Inter-Individual Differences Explain More Variance in Conditioned Pain Modulation Than Age, Sex and Conditioning Stimulus Intensity Combined

Conditioned pain modulation (CPM) describes the reduction in pain evoked by a test stimulus (TS) when presented together with a heterotopic painful conditioning stimulus (CS). CPM has been proposed to reflect inter-individual differences in endogenous pain modulation, which may predict susceptibility for acute and chronic pain. Here, we aimed to estimate the relative variance in CPM explained by inter-individual differences compared to age, sex, and CS physical and pain intensity. We constructed linear and mixed effect models on pooled data from 171 participants of several studies, of which 97 had repeated measures. Cross-sectional analyses showed no significant effect of age, sex or CS intensity. Repeated measures analyses revealed a significant effect of CS physical intensity (p = 0.002) but not CS pain intensity (p = 0.159). Variance decomposition showed that inter-individual differences accounted for 24% to 34% of the variance in CPM while age, sex, and CS intensity together explained <3% to 12%. In conclusion, the variance in CPM explained by inter-individual differences largely exceeds that of commonly considered factors such as age, sex and CS intensity. This may explain why predictive capability of these factors has had conflicting results and suggests that future models investigating them should account for inter-individual differences.

Effects of Percutaneous Electrolysis on Endogenous Pain Modulation: A Randomized Controlled Trial Study Protocol

Percutaneous electrolysis consists of the application of a galvanic electrical current throughout an acupuncture needle. It has been previously hypothesized that needling procedures’ neurophysiological effects may be related to endogenous pain modulation (EPM). This protocol study describes the design of a double-blind (participant, assessor) randomized controlled trial with the aim to investigate whether percutaneous electrolysis is able to enhance EPM and whether the effect is different between two applications depending on the dosage of the galvanic electrical current. Seventy-two asymptomatic subjects not reporting the presence of pain symptoms the previous 6 months before the study, aged 18–40 years, are randomized into one of four groups: a control group who does not receive any intervention, a needling group who receives a needling intervention without electrical current, a low-intensity percutaneous electrolysis group (0.3 mA × 90 s), and a high-intensity percutaneous electrolysis group (three bouts of 3 mA × 3 s). Needling intervention consists of ultrasound-guided insertion of the needle on the common extensor tendon of the lateral epicondyle. The primary outcome is conditioned pain modulation (CPM), and secondary outcomes include widespread pressure pain sensitivity (pressure pain thresholds (PPT) over the lateral epicondyle, the cervical spine, and the tibialis anterior muscle) and temporal summation (TS). We expected that percutaneous electrolysis would have a greater influence on CPM than an isolated needling procedure and no intervention. In addition, we also postulated that there might be differences in outcome measures depending on the intensity of the electrical current during the percutaneous electrolysis application. This study makes a new contribution to the field of neurophysiological effects of percutaneous electrolysis and needling interventions.

The effect of sex and gender on child and adolescent pain

Male–female differences in pain perception and experience have been consistently observed in adult populations. Such differences are theorized to be related to differences in biological (e.g., sex hormones, endogenous pain modulation, and genetics), psychological (e.g., differences in coping), and social (e.g., gender role socialization) factors. In comparison to the adult literature, male–female differences in pediatric pain are less consistently observed, and differences in the prevalence rates of chronic pain conditions appear to emerge around the time of puberty. This chapter explores the evidence for sex and gender differences in pain within pediatric groups. We argue that it is critical to take a development biopsychosocial perspective to fully understand the similarities and differences between boys and girls in pain.

Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls

The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5‐HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5‐HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5‐HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5‐HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5‐HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.

Efficacy of Manual Therapy on Facilitatory Nociception and Endogenous Pain Modulation in Older Adults with Knee Osteoarthritis: A Case Series

Background: manual therapy (MT) has been shown to have positive effects in patients with osteoarthritis (OA)-related pain, and its use in clinical settings is recommended. However, the mechanisms of action for how these positive effects occur are not yet well understood. The aim of the present study was to investigate the influence of MT treatment on facilitatory nociception and endogenous pain modulation in patients with knee OA related pain. Methods: Twenty-eight patients with knee OA were included in this study. Pain intensity using the numerical pain rating scale (NPRS), temporal summation (TS), conditioned pain modulation (CPM), and local (knee) and distant (elbow) hyperalgesia through the pressure pain threshold (PPT), were assessed to evaluate the pain modulatory system. Patients underwent four sessions of MT treatments within 3 weeks and were evaluated at the baseline, after the first session and after the fourth session. Results: the MT treatment reduced knee pain after the first session (p = 0.03) and after the fourth session (p = 0.04). TS decreased significantly after the fourth session of MT (p = 0.02), while a significant increase in the CPM assessment was detected after the fourth session (p = 0.05). No significant changes in the PPT over the knee and elbow were found in the follow-ups. Conclusions: The results from our study suggest that MT might be an effective and safe method for improving pain and for decreasing temporal summation.

Investigation of Correlations Between Pain Modulation Paradigms

Objective Endogenous pain modulation can be quantified through the use of various paradigms. Commonly used paradigms include conditioned pain modulation (CPM), offset analgesia (OA), spatial summation of pain (SSP), and temporal summation of pain (TSP), which reflect spatial and temporal aspects of pro- and antinociceptive processing. Although these paradigms are regularly used and are of high clinical relevance, the underlying physiological mechanisms are not fully understood. Design The aim of this study is therefore to assess the association between these paradigms by using comparable protocols and methodological approaches. Setting University campus. Subjects Healthy and pain-free volunteers (n = 48) underwent psychophysical assessment of CPM, OA, SSP, and TSP (random order) at the same body area (volar nondominant forearm) with individualized noxious stimuli. Methods CPM included heat stimuli before, during, and after a noxious cold-water bath, whereas for OA, three heat stimuli were applied: baseline trial, offset trial, and constant trial. For the SSP paradigm, two differently sized heat stimulation areas were evaluated, whereas for TSP, the first and last stimulus of 10 consecutive short heat stimuli were assessed. A computerized visual analog scale was used to continuously evaluate pain intensity. The magnitudes of all associations between all paradigm pairs were analyzed with Spearman’s correlation, and individual influencing factors were assessed with a multivariate linear regression model. Results Weak to moderate correlations among all four paradigms were found (P &gt; 0.05), and no distinct influencing factors were identified. Conclusions A limited association between pain modulation paradigms suggests that CPM, OA, SSP, and TSP assess distinct aspects of endogenous analgesia with different underlying physiological mechanisms.

Biopsychosocial Aspects in Individuals with Acute and Chronic Rotator Cuff Related Shoulder Pain: Classification Based on a Decision Tree Analysis

Biopsychosocial aspects seem to influence the clinical condition of rotator cuff related shoulder pain (RCRSP). However, traditional bivariate and linear analyses may not be sufficiently robust to capture the complex relationships among these aspects. This study determined which biopsychosocial aspects would better classify individuals with acute and chronic RCRSP and described how these aspects interact to create biopsychosocial phenotypes in individuals with acute and chronic RCRSP. Individuals with acute (<six months of pain, n = 15) and chronic (≥six months of pain, n = 38) RCRSP were included. Sociodemographic data, biological data related to general clinical health status, to shoulder clinical condition and to sensory function, and psychosocial data were collected. Outcomes were compared between groups and a decision tree was used to classify the individuals with acute and chronic RCRSP into different phenotypes hierarchically organized in nodes. Only conditioned pain modulation was different between the groups. However, the tree combined six biopsychosocial aspects to identify seven distinct phenotypes in individuals with RCRSP: three phenotypes of individuals with acute, and four with chronic RCRSP. While the majority of the individuals with chronic RCRSP have no other previous painful complaint besides the shoulder pain and low efficiency of endogenous pain modulation with no signs of biomechanical related pain, individuals with acute RCRSP are more likely to have preserved endogenous pain modulation and unilateral pain with signs of kinesiophobia.