Bisphosphonates (BP) are a recommended treatment for osteoporosis and an analgesic effect has been suggested. Magnesium is involved in pain mechanisms, mood disorders and also in bone homeostasis. Association of BPs and magnesium has however not been studied to explore pain processes in post-menopausal osteoporosis. In this pilot ancillary study of a randomized clinical trial in post-menopausal osteoporosis, women were randomized to standard care with intravenous Zoledronate (BP group, n = 22) or BP with oral magnesium (BPMg group, n = 22), 200mg/day for 3 months. Endpoints were quantified before and 1 year after treatment as spontaneous pain, anxiety, depression and sleep quality, as well as quantitative sensory testing of pain sensitivity by thermal thresholds and conditioned pain modulation (CPM), a psychophysical marker of the functionality of pain modulation at spinal level. Thirty-five women (68.2 ± 7.3 years old) with post-menopausal osteoporosis completed the analysis. Compared with baseline, magnesium supplementation did not change significantly any of the endpoints. CPM at baseline was low (-0.92 ± 1.14) and not reversed by treatment. This study in post-menopausal osteoporosis underlines for the first time that zoledronate or zoledronate with magnesium have no effect on pain characteristics and thresholds. It shows a dysfunction of pain inhibitory pain pathways and its non-reversibility with treatments. It points towards the lack of any analgesic effect of zoledronate, and above all to a latent vulnerability of osteoporotic women who are at a potential risk of fracture with a poor pain modulation that needs to be researched further to limit future chronification. (NCT05328154), 15/03/2022. Protocol, statistical analysis plan, participant data and other materials (including data dictionary) can be accessed on request to the corresponding author.

Transauricular vagal nerve stimulation (taVNS) is gaining interest as a chronic pain treatment due to its convergence with nociceptive pathways. Although pain-modulation by taVNS has been demonstrated, this research often lacks the use of active control or does not simultaneously explore effects on associated interoceptive pathways or vagal activation. This double-blind, active-controlled, cross-over study aimed to corroborate the pain-modulating effect of taVNS whilst further investigating cardioception and vagal-activation markers. Thirty healthy individuals underwent 20 minutes of continuous 25-Hz electrical stimulation of the left concha cymba (taVNS) or earlobe (active control). Stimulation intensity was individually adjusted at two-thirds between perception and suprapain thresholds. Assessments were obtained before, immediately after, and 30 minutes after stimulation. These included pressure pain sensitivity measures including, pressure pain perception, detection, tolerance thresholds and conditioned pain modulation (CPM) as well as heart rate variability (HRV), pupillometry and cardioception measures. Although stimulation intensities were higher for control stimulation than taVNS (P < 0.001), participants reported no significant differences in subjective perception of stimulation or in their beliefs regarding the effects of the stimulations on the assessments. Compared to control stimulation, taVNS did not significantly modulate pressure pain sensitivity, cardioception, HRV, or pupillometry. Explorative analysis revealed a negative correlation between taVNS-associated changes in CPM and parasympathetic-HRV (P = 0.005), supporting a potential link between pain modulation and vagal activation. Although the findings offer partial support for the proposed vagal mechanism of taVNS, they highlight the limited understanding of which parameters and when stimulation exerts effects.

Objectives: To estimate the preliminary effects of adding percutaneous electrical nerve stimulation (PENS) to a pain education and exercise program on pain sensitization, function, and psychological factors in patients with knee osteoarthritis (KOA), compared with adding a control transcutaneous electrical nerve stimulation (TENS) intervention or sham PENS. Feasibility, safety, and the success of participant blinding were also evaluated. Methods: Thirty patients with KOA were randomly assigned to one of three intervention groups: PENS, control TENS, or sham PENS. All interventions were delivered in addition to a program comprising four pain education sessions and a structured 12-week exercise plan. Primary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analogue Scale (VAS), Chronic Pain Grading Scale (CPGS), Pressure Pain Threshold (PPT), Conditioned Pain Modulation (CPM), and Temporal Summation of Pain (TSP). Psychological variables were assessed as secondary outcomes. Feasibility outcomes included recruitment and retention rates, adherence, adverse events, and blinding success. Results: Significant and consistent improvements over time were observed across the full sample for VAS (Chi2 = 13.38; p = 0.004), CPGS (Chi2 = 15.22; p = 0.002), WOMAC (Chi2 = 31.44; p < 0.001), CPM (Chi2 = 8.77; p = 0.032) and TSP (Chi2 = 53.11; p < 0.001) with changes in potential clinical relevance at the within-group level. However, no statistically significant group-time interactions were found for any variable, suggesting no clear differential effects between interventions. Feasibility outcomes were favorable, with high retention and adherence, a low incidence of mild adverse events, and generally adequate participant blinding. Conclusions: Within the limits of this small exploratory trial, adding PENS to a pain education and exercise program did not appear to provide additional benefits in pain sensitization, function, or psychological factors beyond those achieved with the multimodal program and sham or control electrical stimulation. Feasibility, safety, and blinding outcomes support the viability of conducting a larger definitive trial.

Orthopedic trauma is a major cause of disability worldwide; around half of people who sustain orthopedic trauma develop chronic pain. Quantitative sensory testing (QST) is a standardized method of assessing pain sensitivity, which may be useful in characterizing pain after injury and predicting chronic pain. This primary aim of this project was to test the feasibility of a portable QST battery, administered to adults 6-weeks post major orthopedic trauma and surgery. 29 participants (62% male; 52% black) who sustained major orthopedic trauma and surgery completed QST testing (including static measures, conditioned pain modulation, mechanical temporal summation) at their 6-week post-operative visit and were invited to complete a 6-month follow-up survey. We examined feasibility and acceptability indices and explored associations between QST and clinical pain ratings. Of all eligible patients, 77% were recruited. QST procedures were feasible and tolerable. No participant declined participation, withdrew for reasons related to study procedures, or discontinued QST due to discomfort. No patient experienced increased clinical pain after QST. Exploratory analyses identified a positive association between static QST and pain interference at T1. Feasibility challenges included poor 6-month retention (57%), and difficulty administering QST to patients with upper extremity injuries. High rates of analgesic use prior to testing (38%) poses an additional barrier for future QST studies in this population. QST was acceptable and partially feasible; challenges included poor retention, high rates of analgesic use, and logistical barriers to accessing injury sites for testing. We pose several potential solutions for future research.

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/.

Background/Objectives: Biopsychosocial pain neuroscience education (PNE) has recently gained attention in preparing patients for surgery. PNE is expected to influence pain coping strategies and descending nociceptive inhibition. The goal of this study was to compare cortical evoked responses during experimental pain processing using a conditioned pain modulation (CPM) paradigm between patients receiving perioperative PNE (PPNE) or perioperative biomedical back school education (PBSE). Methods: This predefined EEG subgroup analysis included only participants with complete EEG recordings at baseline and 6 weeks. Of these, twenty-three patients with low back-related leg pain, scheduled for lumbar spine surgery, were randomized to either two sessions of PPNE or two sessions of PBSE. All patients were stimulated electrically at the median nerve of the symptomatic side and the sural nerve of the symptomatic and non-symptomatic side before and 6 weeks after the educational sessions, while evoked potentials were recorded by electroencephalography (EEG). Subsequently, this protocol was repeated during the application of the CPM paradigm by immersing the hand contralateral to the symptomatic side into cold water. Results: A significant decrease in the amplitude of the waveforms during CPM was found compared to the waveforms before CPM at the non-symptomatic sural nerve. No significant differences were found at the other test locations. For the waveforms of the CPM effect (subtracted waveforms), no significant treatment effects were revealed between the PPNE and PBSE groups. Conclusions: These exploratory findings suggest that PPNE was not associated with differential modulation of EEG evoked potentials during CPM compared with PBSE at 6 weeks post-surgery.

Aerobic exercise leads to transient hypoalgesia, but little is known about these effects over extended periods. This study aimed to investigate exercise-induced hypoalgesia (EIH) responses in healthy individuals during long-distance running on a treadmill. Thirty healthy participants (18-50 years) completed a 15 km treadmill run. Pain sensitivity was assessed using pain pressure threshold (PPT) before and during the run. Additionally, cuff-PPT (cPPT), cuff-pressure pain tolerance threshold (cPTT), temporal summation of pain (TSP) and conditioned pain modulation (CPM) were assessed with pressure cuff algometry before and during the run. Data were analysed using repeated measures ANOVA. Exploratory subgroups, based on changes in PPT, were identified using latent growth mixture models, and logistic regression was used to predict subgroup membership. No significant changes were observed over time for PPT, PTT, cPPT or CPM at the group level. TSP decreased significantly after 10 and 15 km (p ≤ 0.004) when compared to baseline. Exploratory analysis identified two distinct subgroups: 'increasing PPT' and 'decreasing PPT'. Subgroup membership was predicted using baseline CPM and EIH (p < 0.045). This study found no significant changes in PPT, cPPT, or CPM following aerobic exercise. A significant change was observed in TSP. CPM and EIH predicted changes in PPT during the 15 km run (increasing vs. decreasing) in an explorative analysis. Further research should test if baseline tests can predict pro- or anti-nociceptive responses to long-distance running. These findings highlight the importance of individual variability in endogenous pain modulation during endurance exercise. The lack of group-level effects underscores the need to move beyond average responses and consider subgroups when studying exercise-induced hypoalgesia. Identifying distinct modulatory profiles may offer insight into personalized exercise interventions and reveal stable traits related to pain regulation. This has potential clinical implications for tailoring exercise as a pain management strategy and for identifying individuals at risk of negative or absent hypoalgesic responses.

Temporomandibular disorders (TMD) frequently occur with other pain conditions, and existing research has yielded mixed results regarding the presence or absence of endogenous pain modulation (EPM). This study aimed to investigate EPM in TMD patients with comorbid migraine and fibromyalgia (FM) in the non-trigeminal innervated area. Conditioned pain modulation (CPM) and temporal summation (TS) were assessed in healthy controls (n = 30), TMD without comorbidity (n = 30), migraine (n = 30), TMD with migraine (n = 30), and TMD with migraine + FM (n = 19). Based on the TS and CPM responses, participants were categorized into pain modulation profiles (PMP, I-IV). In serial stimulation, patients with migraine, TMD + migraine, and TMDs + migraine + FM showed significantly reduced pain inhibition compared with controls (p = 0.003, p < 0.001, and p = 0.001, respectively), while TMD patients without comorbidity exhibited intact modulation. Increasing comorbidities were also linked to weaker CPM (single stimulation: R = -0.312, p < 0.001; serial stimulation: R = -0.344, p < 0.001). The PMP categorization demonstrated distinctions among the study population, although further subgroup analysis proved challenging. TMD patients without comorbid pain exhibited intact EPM in non-painful areas. However, when these individuals experience comorbid pain conditions, their ability to modulate pain may be compromised due to the pain amplification and central sensitization associated with multiple comorbid pain conditions.

Cytokines, Somatosensory Functioning, and Psychological Distress in Post-Breast Cancer Surgery Pain: A longitudinal study.

Knee osteoarthritis is hallmarked by pain and structural changes, impacting biomechanical function. However, the interplay between pain and biomechanics is poorly understood. Experimental knee pain may act as a surrogate model of clinical pain to study potential changes in pain mechanisms and biomechanics. This randomised, controlled crossover study induced knee pain with hypertonic saline (7%) injected into the infrapatellar fat pad, controlled by isotonic saline (0.9%) injections. Gait biomechanics (speed, braking impulse, propulsion impulse) were measured using motion capture. Cuff-pressure algometry estimated pressure pain and tolerance thresholds (PPT and PTT), temporal summation of pain and conditioned pain modulation. Sleep, depression, anxiety, pain catastrophizing and pain were assessed by questionnaires. Thirty-four young, healthy participants had a mean peak pain of 58 (0-100) after the hypertonic saline injection. Changes in PPT (F(2,62) = 8.0, p < 0.001) and propulsion impulse (F(1.8,50.0) = 1.79, p = 0.039) were observed after pain induction. Multiple linear regression revealed that a combination of baseline PPT, depression scores, speed and propulsion impulse explained 38.7% of the variability in peak knee pain (F(4,29) = 4.6, p < 0.01), while a combination of PTT, speed, braking and propulsion impulse measured during experimental pain explained 57.4% (F(4,29) = 9.8, p < 0.001) of the variability. Changes in PPTs and propulsion impulse were observed after the knee pain induction. Peak knee pain variability can be partly explained using a combination of biomechanics, pain sensitivity and cognitive factors. This forms the basis for a targeted clinical evaluation of patients. Knee osteoarthritis has been increasingly recognised as a multifactorial condition influenced by, for example, cognitive factors and pain sensitivity. This study demonstrated an experimental pain model that mimicked clinical pain experienced by people with moderate-to-severe OA pain. Additionally, this study provides novel insights into the interplay between pain sensitivity, biomechanics and cognitive factors and experimental knee pain.

OnabotulinumtoxinA (BoNT-A) is an established preventive treatment for chronic migraine but involves 31 to 40 injections per session, often causing discomfort and post-procedural headaches. Remote electrical neuromodulation (REN) is a noninvasive therapy with efficacy in migraine treatment via conditioned pain modulation but has not been evaluated for procedural pain. This study evaluated REN's effectiveness in reducing acute procedural pain and postprocedural headache associated with BoNT-A injections. This was an investigator-initiated single-center, randomized, single-blind, sham-controlled crossover study enrolled 80 adults (aged 22 to 74 years) with chronic migraine undergoing routine BoNT-A treatment. Each participant received one injection session without a device, followed by sessions using active REN and sham in randomized order. REN was applied to the upper arm 10 min prior to injections and removed after injection completion. Pain intensity was measured using a visual analog scale (0 to 100) at pre-procedure, intra-procedure, and post-procedure time points. The primary outcome was procedural pain intensity, and secondary outcomes included post-procedural headache incidence and adverse events. Due to clear benefit, the study was terminated early based on predefined stopping criteria. Final analysis of 60 participants (mean age 48.0 years; 49/60, 82% female) demonstrated that pre-procedural pain levels were not significantly different between baseline and the active REN or sham (p > 0.999 and p = 0.485, respectively). However, during and after BoNT-A administration, the active REN group reported significantly lower pain scores compared to both the sham and baseline conditions. At intra-procedure, the REN group experienced a mean pain reduction of 15.0 points (p < 0.001), and at post-procedure experienced a 19.1-point reduction (p < 0.001). Sham treatment did not result in significant pain reduction compared to baseline (p > 0.999 for both intra-procedure and post-procedure). Additionally, REN lowered the incidence of headache as an adverse event, with only 15% (8/52) of participants experiencing post-procedural headache compared to 55% (29/53) in the sham group and 39% (23/59) at baseline (odds ratio = 0.28, 95% confidence interval: 0.10 to 0.69, p = 0.008). No additional adverse events were reported. REN significantly reduces procedural pain and post-procedural headache associated with BoNT-A injections for chronic migraine and may serve as a noninvasive, easily implemented pain management strategy for acute procedural pain. REN represents a promising approach to improving patient comfort during routine migraine treatment as well as reducing post-procedural headache.

This within-subject, double-blind, randomized, placebo-controlled study aimed to determine the acute analgesic and drug effects, and risk for extramedical use, of synthetic delta-9-tetrahydrocannabinol and hydromorphone, alone and in combination, in individuals with knee osteoarthritis (KOA). Participants (N=21; 57% women; Mean age=63.4±6.4) with KOA received oral combinations of placebo, hydromorphone (2 mg), and dronabinol (10 mg): (1, initial session) hydromorphone+placebo, (remaining sessions randomized) (2) placebo+placebo, (3) dronabinol+placebo, and (4) hydromorphone+dronabinol. Clinical and experimentally induced pain (quantitative sensory testing; QST), physical and cognitive function, subjective drug ratings, and adverse events (AEs) were evaluated at baseline and 60-, 120-, 180-, 240-minutes post-dosing. Primary Outcomes: Hydromorphone produced greater pressure pain threshold analgesia than dronabinol, p=0.029, ηp 2 =0.074; greater capsaicin (p=0.045, ηp 2 =0.062) and non-capsaicin (p=0.017, ηp 2 =0.087) sensitized mechanical temporal summation analgesia than placebo. There were no significant drug-related differences for clinical pain severity ηp 2 =0.011, thermal threshold ηp 2 =-0.025 or tolerance ηp 2 =-0.008, temporal summation ηp 2 =0.009, cold pressor ηp 2 =0.056, conditioned pain modulation ηp 2 =0.038, capsaicin-induced thermal threshold ηp 2 =-0.030, central sensitization ηp 2 =0.006, general pain sensitivity ηp 2 =0.021, or physical functioning (2-minute walking distance ηp 2 =0.028, Timed Up and Go ηp 2 =-0.027, total stair climb time ηp 2 =-0.005); all ps>.05. Secondary Outcomes : Hydromorphone impaired working memory accuracy compared to all conditions and produced greater Good Effects than placebo, ps≤.005; Hydromorphone+dronabinol impaired working memory reaction time and produced greater High ratings compared to placebo, greater Drug Effects than placebo and hydromorphone, and higher Nausea than hydromorphone, ps<.05; and Dronabinol had greater High ratings than hydromorphone, p=0.001. There were no significant drug-related differences for fine motor movement, Bad Effects, drug liking, or AE occurrence or severity (ps>.05). Opioid and cannabinoid medications failed to produce robust analgesia in experimentally induced pain among patients with KOA. In contrast to preclinical studies, there was no evidence of synergistic analgesic effects by combining hydromorphone and dronabinol.

Exercise and primary motor cortex (M1) stimulation may alleviate pain by enhancing the endogenous pain-inhibitory system, with its efficacy assessed through conditioned pain modulation (CPM). This study examined whether combining exercise with M1-targeted transcranial electrical stimulation enhances CPM more effectively than either intervention alone. Two randomized, sham-controlled experiments were conducted. In Experiment 1 (N = 70), participants completed a 3-min isometric handgrip exercise or quiet rest. In Experiment 2 (N = 140), participants received 20 min of M1-targeted transcranial random noise stimulation with direct current offset (tRNS + DC-offset) or sham stimulation, followed by either exercise or rest. CPM was assessed at baseline, immediately after, and 30 min post-intervention. Results showed that exercise alone did not significantly enhance CPM efficacy. In contrast, M1-targeted tRNS + DC-offset significantly enhanced CPM efficacy at both post-intervention time points. Critically, individuals with low baseline CPM showed greater benefits from the combination of tRNS + DC-offset and exercise compared to either exercise alone or tRNS + DC-offset alone, particularly at 30 min post-intervention. These results highlight the potential of combining motor cortex stimulation with exercise to optimize endogenous pain inhibition, particularly as a personalized, nonpharmacological intervention for individuals with impaired pain modulation.

Introduction: Migraine is featured by altered nociceptive processing and the presence of cognitive impairments. No study has previously investigated the influence of neurocognitive performance and executive functions in descending pain processing in this population. Aim: To assess the influence of neurocognitive processes and executive functions in conditioned pain modulation (CPM) activation in women with migraine. Methods: A cross-sectional case–control study including 140 women with migraine (50% chronic) and 70 control women was conducted. Clinical migraine features, neurocognitive processes (e.g., attention), and executive functions (memory, mental inhibition, speed of processing) were evaluated. Pressure pain thresholds (PPTs) were bilaterally assessed at the temporalis muscle, lateral epicondyle, and tibialis anterior muscle. Heat (HPT) and cold (CPT) pain thresholds were assessed at the frontalis (trigeminal area) muscle. Thus, CPM was evaluated with the cold pressor test paradigm by analyzing changes in mechanical/thermal stimuli after a conditioned stimulus. Results: Significant group*time interactions not associated with neurocognitive process/executive function, educational level, and employment status were found for PPTs at the temporalis muscle (Wilk’s λ = 0.588, F[2,199] = 69.756, p < 0.001, n2p = 0.412, 1 − β = 0.999), lateral epicondyle (Wilk’s λ = 0.674, F[2,200] = 48.331, p < 0.001, n2p = 0.326, 1 − β = 0.999), and tibialis anterior (Wilk’s λ = 0.751, F[2,200] = 33.110, p < 0.001, n2p= 0.249, 1 − β = 0.999): PPTs were higher after the conditioned stimulus in all points in control women (increases ranging from 11% to 17%), whereas PPTs were lower after the conditioned stimulus in women with migraine (decrease from −7.5% to −0.1%) when compared with PPTs at baseline. Changes in HPT and CPT were small and not significant, ranging from 0.1% to 0.5%. Conclusion: This study revealed that women with episodic or chronic migraine showed CPM deficits particularly against mechanical stimuli when compared with pain-free women. Neurocognitive (e.g., attention) processes or executive functions (e.g., working memory, mental inhibition) did not modulate CPM activity in women with migraine.

Acute musculoskeletal (MSK) injuries are common in youth and prior research has identified somatosensory experiences such as conditioned pain modulation (CPM) as a predictor of the transition from acute to chronic pain. Prior pediatric studies are limited by small samples, single quantitative sensory testing (QST) modalities, and short-term follow-up, so the utility of QST in predicting longer-term pain outcomes following acute injury is unknown. To fill this gap, we examined somatosensory function in the acute pain period as a predictor of pain outcomes over 12 months. Participants were 226 youth (and a caregiver) taking part in a prospective longitudinal study. Youth completed a QST battery (pain threshold, pain tolerance, temporal summation, and CPM) at baseline (post-injury), and questionnaires assessing pain (average pain, movement-evoked pain; MEP) at three timepoints over 12 months. A subset of youth developed persistent pain (≥3/0-10 NRS) at 3 months (15-21% depending on pain measure). Regression models indicated CPM was the sole QST measure that predicted pain intensity and persistence at 3 months (both average and MEP). No QST measures predicted pain outcomes at 12 months. Female sex was associated with pain persistence in multiple models. CPM in the acute pain period is a potential marker for short-term pain outcomes. Future research can examine the utility of using QST in predicting pain outcomes in other pediatric pain samples (e.g., non-MSK locations, more severe injuries) and can expand assessment of MEP using standardized performance tasks.

A randomised, double-blind, sham-controlled, 2×2 factorial trial of aerobic vs. non-aerobic exercise and motor cortex transcranial direct current stimulation in fibromyalgia: effects on clinical outcomes and descending pain modulation

ABSTRACTBackgroundConditioned pain modulation (CPM) assesses descending pain inhibition, but behavioural approaches are limited by subjectivity and variable reproducibility. We tested a CPM protocol combining nociceptive‐selective laser‐evoked potentials (LEPs) with a repeated‐trial design to determine whether neurophysiological markers complement behavioural measures and improve reliability.MethodsTwenty‐seven healthy adults (mean age 24.6 years; 14 female) completed two sessions ≥ 1 week apart. Nociceptive‐selective laser stimuli were applied to the left hand before and after a cold pressor task, and EEG was recorded to extract LEP‐N2P2 components. Temporal LEP‐N1 was measured as a secondary outcome. Behavioural CPM (B_CPM) was indexed by pain ratings; neurophysiological CPM (N_CPM) was defined by reductions in LEP‐N2P2 amplitude.ResultsConsistent behavioural responders were observed in 92.6% of participants, and N_CPM responder rates exceeded 74% across electrodes. B_CPM and N_CPM magnitudes correlated at C3, C4, and Cz (ρ = 0.54–0.56; FDR‐adjusted p < 0.05). Test–retest reliability was good to excellent for B_CPM (ICC3,1 = 0.69; ICC3,2 = 0.81) and for N_CPM at Cz (ICC3,1 = 0.63; ICC3,2 = 0.77). N1_CPM showed mean attenuation but poorer test–retest reliability (ICC3,1 = −0.21; ICC3,2 = −0.51) and no significant correlation with B_CPM. Psychological measures were stable across visits and unrelated to outcomes in this cohort at baseline.ConclusionThe repeated‐trial design enabled assessment of within‐subject consistency via the B_CPM induction rate. Combining behavioural and neurophysiological measures in this dual‐domain framework may improve interpretability and advance standardisation of CPM methodology. LEP‐based N_CPM markers showed reproducibility across sessions and may contribute to the development of brain‐based biomarkers for patient stratification and treatment selection in chronic pain.Significance StatementThis study establishes a reproducible dual‐domain framework for assessing descending pain inhibition by integrating behavioural conditioned pain modulation with nociceptive‐specific laser‐evoked potentials. Using a repeated‐trial design, both behavioural and cortical measures showed high responder rates, strong correlations, and good test–retest reliability. The findings advance standardisation of CPM methodology and demonstrate that LEP‐based neurophysiological markers can objectively index inhibitory function, supporting the development of reliable, brain‐based biomarkers to guide mechanism‐driven pain assessment and personalised neuromodulation therapies.

The effects of neighborhood disadvantage and adverse childhood experiences on conditioned pain modulation in adults with chronic low back pain.

Both facilitation of ascending nociceptive pathways and impaired inhibition of descending ones may contribute to pain sensitization in fibromyalgia (FM). The slowly repeated evoked pain (SREP) protocol is a potential diagnostic marker for assessing this sensitization. Though its mechanisms are unclear, SREP appears linked to ascending facilitation, while the role of descending inhibitory dysfunction in SREP sensitization remains to be clarified. To quantify descending pain inhibition in FM compared with healthy individuals and to assess its relationship with pain sensitization via SREP. In addition, associations between descending pain inhibition and clinical symptoms were examined. In 55 women with FM and 45 pain-free women, descending pain inhibition was estimated using the conditioned pain modulation (CPM) paradigm, with interdigital web pinching as the conditioning stimulus. The use of the SREP protocol consisted of applying pressure stimuli to the nail of the third finger of the nondominant hand. Clinical symptoms were assessed using self-report questionnaires. SREP sensitization was stronger and CPM smaller in FM patients than in pain-free women. In individuals with FM , SREP sensitization was inversely associated with CPM, and both were related to clinical symptoms. Individuals with FM who did not show CPM reported greater severity of FM symptoms and higher anxiety and fatigue levels than those who showed CPM. Impaired endogenous pain inhibition contributes to pain sensitization in FM and may partly explain SREP sensitization. This reduced pain inhibition could also underlie the clinical symptoms commonly seen in FM. Future research may clarify the altered balance between ascending and descending pain processes in FM.

ABSTRACTThe autonomic nervous system (ANS) plays a crucial role in maintaining homeostasis, and its dysfunction is linked to numerous clinical conditions, including chronic pain. Neuromodulatory interventions such as transcutaneous auricular vagus nerve stimulation (taVNS), transcutaneous cervical magnetic stimulation (tCMS), and intermittent theta burst stimulation (iTBS) have been investigated for their potential to modulate autonomic responses and pain perception. However, the efficacy and safety of these techniques remain unclear. This study aimed to evaluate the feasibility and safety of a single session of neuromodulatory stimulation in modulating autonomic function and pain processing in healthy individuals. A double‐blind, randomized, crossover clinical trial was conducted with 22 healthy participants, each undergoing four intervention sessions (taVNS, tCMS, iTBS, and Sham‐taVNS) in randomized order, with a washout period of at least 36 h between sessions. Heart rate variability (HRV) and conditioned pain modulation (CPM) were assessed pre‐ and post‐intervention using a Polar H10 cardiac sensor and a digital pressure algometer. Adverse effects were recorded immediately after each session. No statistically significant differences were observed in HRV or CPM outcomes across active stimulation conditions when compared to Sham. Among the techniques evaluated, tCMS presented the most favorable safety profile, with fewer reported adverse effects relative to iTBS and taVNS. The absence of significant modulation effects suggests that a single session may be insufficient to induce detectable changes in autonomic or pain processing. However, the tolerability and safety of tCMS indicate its potential for future research involving repeated sessions and clinical populations.