A number of neuropeptides including pituitary adenylate cyclase-activating polypeptide (PACAP) play an important role in the pathophysiology of migraine. Infusions of PACAP in patients with migraine can provoked migraine attacks. A placebo-controlled study with a monoclonal antibody directed against the PACAP-receptor failed to show efficacy. In a small, short, proof of concept study a monoclonal antibody directed against PACAP (Lu AG09222) showed efficacy in the reduction of monthly migraine days compared to placebo, but failed for the endpoint 50%-reduction in migraine days. The ongoing PROCEED-study is a double-blind, placebo-controlled, dose-finding study investigating four different doses of Lu AG09222 vs placebo for migraine prevention is expected to complete in the second half of 2025.

Chronic pain affects more than 50 million Americans, with women disproportionately affected by severe pain, pain interference, and overall disability. The development of chronic pain is multifactorial and often begins with an incident of acute pain associated with an injury or a surgical procedure that transitions to persistent pain lasting for months or years. Despite this, there are limited clinical studies investigating sex differences in predictors and biomarkers for the transition to chronic pain. Several preclinical animal models have been developed to gain a better understanding of the mechanisms for the transition to chronic pain, and several sex-specific mechanisms have been identified across multiple systems. These preclinical models generally involve a multiple-insult approach, in which a priming insult enhances sensitivity to a subsequent induction stimulus. There is emerging evidence from preclinical research for several male-specific and female-specific mechanisms, as well as several studies showing shared mechanisms. Here, we review the clinical and preclinical literature covering sex differences in the periphery and immune system, the central nervous system, and the endocrine system related to the transition to chronic pain. We further highlight gaps in the literature and provide recommendations for future research to understand sex-specific differences in the transition to chronic pain.

Acute pain management has historically been dominated by opioids, whose efficacy is overshadowed by the risks of addiction, tolerance, and dependence, culminating in the global opioid crisis. To transcend this issue, we must innovate beyond opioid-based μ receptor treatments, identifying nonopioid analgesics with high efficacy and minimal adverse effects. This Review navigates the multifaceted landscape of inflammatory, neuropathic, and nociplastic pain, emphasizing mechanism-based analgesic targets tailored to specific pain conditions. We delve into the challenges and breakthroughs in clinical trials targeting ion channels, GPCRs, and other molecular targets. We also highlight the intricate crosstalk between different physiological systems and the need for multimodal interventions with distinct pharmacodynamics to manage acute and chronic pain, respectively. Furthermore, we explore emerging strategies, including gene therapy, stem cell therapy, cell type-specific neuromodulation, and AI-driven techniques for objective, unbiased pain assessment and research. These innovative approaches are poised to revolutionize pain management, paving the way for the discovery of safer and more effective analgesics.

Polyneuropathy remains a diagnostic and clinical challenge, with limited understanding of the mechanisms underlying painful and nonpainful phenotypes. While previous studies have examined various characteristics of these patients, the temporal and spatial dynamics of endogenous pain modulation remains not fully elucidated. In this study, offset analgesia (OA) and spatial summation of pain (SSp) were used as measures of pain modulation in individuals with distal symmetric polyneuropathy, stratified by the presence (n = 30) or absence of pain (n = 30), and compared with healthy controls (n = 30). All participants underwent quantitative sensory testing and assessments of OA and SSp using a thermal stimulator applied to the dorsum of the foot. Patients with painful polyneuropathy exhibited enhanced SSp compared with the pain-free polyneuropathy group and healthy controls (P < 0.05), and impaired OA compared with healthy controls (P < 0.05). The pain-free neuropathy group showed less efficient OA and a slightly enhanced SSp, but this finding did not reach significance. The data suggest that changes in spatial summation were primarily driven by heightened pain responses to nociceptive input from smaller areas, rather than larger ones. Notably, spatial summation and the effects of OA were found to be correlated, irrespective of pain diagnosis. These findings underscore specific impairments in endogenous pain modulation in individuals with painful neuropathy, thus advancing our understanding of its pathophysiological mechanisms. They further highlight the differential roles of spatial and temporal dynamics in pain modulation across various neuropathic populations, offering promising avenues for improved diagnostics and prognostics related to polyneuropathy-associated pain.

Nav1.8 voltage-gated sodium channels are strongly expressed in human primary pain-sensing neurons (nociceptors) and a selective Nav1.8 inhibitor VX-548 (suzetrigine) has shown efficacy for treating acute pain in clinical trials. Nociceptors also express other sodium channels, notably Nav1.7, raising the question of how effectively excitability of the neurons is reduced by inhibition of Nav1.8 channels alone. We used VX-548 to explore this question, recording from dissociated human dorsal root ganglion neurons at 37 °C. Applying VX-548 at 10 nM (about 25 times the IC determined using cloned human Nav1.8 channels at 37 °C) had only small effects on action potential threshold and upstroke velocity but substantially reduced the peak and shoulder. Counterintuitively, VX-548 shortened the refractory period-likely reflecting reduced potassium channel activation by the smaller, narrower action potential-sometimes resulting in faster firing. Generally, repetitive firing during depolarizations was diminished but not eliminated by VX-548. Voltage clamp analysis suggested two reasons that repetitive firing often remains in 10 to 100 nM VX-548. First, many neurons had such large Nav1.8 currents that even 99% inhibition leaves nA-level Nav1.8 current that could help drive repetitive firing. Second, Nav1.7 current dominated during initial spikes and could also contribute to repetitive firing. The ability of human neurons to fire repetitively even with >99% inhibition of Nav1.8 channels may help explain the incomplete analgesia produced by even the largest concentrations of VX-548 in clinical studies.

Emotional responses to sensory experience are central to the human condition in health and disease. We hypothesized that principles governing the emergence of emotion from sensation might be discoverable through their conservation across the mammalian lineage. We therefore designed a cross-species neural activity screen, applicable to humans and mice, combining precise affective behavioral measurements, clinical medication administration, and brain-wide intracranial electrophysiology. This screen revealed conserved biphasic dynamics in which emotionally salient sensory signals are swiftly broadcast throughout the brain and followed by a characteristic persistent activity pattern. Medication-based interventions that selectively blocked persistent dynamics while preserving fast broadcast selectively inhibited emotional responses in humans and mice. Mammalian emotion appears to emerge as a specifically distributed neural context, driven by persistent dynamics and shaped by a global intrinsic timescale.

Tumor necrosis factor receptor 2 (TNFR2) activation is a promising-therapeutic strategy for autoimmune disorders such as multiple sclerosis (MS) and chronic neuropathic pain (CNP). This study aimed to identify mechanisms governing the sex-specific efficacy of TNFR2 activation on abrogating pain and motor disease severity in mice experiencing experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We find that the XX sex-chromosome complement is indispensable for TNFR2-mediated attenuation of EAE-associated motor disease. Mice with XY chromosomes experienced exacerbated motor disease severity, associated with an elevated magnitude of neurodegeneration and demyelination. Contrasting this, we show that TNFR2-mediated alleviation of EAE induced CNP is both sex and sex-chromosome independent. However, the alleviation of CNP following TNFR2 activation across two different neuropathic pain models (EAE and chronic constriction injury) was dependent on the gonadal hormone Activin-A. This suggests a shared mechanism through which gonadal-derived factors impact TNFR2-mediated pain relief, independent of sex hormones. These findings highlight the importance of considering sex chromosomes and sex-independent gonadal hormones in evaluating potential sex-specific differences in drug efficacy during therapeutic development.

Activation of spinal microglia following peripheral nerve injury is a central component of neuropathic pain pathology. While the contributions of microglia-mediated immune and neurotrophic signalling have been well-characterized, the phagocytic and synaptic pruning roles of microglia in neuropathic pain remain less understood. Here, we show that peripheral nerve injury induces microglial engulfment of dorsal horn synapses, leading to a preferential loss of inhibitory synapses and a shift in the balance between inhibitory and excitatory synapse density. This synapse removal is dependent on the microglial complement-mediated synapse pruning pathway, as mice deficient in complement C3 and C4 do not exhibit synapse elimination. Furthermore, pharmacological inhibition of the complement protein C1q prevents dorsal horn inhibitory synapse loss and attenuates neuropathic pain. Therefore, these results demonstrate that the complement pathway promotes persistent pain hypersensitivity via microglia-mediated engulfment of dorsal horn synapses in the spinal cord, revealing C1q as a therapeutic target in neuropathic pain.

One in five of the population lives with chronic pain. Psychological interventions for pain reveal core principles that can be used to create opportunities for chronic pain self-management in primary practice, across health-care settings, and at home. We highlight the different types of chronic pain and illustrate the psychoneurobiological mechanisms involved. We review core principles for psychological pain management, evaluate the evidence, and illustrate the underlying neurobiology involved. We provide practical advice for how to facilitate pain self-management in clinical practice. Finally, we discuss scientific caveats and practical obstacles to improvement, suggesting possible pathways to implementation.

The peripheral nervous system (PNS) plays a critical role in pathological conditions, including chronic pain disorders, that manifest differently in men and women. To investigate this sexual dimorphism at the molecular level, we integrated quantitative proteomic profiling of human dorsal root ganglia (hDRG) and peripheral nerve tissue into the expanding omics framework of the PNS. Using data-independent acquisition (DIA) mass spectrometry, we characterized a comprehensive proteomic profile, validating tissue-specific differences between the hDRG and peripheral nerve. Through multi-omic analyses and in vitro functional assays, we identified sex-specific molecular differences, with TNFα signalling emerging as a key sexually dimorphic pathway with higher prominence in men. Genetic evidence from genome-wide association studies further supports the functional relevance of TNFα signalling in the periphery, while clinical trial data and meta-analyses indicate a sex-dependent response to TNFα inhibitors. Collectively, these findings underscore a functionally sexual dimorphism in the PNS, with direct implications for sensory and pain-related clinical translation.