Ò
PAIN 155 (2014) 1047–1048
www.elsevier.com/locate/pain
Commentary
A possible mechanism underlying conditioned pain modulation Over the past few years, interest in the ability to inhibit pain particularly related to conditioned pain modulation (CPM) has grown. CPM is commonly used to measure the efficacy of endogenous pain inhibition in humans by applying two painful stimuli in some temporal pattern and evaluating the degree of pain reduction of the primary stimulus by the second ‘‘conditioning’’ stimulus. The resulting inhibition is thought to be a consequence of the activation of descending inhibitory mechanisms. The application of CPM in clinical studies has provided insights into the possible dysfunction of these descending inhibitory mechanisms in chronic pain [14,26]. Although it has been shown that patients with fibromyalgia syndrome (FMS) exhibit reduced CPM, deficits in our understanding of the underlying mechanisms of endogenous pain modulation highlight the need for additional research particularly in the context of chronic pain. One potential mechanism was recently evaluated by Chalaye et al. [5]. A previous study by this group [4] found that cardiovascular responses to the conditioning stimulus (ie, cold water bath) were positively associated with the magnitude of CPM in healthy controls. In the current study [5], the paradigm was evaluated in patients with FMS. Several interesting observations were made during the CPM procedure: (1) individuals with FMS exhibited an attenuated cardiovascular response (ie, smaller changes in systolic blood pressure [SBP]) during a 2-minute immersion at 12°C compared to that in controls; and (2) the magnitude of the SBP change was positively associated with the magnitude of CPM (ie, greater increase in SBP during immersion = greater reduction in heat sensitivity). Additional cardiovascular factors were not associated with CPM after controlling for immersion time. Chalaye et al. may have offered 1 piece of the puzzle regarding deficits in pain modulation in FMS, namely, attenuated cardiovascular responsiveness to the conditioning stimulus. Previous studies have shown that individuals with FMS have an impaired ability to regulate cardiovascular functioning [25], including reduced sympathetic reactivity to cold immersion [20]. Overall, dysfunction of pain inhibition in FMS could be, in part, a result of an inability to mount a ‘‘proper’’ cardiovascular response to the conditioning stimulus. The study raises several questions related to the interaction between SBP and CPM efficiency that may direct this area of research in the future: Based on the observation of a positive linear relationship between SBP and CPM efficiency in the FMS cohort, what characterizes the subgroups of FMS patients with greater SBP and CPM efficiency? Although the current study was not powered to evaluate the presence of subgroups in the FMS cohort, the ability to exhibit an ‘‘effective’’ SBP and CPM response appears to occur in some FMS patients. q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2013.12.023
Case-control differences in CPM are common, but a recent study by Greenspan et al. [9] and preliminary data in our laboratory show no differences in temporomandibular disorders and controls with regard to the efficiency of CPM. Although overly simplistic, the lack of case-control differences could be partially explained by the idea that chronic pain is represented by a continuum with different subgroups including mild, moderate, and severe phenotypes. Each phenotype could be characterized by a gradation of impairments (ie, more severe symptoms = greater pain sensitivity, poor pain inhibition, abnormal autonomic responding) as a function of symptom severity. Further support for this idea is found in osteoarthritis [2,8,11] and others [6] related to general experimental sensitivity in subgroups of patients based on the severity of knee OA in which the high-severity group exhibited greater experimental pain sensitivity. In terms of FMS patients, it would be helpful to determine whether subgroups of FMS patients also exhibit differences in SBP reactivity and CPM efficiency as a function of severity. For example, would individuals in the ‘‘less severe FMS group’’ show SBP reactivity and CPM efficiency comparable to that in the control cohort? The possibility of subgroup differences raises another potential avenue of research. Would the association between cardiovascular functioning and CPM be observed with conditioning stimuli that are less likely to engage mechanisms underlying thermoregulation and cardiovascular (eg, pressure cuff)? The most common method to evaluate CPM is immersion of the hand (or foot) into a cold-water bath, which has been used as an independent test to evaluate ‘‘physiological stress’’ [15,16]) and is associated with a number of stress-related responses (ie, increased blood pressure [1,19]: release of cortisol [10,17,23]). Although most would accept that the experience of pain is accompanied with some level of stress, the degree to which specific pain stimuli engage stress-related physiological systems appear to be different. For example, cortisol shows different profiles depending on the type of modality even when the level of pain is equated [7,10]. It is unclear whether the magnitude of cardiovascular responses varies as a function of the pain stimulus characteristics. Likewise, pain stimuli may also exhibit differences in the magnitude of CPM. Other conditioning stimuli (ie, pressure cuff to the arm or leg) are associated with inhibition [3,12,13], but some evidence suggests that ‘‘less stressful’’ stimuli induce slightly less pain inhibition [13,22], which would presumably be associated with lower levels of cardiovascular reactivity [12,21,22]. However, regardless of the modality, the level of inhibition may also be influenced by the intensity of the conditioning stimulus in which more intense conditioning stimulus would be expected to produce greater pain inhibition [18,24] and possibly greater changes in cardiovascular reactivity. Thus, different pain stimuli may produce endogenous inhibition through slightly different mechanisms. In
http://dx.doi.org/10.1016/j.pain.2014.02.011 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1048
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Commentary / PAIN 155 (2014) 1047–1048
agreement with the authors, additional research is needed to clarify this issue, and to determine whether the association of cardiovascular functioning and CPM is specific to cold immersion or is a universal feature of all conditioning stimuli. In sum, the current study [5] shows the need for further research to elucidate the mechanisms into the mechanisms of CPM and how these mechanisms differ in individuals with chronic pain. Hopefully, the current study will spur further inquiry into the involvement (or lack thereof) of the cardiovascular system in CPM. I would like to thank PAIN for the opportunity to comment on the study. Conflict of interest statement The author declares no conflict of interest. References [1] al’Absi M, Petersen KL. Blood pressure but not cortisol mediates stress effects on subsequent pain perception in healthy men and women. PAINÒ 2003;106: 285–95. [2] Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T. Sensitization in patients with painful knee osteoarthritis. PAINÒ 2010;149:573–81. [3] Bartley EJ, Rhudy JL. Endogenous inhibition of the nociceptive flexion reflex (NFR) and pain ratings during the menstrual cycle in healthy women. Ann Behav Med 2012;43:343–51. [4] Chalaye P, Devoize L, Lafrenaye S, Dallel R, Marchand S. Cardiovascular influences on conditioned pain modulation. PAINÒ 2013;154:1377–82. [5] Chalaye P, Lafrenaye S, Goffaux P, Marchand S. The role of cardiovascular activity in fibromyalgia and conditioned pain modulation. PAINÒ 2014;155: 1064–9. [6] Chen H, Nackley A, Miller V, Diatchenko L, Maixner W. Multisystem dysregulation in painful temporomandibular disorders. J Pain 2013;14: 983–96. [7] Cruz-Almeida Y, King CD, Wallet SM, Riley 3rd JL. Immune biomarker response depends on choice of experimental pain stimulus in healthy adults: a preliminary study. Pain Res Treat 2012:1–7 [Article ID 538739]. [8] Finan PH, Buenaver LF, Bounds SC, Hussain S, Park RJ, Haque UJ, Campbell CM, Haythornthwaite JA, Edwards RR, Smith MT. Discordance between pain and radiographic severity in knee osteoarthritis: findings from quantitative sensory testing of central sensitization. Arthritis Rheum 2013;65:363–72. [9] 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. [10] Goodin BR, Quinn NB, King CD, Page GG, Haythornthwaite JA, Edwards RR, Stapleton L, McGuire L. Salivary cortisol and soluble tumor necrosis factoralpha receptor II responses to multiple experimental modalities of acute pain. Psychophysiology 2012;49:118–27. [11] King CD, Sibille KT, Goodin BR, Cruz-Almeida Y, Glover TL, Bartley E, Riley JL, Herbert MS, Sotolongo A, Schmidt J, Fessler BJ, Redden DT, Staud R, Bradley LA, Fillingim RB. Experimental pain sensitivity differs as a function of clinical pain
[12]
[13]
[14]
[15] [16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
severity in symptomatic knee osteoarthritis. Osteoarthritis Cartilage 2013;21:1243–52. Kosek E, Hansson P. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. PAINÒ 1997;70:41–51. Lewis GN, Heales L, Rice DA, Rome K, McNair PJ. Reliability of the conditioned pain modulation paradigm to assess endogenous inhibitory pain pathways. Pain Res Manage 2012;17:98–102. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain 2012;13: 936–44. Lovallo W. The cold pressor test and autonomic function: a review and integration. Psychophysiology 1975;12:268–82. Lovallo W, Zeiner AR. Some factors influencing the vasomotor response to cold pressor stimulation. Psychophysiology 1975;12:499–505. McRae AL, Saladin ME, Brady KT, Upadhyaya H, Back SE, Timmerman MA. Stress reactivity: biological and subjective responses to the cold pressor and Trier social stressors. Hum Psychopharmacol 2006;21:377–85. Oono Y, Wang K, Svensson P, Arendt-Nielsen L. Conditioned pain modulation evoked by different intensities of mechanical stimuli applied to the craniofacial region in healthy men and women. J Orofac Pain 2011;25:364–75. Peckerman A, Hurwitz BE, Saab PG, Llabre MM, McCabe PM, Schneiderman N. Stimulus dimensions of the cold pressor test and the associated patterns of cardiovascular response. Psychophysiology 1994;31:282–90. Reyes del Paso GA, Garrido S, Pulgar A, Duschek S. Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome. J Psychosom Res 2011;70:125–34. Streff A, Kuehl LK, Michaux G, Anton F. Differential physiological effects during tonic painful hand immersion tests using hot and ice water. Eur J Pain 2010;14:266–72. Streff A, Michaux G, Anton F. Internal validity of inter-digital Web pinching as a model for perceptual diffuse noxious inhibitory controls-induced hypoalgesia in healthy humans. Eur J Pain 2011;15:45–52. Suzuki K, Maekawa K, Minakuchi H, Yatani H, Clark GT, Matsuka Y, Kuboki T. Responses of the hypothalamic–pituitary–adrenal axis and pain threshold changes in the orofacial region upon cold pressor stimulation in normal volunteers. Arch Oral Biol 2007;52:797–802. Tousignant-Laflamme Y, Page S, Goffaux P, Marchand S. An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res 2008;1230:73–9. Vierck CJ. A mechanism-based approach to prevention of and therapy for fibromyalgia. Pain Res Treat 2012:1–12 [Article ID 951354]. 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.
Christopher D. King University of Florida Pain Research and Intervention Center of Excellence (PRICE), University of Florida College of Dentistry, Department of Community Dentistry and Behavioral Science, Gainesville, FL, USA E-mail address: [email protected]fl.edu
PAIN 155 (2014) 1047–1048
www.elsevier.com/locate/pain
Commentary
A possible mechanism underlying conditioned pain modulation Over the past few years, interest in the ability to inhibit pain particularly related to conditioned pain modulation (CPM) has grown. CPM is commonly used to measure the efficacy of endogenous pain inhibition in humans by applying two painful stimuli in some temporal pattern and evaluating the degree of pain reduction of the primary stimulus by the second ‘‘conditioning’’ stimulus. The resulting inhibition is thought to be a consequence of the activation of descending inhibitory mechanisms. The application of CPM in clinical studies has provided insights into the possible dysfunction of these descending inhibitory mechanisms in chronic pain [14,26]. Although it has been shown that patients with fibromyalgia syndrome (FMS) exhibit reduced CPM, deficits in our understanding of the underlying mechanisms of endogenous pain modulation highlight the need for additional research particularly in the context of chronic pain. One potential mechanism was recently evaluated by Chalaye et al. [5]. A previous study by this group [4] found that cardiovascular responses to the conditioning stimulus (ie, cold water bath) were positively associated with the magnitude of CPM in healthy controls. In the current study [5], the paradigm was evaluated in patients with FMS. Several interesting observations were made during the CPM procedure: (1) individuals with FMS exhibited an attenuated cardiovascular response (ie, smaller changes in systolic blood pressure [SBP]) during a 2-minute immersion at 12°C compared to that in controls; and (2) the magnitude of the SBP change was positively associated with the magnitude of CPM (ie, greater increase in SBP during immersion = greater reduction in heat sensitivity). Additional cardiovascular factors were not associated with CPM after controlling for immersion time. Chalaye et al. may have offered 1 piece of the puzzle regarding deficits in pain modulation in FMS, namely, attenuated cardiovascular responsiveness to the conditioning stimulus. Previous studies have shown that individuals with FMS have an impaired ability to regulate cardiovascular functioning [25], including reduced sympathetic reactivity to cold immersion [20]. Overall, dysfunction of pain inhibition in FMS could be, in part, a result of an inability to mount a ‘‘proper’’ cardiovascular response to the conditioning stimulus. The study raises several questions related to the interaction between SBP and CPM efficiency that may direct this area of research in the future: Based on the observation of a positive linear relationship between SBP and CPM efficiency in the FMS cohort, what characterizes the subgroups of FMS patients with greater SBP and CPM efficiency? Although the current study was not powered to evaluate the presence of subgroups in the FMS cohort, the ability to exhibit an ‘‘effective’’ SBP and CPM response appears to occur in some FMS patients. q
DOI of original article: http://dx.doi.org/10.1016/j.pain.2013.12.023
Case-control differences in CPM are common, but a recent study by Greenspan et al. [9] and preliminary data in our laboratory show no differences in temporomandibular disorders and controls with regard to the efficiency of CPM. Although overly simplistic, the lack of case-control differences could be partially explained by the idea that chronic pain is represented by a continuum with different subgroups including mild, moderate, and severe phenotypes. Each phenotype could be characterized by a gradation of impairments (ie, more severe symptoms = greater pain sensitivity, poor pain inhibition, abnormal autonomic responding) as a function of symptom severity. Further support for this idea is found in osteoarthritis [2,8,11] and others [6] related to general experimental sensitivity in subgroups of patients based on the severity of knee OA in which the high-severity group exhibited greater experimental pain sensitivity. In terms of FMS patients, it would be helpful to determine whether subgroups of FMS patients also exhibit differences in SBP reactivity and CPM efficiency as a function of severity. For example, would individuals in the ‘‘less severe FMS group’’ show SBP reactivity and CPM efficiency comparable to that in the control cohort? The possibility of subgroup differences raises another potential avenue of research. Would the association between cardiovascular functioning and CPM be observed with conditioning stimuli that are less likely to engage mechanisms underlying thermoregulation and cardiovascular (eg, pressure cuff)? The most common method to evaluate CPM is immersion of the hand (or foot) into a cold-water bath, which has been used as an independent test to evaluate ‘‘physiological stress’’ [15,16]) and is associated with a number of stress-related responses (ie, increased blood pressure [1,19]: release of cortisol [10,17,23]). Although most would accept that the experience of pain is accompanied with some level of stress, the degree to which specific pain stimuli engage stress-related physiological systems appear to be different. For example, cortisol shows different profiles depending on the type of modality even when the level of pain is equated [7,10]. It is unclear whether the magnitude of cardiovascular responses varies as a function of the pain stimulus characteristics. Likewise, pain stimuli may also exhibit differences in the magnitude of CPM. Other conditioning stimuli (ie, pressure cuff to the arm or leg) are associated with inhibition [3,12,13], but some evidence suggests that ‘‘less stressful’’ stimuli induce slightly less pain inhibition [13,22], which would presumably be associated with lower levels of cardiovascular reactivity [12,21,22]. However, regardless of the modality, the level of inhibition may also be influenced by the intensity of the conditioning stimulus in which more intense conditioning stimulus would be expected to produce greater pain inhibition [18,24] and possibly greater changes in cardiovascular reactivity. Thus, different pain stimuli may produce endogenous inhibition through slightly different mechanisms. In
http://dx.doi.org/10.1016/j.pain.2014.02.011 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1048
Ò
Commentary / PAIN 155 (2014) 1047–1048
agreement with the authors, additional research is needed to clarify this issue, and to determine whether the association of cardiovascular functioning and CPM is specific to cold immersion or is a universal feature of all conditioning stimuli. In sum, the current study [5] shows the need for further research to elucidate the mechanisms into the mechanisms of CPM and how these mechanisms differ in individuals with chronic pain. Hopefully, the current study will spur further inquiry into the involvement (or lack thereof) of the cardiovascular system in CPM. I would like to thank PAIN for the opportunity to comment on the study. Conflict of interest statement The author declares no conflict of interest. References [1] al’Absi M, Petersen KL. Blood pressure but not cortisol mediates stress effects on subsequent pain perception in healthy men and women. PAINÒ 2003;106: 285–95. [2] Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T. Sensitization in patients with painful knee osteoarthritis. PAINÒ 2010;149:573–81. [3] Bartley EJ, Rhudy JL. Endogenous inhibition of the nociceptive flexion reflex (NFR) and pain ratings during the menstrual cycle in healthy women. Ann Behav Med 2012;43:343–51. [4] Chalaye P, Devoize L, Lafrenaye S, Dallel R, Marchand S. Cardiovascular influences on conditioned pain modulation. PAINÒ 2013;154:1377–82. [5] Chalaye P, Lafrenaye S, Goffaux P, Marchand S. The role of cardiovascular activity in fibromyalgia and conditioned pain modulation. PAINÒ 2014;155: 1064–9. [6] Chen H, Nackley A, Miller V, Diatchenko L, Maixner W. Multisystem dysregulation in painful temporomandibular disorders. J Pain 2013;14: 983–96. [7] Cruz-Almeida Y, King CD, Wallet SM, Riley 3rd JL. Immune biomarker response depends on choice of experimental pain stimulus in healthy adults: a preliminary study. Pain Res Treat 2012:1–7 [Article ID 538739]. [8] Finan PH, Buenaver LF, Bounds SC, Hussain S, Park RJ, Haque UJ, Campbell CM, Haythornthwaite JA, Edwards RR, Smith MT. Discordance between pain and radiographic severity in knee osteoarthritis: findings from quantitative sensory testing of central sensitization. Arthritis Rheum 2013;65:363–72. [9] 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. [10] Goodin BR, Quinn NB, King CD, Page GG, Haythornthwaite JA, Edwards RR, Stapleton L, McGuire L. Salivary cortisol and soluble tumor necrosis factoralpha receptor II responses to multiple experimental modalities of acute pain. Psychophysiology 2012;49:118–27. [11] King CD, Sibille KT, Goodin BR, Cruz-Almeida Y, Glover TL, Bartley E, Riley JL, Herbert MS, Sotolongo A, Schmidt J, Fessler BJ, Redden DT, Staud R, Bradley LA, Fillingim RB. Experimental pain sensitivity differs as a function of clinical pain
[12]
[13]
[14]
[15] [16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25] [26]
severity in symptomatic knee osteoarthritis. Osteoarthritis Cartilage 2013;21:1243–52. Kosek E, Hansson P. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. PAINÒ 1997;70:41–51. Lewis GN, Heales L, Rice DA, Rome K, McNair PJ. Reliability of the conditioned pain modulation paradigm to assess endogenous inhibitory pain pathways. Pain Res Manage 2012;17:98–102. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain 2012;13: 936–44. Lovallo W. The cold pressor test and autonomic function: a review and integration. Psychophysiology 1975;12:268–82. Lovallo W, Zeiner AR. Some factors influencing the vasomotor response to cold pressor stimulation. Psychophysiology 1975;12:499–505. McRae AL, Saladin ME, Brady KT, Upadhyaya H, Back SE, Timmerman MA. Stress reactivity: biological and subjective responses to the cold pressor and Trier social stressors. Hum Psychopharmacol 2006;21:377–85. Oono Y, Wang K, Svensson P, Arendt-Nielsen L. Conditioned pain modulation evoked by different intensities of mechanical stimuli applied to the craniofacial region in healthy men and women. J Orofac Pain 2011;25:364–75. Peckerman A, Hurwitz BE, Saab PG, Llabre MM, McCabe PM, Schneiderman N. Stimulus dimensions of the cold pressor test and the associated patterns of cardiovascular response. Psychophysiology 1994;31:282–90. Reyes del Paso GA, Garrido S, Pulgar A, Duschek S. Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome. J Psychosom Res 2011;70:125–34. Streff A, Kuehl LK, Michaux G, Anton F. Differential physiological effects during tonic painful hand immersion tests using hot and ice water. Eur J Pain 2010;14:266–72. Streff A, Michaux G, Anton F. Internal validity of inter-digital Web pinching as a model for perceptual diffuse noxious inhibitory controls-induced hypoalgesia in healthy humans. Eur J Pain 2011;15:45–52. Suzuki K, Maekawa K, Minakuchi H, Yatani H, Clark GT, Matsuka Y, Kuboki T. Responses of the hypothalamic–pituitary–adrenal axis and pain threshold changes in the orofacial region upon cold pressor stimulation in normal volunteers. Arch Oral Biol 2007;52:797–802. Tousignant-Laflamme Y, Page S, Goffaux P, Marchand S. An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res 2008;1230:73–9. Vierck CJ. A mechanism-based approach to prevention of and therapy for fibromyalgia. Pain Res Treat 2012:1–12 [Article ID 951354]. 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.
Christopher D. King University of Florida Pain Research and Intervention Center of Excellence (PRICE), University of Florida College of Dentistry, Department of Community Dentistry and Behavioral Science, Gainesville, FL, USA E-mail address: [email protected]fl.edu
