Distraction by a cognitive task has a higher impact on electrophysiological measures compared with conditioned pain modulation

IntroductionApplication of noxious stimulation to one body area reduces pain sensitivity in a remote body area through activation of an endogenous pain-inhibitory network, a behavioral phenomenon referred to as conditioned pain modulation (CPM). The efficiency of CPM is predictive of a variety of health outcomes, while impaired CPM has been associated with various chronic pain conditions. Current methods used to assess CPM vary widely, and interest in CPM method development remains strong. Here, we evaluated a novel method for assessing CPM in healthy controls and fibromyalgia (FM) patients using thumb pressure as both a test and conditioning stimulus.MethodsSixteen female FM patients and 14 matched healthy controls underwent CPM testing with thumbnail pressure as the test stimulus, and either cold water or noxious pressure as the conditioning stimulus. CPM magnitude was evaluated as the difference in pain rating of the test stimulus applied before and during the conditioning stimulus.ResultsIn healthy controls, application of either pressure or cold water conditioning stimulation induced CPM as evidenced by a significant reduction in test stimulus pain rating during conditioning (P=0.007 and P=0.021, respectively). In contrast, in FM patients, neither conditioning stimulus induced a significant CPM effect (P>0.274). There was a significant difference in CPM magnitude for FM patients compared to healthy controls with noxious pressure conditioning stimulation (P=0.023); however, no significant difference in CPM was found between groups using cold water as a conditioning stimulus (P=0.269).ConclusionThe current study demonstrates that thumbnail pressure can be used as both a test and conditioning stimulus in the assessment of CPM. This study further confirms previous findings of attenuated CPM in FM patients compared with healthy controls.

Despite extensive research on conditioned pain modulation (CPM), uncertainties remain regarding the role of cognitive mechanisms, such as attentional focus, distraction, and intrinsic a priori expectations, and the most optimal CPM protocol design (parallel vs. sequential). This study examined whether these cognitive factors influence CPM efficacy, and whether CPM magnitude differs between a parallel and sequential protocol. Seventy-two healthy adults participated in this randomised cross-over study undergoing CPM evaluation, that is, pain pressure threshold assessment (=test stimulus) in response to hot water immersion (=conditioning stimulus (CS)) during four experimental protocols, that is, a neutral parallel protocol, a neutral sequential protocol, a sequential protocol with attentional focus on the CS-induced pain intensity, and a sequential protocol with attentional distraction from the CS. Pain expectations were recorded before each protocol. Focusing attention on the CS during CPM assessment resulted in smaller CPM magnitudes compared to no attentional manipulation or distracting from the CS. Distracting from the CS did not affect CPM magnitude compared to no attentional manipulation, nor did a priori expectations. Although CPM magnitudes were not statistically different between the parallel and sequential CPM protocol, a sequential protocol provides higher mean magnitudes and responder rates. Since attentional focus on the CS reduces CPM efficacy, it is recommended to not rate the CS pain intensity during CS application to prevent a reduction of the inhibitory effect. Furthermore, a sequential protocol is recommended over a parallel protocol as a 'cleaner' representation of pain modulation free of attentional sources of biases. Conditioned pain modulation (CPM) is an important biomarker reflecting pain processing, however, there is a high variability in CPM response, making it important to gain insight into the influencing factors and mechanisms of CPM. The results of this study suggest that attentional focus on the conditioning stimulus influences CPM magnitude, whereas a distraction task and intrinsic a priori expectations do not. In both therapeutic and preventive approaches, it is of great interest for clinicians to positively address factors influencing CPM. ClinicalTrials.gov identifier: NCT05161286.

Reply to the letter to the editor by G. Michaux

This scoping review aimed to explore and summarize studies investigating the relationship between physical activity and endogenous pain modulation in older people, using conditioned pain modulation as an assessment tool. Pain is a common problem in older adults and significantly affects their quality of life. While physical activity is widely recommended as a non-pharmacological strategy to mitigate pain, the mechanisms underlying its potential analgesic benefits are not completely understood. One possible mechanism may be related to the influence of physical activity on endogenous pain modulation. This review focused on i) the different types of physical activity in relation to endogenous pain modulation in older adults; ii) the protocols applied to assess this relationship, particularly those using conditioned pain modulation; and iii) existing knowledge gaps requiring further research or interventions adapted for older people with pain. Studies were included if they examined people aged 60 years or older, investigating physical activity as an intervention and its relationship with pain modulation, and used conditioned pain modulation as an outcome measure. Studies that did not use this outcome, or studies that included younger populations without subgroup analysis, were excluded. The review followed the JBI methodology for scoping reviews. A comprehensive search was conducted across MEDLINE (Ovid), CINAHL (EBSCOhost), Embase (Embase.com), Cochrane Database of Systematic Reviews, Web of Science, the JBI EBP Database (Ovid), PsycINFO (Ovid), and PEDro. Gray literature was also searched (ProQuest, OpenGrey, DART-Europe E-theses Portal, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, BASE). The searches covered studies published from 2000 to 2024 with no language or geographic restrictions. Two reviewers independently conducted eligibility screening and data extraction. The results were organized narratively and presented using summary tables and figures. A total of 1717 articles was identified through database searches, and an additional 131 from gray literature sources. After screening titles and abstracts, and assessing full texts against the eligibility criteria, 6 studies were included in the review. Participants were older adults, generally between 60-75 years of age, and 4 of the studies focused specifically on people with knee osteoarthritis. The studies described a range of physical activity formats, including acute isometric or aerobic exercise protocols, longer-term exercise programs, and habitual physical activity measured through accelerometry. Conditioned pain modulation was investigated using varied methodological approaches, including different test and conditioning stimuli, anatomical application sites, sequences, and calculation strategies. Across the included literature, the conceptualization of physical activity and endogenous pain modulation differed substantially, as did reporting of intervention characteristics. Commonly reported limitations included small sample sizes, methodological heterogeneity, restricted study populations, and limited detail on how physical activity interventions were adapted for older participants. The variability in methodologies across studies underscores the need to standardize pain modulation protocols before applying them more broadly to older adults, a population with added complexities and age-related factors that challenge result interpretation. Future research should aim to refine recommendations by developing tailored physical activity interventions for older adults, with particular attention to feasibility and adherence in this population. OSF https://osf.io/e7ndy/.

When investigating the role of facilitatory and inhibitory pain mechanisms such as conditioned pain modulation (CPM) and temporal summation of pain (TSP), it is important to take both into consideration in a single experimental model to provide the most information on subgroups of patients. Therefore, the objective of this study was to identify subgroups in a large population of pediatric patients with chronic pain based on their facilitatory and inhibitory pain mechanisms and compare them with control subjects. Five hundred twenty-one female subjects and 147 male subjects between 8 and 21 years old underwent a CPM assessment using a 2-minute tonic noxious heat stimulation as the test stimulus and a 2-minute cold-pressor task (CPT) (12°C) as the conditioning stimulus. The best partition of clusters of patients was 3 clusters accounting for 27.15% of the total variation in the data. Cluster 1 (n = 271) was best characterized by high pain intensity during the CPT, lack of TSP during the test stimuli, and efficient inhibitory CPM. Cluster 2 (n = 186) was best characterized by low pain intensity during the CPT, lack of TSP during the test stimuli, and efficient inhibitory CPM. Cluster 3 (n = 151) was best characterized by high pain intensity during the CPT, presence of TSP during the test stimuli, and inefficient inhibitory CPM. A single thermal CPM experimental design can identify combinations of facilitatory and inhibitory pain modulation responses. Findings from the current study add to the literature by describing different clinical phenotypes of central pain mechanisms of youth with chronic pain.

Effect of Sensory Sensitivity on Pain Processing Following Noxious Electrical Stimulation in Healthy Participants

The hypermobile type of Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder, associated with joint hypermobility and prominent chronic pain. Because experimental pain testing in hEDS is scarce, the underlying mechanisms are still poorly understood. The present study assesses endogenous pain facilitation and pain inhibition in hEDS, using a protocol for temporal summation of pain (TSP), conditioned pain modulation (CPM) and exercise-induced hypoalgesia (EIH). Twenty women with hEDS and 20 age-matched healthy controls participated. After evaluating thermal and mechanical pain thresholds (PPT), TSP was assessed using 10 repetitive painful pressure stimuli. CPM was provoked using pressure as the test stimulus and hand immersion in hot water (46°) as the conditioning stimulus. EIH was assessed after a submaximal cycling protocol. The hEDS group demonstrated reduced PPTs and showed significantly more TSP after repeated painful stimuli than the control group. In comparison to the healthy control group, the hEDS group demonstrated significantly less EIH at the quadriceps test location. At the trapezius, EIH did not significantly differ between groups. No significant differences were found between the hEDS group and control group in the CPM response. The results demonstrate increased TSP in hEDS, suggesting increased central pain facilitation. EIH should be studied more extensively but may be disturbed when evaluated in the muscles that are activated during exercise. The CPM results are inconclusive and require more research. Studies regarding the mechanisms that underlie pain in hEDS are scarce, although it is the most prevalent and disabling symptom in this patient population. This study demonstrates increased temporal summation in hEDS and suggests that exercise-induced hypoalgesia may be reduced. Because exercise is a cornerstone in the multidisciplinary treatment of heritable connective tissue disorders, gaining knowledge in this field is important. Pressure stimuli were used to facilitate the international usability of the protocols, allowing for future data acquisition in large cohorts.

Endogenous pain modulation has been studied with the conditioned pain modulation (CPM) paradigm with large differences in the magnitude of the CPM effect. We hypothesized that differences in CPM effects might be associated with differences in blood pressure responses to the conditioning stimulus when comparing the CPM effects using two different conditioning stimuli. A single-blind repeated-measures design with block-randomization was applied on 25 healthy male subjects. The test stimulus (TS; tonic heat pain for 120 s) was first presented alone, thereafter in parallel with a conditioning stimulus (CS). Conditioning stimuli were either a cold pressor test (CPT) or equally painful ischaemic muscle pain (ISC), both lasting 120 s. Finger blood pressure and heart rate were recorded continuously. Data were analysed in a linear mixed model framework with CS type (CPT or ISC) and conditioning (TS or TS + CS) as independent factors. An inhibitory CPM effect was found for both types of conditioning (p < 0.001). The CPM effect was larger during CPT conditioning compared with ISC conditioning (p = 0.001). No association with the concomitant cardiovascular response (blood pressure and heart rate) was found (p > 0.34). Cold pressor pain CS induces larger CPM effects than ischaemic pain CS. The larger CPM effect is, however, not associated with a larger blood pressure response. Other factors related to the CS should be investigated to understand why different CS modalities give different CPM effects.

BackgroundConditioned Pain Modulation (CPM) is often used to assess human descending pain inhibition. Nine different studies on the test-retest-reliability of different CPM paradigms have been published, but none of them has investigated the commonly used heat-cold-pain method. The results vary widely and therefore, reliability measures cannot be extrapolated from one CPM paradigm to another. Aim of the present study was to analyse the test-retest-reliability of the common heat-cold-pain method and its correlation to pain thresholds.MethodsWe tested the short-term test-retest-reliability within 40 ± 19.9 h using a cold-water immersion (10 °C, left hand) as conditioning stimulus (CS) and heat pain (43-49 °C, pain intensity 60 ± 5 on the 101-point numeric rating scale, right forearm) as test stimulus (TS) in 25 healthy right-handed subjects (12females, 31.6 ± 14.1 years). The TS was applied 30s before (TSbefore), during (TSduring) and after (TSafter) the 60s CS. The difference between the pain ratings for TSbefore and TSduring represents the early CPM-effect, between TSbefore and TSafter the late CPM-effect. Quantitative sensory testing (QST, DFNS protocol) was performed on both sessions before the CPM assessment. Statistics: paired t-tests, Intraclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Pearson’s correlation, Bland-Altman analysis, significance level p < 0.05 with Bonferroni correction for multiple comparisons, when necessary.ResultsPain ratings during CPM correlated significantly (ICC: 0.411…0.962) between both days, though ratings for TSafter were lower on day 2 (p < 0.005). The early (day 1: 16.7 ± 11.7; day 2: 19.5 ± 11.9; ICC: 0.618, SRD: 20.2) and late (day 1: 1.7 ± 9.2; day 2: 7.6 ± 11.5; ICC: 0.178, SRD: 27.0) CPM effect did not differ significantly between both days. Both early and late CPM-effects did not correlate with the pain thresholds.ConclusionsThe short-term test-retest-reliability of the early CPM-effect using the heat-cold-pain method in healthy subjects achieved satisfying results in terms of the ICC. The SRD of the early CPM effect showed that an individual change of > 20 NRS can be attributed to a real change rather than chance. The late CPM-effect was weaker and not reliable.

Pro-nociceptive and anti-nociceptive effects of a conditioned pain modulation protocol in participants with chronic low back pain and healthy control subjects

Reliability of conditioned pain modulation in healthy individuals and chronic pain patients: a systematic review and meta-analysis.

BackgroundIn rheumatoid arthritis (RA) and spondyloarthritis (Spa), persistent pain remains challenging. It is thought to result from central pain sensitisation, which can be measured by quantitative sensory testing (QST) and...

Electrical-induced pain diminishes somatosensory evoked magnetic cortical fields.

The contribution of endogenous pain modulation dysfunction to clinical and sensory measures of neuropathic pain (NP) has not been fully explored. Habituation, temporal summation, and heterotopic noxious conditioning stimulus-induced modulation of tonic heat pain intensity were examined in healthy noninjured subjects (n = 10), and above the level of spinal cord injury (SCI) in individuals without (SCI-noNP, n = 10) and with NP (SCI-NP, n = 10). Thermoalgesic thresholds, Cz/AFz contact heat evoked potentials (CHEPs), and phasic or tonic (30 seconds) heat pain intensity were assessed within the C6 dermatome. Although habituation to tonic heat pain intensity (0-10) was reported by the noninjured (10 s: 3.5 ± 0.3 vs 30 s: 2.2 ± 0.5 numerical rating scale; P = 0.003), loss of habituation was identified in both the SCI-noNP (3.8 ± 0.3 vs 3.6 ± 0.5) and SCI-NP group (4.2 ± 0.4 vs 4.9 ± 0.8). Significant temporal summation of tonic heat pain intensity was not observed in the 3 groups. Inhibition of tonic heat pain intensity induced by heterotopic noxious conditioning stimulus was identified in the noninjured (-29.7% ± 9.7%) and SCI-noNP groups (-19.6% ± 7.0%), but not in subjects with SCI-NP (+1.1% ± 8.0%; P < 0.05). Additionally, the mean conditioned pain modulation response correlated positively with Cz/AFz CHEP amplitude (ρ = 0.8; P = 0.015) and evoked heat pain intensity (ρ = 0.8; P = 0.007) in the SCI-NP group. Stepwise regression analysis revealed that the mean conditioned pain modulation (R = 0.72) correlated with pain severity and pressing spontaneous pain in the SCI-NP group. Comprehensive assessment of sensory dysfunction above the level of injury with tonic thermal test and conditioning stimuli revealed less-efficient endogenous pain modulation in subjects with SCI-NP.

Effect of conditioned pain modulation on trigeminal somatosensory function evaluated by quantitative sensory testing