhibitory and facilitatory function. Med Sci Sports Exerc 2014;46:622–9. [18] Niesters M, Dahan A, Swartjes M, Noppers I, Fillingim RB, Aarts L, Sarton EY. Effect of ketamine on endogenous pain modulation in healthy volunteers. PAINÒ 2011;152:656–63. [19] Niesters M, Hoitsma E, Sarton E, Aarts L, Dahan A. Offset analgesia in neuropathic pain patients and effect of treatment with morphine and ketamine. Anesthesiology 2011;115:1063–71. [20] Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth 2014;113:148–56. [21] Pertovaara A, Kemppainen P, Johansson G, Karonen SL. Ischemic pain nonsegmentally produces a predominant reduction of pain and thermal sensitivity in man—a selective role for endogenous opioids. Brain Res 1982;251:83–92. [22] Piche M, Arsenault M, Rainville P. Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci 2009;29:14236–46. [23] Riley 3rd JL, King CD, Wong F, Fillingim RB, Mauderli AP. Lack of endogenous modulation and reduced decay of prolonged heat pain in older adults. PAINÒ 2010;150:153–60. [24] Sprenger C, Bingel U, Buchel C. Treating pain with pain: supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation. PAINÒ 2011;152:428–39. [25] Staud R, Robinson ME, Goldman CT, Price DD. Attenuation of experimental pain by vibro-tactile stimulation in patients with chronic local or widespread musculoskeletal pain. Eur J Pain 2011;15:836–42. [26] Willer JC, Le Bars D, De Broucker T. Diffuse noxious inhibitory controls in man: involvement of an opioidergic link. Eur J Pharmacol 1990;182:347–55. [27] Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 2010;23:611–5. [28] Yarnitsky D, Arendt-Nielsen L, Bouhassira D, Edwards RR, Fillingim RB, Granot M, Hansson P, Lautenbacher S, Marchand S, Wilder-Smith O. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 2010;14:339. [29] Yelle MD, Oshiro Y, Kraft RA, Coghill RC. Temporal filtering of nociceptive information by dynamic activation of endogenous pain modulatory systems. J Neurosci 2009;29:10264–71. [30] Yelle MD, Rogers JM, Coghill RC. Offset analgesia: a temporal contrast mechanism for nociceptive information. PAINÒ 2008;134:174–86.
Christopher D. King University of Florida Pain Research and Intervention Center of Excellence (PRICE), Gainesville, FL 32610, USA E-mail address: [email protected]fl.edu
