We read with great interest the study by Bilika et al [...].

OBJECTIVES:In this retrospective study, we evaluated high-frequency spinal cord stimulation (SCS) as an alternative neuromodulation strategy for patients with medically intractable chronic cluster headache (MICCH) in whom occipital nerve stimulation (ONS) had failed. BACKGROUND:MICCH represents a severe and treatment-resistant form of cluster headache, for which preventive pharmacologic treatment options are limited. ONS is increasingly used as a peripheral neuromodulation strategy for MICCH, but a subset of patients remains refractory despite treatment. Cervical SCS could be a central neuromodulation strategy for these patients. MATERIALS AND METHODS:This retrospective study included 14 patients with MICCH (nine female, five male; mean age 47 years) who were treated with high cervical 10 kHz SCS after ONS failure. Clinical data were collected on attack frequency, attack duration, intensity of attacks, and quality of life throughout the duration of neuromodulation treatment. RESULTS:Mean SCS follow up duration is 33 ± 21 months. At the last SCS follow-up, ten of 14 patients had a lower mean attack frequency compared with their last ONS assessment (64 ± 33 vs 36 ± 34 weekly attacks, p = 0.02). At the last SCS follow-up six patients obtained a reduction in attack frequency relative to baseline. Mean attack duration decreased from 110 ± 86 to 88 ± 56 minutes, whereas attack intensity remained unchanged. Quality-of-life outcomes were inconsistent and did not uniformly correspond with clinical improvement. CONCLUSIONS:High cervical 10 kHz SCS may represent a feasible rescue neuromodulation strategy for patients with MICCH unresponsive to ONS, with a subset achieving sustained reductions in attack frequency. Interpretation of the effects of SCS on attack duration and pain intensity is limited due to missing data. Nevertheless, these findings support its potential as a treatment option in this highly resistant population. Well-controlled prospective studies are needed to confirm efficacy and further define the role of SCS in treatment algorithms. CLINICAL TRIAL REGISTRATION:This study was not registered as a clinical trial it is a retrospective observational cohort study. The intervention was offered as a last-resort treatment within regular clinical care to patients with medically intractable chronic cluster headache and was therefore not prospectively designed or conducted as a trial.

OBJECTIVE:The objective of this review is to systematically assess and synthesize textual evidence regarding the concept, including the terminology and definition, and International Association for the Study of Pain (IASP) criteria on the nociplastic pain descriptor. INTRODUCTION:Since its formal recognition by the IASP in 2017, the nociplastic pain descriptor has elicited both endorsement and critique. Currently, no systematic overview critically synthesizes the diverse expert perspectives on the nociplastic pain descriptor, contributing to misinterpretation, conceptual confusion, clinical challenges, and ongoing debate. ELIGIBILITY CRITERIA:This review will include published and unpublished textual evidence reflecting expert perspectives on the nociplastic pain descriptor, including clinician narratives, expert opinion, and policy papers. Textual evidence on all body systems and any pain duration will be eligible, without restrictions based on contextual factors. Social media and video content will be excluded. METHODS:This review will follow the JBI methodology for systematic reviews of textual evidence. Published textual evidence in any language from 2016 onwards will be searched in Embase, MEDLINE, CINAHL, Web of Science, Scopus, and PsycINFO. Unpublished textual evidence will be searched for in specialized gray literature databases, Google, and international pain organization websites. Methodological quality will be assessed using the JBI critical appraisal checklists for textual evidence. Study selection, appraisal, data extraction, and synthesis will be conducted independently by 2 reviewers. Data synthesis will follow a meta-aggregative approach. Confidence in the findings will be graded using a modified ConQual approach. Good practice statements will be issued, where appropriate. REVIEW REGISTRATION:PROSPERO CRD420251270659.

Objectives: Complex regional pain syndrome (CRPS) is a heterogeneous pain disorder with incompletely understood immunoinflammatory features. This study investigated whether autonomic receptor autoantibodies differentiate CRPS from other chronic pain conditions and healthy controls. Methods: We conducted a cross-sectional analysis of serum samples from patients referred with suspected CRPS. Patients were subsequently classified as having either CRPS or another chronic pain condition, based on the Budapest criteria. Healthy controls were included for comparison. Serum levels of autoantibodies targeting the muscarinic M2 receptor (M2R), β1-adrenergic receptor (β1AR), and the β2-adrenergic receptor (β2AR) were assessed using enzyme-linked immunosorbent assay. All analyses were performed blinded to group assignment. Results: Seventy participants were analyzed (CRPS = 22, other chronic pain = 25, healthy controls = 23). M2R autoantibody levels were higher in both CRPS and other chronic pain compared with healthy controls (mean difference [MD] = 0.37, 95%CI 0.22–0.51; and MD = 0.31 95%CI 0.19–0.44, respectively). β2AR levels were higher in other chronic pain compared with healthy controls (MD = 0.29, 95%CI 0.04–0.54), whereas no significant difference was observed in CRPS (MD = 0.21 95%CI −0.01–0.42). No meaningful differences were observed between CRPS and other chronic pain for any receptor. β1AR levels did not differ between groups. Seropositivity for any autoantibody was 55% in CRPS, 44% in other chronic pain, and 22% in healthy controls. Conclusions: Elevated autonomic receptor autoantibody levels were observed across chronic pain conditions but were not specific for CRPS.

Intravenous ketamine is used for complex regional pain syndrome (CRPS), but variable response and uncertain durability limit patient selection. This systematic review evaluated reported predictors of response to intravenous ketamine in CRPS and quantified the extent and duration of pain relief. The protocol is registered in PROSPERO (CRD420250655066). Databases were searched from inception through March 26, 2026. Randomized trials and observational studies reporting intravenous ketamine in CRPS were included. Pain scores were rescaled to a 0-10 scale, and the mean difference in change from baseline was pooled for the earliest post-infusion assessment within 14 days using inverse-variance random-effects meta-analysis. Random-effects meta-regression modeled outcomes at 14 days or later. Predictors of response were synthesized narratively. Twenty-one studies (3 randomized trials) included 605 ketamine-treated patients, with most studies having a moderate to high risk of bias. The pooled mean baseline pain score was 7.4. At the earliest post-infusion assessment within 14 days, the mean change in pain was -3.6 (95%CI -4.7 to -2.5). Limited longer-term data up to 90 days suggested attenuation of effect, with a gradual return toward baseline. Responder definitions varied widely, with a median responder rate of 65% (range 0-100%). Only 3 studies formally evaluated predictors, and quantitative synthesis was not feasible. Reported associations included sympathetically maintained pain (aOR 6.54, 95%CI 1.83-23.44) and obesity (aOR 8.75, 95%CI 1.45-52.73). Other exploratory predictors included bone scintigraphy phase ratios and baseline microRNAs. Intravenous ketamine may reduce pain, but limited predictor evidence precludes firm conclusions for individualized treatment selection. PERSPECTIVE: This systematic review supports intravenous ketamine as a potential interventional option for complex regional pain syndrome, while emphasizing that standardized outcome reporting and validated predictors are needed before treatment can be reliably individualized.

Purpose:Pamidronate is a nitrogen-containing bisphosphonate with immunomodulatory and anti-osteoclastic properties that has shown benefit in early-onset complex regional pain syndrome (CRPS), yet evidence in persistent CRPS remains limited. Given that chronicity may attenuate therapeutic response, this study evaluates the effectiveness and tolerability of intravenous pamidronate in CRPS patients managed in routine clinical practice. Patients and Methods:We conducted a single-center retrospective observational study, including all adult CRPS patients treated with pamidronate between 2014 and 2024 at our tertiary referral center. Data were collected from medical records at baseline, during treatment and at routine follow-up at approximately 1-, 3-, 6-, and 12-months post-treatment. The primary outcome was the pain trajectory, analyzed using a linear mixed-effects model. Responders were defined by a ≥2-point NRS reduction or subjective benefit when NRS data were unavailable. Results:Of 110 eligible patients, 97 were included with a median age of 45 (IQR 32-54), and a median disease duration of 31 months (IQR 9-97). Baseline mean NRS was 7.95 (95% CI: 7.66 to 8.25), declining by 1.10 points (95% CI: -1.49 to -0.70; p<0.001) at 1 month and by 0.66 points (95% CI: -1.13 to -0.20; p<0.01) at 3 months. Responder rates were 34% and 22%, respectively. Treatment-related adverse events occurred in 91% of patients but led to discontinuation in only 6%. Conclusion:In patients with predominantly persistent CRPS, intravenous pamidronate was well tolerated and associated with a modest, short-term pain relief up to 3 months. No sustained analgesic benefit was evident at later timepoints.

Background Sympathetic interventions are frequently used in complex regional pain syndrome (CRPS). However, the evidence is inconclusive, and the response may depend on phenotype, anatomical target, and treatment durability. For upper-extremity CRPS, clinical data on thoracic sympathetic block (TSB) with botulinum toxin type A (BoNT-A) are lacking. Objective To describe patient characteristics, procedural details, and clinical and thermographic outcomes after computed tomography (CT)-guided TSB with BoNT-A in upper-extremity CRPS. Methods We performed a retrospective single-center case series of consecutive adults with upper-extremity CRPS who underwent CT-guided TSB with BoNT-A between January 2023 and March 2026. For each procedure, medical records were reviewed to descriptively assess pain change, duration of effect, repeat procedures, thermographic change, and adverse events. Results Six patients underwent 7 procedures. Most suffered from persistent, treatment-refractory CRPS. Responses varied: 3 patients experienced a clinically meaningful analgesic benefit, 1 had thermographic improvement without clear analgesic benefit, and 2 had no meaningful response. No serious procedure-related complications were observed. Conclusion CT-guided TSB with BoNT-A was feasible in this small retrospective series of refractory upper-extremity CRPS. Responses were heterogeneous, and thermographic improvement was not always accompanied by pain relief. The findings may prompt hypotheses regarding phenotype-based patient selection and the role of thermography.

Introduction Spinal cord stimulation (SCS) is an effective treatment for certain chronic pain conditions. Proposed mechanisms of SCS include modulation of the ascending lateral, ascending medial, and descending pain pathways. Conditioned pain modulation (CPM) evaluates the descending pathway by measuring ways a first painful stimulus is affected by a second painful stimulus. Objectives We aim to increase insight into SCS mechanisms by exploring cortical activity in response to painful stimuli under various SCS paradigms and assessing how these responses are influenced by CPM. Materials and Methods 21 patients with persistent spinal pain syndrome type 2 treated with SCS underwent three sessions (under tonic, burst, and sham SCS) with a one-week interval. Using magnetoencephalography, we measured the cortical responses to painful electrical stimuli before, during, and after CPM. Cortical activity was analyzed in the time domain (evoked response) and time-frequency domain (beta event-related synchronization [ERS]). Results Data from 14 patients qualified for analysis. Before CPM, the lowest amplitude of evoked responses occurred under tonic SCS, followed by sham SCS (p > 0.05). The lowest power of beta ERS occurred under sham SCS (p > 0.05). Pain ratings of the stimuli were statistically significantly reduced during CPM (p < 0.05). The amplitude of evoked responses was statistically significantly reduced in multiple regions during CPM under sham and burst SCS (p < 0.05). The power of beta ERS was reduced during CPM under tonic and burst SCS, whereas no reduction was observed under sham SCS (p > 0.05). Discussion This exploratory study indicates that evoked and induced cortical responses reflect distinct mechanisms during CPM under SCS. Evoked responses, which primarily reflect bottom-up sensory processing, may be reduced by tonic SCS in the ascending lateral pathway areas before CPM. This reduction may suggest that tonic SCS suppresses input of the ascending lateral pathway, limiting additional inhibition by CPM. Beta ERS (induced response), which primarily reflects top-down modulation, decreased during CPM under tonic and burst SCS, suggesting engagement of the descending pain pathway.

Introduction:Herpes zoster (HZ) predominantly affects sensory nerves and can lead to postherpetic neuralgia. A motor deficit in the corresponding myotome is a rare but severe complication. Objectives: The objective of this study was to further characterize patients with HZ-related motor deficits and to explore potential risk factors.Methods:This retrospective cohort study in the tertiary pain clinic of the University Medical Center Utrecht, includes a comparative analysis of patients presenting with and without motor deficit resulting from HZ. Patient characteristics including psychological distress were assessed using standardized questionnaires, and Quantitative Sensory Testing outcomes were analysed between the 2 groups.Results:The study population included 158 patients with postherpetic neuralgia, of whom 17 patients had motor paralysis. In the motor paralysis group, most were male (94.1%). The median pain intensity was NRS 7, similar in both groups. Anxiety, depression, Pain Catastrophizing Scale, and DN4 scores did not differ significantly between groups. Tampa Scale of Kinesiophobia, indicating kinesiophobia did significantly differ between both groups (P = 0.043). Patients with motor deficit showed distinct sensory profiles characterized by sensory loss in 70.6% of patients compared with 35.5% in the group without motor deficit (P = 0.017).Conclusion:Motor deficit may be more common than we realize and is a serious complication of HZ. Patients who experienced motor deficit as a complication of herpes zoster demonstrated more severe nerve damage, with sensory loss being the most frequent sensory phenotype. More awareness is needed for this serious complication accompanied with research guiding treatment and rehabilitation protocols.

BACKGROUND:Given the impact of chronic pain on cognition, CRPS may affect specific cognitive functions. However, cognitive functioning is rarely assessed in CRPS, and previous studies have examined only limited domains. As a result, it remains unclear which cognitive functions are affected and whether impairments are CRPS-specific. This study comprehensively evaluates cognition in CRPS and compares it to carpal tunnel syndrome (CTS) to determine whether cognitive dysfunction is specific to CRPS. METHODS:All patients underwent a standardised cognitive assessment consisting of ten tests, evaluating the domains of memory, concentration, executive functioning, social cognition and performance validity. Standardised z-scores and proportion of low-performing patients (< -1.5 SD from age-, sex- and education adjusted normative data) were examined. Both patient groups were compared with each other and the expected population proportion. RESULTS:Sixty-four patients (n = 39 CRPS and n = 25 CTS) with a mean age of 52.5 (range 20-81) were included. Compared with patients with CTS, patients with CRPS had significantly higher pain scores 24 h before and during the visit (p < 0.001). All cognitive test results were similar between the two groups. Z-scores of both groups were comparable or better than the population norm. Furthermore, proportions of patients with Z-scores below -1.5 SD were similar or better than expected. CONCLUSIONS:Our results consistently showed no cognitive impairment in either patient group. Both groups met or exceeded population norms on all tests. However, despite our clear results, attention should be paid to factors affecting cognition, like depression, anxiety and stress. SIGNIFICANCE STATEMENT:This study explores the underexamined cognitive dysfunction in Complex Regional Pain Syndrome (CRPS). Cognitive issues, often reported by CRPS patients, can add to the burden on daily life and quality of life (QoL) but are rarely assessed. By comparing CRPS with CTS, this research examines whether cognitive impairments are specific to CRPS. Identifying these issues may lead to targeted therapies addressing both pain and cognitive challenges, ultimately improving patient outcomes and QoL.

INTRODUCTION:Cluster headache is a rare primary headache disorder characterized by excruciating unilateral pain around the eye, lasting between 15 and 180 min, accompanied by ipsilateral cranial autonomic symptoms. Cluster headache is classified into two forms: episodic and chronic, with chronic cluster headache defined by pain-free intervals of less than 3 months between bouts. Both drug-based and invasive treatments are available for abortive and preventive purposes. Treatment selection depends on individual efficacy and tolerance, with invasive options considered when pharmacological treatments prove ineffective. METHODS:This narrative review summarizes the literature on common practice and the evidence in the treatment of cluster headache. RESULTS:Oxygen therapy and subcutaneous sumatriptan are the most effective abortive treatments for cluster headache. Oral corticosteroid tapering regimens can be used as bridging therapy. Verapamil, lithium, topiramate, and CGRP antagonists are potential preventive medication options. Greater occipital nerve (GON) injections and radiofrequency (RF) therapy can be used as preventive treatments, though their effects are often temporary. For refractory chronic cluster headache, occipital nerve stimulation (ONS) has proven to be effective. Deep brain stimulation (DBS) may also be considered if all other treatments have failed. CONCLUSIONS:The management of cluster headache is complex due to the variable efficacy of treatments across different patients and limited evidence.

Abstract. High-concentration capsaicin patch (HC capsaicin patch) is a locally acting treatment option for adults with peripheral neuropathic pain (pNeP) of various etiologies. Numerous clinical trials, post hoc analyses, and meta-analyses have investigated the efficacy and tolerability of the HC capsaicin patch. Despite this extensive body of research, a comprehensive narrative review covering publications on different pNeP conditions is lacking. This narrative review aims to fill the gap by analyzing 52 studies, including randomized controlled trials and real-world evidence. The results show that the HC capsaicin patch consistently provides pain relief and improves quality of life for several pNeP conditions, with increasing benefits seen with repeated treatments. It was found to be superior to placebo and comparable to standard care, regardless of the origin of the pain. Early initiation of therapy appears to improve efficacy, although patients with more prolonged pain also benefit. While the exact mechanisms of action are still unclear, there is evidence to suggest a potential benefit from nerve regeneration in some conditions. However, limited information exists regarding the alteration of treatment intervals and the variation in the size of the painful area upon re-treatment. The review also identifies variability in response rates for different types of pNeP and a lack of reliable predictors of treatment success, indicating a need for further research. In conclusion, the HC capsaicin patch is effective and well tolerated across a range of pNeP conditions, with increasing efficacy upon retreatment. It is a valuable treatment option, although more research is needed to refine its clinical use and explore its full therapeutic potential.

Introduction Chronic postsurgical pain (CPSP) represents a widely underdiagnosed and often poorly treated medical problem, affecting 10–50% of all surgical patients, exhibiting neuropathic features in 35–60%. It is hypothesised that surgery-induced tissue damage and the subsequent immune response cause sensory alterations in the early postoperative period, ultimately leading to a chronic neuropathic or nociplastic pain state. The ‘Sensory Changes and Immunological parameters in Postsurgical pain’ study (SCIP-Pain study) was designed to test this hypothesis and identify sensory alterations and changes in the immunological response that are related to the development of CPSP with neuropathic features.Methods and analysis This protocol describes the SCIP-Pain study—an ongoing prospective observational cohort study involving 150 adult patients undergoing elective lower extremity orthopaedic surgery. Study participants complete questionnaires, undergo quantitative sensory testing (QST) and provide blood samples to assess the immunological response at various time points: before surgery, 2 weeks and 3 months after surgery. To reduce dimensionality, cluster analyses will be conducted on QST and immunological parameters. Cluster allocation, along with other preselected candidate predictors, will subsequently be used in a generalised mixed-effects model to predict CPSP with neuropathic features within 3 months after surgery as the primary outcome.Ethics and dissemination This study received approval from the Medical Ethics Committee NedMec (protocol NL77085.041.21), as well as from all participating centres. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences.

OBJECTIVE:Cluster headache (CH) significantly impacts patients' quality of life (QoL). We aim to validate the Cluster Headache Quality of Life scale (CHQ) for measuring QoL changes in patients with CH. METHODS:In this multicenter, prospective, longitudinal psychometric validation study, participants, all with chronic CH (CCH), completed the CHQ at a 3-monthly interval alongside headache diaries and general QoL questionnaires (36-item Short Form [SF-36], Hospital Anxiety and Depression Scale [HADS], and EuroQol 5 Dimensions [EQ-5D]). CHQ's ability to measure changes was validated in three steps following COSMIN guidelines: (1) convergent validity, (2) responsiveness, and (3) interpretability. Baseline scores were used for step 1; change scores for steps 2 and 3 (Δ baseline-follow-up). Twelve correlation hypotheses were formulated and tested for steps 1 and 2. Validity was rated by % rejected hypotheses (high: ≤25%, moderate: 26%-50%, poor: ≥50%). Data were collected in the Netherlands (Leiden, Nijmegen, Heerlen) between 9 December 2021 and 18 November 2024. RESULTS:For step 1, 117 participants were included (n = 70 for SF-36/HADS analyses, n = 42 for EQ-5D analyses) and 82 were included for steps 2 and 3 (n = 48 for SF-36/HADS analyses, n = 29 for EQ-5D analyses). At baseline, overall QoL was poor (CHQ: 60.9 ± 23.1, SF-36: 46.7 ± 19.9) and worse in participants with more intense and frequent CH attacks (>CHQ scores: β = 2.92 (95% confidence interval [CI] 0.91 to 4.93), p = 0.005; β = 0.27 (95% CI 0.02 to 0.53), p = 0.033). Convergent and responsiveness validity was high (≤25% hypotheses rejected). CHQ baseline scores correlated strongly with the HADS, SF-36, and EQ-5D (ρ = 0.68, ρ = -0.60, ρ = -0.52), but weakly with attack frequency (ρ = 0.27). Change scores correlated strongly with HADS and SF-36 (ρ = 0.51, ρ = -0.56) and moderately with EQ-5D (ρ = -0.38). Step 3 indicated ≤ -3.5 points change as clinically relevant improvement and ≥7.5 points as deterioration. CONCLUSION:The CHQ has a high validity to measure change in QoL. CH attack frequency influences QoL, but QoL is more strongly correlated with mental health and activity restrictions than attack frequency. Implementing the CHQ may improve understanding of disease burden, enabling more targeted treatment strategies and thus improving overall disease management.

BACKGROUND CONTEXT: Mechanical Diagnosis and Treatment (MDT) and epidural steroid injections have the potential to reduce pain and disability in sciatica patients and prevent surgery. However, data on their combined influence in reducing the amount of sciatica surgeries is lacking. PURPOSE: To assess if a combination therapy (MDT and TESIs), administered while being on the waiting list for lumbar herniated disc surgery, is effective and cost-effective compared to no intervention (ie, usual care). STUDY DESIGN: Multicentre randomized controlled trial with economic evaluation and 1-year follow-up. PATIENT SAMPLE: Seventy-two adult patients on a waiting list for lumbar herniated disc surgery. OUTCOME MEASURES: Primary outcome was undergoing lumbar disc surgery during followup (yes/no). Secondary outcomes included back and leg pain intensity (NPRS), physical functioning (RMDQ-23), self-perceived recovery (GPE), and health-related quality of life (EQ-5D-5L). Total societal and total healthcare were measured. METHODS: Participants were randomly assigned to combination therapy (intervention group, n=34) or no intervention (control group, n=38). RESULTS: Twenty-nine out of 38 control group patients and 11 out of 34 intervention group patients received surgery. The adjusted odds ratio of receiving surgery in the intervention group compared to the control group was 0.09 (95% CI, 0.02-0.35) and the adjusted risk ratio 0.29 (95% CI, 0.08-0.69). There were no differences in clinical effects between both groups. Surgical, total societal, and total healthcare costs were on average 1,969, 1,754, and 2,363 lower in the intervention group, respectively. The combination therapy's probability of being cost-effective was moderate (<= 0.66) across a range of willingness-to-pay values from 20,000/QALY to 80,000/ QALY, from a societal perspective. CONCLUSION: Patients on the waiting list for lumbar disc surgery and who are open to postpone surgery, may benefit from the combination therapy intervention. (c) 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)