Abstract 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.
Abstract Neuropathic pain arises from dysfunction of the peripheral or central nervous system and affects up to 10% of the population worldwide. Aberrant activity in injured sensory nerve fibers, particularly spontaneous firing and altered conduction properties of nociceptors, is tightly linked to pain, yet its molecular underpinnings in humans have long remained elusive. Over recent years, major technological advances have transformed both functional and molecular analyses of sensory neurons. High-resolution single-cell and spatial transcriptomics have produced detailed atlases of sensory neuron diversity, while traditional electrophysiological approaches such as patch-clamp and microneurography have provided unparalleled insight into nerve fiber properties. Despite their individual strengths, molecular and functional classifications of sensory neurons have largely evolved in parallel. This review focuses on emerging strategies that bridge these approaches to achieve an integrated, mechanistic understanding of neuropathic pain. We discuss how microneurography-defined biophysical hallmarks, such as activity-dependent slowing, recovery cycle signatures, and following frequency, can be transferred into in vitro patch-clamp paradigms, enabling direct functional comparison with dissociated human and large-animal sensory neurons. The incorporation of Patch-seq approaches has further enabled the assignment of molecular identity to functionally defined nociceptor subtypes, exemplified by the characterization of the mechano-insensitive “sleeping” nociceptors. Finally, we highlight how multimodal datasets combining electrophysiology, transcriptomics, and computational modeling provide new opportunities to unravel the ion channel mechanisms, particularly sodium channel subtypes, that shape pathological firing states. By directly linking human nerve fiber function to molecular programs, this integrative framework paves the way toward stratified, mechanism-based therapies for neuropathic pain.
Abstract Pharmacotherapy remains an important component of multidisciplinary, multimodal pain treatment. Based on a well-established understanding of multiple concurrent mechanisms of nociceptive transmission and modulation, the demonstrated potential for synergistic interactions of drug combinations seen in preclinical studies supports the hypothesis of superior analgesia, and possibly also, fewer side-effects as compared with monotherapy. Likely related to this hypothesis and rationale, real-world evidence shows that approximately half of all patients with chronic pain, and even more with acute pain, concurrently receive 2 or more drugs from different mechanistic classes. To date, many dozens of randomized controlled trials have evaluated various analgesic combinations for the treatment of postoperative, neuropathic, back, arthritis, fibromyalgia, pelvic, and cancer-related pain conditions. Despite this growing area of research, most analgesic drug combinations are currently administered without rigorous evidence, thus exposing patients to the added cost or risk of some combinations that are not necessarily superior to monotherapy. As such, we propose future efforts to more efficiently exploit the potential benefits of combination therapy including: (1) expansion and coordination of translational collaborations to prioritize the most beneficial and clinically relevant combinations; (2) ensuring that preclinical combination studies evaluate multiple drug dosages and multiple relevant adverse effects; (3) ensuring that clinical trials include comparisons with each and every monotherapy component of the combination; (4) conducting further real-world studies of clinically beneficial combinations to ensure safety and efficacy in broader clinical settings; and (5) the application of these principles also to the evaluation of nonpharmacological treatment combinations.
Abstract Pediatric pain science is at an inflection point. Advances in neuroscience, behavioral science, digital health technologies, and patient engagement are rapidly expanding how chronic pain in youth can be understood, measured, and treated. Yet despite these advances, many children and adolescents continue to experience persistent pain-related disability and limited access to effective care, reflecting a gap between scientific discovery and real-world clinical practice. In this perspective, we propose the BRIDGE framework (Biobehavioral Research Integrated with Digital Monitoring and Guided Engagement) as a model for advancing pediatric pain research and care. Mechanistic science is increasingly identifying neural, behavioral, and contextual processes that contribute to pain persistence and recovery, creating opportunities to target modifiable mechanisms underlying pain-related disability. At the same time, digital health technologies including wearable sensors and ecological momentary assessment enable continuous measurement of activity, physiology, and patient-reported experiences in daily life, offering new insights into the dynamic nature of pain and the potential to develop digital biomarkers of risk, recovery, and treatment response. Central to this framework is meaningful partnership with youth and families, ensuring that innovations in measurement and intervention remain aligned with patient priorities and lived experience. Integrating these domains can support precision behavioral interventions, adaptive treatment strategies, and scalable models of care that expand access to evidence-based pediatric pain treatment.
Abstract I am deeply honored to receive the 2026 John Bonica Prize for distinguished lifetime achievement in the basic science of pain. Reflecting on 40 years of research, this review paper will summarize my key findings to date. For the past four decades, my research has focused on elucidating the molecular mechanisms of pain using animal models. By integrating morphological techniques with molecular biology, behavioral analysis, and electrophysiological recordings, I have sought to clarify how pain signals are modulated and sustained under chronic pain conditions. Since the early stages of my career, I have been particularly interested in the diverse molecular dynamics within pain pathways and their functional significance. This long-term research has been driven by the conviction that a detailed analysis of gene expression changes within pain pathways—particularly those associated with neuroplasticity—is essential to understanding the mechanisms underlying intractable pain. This review provides a comprehensive overview of our investigation into the molecular and cellular mechanisms of chronic pain, focusing on gene expression analyses related mainly to dorsal root ganglion and spinal cord plasticity, alongside historically significant contributions from the global pain research community. Finally, I will also discuss recent methodological advances and their applications, as well as the challenges and future directions facing basic pain research.
