Daniel Segelcke

Trustworthy pain research is essential for developing a deeper understanding of the phenomena, how it is experienced, its many impacts and how it might be reduced, prevented or managed to improve the lives of those who live with pain. Recognising multiple critical challenges that undermine trust in health research, an international, interdisciplinary network was convened to create an integrated framework for enhancing the trustworthiness of research in pain. The ENTRUST-PE framework was launched in 2024 with a call to action, proposing that trustworthiness in pain research is multidimensional and underpinned by 7 Core Values: Integrity and Governance; Equity, Diversity and Inclusivity; Patient and Public Involvement and Engagement; Methodological Rigour; Openness and Transparency; Balanced Communication and Data Authenticity. The framework includes specific recommendations for a range of interest holders and resources to support those recommendations. In this paper, we summarise the framework, reflect on the response to the framework from the pain research community, consider challenges and opportunities in the evolving research landscape and suggest how we might move towards deeper implementation to enhance the trustworthiness of pain research.

Postoperative pain is common and has substantial clinical consequences for patients, their families, and society. Acute pain is not the only problem: a meaningful subset of patients develops chronic postsurgical pain, which is associated with considerable functional and psychosocial burden. Because established chronic postsurgical pain is difficult to treat, prevention is a key clinical objective, but it depends on the early identification of vulnerable patients and timely mechanism-informed interventions. This review examines mechanisms of postsurgical pain, as well as the prediction and prevention of unfavorable outcomes, from a translational perspective that integrates clinical evidence with mechanistic insights from preclinical models. After briefly summarizing recent developments, we outline current challenges and argue that progress requires alignment of outcome constructs across species, rigorous selection and reporting of experimental models, and identification of shared intermediate phenotypes linking mechanisms to patient trajectories. We then summarize the perioperative risk architecture underlying the transition from acute to chronic postsurgical pain, focusing on bio-psycho-social patient-related and surgical factors. Because current risk assessment tools do not yet provide sufficiently precise, reliable, and generalizable prediction, we discuss emerging evidence, including biological signatures that may refine prediction and risk stratification. We further argue that risk emerges dynamically through interactions across pre-, intra- and postsurgical phases. Building on this multi-stage, interactive framework, we propose a strategy integrating bio-psycho-social factors into clinically relevant prognostic models. Finally, we outline how this may not only help identify patients at risk, but also support mechanism-based, personalized prevention in vulnerable patients.

Systematic literature reviews (SLR) require labor-intensive data extraction, limiting the scalability of evidence synthesis. We evaluated an auditable large language model (LLM)- pipeline against the archived outputs of a published preclinical SLR. Title-and-abstract screening was assessed across 6,474 records, and full-text extraction across 674 studies, 47 questions, 110 fields, and 74,140 data points. Human–LLM agreement was 94.2% for screening and 89.4% for extraction. After blinded expert adjudication of all 7,835 extraction disagreements, estimated LLM correctness was 93.9%, with experts favoring the LLM in 42.4% of conflicts. Performance varied strongly by answer type: free-text and multi-select fields reached 99.0% estimated correctness, whereas yes/no fields reached 76.9%, largely because the model struggled with absent or unreported information from primary literature source. These findings support LLMs as auditable second readers for evidence synthesis, with human oversight targeted to predictable failure modes.

Introduction: Postoperative pain is common, with approximately one-third of surgical patients experiencing severe acute pain and 10–20% developing chronic post-surgical pain (CPSP). Evidence shows that female patients are at higher risk of pain after sex non-specific surgery, thus sex- or gender-specific differences in pain treatment efficacy with potential consequences for perioperative pain management are to be expected. Considering the clinical and societal burden of poorly managed postoperative pain, the GEPard project comprises two systematic reviews, GEPard 1: sex- and/or gender-specific differences in efficacy of perioperative pain management for certain (major) surgical procedures in adult patients; and GEPard 2: sex- and/or gender-specific differences in the dosing, efficacy and adverse effects of the most common systemic perioperative non-opioid- and co-analgesics across all sex non-specific surgical procedures in adult patients. Methods and analysis: The reviews will be conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook. MEDLINE, Embase, Cochrane Library, Web of Science, Scopus, ClinicalTrials.gov and PsycINFO will be searched. We will include randomised controlled trials (RCTs) and systematic reviews/meta-analyses reporting outcomes disaggregated by sex and/or gender in adult surgical patients. For GEPard 1, this applies to selected major surgical procedures; for GEPard 2, to all non-sex-specific surgical procedures. Interventions include regional anaesthesia, systemic analgesics and psychological strategies for GEPard 1 and non-opioid- as well as co-analgesics for GEPard 2. Two reviewers will independently screen and extract the data. Cochrane Risk of Bias Tool 2.0 (RoB 2) and AMSTAR 2 tools will assess study quality. Random-effects or Bayesian meta-analyses will be performed where possible; otherwise, narrative synthesis will be applied. GRADE methodology will assess evidence certainty. Ethics and dissemination: No ethical approval is required for these reviews. Findings will be disseminated via peer-reviewed publications, patient organisations and professional societies. Data will be shared via Zenodo or Open Science Framework (OSF), following FAIR principles. PROSPERO registration number: The systematic review protocols for both reviews have been registered in PROSPERO on 29 August 2025 (Registration-ID: CRD420251121393 (GEPard1), CRD420251121536 (GEPard2).

Background: Peripheral neuropathies (PNP) cause a wide range of symptoms of which pruritus and pain are a major burden to patients. Clarifying their mechanisms will facilitate the adequate symptom management. In contrast to neuropathic pain, neuropathic pruritus has long been understudied. We investigate inhibitory pruritus mechanisms in patients with PNP. Methods: A total of 39 participants (median age: 57 years [27–81], 25♀/14♂), including 16 patients with PNP and pruritus (PNP _PRU ) and 8 with PNP but without pruritus (PNP _NO‐PRU ), and 15 controls, were enrolled and phenotyped using dynamic and static quantitative sensory testing, determination of intradermal nerve fibre density, and conditioned pain (CPM) and itch (CIM) modulation. For CIM, an electrically induced itch test stimulus (TS) was applied with an individual itch intensity of > 30 NRS (0–100). A cold‐water bath (contralateral side) served as the conditioning stimulus (CS). Itch, pain intensity and the desire to scratch upon TS were rated before, during and after the CS was applied. Results: Using our novel CIM protocol, well‐controlled and stable itch was electrically induced in controls and in both PNP groups, regardless of whether or not pruritus was a symptom. Concomitant painful cold stimuli reduced electrically induced itch in all three groups to a similar degree. However, PNP _PRU patients had significantly shorter itch inhibition (CIM effects) compared to controls and PNP _NO‐PRU , whereas CPM effects were not different between groups. Conclusions: The results show reduced endogenous itch inhibition in patients with chronic itch, which represents a possible mechanism of chronic pruritus in PNP. Significance Statement: Reduced itch inhibition is associated with the symptom of chronic pruritus in PNP patients, suggesting that reduced descending itch inhibition may facilitate chronic itch in peripheral neuropathy.