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Abstract: Endogenous pain modulation, as tested by the conditioned pain modulation (CPM) protocol, is typically less efficient in patients with chronic pain compared with healthy controls. We aimed to assess whether CPM is less efficient in patients with painful diabetic polyneuropathy (DPN) compared with those with nonpainful DPN. Characterization of the differences in central pain processing between these 2 groups might provide a central nervous system explanation to the presence or absence of pain in diabetic neuropathy in addition to the peripheral one. Two hundred seventy-one patients with DPN underwent CPM testing and clinical assessment, including quantitative sensory testing. Two modalities of the test stimuli (heat and pressure) conditioned to cold noxious water were assessed and compared between patients with painful and nonpainful DPN. No significant difference was found between the groups for pressure pain CPM; however, patients with painful DPN demonstrated unexpectedly more efficient CPMHEAT (-7.4 ± 1.0 vs -2.3 ± 1.6; P = 0.008). Efficient CPMHEAT was associated with higher clinical pain experienced in the 24 hours before testing (r = -0.15; P = 0.029) and greater loss of mechanical sensation (r = -0.135; P = 0.042). Moreover, patients who had mechanical hypoesthesia demonstrated more efficient CPMHEAT (P = 0.005). More efficient CPM among patients with painful DPN might result from not only central changes in pain modulation but also from altered sensory messages coming from tested affected body sites. This calls for the use of intact sites for proper assessment of pain modulation in patients with neuropathy. [ABSTRACT FROM AUTHOR]

Studies in interictal migraine show either normal or impaired pain modulation, at the psychophysical level. To date, pain modulation in migraineurs has yet to be explored concurrent with imaging methods. We aimed to investigate brain activity associated with endogenous analgesia by functional magnetic resonance imaging in attack-free migraineurs. Thirty-nine episodic migraineurs and 35 controls participated. Endogenous analgesia efficiency was assessed by the conditioned pain modulation (CPM) paradigm during functional magnetic resonance imaging. Conditioned pain modulation included 4 stimulation sequences of either test stimulus (noxious contact heat at forearm) given stand alone (Ts_alone) or concomitant to contralateral foot immersion in cold water (Ts_conditioned). The psychophysical CPM (Ts_conditioned minus Ts_alone; 0-10 numerical rating scale) and related brain activity were examined. No group differences were found in the psychophysical CPM (controls: -0.52 +/- 0.80; migraineurs: -0.20 +/- 0.88; repeated-measures analysis of variance: P = 0.110) or related brain activity (family wise error [ P < 0.05] correction at the voxel level). Within groups, controls showed a significant CPM effect (Ts_alone: 6.15 +/- 2.03 vs Ts_conditioned: 5.63 +/- 1.97; P < 0.001), whereas migraineurs did not (Ts_alone: 5.60 +/- 1.92 vs Ts_conditioned: 5.39 +/- 2.30; P = 0.153); yet, both groups showed significant CPM-related decreased deactivation in prefrontal areas including the superior frontal gyrus and parietal regions including precuneus. The change in brain activity seems related to task demands rather than to pain reduction. The lack of group difference between migraineurs and controls in CPM and its related brain activity may result from (1) the specific CPM methodology used in this study, since migraineurs are reported to show various pain modulation efficiency for different test paradigms and/or (2) pathophysiological diversity of patients with migraine. [ABSTRACT FROM AUTHOR]

Objectives. Assessment of pain inhibitory mechanisms using conditioned pain modulation (CPM) is relevant clinically in prediction of pain and analgesic efficacy. Our objective is to provide necessary estimates of intersession CPM reliability, to enable transformation of the CPM paradigm into a clinical tool. Design. Two cohorts of young healthy subjects (N565) participated in two dual-session studies. In Study I, a Bath-Thermode CPM protocol was used, with hot water immersion and contact heat as conditioning- and test-stimuli, respectively, in a classical parallel CPM design introducing teststimulus first, and then the conditioning- and repeated test-stimuli in parallel. Study II consisted of two CPM protocols: 1) Two-Thermodes, one for each of the stimuli, in the same parallel design as above, and 2) single test-stimulus (STS) protocol with a single administration of a contact heat teststimulus, partially overlapped in time by a remote shorter contact heat as conditioning stimulus. Test- retest reliability was assessed within 3-7 days. Results. The STS-CPM had superior reliability intraclass correlation (ICC2,1 = 0.59) over Bath-Thermode (ICC2,1 = 0.34) or Two-Thermodes (ICC2,1 = 0.21) protocols. The hand immersion conditioning pain had higher reliability than thermode pain (ICC2,1 = 0.76 vs ICC2,1 = 0.16). Conditioned test-stimulus pain scores were of good (ICC2,1 = 0.62) or fair (ICC2,1 = 0.43) reliability for the Bath-Thermode and the STS, respectively, but not for the Two-Thermodes protocol (ICC2,1 = 0.20). Conclusions. The newly developed STS-CPM paradigm was more reliable than other CPM protocols tested here, and should be further investigated for its clinical relevance. It appears that large contact size of the conditioning-stimulus and use of single rather than dual test-stimulus pain contribute to augmentation of CPM reliability. [ABSTRACT FROM AUTHOR]

Background Whether psychological factors such as anxiety and pain catastrophizing levels influence the expression of endogenous analgesia in general and, more specifically, the conditioned pain modulation (CPM) response is still under debate. It may be assumed that other psychological characteristics also play a role in the CPM response. The neurotransmitters serotonin, dopamine, and norepinephrine are involved both in CPM, as well as personality traits such as harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), which can be obtained by the Tridimensional Personality Questionnaire (TPQ). However, the associations between these traits (HA, NS, and RD) with endogenous analgesia revealed by CPM have not yet been explored. Methods Healthy middle-age subjects ( n = 28) completed the TPQ, Spielberger's State Anxiety Inventory, and the Pain Catastrophizing Scale and were assessed for CPM paradigms using thermal phasic temporal summation as the 'test stimulus' and hand immersion into hot water bath (CPM water) or contact heat (CPM contact) for 'conditioning stimulus.' Results Higher levels of HA were associated with less-efficient CPM responses obtained by both paradigms: CPM water ( r = 0.418, P = 0.027) and CPM contact ( r = 0.374, P = 0.050). However, NS and RD were not associated with the other measurements. No significant relationship was observed between state anxiety and pain catastrophizing levels and the CPM responses. Conclusions The relationship between the capacity of endogenous analgesia and the tendency to avoid aversive experience can be explained by mutual mechanisms involving similar neurotransmitters or brain areas. These findings illuminate the key role of harm avoidance obtained by the TPQ in determining the characteristics of pain modulation profile. [ABSTRACT FROM AUTHOR]

Experimental pain stimuli can be used to simulate patients' pain experience. We review recent developments in psychophysical pain testing, focusing on the application of the dynamic tests--conditioned pain modulation (CPM) and temporal summation (TS). Typically, patients with clinical pain of various types express either less efficient CPM or enhanced TS, or both. These tests can be used in prediction of incidence of acquiring pain and of its intensity, as well as in assisting the correct choice of analgesic agents for individual patients. This can help to shorten the commonly occurring long and frustrating process of adjusting analgesic agents to the individual patients. We propose that evaluating pain modulation can serve as a step forward in individualizing pain medicine. [ABSTRACT FROM AUTHOR]

Objective To assess the decay of the conditioned pain modulation ( CPM) response along repeated applications as a possible expression of subtle pronociception in migraine. Background One of the most explored mechanisms underlying the pain modulation system is 'diffuse noxious inhibitory controls,' which is measured psychophysically in the lab by the CPM paradigm. There are contradicting reports on CPM response in migraine, questioning whether migraineurs express pronociceptive pain modulation. Methods Migraineurs (n = 26) and healthy controls (n = 35), all females, underwent 3 stimulation series, consisting of repeated (1) 'test-stimulus' ( Ts) alone that was given first followed by (2) parallel CPM application ( CPM-parallel), and (3) sequential CPM application ( CPM-sequential), in which the Ts is delivered during or following the conditioning-stimulus, respectively. In all series, the Ts repeated 4 times (0-3). In the CPM series, repetition '0' consisted of the Ts-alone that was followed by 3 repetitions of the Ts with a conditioning-stimulus application. Results Although there was no difference between migraineurs and controls for the first CPM response in each series, we found waning of CPM-parallel efficiency along the series for migraineurs ( P = .005 for third vs first CPM), but not for controls. Further, greater CPM waning in the CPM-sequential series was correlated with less reported extent of pain reduction by episodic medication (r = 0.493, P = .028). Conclusions Migraineurs have subtle deficits in endogenous pain modulation which requires a more challenging test protocol than the commonly used single CPM. Waning of CPM response seems to reveal this pronociceptive state. The clinical relevance of the CPM waning effect is highlighted by its association with clinical parameters of migraine. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Conditioned pain modulation (CPM) is a testing paradigm representing features of diffuse noxious inhibitory control. There is large diversity in the paradigms applied to induce CPM, and the consistency in CPM responses assessed by different paradigms is largely unknown. We aimed to characterize and explore the associations between the CPM responses assessed by different paradigms in the same cohort. Methods: Thirty-three healthy middle-aged subjects underwent six CPM paradigms. The ‘test-stimuli’, consisted of thermal and mechanical modalities, using pain thresholds, suprathreshold pain and temporal summation types of measurements. The ‘conditioning-stimulus’ consisted of a contact heat stimulus applied to the thener of the left hand for 60s at an intensity of 46.5°C. Results: Large variability was observed among the responses to the different CPM paradigms. Surprisingly, no correlations were found between the various CPM responses. Conclusions: The variability in the CPM responses may suggest that the capacity of pain modulation is a multifaceted trait, whose expression varies with the application of different CPM paradigms. Implications: Considering that CPM responses may represent different processes when assessed by different paradigms, we encourage the use of more than one CPM paradigm. [Copyright &y& Elsevier]

The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information. [ABSTRACT FROM AUTHOR]

Compression therapy, a well-recognized treatment for lymphoedema and venous disorders, pressurizes limbs and generates massive non-noxious afferent sensory barrages. The aim of this study was to study whether such afferent activity has an analgesic effect when applied on the lower limbs, hypothesizing that larger compression areas will induce stronger analgesic effects, and whether this effect correlates with conditioned pain modulation (CPM). Thirty young healthy subjects received painful heat and pressure stimuli (47°C for 30 seconds, forearm; 300 kPa for 15 seconds, wrist) before and during 3 compression protocols of either SMALL (up to ankles), MEDIUM (up to knees), or LARGE (up to hips) compression areas. Conditioned pain modulation (heat pain conditioned by noxious cold water) was tested before and after each compression protocol. The LARGE protocol induced more analgesia for heat than the SMALL protocol (P < 0.001). The analgesic effect interacted with gender (P = 0.015). The LARGE protocol was more efficient for females, whereas the MEDIUM protocol was more efficient for males. Pressure pain was reduced by all protocols (P < 0.001) with no differences between protocols and no gender effect. Conditioned pain modulation was more efficient than the compression-induced analgesia. For the LARGE protocol, precompression CPM efficiency positively correlated with compression-induced analgesia. Large body area compression exerts an area-dependent analgesic effect on experimental pain stimuli. The observed correlation with pain inhibition in response to robust non-noxious sensory stimulation may suggest that compression therapy shares similar mechanisms with inhibitory pain modulation assessed through CPM. [ABSTRACT FROM AUTHOR]

Abstract: This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug’s mechanism of action with the patient’s pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1week of placebo, 1week of 30mg/d duloxetine, and 4weeks of 60mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study’s primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P <.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R2 =0.673; P =.012) showed that drug efficacy was predicted only by CPM (P =.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=−0.411, P =.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to −1.1±15.5, P <.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy. [Copyright &y& Elsevier]