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Conditioned pain modulation Rony-Reuven Nir and David Yarnitsky
Purpose of review Conditioned pain modulation (CPM) paradigms have been increasingly used over the past few years to assess endogenous analgesia capacity in healthy individuals and pain patients. The current review concentrates on selected recent literature advancing our understanding and practice of CPM. Recent findings The main themes covered by the present CPM review include underlying mechanisms, approaches to experimental investigation, practicality in clinical practice, neurophysiological and psychophysiological correlates, and pharmacological solutions to pain modulation dysfunction. Summary The reviewed literature refines the methodology used for eliciting CPM responses and characterizing their physiological attributes in healthy individuals and pain patients, and exemplifies the materializing concept of individualized pain medicine through targeting impaired mechanisms of pain modulation by designated drugs for optimal pain alleviation. Keywords conditioned pain modulation, conditioning stimulus, diffuse noxious inhibitory controls, endogenous analgesia, test stimulus
INTRODUCTION Endogenous circuits of pain modulation possess the capacity to enhance or diminish the perceived magnitude of afferent noxious stimuli. Of the central pain modulation mechanisms, the inhibitory ones are collectively termed endogenous analgesia. In the experimental setup, endogenous analgesia is predominantly probed in humans using the psychophysical paradigm of conditioned pain modulation (CPM) [1], which is characteristically tested using a variety of ‘pain inhibits pain’ models [2], in which one noxious stimulus, the conditioning stimulus, modulates another, the test stimulus (Fig. 1). CPM is based on mechanisms originally investigated in rats by Le Bars et al. [3,4], who demonstrated a spinobulbospinal loop, through which wide dynamic range neurons in the spinal dorsal horn receive a noxious conditioning stimulus from one body part and send a signal upward to the subnucleus reticularis dorsalis of the caudal medulla, which then conveys widespread descending inhibition to spinal secondary neurons via the dorsolateral funiculi [5]. This phenomenon has been described using various terms, including ‘diffuse noxious inhibitory controls’, ‘counterirritation’, and ‘heterotopic noxious counter-stimulation’. To standardize terminology, experts recommended
using ‘diffuse noxious inhibitory controls’ to describe the lower brainstem-mediated inhibitory mechanism directly observed in animal studies, and ‘CPM’ to portray the human behavioral correlate [1]. The relevance of modulatory pain mechanisms in the clinical arena is represented through cumulative research reporting impaired pain inhibition associated with pain disorders, particularly fibromyalgia, irritable bowel syndrome, migraine, tension-type headache, temporomandibular joint (TMJ) disorders, osteoarthritis and muscle pain, whiplash-associated disorders [6], interstitial cystitis [7], patients at risk of developing chronic postsurgical pain [8], and cancer pain patients who demonstrated greater opioid-induced hyperalgesia [9]. Healthy individuals demonstrate more efficacious
The Laboratory of Clinical Neurophysiology, The Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, and Department of Neurology, Rambam Health Care Campus, Haifa, Israel Correspondence to Rony-Reuven Nir, PhD, Department of Neurology, Rambam Health Care Campus, Haifa 31096, Israel. Tel: +972 4 854 2605; fax: +972 4 854 2944; e-mail: [email protected] Curr Opin Support Palliat Care 2015, 9:000–000 DOI:10.1097/SPC.0000000000000126
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KEY POINTS CPM is a reliable test. Various CPM protocols have been substantiated as valid. The autonomic nervous system seems to participate in endogenous analgesia as reflected through CPM. Positioning patients on a spectrum of pain modulation, between pronociception and antinociception, can assist in individualizing pain treatments.
CPM, associated with fewer reports of past pain and better physical functioning [10]. The subjective painfulness of the administered conditioning stimulus plays a key role in the
emergence and degree of CPM. The extent of this role was addressed by utilizing heat conditioning stimuli eliciting mild, moderate, and intense pain experiences within the same experimental setup and subsequently characterizing the induced CPM responses and their intraindividual associations [11]. Two main findings were observed. First, once endogenous analgesia processes were evoked by a required degree of conditioning painfulness, their magnitude was not further affected by increased conditioning pain levels. This could suggest that CPM is a phenomenon that reaches a ceiling effect, corroborating the postulation that pain inhibition may be a saturable phenomenon [12]. Second, across all three conditioning intensities, CPM magnitudes were associated with one another as were all pain ratings of the conditioning stimuli; these observations suggest that CPM responses represent
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FIGURE 1. Schematic illustration of CPM experimental design. CPM is expressed by the reduced painfulness of the test stimulus induced by the application of the conditioning stimulus. This may be depicted by either subjective numerical pain scores (a) or objective features of pain-evoked potentials recorded using an electroencephalogram, namely, magnitude and latency (b). Representative test stimuli include thermal contact-heat administered using a thermode (c), mechanic pressure applied via Von Frey filaments (d), electrical pain detection threshold (e1) and suprathreshold pain ratings (e2), and nociceptive withdrawal reflex responses (f). Typical conditioning stimuli primarily consist of thermal contact-heat (g), cold pressor test (h), and hot water bath (i). CPM, conditioned pain modulation. 2
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Conditioned pain modulation Nir and Yarnitsky
an intrinsic element of an individual’s endogenous analgesia capacity, which are not significantly altered by the experienced conditioning pain. Expanding on the impact of the perceived painfulness of the conditioning stimulus on the consequent CPM, a recent study [13] altered the pain perception of the conditioning stimulus using placebo and nocebo manipulations, and subsequently assessed the induced CPM responses. Findings demonstrated that the placebo intervention diminished the perceived conditioning stimulus painfulness and, in turn, reduced CPM magnitudes, whereas the nocebo administration augmented the perceived conditioning stimulus painfulness but evoked no change in the CPM extent, stressing still the aforementioned ceiling effect of descending pain inhibition. These findings indicate that CPM is not an exclusive expression of a spinobulbospinal pathway leading to the inhibition of wide-dynamic-range neurons in the spinal cord dorsal horn [3,4]; rather, CPM seems to comprise the interaction between such physiological pathways and psychological– cognitive ones. A commonly raised critique on CPM tests is the possible inconsistency of results because of being derived from subjective pain reports. In that regard, Jurth et al. [14] recently demonstrated good intersession test–retest reliability for CPM-induced psychophysical changes tested 28 days apart utilizing a painful hot water conditioning stimulus on a noxious electrical test stimulus. In keeping, Biurrun Manresa et al. [15 ] reported the reliability of CPM paradigms, which were tested twice, separated by 1–3 weeks, using the cold pressor test as the conditioning stimulus, and one of three different test stimuli at a time, namely, the objective electrophysiological nociceptive withdrawal reflex, electrical pain detection threshold, and subjective pain intensity ratings to suprathreshold electrical stimulation. Earlier studies demonstrated good intersession reliability using the cold pressor test as the conditioning stimulus and either pressure pain threshold (PPT) or pressure pain tolerance threshold as the test stimulus [16,17]. These findings attest to the reliability of CPM paradigms for assessing endogenous analgesia in experimental and clinical pain. &&
PURPOSE AND METHODS The chief purpose of this review was to focus on selected studies published in the past 12 months, which add novel insights to the field of CPM. We systematically searched peer-reviewed literature published throughout 2014 using Central PubMed and EMBASE engines for original studies and reviews related to the search terms ‘‘conditioned pain
modulation’, ‘diffuse noxious inhibitory controls’, and ‘heterotopic noxious counter-stimulation’.
TEST PROTOCOLS The pressing need to enable proper comparisons of CPM results in various research projects was recently addressed by Klyne et al. [18 ]. To that end, authors met experts’ recommendations [19 ] to apply two different test stimuli, namely PPT and suprathreshold heat, and to determine the intensity of the latter as inducing a pain score of 45/100 (Pain-45). These test stimuli were assessed before and during the application of a noxious or innocuous (328C contact stimulation) conditioning stimulus. The test and conditioning stimuli were applied at the back and forearms in homotopical and heterotopical variations and on both sides, so as to compare available protocols in terms of CPM actuation. The induction and magnitude of CPM were comparable independently of the stimuli arrangement, except for the case of ipsilateral and homotopic sites. Moreover, although PPT as the test stimulus increased during the application of the noxious – but not innocuous – conditioning stimulus, the Pain-45 scores decreased during both conditioning stimuli. The authors concluded that suprathreshold test stimuli might be less valid in CPM testing compared with PPT. In our opinion, a more likely interpretation of this observation may be that the chosen suprathreshold test stimulus demonstrated a floor effect as a result of its relatively low initial painfulness, and therefore exhibited no further decrease in response to the conditioning stimuli. Thus, utilizing test stimuli of greater painfulness may be apposite for potentiating psychophysical changes consistent with paininduced CPM [11–13], notwithstanding the aforementioned recommendations. This might be a call for a revision of the recommendations [19 ] with regards to the test stimulus, suggesting its perceived pain magnitude should be higher than 40/100. Haefeli et al. [20] investigated in healthy individuals the effects of the order of nociceptive stimulation at anatomically distinct locations – shoulder (dermatome C4) and hand (dermatome C6) – on pain perception. Either test stimulus was administered on the hand and the conditioning stimulus on the shoulder, or vice versa. Findings demonstrate that heterotopic stimulation has location-dependent effects, such that stimulation of the proximal shoulder area as the conditioning stimulus resulted in a more efficient CPM response distally in the hand, compared with the vice-versa stimulation array. We rationalize this response pattern teleologically by the notion that a potentially harmful stimulation experienced proximally may necessitate
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optimal vigilance recruitment through the nociceptive system, and accordingly marginalize the perception of less detrimental distal stimuli via their inhibition. Conversely, distal noxious stimuli may signify that a proximal hazardous stimulation is imminent, and therefore the perception of stimuli therein is enhanced.
CONDITIONED PAIN MODULATION IN PAIN PATIENTS CPM has been regarded, and accordingly investigated, as a systemic – rather than localized – phenomenon, which reliably reflects an individual’s endogenous analgesia capacity provided that the tested tissues and their innervation are intact. Tissues that are acutely or chronically afflicted with pain, nerve damage, or inflammation may compromise local neural mechanisms conveying endogenous analgesia, such that CPM applied therein will reflect both the local abnormal processes and central pain modulation. Theoretically, comparison of CPM responses elicited from healthy and affected tissues is of considerable interest in understanding pain pathophysiology. Oono et al. [21 ] tested CPM in TMJ disorder patients using mechanical conditioning stimulus applied to the vertex, which is anatomically adjacent to – yet sufficiently remote from – the painful TMJ region, and PPTs administered as test stimuli to the segmental painful TMJ and masseter regions and extrasegmental forearm region. One pivotal observation was that CPM assessed at the segmental, chronically painful sites was impaired, whereas CPM assessed at the extrasegmental, pain-free site was intact. This stresses the need to enquire into the differences within pain populations in terms of CPM expression at injured vs. intact tissues. Furthermore, Oono et al. reported no association between the patients’ clinical pain intensity or duration and CPM magnitudes, signifying that clinical pain characteristics do not influence CPM. A novel approach to delineate a possible mechanism underlying CPM was taken by the Marchand group, who explored the autonomic cardiovascular responses during CPM tests in healthy individuals [22] and fibromyalgia patients [23 ]. Although increased blood pressure during the conditioning stimulus was associated with more efficient CPM for both groups, fibromyalgia patients demonstrated lower blood pressure increments during the conditioning stimulus, in keeping with demonstrating CPM dysfunction. Thus, reduced cardiovascular reactivity to pain could have important involvement in diminished endogenous analgesia capacity. This line of findings may be explained by the &&
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contribution of the same brain structures to both CPM expression and autonomic cardiovascular regulation, including the anterior cingulate cortex, the orbitofrontal cortex, locus coeruleus, and the amygdala [24–26]. Importantly, the investigated sample size was unpowered to analyze fibromyalgia subgroups with regards to their diverse pharmacological treatments, which may have affected subjective pain ratings and cardiovascular activity. Additionally, these results cannot indicate whether reduced blood pressure responses to the conditioning stimulus are a cause or an effect of reduced CPM efficiency in fibromyalgia patients.
COGNITIVE AND PSYCHOPHYSIOLOGICAL ASPECTS The influence of psychological factors such as anxiety and pain catastrophizing levels on CPM expression has been largely studied but still remains equivocal [12,13]. Additional psychophysiological characteristics may also take part in the determination of CPM responses, as the neurotransmitters serotonin, dopamine, and norepinephrine that are involved in CPM [27,28,29 ] also contribute to the expression of personality traits such as harm avoidance, novelty seeking, and reward dependence, assessed using the Tridimensional Personality Questionnaire [30]. Nahman-Averbuch et al. [31] have examined all of the aforementioned traits and reported the single observation that higher levels of harm avoidance were associated with less efficient CPM responses obtained by either of the two CPM paradigms. This proposes that greater predisposition to react intensely to signals of aversive stimuli, characterizing harm avoidant personalities, is associated with diminished endogenous analgesia capacity. Brain imaging studies provide evidence that specific brain structures activated during harm avoidance behavior also affect endogenous analgesia, including medial prefrontal, premotor, and cingulate cortices; thalamus; amygdala [24,25,32]. Geva et al. [33] studied the psychophysiological effect of acute experimental stress on pain modulation by meticulously testing CPM responses before and during exposure to the Montreal Imaging Stress Task, which induces acute psychosocial stress. Stress reactions were associated with decreased CPM magnitudes. Accordingly, early identification of patients who are high stress responders may benefit from preemptive intervention efforts aimed at reducing perceived stress, and consequently, development of pain. These findings align with a recent animal study demonstrating the endocannabinoid-mediated coupling of stress and hyperresponsivity to noxious stimuli [34]. &
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Although animal studies evince that endogenous analgesia is mediated by a spinobulbospinal loop using objective measures such as neuronal firing, human studies chiefly utilize pain ratings as the end point. As pain reports are subject to cognitive influences, Bernaba et al. [35 ] tested whether cognitive factors would impact CPM results in healthy individuals, by verbally threatening and reassuring evaluations, and by imagery alone relating to the cold conditioning stimulus. Neither intervention modified CPM response. This is in contrast to the study by Nir et al. [13] in which a more intense manipulation consisting of a placebo cream and actual – rather than virtual – expectation reassurance decreased the perceived painfulness of the conditioning stimulus, which, in turn, reduced CPM magnitudes. The fact that only a profound manipulation of the conditioning stimulus painfulness could significantly alter CPM responses attests to the intrinsic and balanced nature of endogenous analgesia capacity. Investigating the relative role of corticocortical vs. corticospinal communications in generating placebo analgesia, Martini et al. [36] recorded laser-evoked potentials in healthy individuals during placebo analgesia, hypothesizing that if placebo analgesia were mediated by inhibition only at the spinal level; this would result in a general suppression of laser-evoked potentials rather than in a selective reduction of their late components. Placebo analgesia was associated with a significant reduction of the amplitude of a late-evoked potential component (P2). In contrast, an early-evoked potential component (N1), reflecting the arrival of the nociceptive input to the primary somatosensory cortex, was affected only by stimulus energy. This selective suppression of late-evoked potential components indicates that placebo analgesia is mediated by intracortical modulation. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the primary somatosensory cortex (SI), suggesting that higher order sensory processes are modulated during placebo analgesia. &
NEUROPHARMACOLOGY The central pain modulatory network includes the cingulate gyrus, periaqueductal gray, dorsolateral pontine tegmentum, and ventromedial medulla, which exert either antinociceptive or pronociceptive effects via descending serotonergic, noradrenergic, and dopaminergic pathways [37]. Focusing on dopaminergic transmission, clinical studies have demonstrated increased sensitivity to pain in conditions associated with dopamine deficiency, such as Parkinson’s disease [38] and fibromyalgia [39].
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These findings lead Treister et al. [29 ] to test the effects of apomorphine, a nonspecific dopamine agonist, on the magnitude of CPM in healthy individuals. CPM following apomorphine administration increased by 27.3% and by only 4% following placebo administration, attesting to the dopaminergic pathways’ prominent participation in pain modulation and its enhancement. Current studies indicate that the activation of the orbitofrontal cortex [24] and its inhibition of nociceptive activity in the amygdala contribute to endogenous analgesia. Recently, Piche´ et al. [40] induced endogenous analgesia by producing the nociceptive flexion reflex as the test stimulus, together with a conditioning stimulus, while recording somatosensory-evoked potentials and measuring basal m-opioid receptor availability using positron emission tomography. Results showed that although no significant reduction of the test stimulus occurred, greater m-opioid receptor availability in the amygdala was associated with a higher reduction of somatosensory-evoked potentials. This suggests that the activation of m-opioid receptors in the amygdala may contribute to the antinociceptive effects of endogenous analgesia. The lack of nociceptive flexion reflex modulation suggests that mopioid receptor activation in the amygdala contributes to decreased pain-related brain activity through a cerebral mechanism possibly independent of descending modulation. The activation–deactivation balance of dopamine and opioids in the nucleus accumbens may account for the modulation of placebo and nocebo responses [41], and could represent an individual vulnerability or resistance to pain-related cognitive manipulation. Administration of nocebo with expected hyperalgesic effects was reported to activate cholecystokinin, which induces opioid resistance and therefore facilitates pain transmission [42].
INDIVIDUALIZED PAIN MEDICINE The current review reinforces the importance of realizing the potential of human pain modulation in general, and CPM and temporal summation in particular, by its productive assimilation in the clinical practice. Temporal summation is an experimental protocol demonstrating pain facilitation through obtaining pain reports along a series of identical stimuli. The common response is an increase in pain ratings along the series, representing the physiological phenomenon of windup. Yarnitsky et al. [43 ] recently hypothesized that this was achievable through recognizing several pivotal concepts. First, CPM and/or temporal summation (TS) responses position individuals on a clinical spectrum
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ranging from pronociception to antinociception. Second, pain modulation malfunction may be the cause of chronic pain development, and not necessarily its effect [8,44]. Third, pain modulation profiles are pliant once changes in clinical pain are achieved [45,46]. Fourth, targeting a dysfunctional mechanism of pain modulation by a designated drug would accomplish the optimal pain alleviation; for instance, and in accordance with the present review, patients with less efficient CPM could benefit from serotonin–norepinephrine reuptake inhibitors (SNRIs) that augment descending inhibition. Likewise, enhanced TS could be rectified by gabapentinoids that inhibit neuronal sensitization. This notion was recently corroborated in two prospective studies, which actuated the concept of individualized pain medicine using a serotonin–norepinephrine reuptake inhibitor [47] and ketamine [48] to resolve increased pain states expressed as decreased CPM and increased TS, respectively. This line of investigation is most encouraged to benefit the patients suffering from pain disorders, and advance the understanding of the mechanisms underlying them.
CONCLUSION The current review proposes new possible mechanisms underlying CPM, advances the techniques used for CPM induction, and aligns the interpretation of CPM responses with preceding literature. Moreover, recent emerging clinical concepts are coupled with corresponding evidence to endorse the integration of CPM tests in the assessment of pain patients so as to identify endogenous analgesia dysfunction to be treated using mechanism-oriented drugs. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Yarnitsky D, Arendt-Nielsen L, Bouhassira D, et al. Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 2010; 14:339. 2. Pud D, Granovsky Y, Yarnitsky D. The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans. Pain 2009; 144:16–19.
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3. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain 1979; 6:283–304. 4. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on nonconvergent neurones, supraspinal involvement and theoretical implications. Pain 1979; 6:305–327. 5. Le Bars D, Willer J-C. Pain modulation triggered by high-intensity stimulation: implication for acupuncture analgesia? Int Congr Ser 2002; 1238:11–29. 6. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain 2012; 13:936–944. 7. Ness TJ, Lloyd LK, Fillingim RB. An endogenous pain control system is altered in subjects with interstitial cystitis. J Urol 2014; 191:364–370. 8. Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic postoperative pain: preoperative DNIC testing identifies patients at risk. Pain 2008; 138: 22–28. 9. Ram KC, Eisenberg E, Haddad M, Pud D. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain: new perspective of opioid induced hyperalgesia. Pain 2008; 139:431–438. 10. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differences in diffuse noxious inhibitory controls (DNIC): association with clinical variables. Pain 2003; 106:427–437. 11. Nir RR, Granovsky Y, Yarnitsky D, et al. A psychophysical study of endogenous analgesia: the role of the conditioning pain in the induction and magnitude of conditioned pain modulation. Eur J Pain 2011; 15:491–497. 12. Granot M, Weissman-Fogel I, Crispel Y, et al. Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: do conditioning-stimulus painfulness, gender and personality variables matter? Pain 2008; 136:142–149. 13. Nir RR, Yarnitsky D, Honigman L, Granot M. Cognitive manipulation targeted at decreasing the conditioning pain perception reduces the efficacy of conditioned pain modulation. Pain 2012; 153:170–176. 14. Jurth C, Rehberg B, von Dincklage F. Reliability of subjective pain ratings and nociceptive flexion reflex responses as measures of conditioned pain modulation. Pain Res Manag 2014; 19:93–96. 15. Biurrun Manresa JA, Fritsche R, Vuilleumier PH, et al. Is the conditioned pain && modulation paradigm reliable? A test–retest assessment using the nociceptive withdrawal reflex. PLoS One 2014; 9:e100241. This investigation utilized three distinct test stimuli in order to investigate the reliability of CPM tests. 16. Lewis GN, Heales L, Rice DA, et al. Reliability of the conditioned pain modulation paradigm to assess endogenous inhibitory pain pathways. Pain Res Manag 2012; 17:98–102. 17. Arendt-Nielsen L, Andresen T, Malver LP, et al. A double-blind, placebocontrolled study on the effect of buprenorphine and fentanyl on descending pain modulation: a human experimental study. Clin J Pain 2012; 28:623–627. 18. Klyne DM, Schmid AB, Moseley LG, et al. Effect of types and anatomical & arrangement of painful stimuli on conditioned pain modulation. J Pain 2015; 16:176–185. A methodological study of CPM, exploring two different modalities of test stimulus as well as noxious and sham conditioning stimuli, both applied heterotopically and homotopically and on both body sides. 19. Yarnitsky D, Bouhassira D, Drewes AM, et al. Recommendations on practice & of conditioned pain modulation (CPM) testing. Eur J Pain 2014; Epub ahead of print. doi: 10.1002/ejp.605. Timely recommendations on effectively designing CPM experiments. 20. Haefeli J, Kramer JL, Blum J, Curt A. Heterotopic and homotopic nociceptive conditioning stimulation: distinct effects of pain modulation. Eur J Pain 2014; 18:1112–1119. 21. Oono Y, Wang K, Baad-Hansen L, et al. Conditioned pain modulation in && temporomandibular disorders (TMD) pain patients. Exp Brain Res 2014; 232:3111–3119. This article represents an interesting line of investigation, looking into the differences in CPM responses in injured vs. intact tissues in chronic pain patients. 22. Chalaye P, Devoize L, Lafrenaye S, et al. Cardiovascular influences on conditioned pain modulation. Pain 2013; 154:1377–1382. 23. Chalaye P, Lafrenaye S, Goffaux P, Marchand S. The role of cardiovascular && activity in fibromyalgia and conditioned pain modulation. Pain 2014; 155:1064–1069. This study represents a novel approach to CPM investigation, focusing on the autonomic cardiovascular responses during CPM tests in fibromyalgia patients following the examination of healthy individuals [22]. 24. Piche´ M, Arsenault M, Rainville P. Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci 2009; 29:14236–14246. 25. Sprenger C, Bingel U, Buchel C. Treating pain with pain: supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation. Pain 2011; 152:428–439. 26. Gianaros PJ, Sheu LK. A review of neuroimaging studies of stressor-evoked blood pressure reactivity: emerging evidence for a brain–body pathway to coronary heart disease risk. Neuroimage 2009; 47:922–936. 27. Baba Y, Kohase H, Oono Y, et al. Effects of dexmedetomidine on conditioned pain modulation in humans. Eur J Pain 2012; 16:1137–1147. 28. Lindstedt F, Berrebi J, Greayer E, et al. Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene. PLoS ONE 2011; 6:e18252.
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40. Piche´ M, Watanabe N, Sakata M, et al. Basal m-opioid receptor availability in the amygdala predicts the inhibition of pain-related brain activity during heterotopic noxious counter-stimulation. Neurosci Res 2014; 81–82:78–84. 41. Scott DJ, Stohler CS, Egnatuk CM, et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008; 65:220–231. 42. Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci 2006; 15:12014–12022. 43. Yarnitsky D, Granot M, Granovsky Y. Pain modulation profile and pain therapy: & between pro- and antinociception. Pain 2014; 155:663–665. A conceptual summary endorsing the utilization of CPM in the clinical setting so as to advance individualized pain treatments based on specific endogenous analgesia dysfunction. 44. Wilder-Smith OH, Schreyer T, Scheffer GJ, Arendt-Nielsen L. Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: a pilot study. J Pain Palliat Care Pharmacother 2010; 24:119–128. 45. Graven-Nielsen T, Wodehouse T, Langford RM, et al. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum 2012; 64:2907–2916. 46. Kosek E, Ordeberg G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain 2000; 88:69–78. 47. Yarnitsky D, Granot M, Nahman-Averbuch H, et al. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 2012; 153:1193–1198. 48. Lavand’homme P, Roelants F. Effect of a low dose of ketamine on postoperative pain after elective Cesarean delivery according to the presence of a preoperative temporal summation. SOAP 2009; SOAP Abstract A-258.
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SPC 090207
REVIEW URRENT C OPINION
Conditioned pain modulation Rony-Reuven Nir and David Yarnitsky
Purpose of review Conditioned pain modulation (CPM) paradigms have been increasingly used over the past few years to assess endogenous analgesia capacity in healthy individuals and pain patients. The current review concentrates on selected recent literature advancing our understanding and practice of CPM. Recent findings The main themes covered by the present CPM review include underlying mechanisms, approaches to experimental investigation, practicality in clinical practice, neurophysiological and psychophysiological correlates, and pharmacological solutions to pain modulation dysfunction. Summary The reviewed literature refines the methodology used for eliciting CPM responses and characterizing their physiological attributes in healthy individuals and pain patients, and exemplifies the materializing concept of individualized pain medicine through targeting impaired mechanisms of pain modulation by designated drugs for optimal pain alleviation. Keywords conditioned pain modulation, conditioning stimulus, diffuse noxious inhibitory controls, endogenous analgesia, test stimulus
INTRODUCTION Endogenous circuits of pain modulation possess the capacity to enhance or diminish the perceived magnitude of afferent noxious stimuli. Of the central pain modulation mechanisms, the inhibitory ones are collectively termed endogenous analgesia. In the experimental setup, endogenous analgesia is predominantly probed in humans using the psychophysical paradigm of conditioned pain modulation (CPM) [1], which is characteristically tested using a variety of ‘pain inhibits pain’ models [2], in which one noxious stimulus, the conditioning stimulus, modulates another, the test stimulus (Fig. 1). CPM is based on mechanisms originally investigated in rats by Le Bars et al. [3,4], who demonstrated a spinobulbospinal loop, through which wide dynamic range neurons in the spinal dorsal horn receive a noxious conditioning stimulus from one body part and send a signal upward to the subnucleus reticularis dorsalis of the caudal medulla, which then conveys widespread descending inhibition to spinal secondary neurons via the dorsolateral funiculi [5]. This phenomenon has been described using various terms, including ‘diffuse noxious inhibitory controls’, ‘counterirritation’, and ‘heterotopic noxious counter-stimulation’. To standardize terminology, experts recommended
using ‘diffuse noxious inhibitory controls’ to describe the lower brainstem-mediated inhibitory mechanism directly observed in animal studies, and ‘CPM’ to portray the human behavioral correlate [1]. The relevance of modulatory pain mechanisms in the clinical arena is represented through cumulative research reporting impaired pain inhibition associated with pain disorders, particularly fibromyalgia, irritable bowel syndrome, migraine, tension-type headache, temporomandibular joint (TMJ) disorders, osteoarthritis and muscle pain, whiplash-associated disorders [6], interstitial cystitis [7], patients at risk of developing chronic postsurgical pain [8], and cancer pain patients who demonstrated greater opioid-induced hyperalgesia [9]. Healthy individuals demonstrate more efficacious
The Laboratory of Clinical Neurophysiology, The Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, and Department of Neurology, Rambam Health Care Campus, Haifa, Israel Correspondence to Rony-Reuven Nir, PhD, Department of Neurology, Rambam Health Care Campus, Haifa 31096, Israel. Tel: +972 4 854 2605; fax: +972 4 854 2944; e-mail: [email protected] Curr Opin Support Palliat Care 2015, 9:000–000 DOI:10.1097/SPC.0000000000000126
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KEY POINTS CPM is a reliable test. Various CPM protocols have been substantiated as valid. The autonomic nervous system seems to participate in endogenous analgesia as reflected through CPM. Positioning patients on a spectrum of pain modulation, between pronociception and antinociception, can assist in individualizing pain treatments.
CPM, associated with fewer reports of past pain and better physical functioning [10]. The subjective painfulness of the administered conditioning stimulus plays a key role in the
emergence and degree of CPM. The extent of this role was addressed by utilizing heat conditioning stimuli eliciting mild, moderate, and intense pain experiences within the same experimental setup and subsequently characterizing the induced CPM responses and their intraindividual associations [11]. Two main findings were observed. First, once endogenous analgesia processes were evoked by a required degree of conditioning painfulness, their magnitude was not further affected by increased conditioning pain levels. This could suggest that CPM is a phenomenon that reaches a ceiling effect, corroborating the postulation that pain inhibition may be a saturable phenomenon [12]. Second, across all three conditioning intensities, CPM magnitudes were associated with one another as were all pain ratings of the conditioning stimuli; these observations suggest that CPM responses represent
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FIGURE 1. Schematic illustration of CPM experimental design. CPM is expressed by the reduced painfulness of the test stimulus induced by the application of the conditioning stimulus. This may be depicted by either subjective numerical pain scores (a) or objective features of pain-evoked potentials recorded using an electroencephalogram, namely, magnitude and latency (b). Representative test stimuli include thermal contact-heat administered using a thermode (c), mechanic pressure applied via Von Frey filaments (d), electrical pain detection threshold (e1) and suprathreshold pain ratings (e2), and nociceptive withdrawal reflex responses (f). Typical conditioning stimuli primarily consist of thermal contact-heat (g), cold pressor test (h), and hot water bath (i). CPM, conditioned pain modulation. 2
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an intrinsic element of an individual’s endogenous analgesia capacity, which are not significantly altered by the experienced conditioning pain. Expanding on the impact of the perceived painfulness of the conditioning stimulus on the consequent CPM, a recent study [13] altered the pain perception of the conditioning stimulus using placebo and nocebo manipulations, and subsequently assessed the induced CPM responses. Findings demonstrated that the placebo intervention diminished the perceived conditioning stimulus painfulness and, in turn, reduced CPM magnitudes, whereas the nocebo administration augmented the perceived conditioning stimulus painfulness but evoked no change in the CPM extent, stressing still the aforementioned ceiling effect of descending pain inhibition. These findings indicate that CPM is not an exclusive expression of a spinobulbospinal pathway leading to the inhibition of wide-dynamic-range neurons in the spinal cord dorsal horn [3,4]; rather, CPM seems to comprise the interaction between such physiological pathways and psychological– cognitive ones. A commonly raised critique on CPM tests is the possible inconsistency of results because of being derived from subjective pain reports. In that regard, Jurth et al. [14] recently demonstrated good intersession test–retest reliability for CPM-induced psychophysical changes tested 28 days apart utilizing a painful hot water conditioning stimulus on a noxious electrical test stimulus. In keeping, Biurrun Manresa et al. [15 ] reported the reliability of CPM paradigms, which were tested twice, separated by 1–3 weeks, using the cold pressor test as the conditioning stimulus, and one of three different test stimuli at a time, namely, the objective electrophysiological nociceptive withdrawal reflex, electrical pain detection threshold, and subjective pain intensity ratings to suprathreshold electrical stimulation. Earlier studies demonstrated good intersession reliability using the cold pressor test as the conditioning stimulus and either pressure pain threshold (PPT) or pressure pain tolerance threshold as the test stimulus [16,17]. These findings attest to the reliability of CPM paradigms for assessing endogenous analgesia in experimental and clinical pain. &&
PURPOSE AND METHODS The chief purpose of this review was to focus on selected studies published in the past 12 months, which add novel insights to the field of CPM. We systematically searched peer-reviewed literature published throughout 2014 using Central PubMed and EMBASE engines for original studies and reviews related to the search terms ‘‘conditioned pain
modulation’, ‘diffuse noxious inhibitory controls’, and ‘heterotopic noxious counter-stimulation’.
TEST PROTOCOLS The pressing need to enable proper comparisons of CPM results in various research projects was recently addressed by Klyne et al. [18 ]. To that end, authors met experts’ recommendations [19 ] to apply two different test stimuli, namely PPT and suprathreshold heat, and to determine the intensity of the latter as inducing a pain score of 45/100 (Pain-45). These test stimuli were assessed before and during the application of a noxious or innocuous (328C contact stimulation) conditioning stimulus. The test and conditioning stimuli were applied at the back and forearms in homotopical and heterotopical variations and on both sides, so as to compare available protocols in terms of CPM actuation. The induction and magnitude of CPM were comparable independently of the stimuli arrangement, except for the case of ipsilateral and homotopic sites. Moreover, although PPT as the test stimulus increased during the application of the noxious – but not innocuous – conditioning stimulus, the Pain-45 scores decreased during both conditioning stimuli. The authors concluded that suprathreshold test stimuli might be less valid in CPM testing compared with PPT. In our opinion, a more likely interpretation of this observation may be that the chosen suprathreshold test stimulus demonstrated a floor effect as a result of its relatively low initial painfulness, and therefore exhibited no further decrease in response to the conditioning stimuli. Thus, utilizing test stimuli of greater painfulness may be apposite for potentiating psychophysical changes consistent with paininduced CPM [11–13], notwithstanding the aforementioned recommendations. This might be a call for a revision of the recommendations [19 ] with regards to the test stimulus, suggesting its perceived pain magnitude should be higher than 40/100. Haefeli et al. [20] investigated in healthy individuals the effects of the order of nociceptive stimulation at anatomically distinct locations – shoulder (dermatome C4) and hand (dermatome C6) – on pain perception. Either test stimulus was administered on the hand and the conditioning stimulus on the shoulder, or vice versa. Findings demonstrate that heterotopic stimulation has location-dependent effects, such that stimulation of the proximal shoulder area as the conditioning stimulus resulted in a more efficient CPM response distally in the hand, compared with the vice-versa stimulation array. We rationalize this response pattern teleologically by the notion that a potentially harmful stimulation experienced proximally may necessitate
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optimal vigilance recruitment through the nociceptive system, and accordingly marginalize the perception of less detrimental distal stimuli via their inhibition. Conversely, distal noxious stimuli may signify that a proximal hazardous stimulation is imminent, and therefore the perception of stimuli therein is enhanced.
CONDITIONED PAIN MODULATION IN PAIN PATIENTS CPM has been regarded, and accordingly investigated, as a systemic – rather than localized – phenomenon, which reliably reflects an individual’s endogenous analgesia capacity provided that the tested tissues and their innervation are intact. Tissues that are acutely or chronically afflicted with pain, nerve damage, or inflammation may compromise local neural mechanisms conveying endogenous analgesia, such that CPM applied therein will reflect both the local abnormal processes and central pain modulation. Theoretically, comparison of CPM responses elicited from healthy and affected tissues is of considerable interest in understanding pain pathophysiology. Oono et al. [21 ] tested CPM in TMJ disorder patients using mechanical conditioning stimulus applied to the vertex, which is anatomically adjacent to – yet sufficiently remote from – the painful TMJ region, and PPTs administered as test stimuli to the segmental painful TMJ and masseter regions and extrasegmental forearm region. One pivotal observation was that CPM assessed at the segmental, chronically painful sites was impaired, whereas CPM assessed at the extrasegmental, pain-free site was intact. This stresses the need to enquire into the differences within pain populations in terms of CPM expression at injured vs. intact tissues. Furthermore, Oono et al. reported no association between the patients’ clinical pain intensity or duration and CPM magnitudes, signifying that clinical pain characteristics do not influence CPM. A novel approach to delineate a possible mechanism underlying CPM was taken by the Marchand group, who explored the autonomic cardiovascular responses during CPM tests in healthy individuals [22] and fibromyalgia patients [23 ]. Although increased blood pressure during the conditioning stimulus was associated with more efficient CPM for both groups, fibromyalgia patients demonstrated lower blood pressure increments during the conditioning stimulus, in keeping with demonstrating CPM dysfunction. Thus, reduced cardiovascular reactivity to pain could have important involvement in diminished endogenous analgesia capacity. This line of findings may be explained by the &&
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contribution of the same brain structures to both CPM expression and autonomic cardiovascular regulation, including the anterior cingulate cortex, the orbitofrontal cortex, locus coeruleus, and the amygdala [24–26]. Importantly, the investigated sample size was unpowered to analyze fibromyalgia subgroups with regards to their diverse pharmacological treatments, which may have affected subjective pain ratings and cardiovascular activity. Additionally, these results cannot indicate whether reduced blood pressure responses to the conditioning stimulus are a cause or an effect of reduced CPM efficiency in fibromyalgia patients.
COGNITIVE AND PSYCHOPHYSIOLOGICAL ASPECTS The influence of psychological factors such as anxiety and pain catastrophizing levels on CPM expression has been largely studied but still remains equivocal [12,13]. Additional psychophysiological characteristics may also take part in the determination of CPM responses, as the neurotransmitters serotonin, dopamine, and norepinephrine that are involved in CPM [27,28,29 ] also contribute to the expression of personality traits such as harm avoidance, novelty seeking, and reward dependence, assessed using the Tridimensional Personality Questionnaire [30]. Nahman-Averbuch et al. [31] have examined all of the aforementioned traits and reported the single observation that higher levels of harm avoidance were associated with less efficient CPM responses obtained by either of the two CPM paradigms. This proposes that greater predisposition to react intensely to signals of aversive stimuli, characterizing harm avoidant personalities, is associated with diminished endogenous analgesia capacity. Brain imaging studies provide evidence that specific brain structures activated during harm avoidance behavior also affect endogenous analgesia, including medial prefrontal, premotor, and cingulate cortices; thalamus; amygdala [24,25,32]. Geva et al. [33] studied the psychophysiological effect of acute experimental stress on pain modulation by meticulously testing CPM responses before and during exposure to the Montreal Imaging Stress Task, which induces acute psychosocial stress. Stress reactions were associated with decreased CPM magnitudes. Accordingly, early identification of patients who are high stress responders may benefit from preemptive intervention efforts aimed at reducing perceived stress, and consequently, development of pain. These findings align with a recent animal study demonstrating the endocannabinoid-mediated coupling of stress and hyperresponsivity to noxious stimuli [34]. &
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Although animal studies evince that endogenous analgesia is mediated by a spinobulbospinal loop using objective measures such as neuronal firing, human studies chiefly utilize pain ratings as the end point. As pain reports are subject to cognitive influences, Bernaba et al. [35 ] tested whether cognitive factors would impact CPM results in healthy individuals, by verbally threatening and reassuring evaluations, and by imagery alone relating to the cold conditioning stimulus. Neither intervention modified CPM response. This is in contrast to the study by Nir et al. [13] in which a more intense manipulation consisting of a placebo cream and actual – rather than virtual – expectation reassurance decreased the perceived painfulness of the conditioning stimulus, which, in turn, reduced CPM magnitudes. The fact that only a profound manipulation of the conditioning stimulus painfulness could significantly alter CPM responses attests to the intrinsic and balanced nature of endogenous analgesia capacity. Investigating the relative role of corticocortical vs. corticospinal communications in generating placebo analgesia, Martini et al. [36] recorded laser-evoked potentials in healthy individuals during placebo analgesia, hypothesizing that if placebo analgesia were mediated by inhibition only at the spinal level; this would result in a general suppression of laser-evoked potentials rather than in a selective reduction of their late components. Placebo analgesia was associated with a significant reduction of the amplitude of a late-evoked potential component (P2). In contrast, an early-evoked potential component (N1), reflecting the arrival of the nociceptive input to the primary somatosensory cortex, was affected only by stimulus energy. This selective suppression of late-evoked potential components indicates that placebo analgesia is mediated by intracortical modulation. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the primary somatosensory cortex (SI), suggesting that higher order sensory processes are modulated during placebo analgesia. &
NEUROPHARMACOLOGY The central pain modulatory network includes the cingulate gyrus, periaqueductal gray, dorsolateral pontine tegmentum, and ventromedial medulla, which exert either antinociceptive or pronociceptive effects via descending serotonergic, noradrenergic, and dopaminergic pathways [37]. Focusing on dopaminergic transmission, clinical studies have demonstrated increased sensitivity to pain in conditions associated with dopamine deficiency, such as Parkinson’s disease [38] and fibromyalgia [39].
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These findings lead Treister et al. [29 ] to test the effects of apomorphine, a nonspecific dopamine agonist, on the magnitude of CPM in healthy individuals. CPM following apomorphine administration increased by 27.3% and by only 4% following placebo administration, attesting to the dopaminergic pathways’ prominent participation in pain modulation and its enhancement. Current studies indicate that the activation of the orbitofrontal cortex [24] and its inhibition of nociceptive activity in the amygdala contribute to endogenous analgesia. Recently, Piche´ et al. [40] induced endogenous analgesia by producing the nociceptive flexion reflex as the test stimulus, together with a conditioning stimulus, while recording somatosensory-evoked potentials and measuring basal m-opioid receptor availability using positron emission tomography. Results showed that although no significant reduction of the test stimulus occurred, greater m-opioid receptor availability in the amygdala was associated with a higher reduction of somatosensory-evoked potentials. This suggests that the activation of m-opioid receptors in the amygdala may contribute to the antinociceptive effects of endogenous analgesia. The lack of nociceptive flexion reflex modulation suggests that mopioid receptor activation in the amygdala contributes to decreased pain-related brain activity through a cerebral mechanism possibly independent of descending modulation. The activation–deactivation balance of dopamine and opioids in the nucleus accumbens may account for the modulation of placebo and nocebo responses [41], and could represent an individual vulnerability or resistance to pain-related cognitive manipulation. Administration of nocebo with expected hyperalgesic effects was reported to activate cholecystokinin, which induces opioid resistance and therefore facilitates pain transmission [42].
INDIVIDUALIZED PAIN MEDICINE The current review reinforces the importance of realizing the potential of human pain modulation in general, and CPM and temporal summation in particular, by its productive assimilation in the clinical practice. Temporal summation is an experimental protocol demonstrating pain facilitation through obtaining pain reports along a series of identical stimuli. The common response is an increase in pain ratings along the series, representing the physiological phenomenon of windup. Yarnitsky et al. [43 ] recently hypothesized that this was achievable through recognizing several pivotal concepts. First, CPM and/or temporal summation (TS) responses position individuals on a clinical spectrum
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ranging from pronociception to antinociception. Second, pain modulation malfunction may be the cause of chronic pain development, and not necessarily its effect [8,44]. Third, pain modulation profiles are pliant once changes in clinical pain are achieved [45,46]. Fourth, targeting a dysfunctional mechanism of pain modulation by a designated drug would accomplish the optimal pain alleviation; for instance, and in accordance with the present review, patients with less efficient CPM could benefit from serotonin–norepinephrine reuptake inhibitors (SNRIs) that augment descending inhibition. Likewise, enhanced TS could be rectified by gabapentinoids that inhibit neuronal sensitization. This notion was recently corroborated in two prospective studies, which actuated the concept of individualized pain medicine using a serotonin–norepinephrine reuptake inhibitor [47] and ketamine [48] to resolve increased pain states expressed as decreased CPM and increased TS, respectively. This line of investigation is most encouraged to benefit the patients suffering from pain disorders, and advance the understanding of the mechanisms underlying them.
CONCLUSION The current review proposes new possible mechanisms underlying CPM, advances the techniques used for CPM induction, and aligns the interpretation of CPM responses with preceding literature. Moreover, recent emerging clinical concepts are coupled with corresponding evidence to endorse the integration of CPM tests in the assessment of pain patients so as to identify endogenous analgesia dysfunction to be treated using mechanism-oriented drugs. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
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