PAIN®最新文献

Abstract: Prescription opioids for noncancer pain in the United Kingdom have increased over the past 2 decades, alongside associated harms. Policies addressing opioid prescribing must be tailored to individual patient needs with specific disease systems. The aim of this study was to evaluate clinical conditions associated with new opioid initiation in noncancer pain using nationally representative UK data. Primary care electronic health records from January 1, 2006, to September 31, 2021, were used from the Clinical Research Practice Datalink to identify incident opioid prescriptions. Patient histories were reviewed using code lists for opioid-related conditions with a 5-year look-back for chronic conditions and a 1-year look-back for surgical indications before opioid initiation. In total, 3,030,077 new opioid use episodes in 2,027,402 patients were identified, with 61% being women, 77% aged 45 years and older, and 48% from the highest deprivation quintile. Ten systems associated with opioid initiation were identified, which were not mutually exclusive, as patients could have opioids prescribed for multiple indications. The most common were musculoskeletal (80.8%), respiratory (57.6%), infections (30.4%), trauma/injury (20.4%), neurology (19.9%), and postsurgical indications (5.5%). Osteoarthritis (60.7%) and low back pain (41.0%) were the most frequent musculoskeletal conditions. Orthopedic surgeries accounted for 41.2% of all postsurgical indications. This is the first study in the United Kingdom evaluating large-scale national data to assess indications associated with opioid initiation. Nearly 3 quarters of new opioid prescriptions for noncancer pain were in patients with musculoskeletal conditions, often for conditions with limited evidence for opioid efficacy. These findings could inform targeted interventions and future policies to support nonpharmacological interventions in the most common conditions where opioid harms outweigh benefits.

Abstract: Advancements in clinical science have shown the necessity for a paradigm shift away from a biomedical toward a biopsychosocial approach. Yet, the translation from clinical science into clinical practice is challenging. The aim of this study was to assess the short-term and mid-term changes in pain knowledge and attitudes and guideline-adherent recommendations of healthcare professionals (HCP) by means of an interdisciplinary training program (ITP) about chronic pain. Belgian HCPs, with a priority for medical doctors, physiotherapists, occupational therapists, nurses, psychologists, and pharmacists in primary care, participated in the ITP, which contained 2 e-learning modules and two 7-hour workshops provided in small interdisciplinary groups in 5 cities. The objective of ITP was to improve HCP's competencies for integrating biopsychosocial chronic pain management with a cognitive behavioral approach into clinical practice. Primary outcomes were changes in knowledge and attitudes about pain and guideline-adherent recommendations for continuation of physical activity, sports, and work; avoiding bed rest; and not supporting opioid usage measured through 2 clinical vignettes. They were measured before, immediately after, and 6 months after the ITP. Changes were analyzed using (generalized) linear mixed models. A total of 405 HCPs participated. The knowledge and attitudes about pain scores improved at post-training (Δ = 9.04, 95% confidence interval 7.72-10.36) and at 6-month follow-up (Δ = 7.16, 95% confidence interval 5.73-8.59). After the training program, HCPs provided significantly more recommendations in accordance with clinical guidelines. Thus, an ITP can improve the biopsychosocial perspective of chronic pain management among HCPs in the short-term and mid-term.

Abstract: Chronic postsurgical pain (CPSP) is a highly prevalent condition. To improve CPSP management, we aimed to develop and internally validate generalizable point-of-care risk tools for preoperative and postoperative prediction of CPSP 3 months after surgery. A multicentre, prospective, cohort study in adult patients undergoing elective surgery was conducted between May 2021 and May 2023. Prediction models were developed for the primary outcome according to the International Association for the Study of Pain criteria and a secondary threshold-based CPSP outcome. Models were developed with multivariable logistic regression and backward stepwise selection. Internal validation was conducted using bootstrap resampling, and optimism was corrected by shrinkage of predictor weights. Model performance was assessed by discrimination and calibration. Clinical utility was assessed by decision curve analysis. The final cohort included 960 patients, 16.3% experienced CPSP according to the primary outcome and 33.6% according to the secondary outcome. The primary CPSP model included age and presence of other preoperative pain. Predictors in the threshold-based models associated with an increased risk of CPSP included younger age, female sex, preoperative pain in the surgical area, other preoperative pain, orthopedic surgery, minimally invasive surgery, expected surgery duration, and acute postsurgical pain intensity. Optimism-corrected area-under-the-receiver-operating curves for preoperative and postoperative threshold-based models were 0.748 and 0.747, respectively. These models demonstrated good calibration and clinical utility. The primary CPSP model demonstrated fair predictive performance including 2 significant predictors. Derivation of a generalizable risk tool with point-of-care predictors was possible for the threshold-based CPSP models but requires independent validation.

Abstract: Cell states are influenced by the regulation of gene expression orchestrated by transcription factors capable of binding to accessible DNA regions. To uncover if sex differences exist in chromatin accessibility in the human dorsal root ganglion (hDRG), where nociceptive neurons innervating the body are found, we performed bulk and spatial assays for transposase-accessible chromatin technology followed by sequencing (ATAC-seq) from organ donors without a history of chronic pain. Using bulk ATAC-seq, we detected abundant sex differences in the hDRG. In women, differentially accessible regions (DARs) mapped mostly to the X chromosome, whereas in men, they mapped to autosomal genes. Hormone-responsive transcription factor binding motifs such as EGR1/3 were abundant within DARs in women, while JUN, FOS, and other activating protein 1 factor motifs were enriched in men, suggesting a higher activation state of cells compared with women. These observations were consistent with spatial ATAC-seq data. Furthermore, we validated that EGR1 expression is biased to female hDRG using RNAscope. In neurons, spatial ATAC-seq revealed higher chromatin accessibility in GABAergic, glutamatergic, and interferon-related genes in women and in Ca2+-signaling-related genes in men. Strikingly, XIST, responsible for inactivating 1 X chromosome by compacting it and maintaining at the periphery of the nucleus, was found to be highly dispersed in female neuronal nuclei. This is likely related to the higher chromatin accessibility in X in female hDRG neurons observed using both ATAC-seq approaches. We have documented baseline epigenomic sex differences in the hDRG which provide important descriptive information to test future hypotheses.

Abstract: Voltage-gated sodium (Na v ) channels present untapped therapeutic value for better and safer pain medications. The Na v 1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. In addition, the relevance of rodent pain assays to the human condition is under increasing scrutiny as a number of mechanisms (or at the very least molecules) that are active in rodents have not translated to humans, and direct impact on pain fibers has not been confirmed in vivo. In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Na v 1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Na v 1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Na v 1.8 inhibition broadly.