Chronic pain is linked to accelerated brain aging, often measured through the brain-age gap (BAG), the difference between chronological age and neuroimaging-derived brain age. Whether endogenous pain modulation declines with brain aging remains unknown. We tested this in participants with temporomandibular disorder (TMD) in a cross-sectional study with 84 TMD participants and 84 age- and sex-matched healthy controls (HCs) from the Cambridge Centre for Ageing and Neuroscience database. Temporomandibular disorder participants completed the Graded Chronic Pain Scale and a placebo procedure combining verbal suggestion and classical conditioning. We estimated brain age using machine-learning and deep-learning approaches: a previously published Gaussian process regression (GPR) model trained on cortical thickness features, and a convolutional neural network (CNN) trained end-to-end on T1-weighted volumes. The brain-age gap was calculated as the difference between the estimated brain age and chronological age. Using both GPR and CNN models, we found that TMD participants exhibited an older estimated brain age compared with HCs. Higher estimated brain age was associated with greater pain severity and statistically mediated the link between chronological age and pain severity. In addition, the CNN model suggested that older brain age was associated with greater pain interference and a higher likelihood of experiencing high-impact pain, controlling for sex and race. However, neither estimated brain age nor BAG influenced the magnitude of placebo effects. These findings suggest that while older brain age is associated with greater chronic pain severity and interference, placebo effects remain robust despite age-related changes in the brain, highlighting the therapeutic potential of placebo effects for older adults living with chronic pain.

Osteoarthritis, especially knee osteoarthritis, is a leading cause of disability and reduced quality of life. The etiology of pain in osteoarthritis is multifactorial, and one promising potential treatment approach involves targeting chemokine systems. The present study was a phase 2, multisite, multiperiod randomized crossover trial of CNTX-6970, a small molecule and selective oral cytokine chemokine receptor type 2 (CCR2) and CCR5 antagonist, in patients with painful knee osteoarthritis (OA). It represents the first trial performed within the National Institutes of Health's Early Phase Pain Investigation Clinical Network. The primary objectives were to evaluate the safety and efficacy of CNTX-6970, relative to placebo, for the treatment of moderate to severe pain related to knee OA. A total of 55 participants were randomized in this multiperiod crossover trial. Linear mixed effects models revealed no significant pain-related benefits of active medication; indeed, trial participants reported slightly higher knee pain intensity when taking the novel chemokine antagonist CNTX-6970 than when taking placebo. In addition, biomarker analysis revealed notably higher level of serum monocyte chemoattractant protein 1 levels when patients were on CNTX-6970 compared to placebo. Overall, although CNTX-6970 was safe and relatively well-tolerated, pharmacologic blockade of specific chemokine receptors with this compound was not effective in reducing moderate-to-severe knee osteoarthritis pain.

Patterns of sensory involvement in diabetic neuropathy vary between studies and diagnostic approaches. Although some report early thermal deficits, others find predominant large-fiber changes, and hypersensitivity in early disease is inconsistently observed. Elevated heat pain thresholds (HPTs) may indicate either selective loss of heat transduction or advanced peripheral denervation of polymodal nociceptors. We examined whether thermal and mechanical pain functions align with psychophysical axonal excitability by combining German Research Network on Neuropathic Pain-quantitative sensory testing with slow depolarizing transdermal electrical stimulation of polymodal C-fibers in 66 adults with diabetes mellitus. Neuropathy was assessed by Toronto Consensus Criteria, quantitative sensory testing (QST), questionnaires, and serum neurofilament light chain (NfL) as a marker of axonal damage. Mechanical pain sensitivity correlated with electrically evoked pain (r ≈ 0.60-0.62, both P < 0.0001), consistent with parallel changes in mechanical transduction and axonal excitability, whereas HPT did not correlate with electrical pain. Many individuals with elevated HPT still exhibited strong electrically evoked pain responses, suggesting impaired heat transduction despite preserved superficial axonal excitability. Participants with sensory loss in QST showed reduced sensitivity to electrical stimuli and higher detection and pain thresholds, consistent with more advanced afferent dysfunction. NfL levels generally correlated with sensory impairment, although at low electrical intensities, higher NfL values were associated with stronger pain ratings, indicating intensity-dependent links between axonal pathology and nociceptor hyperexcitability. Combining QST with C-fiber-targeted electrical testing refines phenotyping of small-fiber dysfunction in diabetic neuropathy by revealing dissociation between thermal and electrical pain modalities and capturing the heterogeneous course from preserved function to selective thermal hypoalgesia and eventual sensory loss.

Many patients with chronic noncancer pain (CNCP) are prescribed opioid medication. However, concerns have been raised about the use of high opioid doses and the misuse of opioids in these patients. Research is needed to better understand the factors that influence day-to-day opioid intake patterns and opioid misuse behaviors in patients with CNCP. The first objective of this study was to examine the contribution of pain intensity, psychological factors, and physical dependence symptoms to daily opioid craving and opioid intake in patients with CNCP. The contribution of these factors to opioid misuse was also examined. In this ecological momentary assessment study, patients with CNCP prescribed short-acting opioids completed diaries, in between opioid doses, for 10 consecutive days. Diaries assessed a host of pain, psychological, and opioid-related variables. Diaries also assessed total daily morphine equivalent doses (MED) used by patients. Multilevel analyses indicated that intra-day increases in pain intensity, negative affect, catastrophizing, and withdrawal symptoms were associated with higher opioid craving (all P 's < 0.05). Day-to-day increases in pain intensity, catastrophizing, and craving were associated with greater opioid intake (ie, MED) (all P 's < 0.05). Patients' daily opioid craving contributed to daily opioid misuse even after accounting for other daily variables ( P < 0.05). Our findings provide new insights into the factors contributing to daily opioid craving, opioid intake, and opioid misuse among patients with CNCP. Interventions targeting these factors could potentially prevent opioid dose escalations and opioid-related harms among those maintained on opioid therapy.

Mechanotransduction is vital for sensing various mechanical stimuli, including blunt force and dynamic light touch. The sensation of a punctate mechanical force is very different from that of a brush swept across the skin, yet both involve mechanical stimulation of the skin and embedded sensory afferent endings. However, the sensory neuron mechanisms contributing to punctate vs light touch somatosensation, and how they might become dysregulated in nerve injury to cause pain, remain unclear. Here, we use mice with sensory neuron-specific PIEZO1 deletion to demonstrate sensory neuron PIEZO1 is required for dynamic light mechanical touch, and possibly punctate mechanical force, in healthy animals. These mice are also protected from acute and chronic tibial spared nerve injury-induced dynamic light touch hypersensitivity. However, dorsal root ganglia neurons from uninjured mice with sensory neuron PIEZO1 deletion displayed evidence of developmental compensation, including sensitized mechanically evoked inward currents. Dorsal root ganglia from these mice also exhibit transcriptional and functional compensation of other ion channels, including PIEZO2, TRPV1, and TRPV4. Thus, the behavioral phenotype of mice with sensory neuron-specific PIEZO1 knockout likely reflects these and possibly other forms of genetic compensation resulting from PIEZO1 absence throughout development, in addition to functional sensory neuron PIEZO1 deletion. Research using this transgenic mouse model must account for these caveats to facilitate accurate data interpretation. Furthermore, this article serves as a call for researchers to critically investigate possible genetic compensation in their mice. Such scrutiny is crucial to prevent replication crises and for advancement of scientific knowledge more broadly.

Chemotherapy-induced peripheral neuropathy accompanied by neuropathic pain (CIPN) is a major neurotoxicity of cisplatin, a platinum-based drug widely used for lung, ovarian, and testicular cancer treatment. Chemotherapy-induced peripheral neuropathy accompanied by neuropathic pain causes drug discontinuation and severely affects life quality with no FDA-approved interventions. We previously reported that platinum-based drugs increase levels of sphingosine 1-phosphate (S1P) in the spinal cord and drive CIPN through activating the S1P receptor subtype 1 (S1PR1). However, the mechanisms engaged downstream of S1PR1 remain poorly understood. Using single-cell transcriptomics on male mouse spinal cord, our findings uncovered subpopulation-specific responses to cisplatin associated with CIPN. Particularly, cisplatin increased the proportion of astrocytes with high expression levels of S1pr1 ( S1pr1high astrocytes), specific to which a Wnt signaling pathway was identified. To this end, several genes involved in Wnt signaling, such as the fibroblast growth factor receptor 3 gene ( Fgfr3 ), were highly expressed in S1pr1high astrocytes. The functional S1PR1 antagonist, ozanimod, prevented cisplatin-induced neuropathic pain and astrocytic upregulation of the Wnt signaling pathway genes. Fibroblast growth factor receptor 3 gene belongs to the FGF/FGFR family which often signals to activate Wnt signaling. Intrathecal injection of the FGFR3 antagonist, PD173074, prevented the development of CIPN in male mice. These data not only highlight FGFR3 as one of the astrocytic targets of S1PR1 but raise the possibility that S1PR1-induced engagement of Wnt signaling in S1pr1high astrocytes may contribute to CIPN. Overall, our results provide a comprehensive mapping of cellular and molecular changes engaged in cisplatin-induced neuropathic pain and decipher novel S1PR1-based mechanisms of action.

Pain and suffering are important to patients, and therefore, their interaction is central to clinical care. It also encompasses issues at the forefront of pain neuroscience, evolution, epidemiology, and treatment development. While Medieval Europe understood pain as a religious problem and Enlightenment theorists framed pain as a social problem, over the past 200 years, we have come to see pain as a medical problem. The medical problem of pain was originally addressed through the diagnosis and treatment of disease, but Pain Medicine has made the causation and treatment of pain a separate focus for research and clinical care. Palliative care reintroduced attention to suffering into the modern hospital. Eric Cassell argued that suffering arises from threats to the person that go beyond threats to the body. His theory of suffering has been criticized for being too focused on patients' narrative and too tied to a nociception-centered notion of pain. In general, modern medicine has promoted a unidirectional linear model of pain causing suffering in the individual patient. However, this model is not consistent with the latest pain neuroscience and is no longer adequate to guide research or clinical care. If we are to finally overcome dualism in pain theory and practice, we must begin by seeing the relationship between pain and suffering as circular rather than linear. Understanding pain and suffering as a unitary construct can advance pain research and clinical practice by providing a new framework for integrating biological, psychological, and social strategies for treating and preventing pain.

Widespread misuse of prescription opioids has resulted in large numbers of opioid-related overdose deaths. It is critical to have a better understanding of the temporal patterns of opioid prescribing practices and associated clinical scenarios. We examined opioid prescription trends over 7 years in a large medical system using electronic health record data. Between 2017 and 2023, we identified 1,019,706 patients from 13 hospitals within a large health system in the northeastern United States, who had at least 1 opioid prescription. In total, there were 3,877,281 associated encounters with 18,225 prescribers. We examined the overall monthly opioid prescription rates and observed an average decrease during the 84 months of study period and discovered 4 distinct stages. A decrease was seen between January 2017 and January 2020 (monthly rate change: -0.70%, 95% CI: -0.89% to -0.41%), followed by a sharp decrease and a fast rebound between February 2020, April 2020, and July 2020 (monthly rate change: -10.60%, 95% CI: -14.73% to -2.52%; 13.06%, 95% CI: 3.42%-18.47%), then back to a gradual decrease from August 2020 to December 2023 (monthly rate change: -0.46%, 95% CI: -0.67% to -0.29%). When prescriptions were further classified by prescribing setting, patient demographics, and patient visit encounter types, we observed variations among these subgroups. We also identified significant associations between patient characteristics and provider specialty with high morphine milligram equivalent dose prescriptions. These results highlight the complexity of opioid prescription practice trends indicating that all these issues need to be considered in developing prescription guidance.

Diabetic neuropathic pain (DNP), characterized by persistent spontaneous pain and evoked pain, poses clinical challenges including treatment resistance and frequent comorbidities with affective disorders such as anxiety and depression. Despite its clinical importance, the underlying mechanisms of DNP remain unclear. In our study, we reveal that hyperactivated astrocytes in the rostral ventromedial medulla (RVM) are functionally associated with both mechanical allodynia and anxiety-like behaviors in DNP. Chemogenetic inhibition of RVM astrocyte activity significantly alleviated mechanical allodynia and anxiety-like behaviors in DNP model rats. Conversely, targeted activation of RVM astrocytes in control rats induced neuropathic pain-like symptoms and pain-related aversion. Furthermore, we discovered that RVM astrocyte bidirectionally modulated glutamatergic neuronal activity; that is, astrocyte activation suppressed neuronal activity, whereas its inhibition increased neuronal excitability. These findings establish RVM astrocyte activation as a critical mediator of DNP pathogenesis, revealing a promising cellular target for the development of novel analgesics and providing therapeutic insights for DNP management.

Limited research has examined psychological treatments for endometriosis-related chronic pain, despite its association with elevated disability, depression, and anxiety. Remotely delivered treatments have the potential to overcome barriers to access face-to-face psychological care, however, no studies have examined this format in endometriosis patients. The current study examined the efficacy and acceptability of an internet-delivered, psychological, pain management program for women with endometriosis-related pain. In this two-arm trial, 193 participants experiencing endometriosis-related pelvic pain were randomly assigned to the 8-week treatment or a waitlist control. The treatment was an adapted version of an established internet-delivered pain management program based on cognitive-behavior therapy principles. Relative to control, the treatment group reported significantly greater improvements (between groups Cohen's d ; average percentage change) in the primary outcomes of pain-related disability ( d = 0.35; 24%), depression ( d = 0.40; 17%), and anxiety ( d = 0.26; 17%) from pre- to post-treatment. Improvements were sustained at 3-month follow-up. No between-group difference was observed on the secondary outcome of average pain intensity ( d = 0.28; 17%, P = 0.054). High lesson completion and treatment satisfaction rates were observed. Mean clinician time per participant was 70 minutes (SD = 68). The current findings indicate the potential of a pain-focused psychological approach in supporting endometriosis-related pain, and the potential of the internet-delivered format in increasing access to care. Future research is needed to examine long-term outcomes and investigate factors associated with optimal treatment response.