Pain is commonly described in sensory terms, yet its spatial characteristics are rarely quantified. We investigated whether lay beliefs about pain distribution influence theoretical decisions to seek care and treatment preferences. In a cross-sectional survey (N = 503; 49% reporting pain), participants completed thought experiments in which both visually presented pain distribution patterns (small, moderate, or large) and pain intensity (Numerical Rating Scale scores: 2, 5, 8/10) were systematically varied. For each scenario, they rated the likelihood of (1) seeking professional help (LoSH) and (2) taking analgesic medication (LoTM) on 0 to 100 scale. Participants also completed a spatial-intensity trade-off task, in which they chose between a fixed 20% reduction in intensity and variable reductions in pain distribution (20%-80%). A reversed version contrasted a fixed 80% reduction in pain distribution with variable reductions in pain intensity. LoSH and LoTM increased significantly with greater pain distribution (P < 0.001), mirroring the gradient observed for pain intensity. In the spatial-intensity trade-off task, participants' choice followed a sigmoid-like function (P < 0.001): 1% reduction in intensity was treated as equivalent to approximately a 3% reduction in distribution, indicating a systematic valuation of pain distribution. This ratio was lower in individuals experiencing pain compared with pain-free individuals. Moreover, 61% reported that pain distribution should be routinely considered in pain management alongside intensity. Results suggest that pain distribution is not merely a trivial descriptor, but a meaningful determinant of healthcare-related decision-making beliefs. Incorporating spatial metrics into clinical assessment and research may better capture how individuals implicitly evaluate pain severity.

Breakthrough cancer pain episodes often require oral immediate release opioids or parenteral opioid treatment. Different formulations and application modalities have been approved for this condition. This study aimed to identify the most effective of the available substances and applications to treat breakthrough cancer pain. We conducted a comprehensive systematic review with network meta-analysis. The database search included MEDLINE, CENTRAL, Embase, and Web of Science. Eligible were randomized controlled trials comparing opioids and application modalities for the treatment of breakthrough cancer pain episodes. Primary end points were the pain intensity difference (PID) at 15 and 30 minutes. Secondary end points were side effects and adverse events, as well as dichotomous outcomes of treatment success. Frequentist network meta-analysis was conducted using the package netmeta in R. From 5133 records initially identified by the literature review, 23 studies were eligible for quantitative analysis. Compared with placebo, the most effective interventions at 15 minutes (PID) were intravenous or subcutaneous applications of morphine, and intranasal fentanyl or sublingual fentanyl tablets. After 30 minutes (PID), the most effective interventions were still subcutaneous and intravenous morphine, but also sublingual fentanyl tablets. Intranasal fentanyl spray was equally effective as buccal and other transmucosal applications by 30 minutes. The quality of evidence on the topic is poor as most studies are phase III trials for drug approval. The risk of publication bias is therefore high. Sublingual fentanyl tablets were as effective as intravenous or subcutaneous morphine and are a practical modality for self-administration.

Pain is a leading cause of disability worldwide, yet undergraduate medical education remains insufficient to prepare future physicians for its assessment and management. The International Association for the Study of Pain (IASP) has proposed a competency-based curriculum framework; however, its implementation in Brazilian medical education is unclear. The aim of this study was to evaluate the availability of pain education in Brazilian medical schools and assess its alignment with the IASP Curriculum Outline on Pain for Medicine. We conducted a national cross-sectional documentary analysis of all medical schools registered in the Brazilian Ministry of Education database between May 2024 and December 2025. Institutional websites were systematically screened for publicly available curricular documentation, and data were independently extracted by 2 reviewers. Variables included the presence of pain-related content, existence of a dedicated pain course, course workload, timing within the curriculum, and type of offering. Among 447 identified schools, 277 (62.0%) provided accessible curricular information. Only 47 institutions (16.9%) offered a stand-alone pain course, and 29 had detailed syllabi for item-level analysis. Most analyzed courses were mandatory and delivered in the early years of training. Alignment with IASP competencies was incomplete across all domains, with greater coverage of neurobiological and pharmacological content and limited inclusion of pain assessment and measurement, psychosocial and behavioral management, public health, ethics, and care for special populations. Pain education in Brazil is inconsistently structured and only partially aligned with international recommendations, indicating the need of comprehensive, competency-based curricular reform.

Physical disuse is a major risk factor for complex regional pain syndrome type I. Using a rat chronic post-cast pain model, we investigated how oxidative stress modulates pain processing across the neuraxis and evaluated sex as a biological variable. Following immobilization, both sexes developed widespread mechanical hyperalgesia, which was markedly attenuated by the antioxidant Tempol. However, we uncovered a striking phenotypic dissociation: whereas male rats also developed tactile and cold allodynia, female rats completely lacked tactile allodynia. Peripherally, Tempol reduced neurogenic inflammation and suppressed p38 MAPK phosphorylation in peptidergic and nonpeptidergic dorsal root ganglion nociceptors, demonstrating a conserved reactive oxygen species-dependent "hardware" for mechanical pain. Centrally, Tempol inhibited plasticity-related pERK expression in neurokinin1 receptor-positive projection neurons and stimulus-evoked c-Fos in the lumbar (L5) and sacral (S2) dorsal horn. Crucially, the sex-specific behavioral divergence correlated with distinct neuroimmune profiles. Quantitative polymerase chain reaction revealed that while male rats exhibited a robust pro-inflammatory cytokine upregulation (C-C motif chemokine ligand 2, interleukin-1beta, interleukin-6) in the soleus muscle, this inflammatory cascade was markedly blunted in female rats. Consistent with this lack of peripheral inflammatory amplification, optogenetic stimulation of nonnociceptive Aβ fibers failed to induce c-Fos in the female spinal cord and central amygdala-a maladaptive sensory processing shift that Tempol successfully reversed in male rats. These findings demonstrate that disuse-induced oxidative stress initiates sensitization across the neuraxis. Importantly, our study reveals that while reactive oxygen species drives mechanical pain uniformly, the development of tactile allodynia requires a sexually dimorphic inflammatory amplification, underscoring the critical need for personalized, sex-specific therapeutic strategies in pain management.

Alpha-band oscillatory activity, assessed using electroencephalography (EEG), is among the most widely studied neurophysiological markers of pain. However, the literature has focused predominantly on resting-state measures, leaving unclear whether pain also alters evoked alpha-band dynamics, measured via cortical perturbation using transcranial magnetic stimulation (TMS). Here, we examined whether prolonged pain alters TMS-evoked alpha event-related spectral perturbation (ERSP) and intertrial coherence (ITC), reflecting cortical reactivity and phase consistency, and whether 10-Hz repetitive TMS (rTMS) modulates these responses. We performed a secondary analysis on 2 previous experiments, which used nerve growth factor (NGF) injection to induce prolonged elbow muscle pain. In experiment 1, participants underwent primary motor cortex (M1) TMS-EEG at baseline (day 0) pre-NGF injection and day 2 (peak pain) and day 7 (pain resolution) post-injection. In experiment 2, M1-TMS-EEG was assessed on day 0 before NGF injection and again on day 4 after injection, with active or sham 10-Hz rTMS delivered to M1 between these assessments. In experiment 1, M1 TMS-EEG showed reductions in alpha ERSP (P = 0.014) and alpha ITC (P = 0.041) from day 0 to day 2. In experiment 2, active rTMS produced a more positive pre-to-post change in alpha ERSP (P = 0.006) relative to sham but did not alter alpha ITC (P = 0.804). Our findings suggest that prolonged experimental pain is associated with diminished evoked alpha oscillatory activity, whereas high-frequency rTMS modulates this activity in the positive direction. These findings suggest that perturbation-evoked alpha metrics warrant further investigation as candidate biomarkers of pain state and response to neuromodulation.

Pain is not a passive readout of nociceptor traffic; it reflects the brain's inference about bodily threat under uncertainty. Building on predictive processing, active inference, and the free energy principle, we frame acute, chronic, and phantom pain as regimes of hierarchical inference in which memory, affect, and context shift the relative influence of prior beliefs vs incoming nociceptive evidence. Prior work links expectations to pain, but translating these ideas into a clinically usable account that links expectation mechanisms to measurable proxies of belief updating and to principled routes for personalized intervention remains challenging. We propose a generative model that links inferred threat to action policies, so that pain intensity and pain behavior can be studied within the same inferential loop. Within this framework, chronic pain can persist when threat beliefs remain overly influential despite corrective evidence. Placebo/nocebo effects illustrate how shifting expectations can amplify or relieve pain. Phantom pain illustrates how stable body-related beliefs can sustain pain-like perception even with minimal or absent afferent input. We outline candidate measurements and falsifiable predictions by linking expectation- and precision-related effects to a cingulate-insula-centered hub and associated descending control circuitry (periaqueductal gray to spinal dorsal horn). This account suggests principles for selecting and sequencing treatments to target belief content (expectations), evidence (corrective sampling), and gain control (context and neuromodulation), for matching mechanisms to patient-specific phenotypes, and for stratifying patients by dominant mechanism (overly threat-biased beliefs, reduced corrective sampling, or biased precision/gain control) to enable more testable trials and clearer interpretation of treatment response.

Chronic pain affects brain gray matter structure, but the magnitude, pattern, and reversibility of brain changes upon pain recovery remain unclear because of inconsistent findings from small-scale studies. We analyzed data from 35,052 UK Biobank participants who completed chronic pain assessments at 2 time points, approximately 9 years apart, evaluating pain lasting 3 months or more, across 8 body sites. Brain magnetic resonance imaging data were available from the second time point. Participants were grouped into 4 categories: Pain-free controls, New chronic pain, Persistent chronic pain, and Resolved chronic pain. We examined relationships between these categories and 313 brain-wide measures across cortical surface area, cortical thickness, and subcortical volume. New chronic pain was associated with surface area reductions in sensorimotor, temporo-parietal, and medial and lateral prefrontal cortices. Persistent chronic pain showed larger and more widespread area reductions and mixed changes in cortical thickness and subcortical volumes, including cerebellar atrophy and hypertrophy in the thalamus and basal ganglia. Resolved pain demonstrated reversibility of most brain changes, except sustained surface area reductions in the primary somatosensory cortex. No areas showed effects consistent with a predisposition to pain. Brain structural changes in chronic pain reflect adaptive neuroplasticity rather than irreversible damage or preexisting vulnerability. Most changes appear reversible with pain resolution, underscoring the importance of effective pain treatment to alleviate symptoms and support recovery of brain structure and function.

Cannabinoid 1 and 2 receptor (CB1R and CB2R) agonists alleviate inflammatory and neuropathic pain symptoms. However, central nervous system (CNS) side effects mediated by CB1Rs limit their widespread use. We developed peripherally restricted cannabinoids (PRCBs), which exhibit analgesic efficacy with minimal CNS side effects. Here, we examined PRCB actions in a mouse model of dural acid-induced hypersensitivity. Supradural injections of pH-6.0 (but not pH-7.4) saline (4.5 µL) in five-week-old female C57BL/6J mice induced periorbital allodynia (assessed with von Frey filaments) with recovery by 48 hours. By 72 hours, allodynia was elicited with a supradural pH-7.0 saline injection in pH-6.0 (but not pH-7.4) mice. The CB1R/CB2R agonist PRCB, 4-{2-[(1E)-1-[(4-propylnaphthalen-1-yl) methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) (5 µM) or the selective CB1R agonist arachidonyl-2'-chloroethylamide (ACEA, 5 µM), coapplied with pH-6.0 saline, prevented both the initial and latent allodynia, but coadministering pH 6.0 with the CB2R-selective agonist RNB61 (5 µM) did not. Coadministering pH-6.0/PrNMI with CB1R- or CB2R-selective inverse agonists abolished the preventative effects of PrNMI. Supradural pH-6.0 saline-evoked allodynia followed 72 hours later by coadministration of pH 7.0/PrNMI did not prevent latent allodynia. Patch recordings obtained from dural trigeminal ganglion neurons (dTGNs) acutely isolated from FluoroGold/pH-6.0 (but not pH-7.4)-injected mice had larger acid-induced depolarizations. All dTGNs had electrophysiological properties of Aδ- or C-type nociceptors. PrNMI (1 µM) suppressed acid-induced depolarizations in dTGNs from pH-7.4 (but not pH-6.0)-treated mice, whereas RNB61 (0.5 µM) had no effect. These findings indicate that PrNMI prevents acid-induced sensitization by coactivating neuronal CB1Rs and non-neuronal CB2Rs. Cannabinoid 2 receptor activation alone is insufficient, and once sensitized, combined CB1R/CB2R activation loses efficacy.

Identifying the neural correlates of chronic pain and their relationship to clinically relevant measures of disease has proven challenging due to high variability in individual patterns of functional brain connectivity and the rarity of ecologically valid scanning paradigms. Here, we address these limitations using data from the Multidisciplinary Approach to the Study of Pelvic Pain Symptom Patterns Study, which recruited a large sample of urologic chronic pain patients (n = 382) imaged repeatedly (range = 2-4) over 36 months. Intrinsic brain connectivity was recorded before and after a naturalistic challenge designed to elicit symptomatic pain and discomfort. Linear mixed-effects models revealed 2 neuroanatomically distinct patterns: pain at the time of scan was linked to connectivity within sensory-discriminative regions, while past-week recalled pain was associated with distributed patterns across regions implicated in memory, salience, and affective processing. These findings emphasize the dynamic roles of brain regions for different aspects of chronic pain.

Self-reported cognitive difficulties are a common, yet underexplored, complaint of patients with chronic pain (CP). These deficits hinder daily functioning and reduce quality of life, contributing to disability. However, the extent and profile of these impairments remain unclear. Our study synthesized findings from a meta-analysis (Study 1; n = 67 studies, 6,899 patients and controls) with data from the UK Biobank (Study 2; n = 37,139 participants with CP and controls) to ascertain the magnitude and profile of cognitive deficits on performance-based measures in CP sufferers relative to healthy controls. Study 1 considered various factors, including cognitive domains, pain diagnosis and intensity, and psychological variables; Study 2 used a novel predictive model of cognitive age to evaluate cognitive deficits between different pain, neurological, and psychiatric conditions. Results from Study 1 demonstrated moderate cognitive difficulties in CP (g = -0.48 [95% CI -0.52 to -0.43], I2 = 82.03) across pain diagnoses and cognitive domains, and proportional to pain severity and psychological symptoms. Study 2 replicated these findings, though to a lesser magnitude (d = 0.04-0.30). Furthermore, participants with higher pain severity (4+ pain sites) showed an advanced cognitive age pattern. The cognitive difficulties observed among CP participants may be indicative of stress-related advanced cognitive age, resulting from persistent and uncontrollable pain. However, it is important to note that these deficits are small to moderate in severity, and, therefore, the observation of more pronounced impairment in CP warrants further clinical evaluation, particularly if their extent appears disproportionate to pain severity.

Post-traumatic headache (PTH) is the most common consequence of mild traumatic brain injury (mTBI) and often resembles migraine. In 20% to 30% of migraine patients, headaches are preceded by aura, transient visual or sensory disturbances, which are caused by cortical spreading depression (CSD) that can induce headache pain. However, whether mTBI promotes the development of aura and CSD and their possible contributions to PTH remains unclear. We examined the incidence of new-onset aura in individuals with PTH who had no history of aura. Thirty-two percent (35/108) developed new aura symptoms within 60 days of injury, suggesting that mTBI can sensitize the cortex to the induction of CSD. To test this, we combined electrophysiology, neuroimaging, and behavioral assays in a mouse model of mTBI-induced PTH. After closed-head mTBI, injured mice exhibited a 160% increase in CSD induction probability (ie, lowered threshold) and became sensitized to CSD induction by brief exposure to stress, a common headache trigger. When evoked optogenetically, CSD produced prolonged periorbital and hind paw allodynia, consistent with headache-like pain. Subcutaneous onabotulinumtoxinA administered to the scalp after mTBI did not alter CSD susceptibility but completely abolished optogenetic CSD-induced allodynia. These findings suggest that mTBI elicits sensitization to CSD induction and promotes the emergence of aura in humans, likely contributing to PTH. It is important that, even after mTBI-induced sensitization, onabotulinumtoxinA decoupled CSD from pain behaviors, suggesting efficacy in treating PTH associated with aura.

Chronic pain after traumatic injury likely reflects interacting processes rather than isolated recovery pathways, yet longitudinal evidence examining the joint development of pain, sleep disturbance, and hyperarousal from the acute postinjury stage is limited. We analysed data from the AURORA cohort of emergency department trauma survivors recruited within 72 hours of injury (n = 2834) to characterise trajectories of pain, sleep discontinuity, and hyperarousal over 12 months, identify shared multitrajectory profiles, and examine factors associated with adverse outcomes. Smartphone-based surveys assessed symptoms repeatedly from 1 to 5 days postinjury to one year. Group-based trajectory modelling identified 5 pain (n = 1635), 6 sleep discontinuity (n = 1635), and 5 hyperarousal (n = 1820) trajectories, ranging from rapid recovery to persistent high symptoms. Persistent high pain occurred in 35.1% of participants, while 23.5% followed persistently high or worsening sleep trajectories and 27.2% followed high hyperarousal trajectories. Multitrajectory modelling (n = 1800) identified 6 joint profiles, with 10.6% experiencing persistently high symptoms across all domains and 25.7% showing medium symptom levels. Older age and higher pretrauma pain were associated with adverse trajectories, whereas resilience and better prior mental health were protective. Baseline sleep discontinuity showed the strongest association with persistent high pain (adjusted odds ratio 3.31; 95% confidence interval 2.61-4.18), while physical activity was associated with a lower likelihood of medium-to-high pain trajectories. Female sex and lower income were associated with the most adverse multidomain profile. These findings highlight early postinjury sleep disruption, hyperarousal, and pain as interconnected processes. Targeting multiple domains may offer a promising strategy to prevent chronic pain after injury.