La estimulación magnética transcraneal repetitiva de la corteza motora primaria (M1-rTMS por sus siglas en inglés) induce efectos analgésicos en el dolor neuropático, pero no todos los pacientes son buenos respondedores y aún no se han identificado predictores clínicos de la respuesta. El presente estudio tiene como objetivo desarrollar y validar un algoritmo predictivo simple y fácil de usar para la respuesta individual a M1-rTMS en dolor neuropático periférico, que pueda ser potencialmente aplicable a cualquier condición de dolor crónico. Este estudio se basa en un análisis secundario de un ensayo reciente doble ciego y controlado con placebo, que demostró la eficacia de M1-rTMS de alta frecuencia frente a placebo-rTMS y rTMS de la corteza prefrontal dorsolateral, en 149 pacientes con dolor neuropático periférico. Las variables basales se incluyeron en el modelo sin preselección y se categorizaron en variables sociodemográficas, de dolor y psicológicas. Se definieron buenos respondedores a rTMS a aquellos con ≥50% de alivio del dolor a las 25 semanas, evaluado según la mejoría en la escala numérica de dolor del 0 al 10. Se emplearon Regresion Ridge, selección de características y validación cruzada Monte Carlo para construir y validar un modelo predictivo específico para la respuesta a M1-rTMS a las 25 semanas. El algoritmo incluyó 3 variables: 2 psicológicas (síntomas depresivos y grado de magnificación en la Escala de Catastrofización del Dolor) y 1 relacionada con la distribución del dolor (dolor distal en miembro inferior). Demostró 85% de sensibilidad (P = 0.005) y 84% de especificidad (P < 0.0001) para predecir una buena respuesta a M1-rTMS a las 25 semanas. No fue predictivo de la respuesta a placebo ni a rTMS de la corteza prefrontal dorsolateral. Este algoritmo simple y fácil de usar puede contribuir a individualizar el tratamiento con M1-rTMS en pacientes con dolor neuropático periférico en la práctica clínica y en futuros ensayos clínicos.Registro del ensayo clínico: NCT02010281.

Postherpetic neuralgia (PHN) is the most common complication of herpes zoster (HZ), characterized by persistent neuropathic pain that significantly impairs quality of life. Despite the availability of multiple treatment options, PHN remains under-recognized and undertreated, with wide variation in management practices across Europe. This Delphi consensus aimed to: (1) identify key challenges and unmet needs in PHN diagnosis and management; (2) determine the optimal use and positioning of topical treatments, such as lidocaine-medicated plasters; and (3) develop best-practice recommendations to support clinical decision-making and improve patient outcomes. A modified Delphi methodology was followed. An international steering group (SG) comprising seven healthcare professionals (HCPs) experienced in PHN management met online and developed 42 consensus statements for inclusion in an HCP survey; 16 statements were adapted for inclusion in a patient survey. Each statement was presented with a four-point Likert scale to assess agreement, and the surveys were distributed online by a third party to 640 HCPs and 205 patients located in France, Germany, Ireland, Italy, and the UK. Consensus was defined a priori as ≥ 75

BACKGROUND:Chronic postsurgical pain is a significant medical concern, particularly in cancer patients. However, most previous studies overlooked the psychological mechanisms contributing to this risk. The present study aimed to identify baseline predictive factors for chronic postsurgical pain in order to build and validate a predictive algorithm based on somatic and psychological predictors in a highly phenotyped longitudinal cohort of adult patients with breast or lung cancer from two European centres. METHODS:Comprehensive preoperative data, including patient characteristics and clinical, psychological, and social variables, were collected between 2017 and 2018. Four distinct machine learning models were trained and validated. Patients were examined at baseline and re-evaluated in face-to-face interviews 1 yr later. RESULTS:The sample included 255 patients (mean age 62.3 [range, 28-83] yr, 89.4% female). Chronic postsurgical pain was present in 83 patients (32.5%), of whom 72 (28% of the total sample) had neuropathic pain. We developed a predictive algorithm based on three independent variables: younger age (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.32-0.69), preoperative pain outside of the surgical area (OR, 2.45; 95% CI, 1.46-4.10), and a specific anxiety symptom (overwhelming worries) (OR, 1.81; 95% CI, 1.05-3.13). CONCLUSIONS:This simple algorithm, requiring only three easily accessible inputs, offers a practical tool in routine preoperative settings, supporting timely, targeted interventions to improve pain management in cancer patients at risk of chronic postsurgical pain. CLINICAL TRIAL REGISTRATION:NCT02368275, NCT03124511, NCT02960971.

BACKGROUND:Pain is a frequent and heterogeneous non-motor symptom of Parkinson's disease (PD). Identifying its various underlying mechanisms remains challenging, while such mechanisms are likely to drive proper therapeutic management. Among the various PD-related pain subtypes, primary Parkinsonian pain (PPP) is particularly difficult to identify and differentiate from musculoskeletal pain, due to the absence of positive diagnostic criteria. OBJECTIVES:The aim is to develop and validate the "Primary Parkinsonian Pain Diagnostic Questionnaire" (3PDQ), a self-reported tool for identifying PPP in PD. METHODS:The 3PDQ was developed through literature review and expert consensus, and refined based on patient feedback. In this multicentric study, 227 PD patients with chronic pain were recruited from 11 French Parkinson's Expert Centers; 179 were analyzed after cases were excluded where two independent expert raters made discordant types of pain diagnoses. Psychometric validation followed COSMIN standards, assessing acceptability, internal consistency, reproducibility, and diagnostic accuracy versus expert diagnosis. RESULTS:PPP was diagnosed in 36.3% of patients, whereas musculoskeletal pain was the most frequent pain subtype (42.5%). The final 11-item 3PDQ showed good acceptability (96.5% computable data), satisfactory internal consistency (Kuder-Richardson = 0.71), and excellent test-retest reliability (Lin's concordance = 0.82). The questionnaire demonstrated good discrimination between PPP and musculoskeletal pain (AUC = 0.82), with sensitivity = 82%, specificity = 74%, and a negative predictive value = 82%. CONCLUSIONS:The 3PDQ is the first validated self-reported tool for diagnosing PPP in PD. It provides a reliable, clinically feasible tool to facilitate pain phenotyping and supports the development of mechanism-based treatment strategies. © 2026 International Parkinson and Movement Disorder Society.

Introduction:Exposure to adverse life experiences (ALEs) renders individuals vulnerable to the emergence of pain, depression, and anxiety. It remains unclear to what extent these symptom categories share common ALEs, especially in cases of comorbidity, and how these relationships manifest in developmental trajectories and neural pathways. Objectives:In this study, we investigated the impact of ALEs, considering their timing, quality, and quantity, as well as structural brain changes, on pain, depression, and anxiety symptoms, and their comorbidity from adolescence to young adulthood. Methods:We used prospective and retrospective questionnaires and magnetic resonance imaging data from a large European longitudinal cohort (N = 1700) spanning from 14 to 25 years. We conducted Latent-Class-Growth-Analysis for symptom levels of pain, depression, and anxiety, subsequent logistic regressions to explore prediction of ALEs on symptom classes, and mediation analysis to examine the role of insula in this association. Results:Physical illness unrelated to pain, bullying, and abuse-maltreatment were associated with pain; sexual abuse, bullying, parental violence, and deprivation with depression; bullying and deprivation with anxiety; substance abuse in the household and abuse-maltreatment with pain-depression comorbidity; deprivation with pain-anxiety comorbidity. Smaller insula volume in late adolescence was a significant mediator for the association between deprivation-related ALEs and the pain-anxiety, but not the pain-depression comorbidity. Conclusion:Together, although various and mainly different types of ALEs strongly impact pain, depression, and anxiety symptoms and their comorbidity, insula volume impacts are specific for pain-anxiety comorbidity. These findings may inform early screening and prevention for individuals affected by ALEs.

BACKGROUND:The NeuPSIG diagnostic algorithm is regarded as the reference framework for the diagnosis of neuropathic pain. It is based on a hierarchical model in which diagnostic certainty increases with the presumed objectivity of the evidence, progressing from patient-reported symptoms to clinical examination and, ultimately, to confirmatory tests demonstrating a neurological lesion. METHODS:In this position paper, we critically examine the conceptual foundations of this framework. We argue that the distinction between subjective and objective evidence is less clear-cut than assumed, as so-called objective biomarkers are themselves influenced by patient-related, examiner-dependent and methodological factors. Moreover, the identification of a neurological lesion does not establish a causal relationship with pain, raising fundamental questions about the validity of using lesion-based markers as surrogates for pain classification. RESULTS:Drawing on evidence from bedside examination, quantitative sensory testing, neurophysiology and structural biomarkers, we highlight the limitations of the current hierarchical approach. We show that clinical reasoning in neuropathic pain does not follow a linear progression from subjective to objective data, but rather relies on the integration of multiple, context-dependent sources of information. CONCLUSION:We propose an alternative framework based on converging evidence, in which patient history, pain characteristics and clinical examination are accorded equivalent weight, and diagnostic confidence emerges from their coherence rather than from a hierarchy of objectivity. Within this model, investigations aimed at identifying a neurological lesion are repositioned as tools for aetiological clarification rather than as determinants of pain classification. In our opinion, this approach offers a more conceptually coherent and clinically relevant framework for the diagnosis of neuropathic pain. SIGNIFICANCE STATEMENT:While the NeuPSIG algorithm has been useful to standardize the diagnosis of neuropathic pain in the research setting, this algorithm is based on a hierarchical model in which objective measures (sensory deficits, complementary investigations) largely outweigh self-reported symptoms. We challenge this assumption by showing that 'objective' measures are also prone to variability and propose a model which gives equivalent weight to patient reported outcomes. This model may offer a more clinically relevant approach to the diagnosis of neuropathic pain.

Currently, there are no quantitative pain biomarkers mechanistically assessing the nociceptive system function or analgesic efficacy, which is crucial for developing personalized pain therapies. This lack of specific biomarkers is likely a significant factor in the failure to develop new targeted pain management strategies, potentially leading to the overuse of opioids in chronic pain. Two methodologies-patient-reported outcomes and quantitative sensory testing-offer potential clinical markers that could help close these gaps. This brief review will discuss the strengths and weaknesses of both approaches as well as their implications for the future.

This review article summarizes key aspects of the placebo response in analgesic trials, including its magnitude across pain syndromes, variation with treatments, and predictors of its strength. It also explores the challenges of distinguishing true therapeutic effects from placebo responses and discusses ethical strategies for leveraging placebo mechanisms in clinical practice. By addressing these issues, the author aims to underscore the complex role the placebo response plays in shaping both the scientific understanding of pain and the clinical approaches used to manage it.

BACKGROUND:Despite affecting 2-4% of the population worldwide, fibromyalgia often remains refractory to treatment. Here we report the first international randomised double-blind, sham-controlled trial developed to assess the efficacy of repetitive transcranial magnetic stimulation (rTMS) as an add-on therapy for fibromyalgia. METHODS:Women aged ≥18 yr with fibromyalgia refractory to best available treatment were enrolled in Brazil, France, and Japan, and randomised to 10 Hz motor cortex (M1) rTMS, 3000 pulses day-1, or sham stimulation. This included 10 induction sessions over 2 weeks, followed by weekly maintenance (6 weeks), and fortnightly extended maintenance (8 weeks). Primary outcome was ≥50% pain reduction at week 8 compared with baseline. Secondary outcomes included pain interference, mood, global impression of change, and Fibromyalgia Impact Questionnaire (FIQ) scores at weeks 8 and 16. RESULTS:We randomised 101 women (mean age 48 [range 25-83] yr) into active (n=52) or sham (n=49) arms. Bayesian analysis revealed a 99.4% probability of ≥50% pain reduction at week 8 in the active group vs sham (odds ratio [OR] 3.04; 95% credible interval [95% CrI] 1.26-8.06), with a number needed to treat of 4.54. Frequentist analysis confirmed that relative pain reduction was higher in the active than in the sham group (40.4% vs 18.4%, P=0.028). At week 16, this probability reduced to 34.2% (OR 0.815; 95% CrI 0.313-2.1), but the likelihood of FIQ score reduction was 79.1%. The intervention appeared safe. CONCLUSIONS:Add-on M1-repetitive transcranial magnetic stimulation reduced pain intensity up to 8 weeks in women with fibromyalgia. Although analgesic effects waned, functional improvements remained during extended maintenance at week 16.

BACKGROUND:We report the efficacy and safety of E-52862-a selective, sigma-1 receptor antagonist-from phase 2, randomized, proof-of-concept studies in patients with moderate-to-severe, neuropathic, chronic postsurgical pain (CPSP) and painful diabetic neuropathy (PDN). METHODS:Adult patients (CPSP [N = 116]; PDN [N = 163]) were randomized at a 1:1 ratio to 4 weeks of treatment with E-52862 (CPSP [n = 55]; PDN [n = 85]) or placebo (CPSP [n = 61]; PDN [n = 78]) orally once daily. Pain intensity scores were measured using a numerical pain rating scale from 0 (no pain) to 10 (worst pain imaginable). The primary analysis population comprised patients who received study drug with ≥1 baseline and on-treatment observation (full analysis set). RESULTS:In CPSP, mean baseline average pain was 6.2 for E-52862 vs. 6.5 for placebo. Week 4 mean change from baseline (CFB) for average pain was -1.6 for E-52862 vs. -0.9 for placebo (least squares mean difference [LSMD]: -0.9; p = 0.029). In PDN, mean baseline average pain was 5.3 for E-52862 vs. 5.4 for placebo. Week 4 mean CFB for average pain was -2.2 for E-52862 vs. -2.1 for placebo (LSMD: -0.1; p = 0.766). Treatment-emergent adverse events (TEAEs) were reported in 90.9% of E-52862-treated patients vs. 76.7% of placebo-treated patients in CPSP and 34.1% vs. 26.9% in PDN. Serious TEAEs occurred in CPSP only: E-52862: 5.5%; placebo: 6.7%. CONCLUSIONS:E-52862 demonstrated superior relief of CPSP vs. placebo after 4 weeks. Reductions in pain intensity were seen in PDN with E-52862; high placebo response rates may have prevented differentiation between treatments. E-52862 had acceptable tolerability in both populations. SIGNIFICANCE STATEMENT:These proof-of-concept studies validate the mode of action of E-52862, a selective sigma-1 receptor antagonist. In CPSP, E-52862 resulted in clinically meaningful pain relief. In PDN, reductions in pain intensity were seen with E-52862; high placebo response rates may have prevented differentiation between E-52862 and placebo. These findings are clinically relevant given that neuropathic pain is highly incapacitating, lacking effective treatments and representing a significant unmet medical need, and support further development of sigma-1 receptor antagonists for peripheral neuropathic pain.

BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) is recommended as a third-line treatment for chronic neuropathic pain. Because of its non-invasive nature and limited side effects, it is considered a good therapeutic option. rTMS efficacy on chronic neuropathic pain has been demonstrated in numerous quantitative studies. However, there are no qualitative studies to support these quantitative data. METHODS:Included patients presented with peripheral neuropathic pain related to polyneuropathy (n = 6), radiculopathy (n = 3) and traumatic or surgical nerve injury (n = 3). The target of the rTMS was the primary motor cortex. We conducted a longitudinal qualitative study consisting of two separate semi-structured interviews for all 12 participants from four different French multidisciplinary pain centres, one before starting treatment and the other after 2 months of rTMS treatment. Two separate manual analyses by two researchers were carried out, as were software analysis and data triangulation. RESULTS:Our study revealed an overall positive impression about rTMS treatment, with improvements in pain and activities of daily living. However, most participants felt that information on this treatment was inadequate because of difficulties in understanding the treatment mechanism. These difficulties frequently led to misrepresentations about the treatment, which could result in secondary fears, particularly in relation to the fear of cognitive capacity loss. CONCLUSIONS:The results suggest possible areas for improvement, both in clinical practice and in care organisation. Information provided to patients could be optimised, with a focus on more personalised care, considering preliminary representations and fears, so as to further encourage adherence to treatment. Furthermore, it is necessary to train healthcare staff in order to optimise the care pathway for patients suffering from intractable chronic pain and to limit the risks of delays in treatment. SIGNIFICANCE STATEMENT:rTMS treatment showed overall positive effects on pain and quality of life. Many participants lacked clear understanding of the treatment mechanism, leading to fear and misinformation. Improvements are needed in patient education and healthcare staff training to support therapy compliance and optimise care.

OBJECTIVE:In rheumatoid arthritis (RA) and spondyloarthritis (SpA), managing persistent pain remains challenging. Little is known regarding impaired pain pathways in these patients and the impact of biologic disease-modifying antirheumatic drugs (bDMARDs). The objective of the Rheumatism Pain Inhibitory Descending Pathways study was to assess pain thresholds and descending pain modulation in patients with active RA or SpA following introduction of a tumor necrosis factor inhibitor (TNFi). METHODS:Patients with active disease (50 with RA and 50 with SpA) naive to bDMARDs or targeted synthetic DMARDs and starting a TNFi were included. Patients were observed for six months after TNFi initiation with clinical, psychological, and pain assessment. At all visits, participants underwent quantitative sensory testing with heat and cold pain thresholds and descending inhibition by conditioned pain modulation (CPM). Descending pain control (CPM effect) was assessed as the change in heat pain threshold (°C) following a conditioning stimulus. RESULTS:Of the 100 patients (59 women, mean ± SD age 45.8 ± 14.6 years), 74 completed the six-month follow-up. Thermal pain thresholds did not significantly change during follow-up. CPM effect improved significantly during follow-up (mean ± SD 0.25 ±2.57°C at baseline and 2.96 ± 2.50°C at six months; P < 0.001). At the end of follow-up, the mean CPM effect was significantly higher in patients without significant pain compared with patients with persistent pain (>3 of 10 on the Brief Pain Inventory) (mean ± SD 3.25 ± 2.68°C vs 2.47 ± 2.11°C; P = 0.04) and in patients achieving remission or low disease activity compared with patients with active rheumatism (mean ± SD 3.31 ± 2.68°C vs 2.18 ± 1.87°C; P = 0.01). CONCLUSION:In active inflammatory rheumatisms, impaired descending pain modulation, but not thermal pain thresholds, is improved after TNFi treatment, suggesting a possible effect of TNFi on central pain modulation.

We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 x 10-8). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the "irritable" nociceptor profile to those with a "nonirritable" nociceptor profile identified a significantly associated variant (rs72669682, P = 4.39 x 10-8) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively.

Parkinson disease (PD) affects up to 2% of the general population older than 65 years and is a major cause offunctional loss. Chronic pain is a common nonmotor symptom that affects up to 80% of patients with (Pw) PD bothin prodromal phases and during the subsequent stages of the disease, negatively affecting patient’s quality of lifeand function. Pain in PwPD is rather heterogeneous and may occur because of different mechanisms. Targetingmotor symptoms by dopamine replacement or with neuromodulatory approaches may only partially control PD---related pain. Pain in general has been classified in PwPD according to the motor signs, pain dimensions, or painsubtypes. Recently, a new classification framework focusing on chronic pain was introduced to group different typesof PD pains according to mechanistic descriptors: nociceptive, neuropathic, or neither nociceptive nor neuropathic.This is also in line with the International Classification of Disease-11, which acknowledges the possibility of chronicsecondary musculoskeletal or nociceptive pain due to disease of the CNS. In this narrative review and opinionarticle, a group of basic and clinical scientists revise the mechanism of pain in PD and the challenges faced whenclassifying it as a stepping stone to discuss an integrative view of the current classification approaches and howclinical practice can be influenced by them. Knowledge gaps to be tackled by coming classification and therapeuticefforts are presented, as well as a potential framework to address them in a patient oriented manner.

It is still unclear how and why some patients develop painful and others painless polyneuropathy. The aim of this study was to identify multiple factors associated with painful polyneuropathies (NeuP). A total of 1181 patients of the multicenter DOLORISK database with painful (probable or definite NeuP) or painless (unlikely NeuP) probable or confirmed neuropathy were investigated clinically, with questionnaires and quantitative sensory testing. Multivariate logistic regression including all variables (demographics, medical history, psychological symptoms, personality items, pain-related worrying, life-style factors, as well as results from clinical examination and quantitative sensory testing) and machine learning was used for the identification of predictors and final risk prediction of painful neuropathy. Multivariate logistic regression demonstrated that severity and idiopathic etiology of neuropathy, presence of chronic pain in family, Patient-Reported Outcomes Measurement Information System Fatigue and Depression T-Score, as well as Pain Catastrophizing Scale total score are the most important features associated with the presence of pain in neuropathy. Machine learning (random forest) identified the same variables. Multivariate logistic regression archived an accuracy above 78%, random forest of 76%; thus, almost 4 out of 5 subjects can be classified correctly. This multicenter analysis shows that pain-related worrying, emotional well-being, and clinical phenotype are factors associated with painful (vs painless) neuropathy. Results may help in the future to identify patients at risk of developing painful neuropathy and identify consequences of pain in longitudinal studies.

Supplemental Digital Content is Available in the Text. Endometriosis, a common cause for chronic pelvic pain, significantly affects quality of life, fertility, and overall productivity of those affected. Therapeutic options remain limited, and collating evidence on treatment efficacy is complicated. One reason could be the heterogeneity of assessed outcomes in nonsurgical clinical trials, impeding meaningful result comparisons. This systematic literature review examines outcome domains and patient-reported outcome measures (PROMs) used in clinical trials. Through comprehensive search of Embase, MEDLINE, and CENTRAL up until July 2022, we screened 1286 records, of which 191 were included in our analyses. Methodological quality (GRADE criteria), information about publication, patient population, and intervention were assessed, and domains as well as PROMs were extracted and analyzed. In accordance with IMMPACT domain framework, the domain pain was assessed in almost all studies (98.4%), followed by adverse events (73.8%). By contrast, assessment of physical functioning (29.8%), improvement and satisfaction (14.1%), and emotional functioning (6.8%) occurred less frequently. Studies of a better methodological quality tended to use more different domains. Nevertheless, combinations of more than 2 domains were rare, failing to comprehensively capture the bio-psycho-social aspects of endometriosis-associated pain. The PROMs used showed an even broader heterogeneity across all studies. Our findings underscore the large heterogeneity of assessed domains and PROMs in clinical pain-related endometriosis trials. This highlights the urgent need for a standardized approach to both, assessed domains and high-quality PROMs ideally realized through development and implementation of a core outcome set, encompassing the most pivotal domains and PROMs for both, stakeholders and patients.

CLINICAL TRIAL REGISTRATION:NCT02010281.