PAIN®最新文献

Abstract: Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. Ischemia with reperfusion injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity caused by I/R injury may be due to sex-specific gene expression in the dorsal root ganglia (DRG) and distinct upregulation of growth factors and cytokines in the affected muscles. To determine how these unique gene expression programs may be established in a sex-dependent manner in a model that more closely mimics clinical scenarios, we used a developed prolonged ischemic myalgia model in mice whereby animals experience repeated I/R injuries and compared behavioral results with unbiased and targeted screening strategies in male and female DRG. Several distinct proteins were found to be differentially expressed in male and female DRG, including phosphorylated AU-rich element RNA-binding protein (pAUF1), which is known to regulate gene expression. Nerve-specific siRNA-mediated knockdown of AUF1 inhibited prolonged hypersensitivity in females only, whereas overexpression of AUF1 in male DRG neurons increased pain-like responses. AUF1 knockdown was able to specifically inhibit repeated I/R-induced gene expression in females potentially downstream of prolactin receptor signaling. Data suggest RNA-binding proteins such as pAUF1 may underlie the sex-specific effects on DRG gene expression that modulates behavioral hypersensitivity after repeated I/R injury through prolactin signaling. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.

Abstract: One-fifth of US adults experience chronic pain, which is associated with increased tobacco and cannabis use. Although bidirectional relationships between tobacco and pain have been demonstrated, pathways between pain, cannabis use, and co-use of cannabis and tobacco are understudied. We aimed to estimate the effects of (1) substance use (exclusive and co-use of cannabis and tobacco) on later pain intensity, and (2) pain intensity on later substance use. Data were from 31,983 adults in biennial surveys (2015-2021) of the US nationally representative longitudinal Population Assessment of Tobacco and Health Study (n = 71,055 pairs of consecutive surveys; T1 and T2). Past-week pain intensity was dichotomized (≤4/10 no/low pain; >4/10 moderate/severe pain). Mutually exclusive substance use categories (past 30 days) were no cannabis/tobacco use; exclusive cannabis/tobacco use; and co-use. Logistic regression assessed whether T1 substance use affected moderate/severe pain at T2. Multinomial models assessed whether pain status at T1 affected substance use at T2. Compared with no cannabis/tobacco use at T1, co-use (OR: 2.29 [95% CI: 2.09-2.51]), exclusive tobacco use (2.00 [1.86-2.14]), and exclusive cannabis use (1.35 [1.13-1.61]) were all associated with moderate/severe pain at T2. Moderate/severe pain at T1 increased odds of co-use (2.43 [2.22-2.66]), exclusive tobacco (2.12 [1.98-2.28]), and exclusive cannabis use (1.46 [1.29-1.65]) compared with no cannabis/tobacco use at T2, and increased odds of co-use at T2 compared with exclusive cannabis/tobacco use. Findings demonstrated bidirectional relationships between pain and the exclusive use and co-use of cannabis and tobacco and indicate potential synergy in the co-use of cannabis and tobacco with respect to pain.

Abstract: Memory biases for pain-related information may contribute to the development and maintenance of chronic pain; however, evidence for when (and for whom) these biases occur is mixed. Therefore, we examined neural, stress, and psychological factors that could influence memory bias, focusing on memories that motivate disabling behaviors: pain perception, conditioned responses to threat-and-safety cues, and responses to aversive nonnoxious stimuli. Two studies were conducted with adolescents with and without chronic pain. Data from 58 participants were included in study 1 (chronic pain n = 34, pain free n = 24, mean age = 16 years), and 39 participants were included in study 2 (chronic pain n = 26, pain free n = 13, mean age = 16 years). Both studies used a threat-safety learning paradigm with memory recall (≈1 month later). Participants completed structural and functional (resting-state) magnetic resonance imaging, salivary cortisol measurements, and self-report measures. Adolescents with pain and pain-free peers consistently recalled being more afraid of safety cues (CS-) and, during heightened stress at encoding (higher cortisol levels), also reported being more afraid of threat cues (CS+). However, no memory bias was present for the emotional response to an aversive stimulus (US; loud scream) or for the recall of pain intensity. Functional connectivity of the amygdala and hippocampus with memory circuits related to the degree of memory bias, but the specific connections varied between the studies, and we observed no relationship between memory bias and brain morphology. Our findings highlight the value of considering the interaction between implicit and explicit memory systems, contributing to a more comprehensive understanding of emotional memory biases in the context of chronic pain.

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.