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Acute and chronic pain are highly prevalent and impactful consequences of surgery across the lifespan, yet a comprehensive conceptual model encompassing biopsychosocial factors underlying acute to chronic pain transition is lacking, particularly in youth. Building on prior chronic postsurgical pain models, we propose a new conceptual model of biopsychosocial mechanisms of transition from acute to chronic postsurgical pain. This review aims to summarize existing research examining key factors underlying acute to chronic postsurgical pain transition in order to guide prevention and intervention efforts aimed at addressing this health issue in children. As pain transitions from acute nociceptive pain to chronic pain, changes in the peripheral and central nervous system contribute to the chronification of pain after surgery. These changes include alterations in sensory pain processing and psychosocial processes (psychological, behavioral, and social components), which promote the development of chronic pain. Patient-related premorbid factors (eg, demographic factors, genetic profile, and medical factors such as premorbid pain) may further modulate these changes. Factors related to acute injury and recovery (eg, surgical and treatment factors), as well as biological response to surgery (eg, epigenetic, inflammatory, and endocrine factors), may also influence this process. Overall, longitudinal studies examining temporal pathways of biopsychosocial processes including both risk and resiliency factors will be essential to identify the mechanisms involved in the transition from acute to chronic pain. Research is also needed to unravel connections between the acute pain experience, opioid exposure, and sensory pain processing during acute to chronic pain transition. Furthermore, future studies should include larger and more diverse samples to more fully explore risk factors in a broader range of pediatric surgeries. The use of conceptual models to guide intervention approaches targeting mechanisms of transition from acute to chronic pain will significantly advance this field and improve outcomes for children and adolescents undergoing surgery.
Endometriosis, affecting approximately 176 million adults and adolescents worldwide, is a debilitating condition in which uterine tissue grows outside the uterus. The condition costs the US economy approximately $78 billion annually in pain-related disability. By understanding the neural underpinnings of endometriosis-associated pain (EAP) and risk factors for chronification, translational research methods could lessen diagnostic delays and maximize successful pain remediation. This can be accomplished by the novel use of a known method, offset analgesia (OA), to better elucidate the neural mechanisms that may contribute to and maintain EAP. This commentary will provide justification and rationale for the use of OA in the study of EAP.
Sustained morphine treatment for cancer pain has been limited due to analgesic tolerance. Opioid receptor internalization and desensitization mediated by downregulation of mu-opioid receptor (MOR) expression have been confirmed as one of the mechanisms of chronic morphine tolerance. In addition to the opiate system, the α2-adrenergic system is involved in the development of morphine tolerance. Several studies reported that co-administration of α2-adrenoceptor agonist dexmedetomidine inhibits morphine tolerance in normal or neuropathic pain animals. However, the effect of dexmedetomidine on morphine tolerance has not been studied in cancer pain. Therefore, we investigated the effect of intrathecal injection of dexmedetomidine on the development of morphine tolerance in cancer pain and on the expression of MOR in the spinal cord of morphine-tolerant cancer pain rats.
Medication overuse headache (MOH), previously known as analgesic abuse headache or medication misuse headaches, is a common form of chronic headache disorder that has a detrimental impact on health and society. Although it has been widely accepted that overusing abortive medications is paradoxically the cause of MOH and drug discontinuation is the treatment of choice, ongoing debates exist as to whether drug consumption per se is the cause or consequence of headache chronification. Certain features in MOH such as their compulsive drug-seeking behavior, withdrawal headaches and high relapse rates share similarities with drug dependence, suggesting that there might be common underlying biological and psychobehavioral mechanisms. In this regard, this article will discuss the updated evidence and current debates on the possible biobehavioral overlap between MOH and drug dependence. To begin with, we will discuss whether MOH has characteristics of substance dependence based on standard psychiatry diagnostic criteria and other widely used dependence scales. Recent epidemiological studies underscoring common psychiatric comorbidities between the two disorders will also be presented. Although both demonstrate seemingly distinct personality traits, recent studies revealed similar decision-making impairment from a cognitive perspective, indicating the presence of a maladaptive reward system in both disorders. In addition, emerging imaging studies also support this notion by showing reversible morphological and functional brain changes related to the mesocorticolimbic reward circuitry in MOH, with a strong resemblance to those in addiction. Finally, an increased familial risk for drug dependence and genetic association with dopaminergic and drug dependence molecular pathways in MOH also support a possible link between MOH and addiction. Understanding the role of dependence in MOH will have a great impact on disease management as this will provide the missing piece of the puzzle in current therapeutic strategies.
Pain is a fundamental feature of inflammation. The immune system plays a critical role in the activation of sensory neurons and there is increasing evidence of neuro-inflammatory mechanisms contributing to painful pathologies. The inflammasomes are signaling multiprotein complexes that are key components of the innate immune system. They are intimately involved in inflammatory responses and their activation leads to production of inflammatory cytokines that in turn can affect sensory neuron function. Accordingly, the contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. NLRP3 is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions. In vitro and in vivo studies have reported the activation and upregulation of NLRP3 in painful conditions including gout and rheumatoid arthritis, while inhibition of NLRP3 function or expression can mediate analgesia. In this review, we discuss painful conditions in which NLRP3 inflammasome signaling has been pathophysiologically implicated, as well as NLRP3 inflammasome-mediated mechanisms and signaling pathways that may lead to the activation of sensory neurons.
Bioactive lipid mediators resulting from the metabolism of polyunsaturated fatty acids (PUFA) are controlled by many pathways that regulate the levels of these mediators and maintain homeostasis to prevent disease. PUFA metabolism is driven primarily through three pathways. Two pathways, the cyclooxygenase (COX) and lipoxygenase (LO) enzymatic pathways, form metabolites that are mostly inflammatory, while the third route of metabolism results from the oxidation by the cytochrome P450 enzymes to form hydroxylated PUFA and epoxide metabolites. These epoxygenated fatty acids (EpFA) demonstrate largely anti-inflammatory and beneficial properties, in contrast to the other metabolites formed from the degradation of PUFA. Dysregulation of these systems often leads to chronic disease. Pharmaceutical targets of disease focus on preventing the formation of inflammatory metabolites from the COX and LO pathways, while maintaining the EpFA and increasing their concentration in the body is seen as beneficial to treating and preventing disease. The soluble epoxide hydrolase (sEH) is the major route of metabolism of EpFA. Inhibiting its activity increases concentrations of beneficial EpFA, and often disease states correlate to mutations in the sEH enzyme that increase its activity and decrease the concentrations of EpFA in the body. Recent approaches to increasing EpFA include synthetic mimics that replicate biological activity of EpFA while preventing their metabolism, while other approaches focus on developing small molecule inhibitors to the sEH. Increasing EpFA concentrations in the body has demonstrated multiple beneficial effects in treating many diseases, including inflammatory and painful conditions, cardiovascular disease, neurological and disease of the central nervous system. Demonstration of efficacy in so many disease states can be explained by the fundamental mechanism that EpFA have of maintaining healthy microvasculature and preventing mitochondrial and endoplasmic reticulum stress. While there are no FDA approved methods that target the sEH or other enzymes responsible for metabolizing EpFA, current clinical efforts to test for efficacy by increasing EpFA that include inhibiting the sEH or administration of EpFA mimics that block metabolism are in progress.
The FUTUREPAIN study develops a short general-purpose questionnaire, based on the biopsychosocial model, to predict the probability of developing or maintaining moderate-to-severe chronic pain 7-10 years into the future.
Post-herpetic neuralgia (PHN) is a common herpes zoster (HZ) complication, where pain persists 90 days after the initial HZ diagnosis. Evaluating PHN risk is essential for determining the burden on patients and health-care systems, but research shows variable estimates. The extent to which these differences are related to the assessment method has not been examined. The purpose of this study is to compare the proportion of PHN among HZ patients measured by medical chart review and self-report surveys.
Opioid related deaths are at epidemic levels in many developed nations globally. Concerns about the contribution of prescribed opioids, and particularly high-dose opioids, continue to mount as do initiatives to reduce prescribing. Evidence around opioid tapering, which can be challenging and potentially hazardous, is not well developed. A recent national guideline has recognized this and recommended referral to multidisciplinary care for challenging cases of opioid tapering. However, multidisciplinary care for opioid tapering is not well understood or defined.
Pain is one of the most significant causes of suffering and disability world-wide, and arguably the most burdensome global health challenge. The growing number of patients suffering from chronic pain conditions such as fibromyalgia, complex regional pain syndrome, migraine and irritable bowel syndrome, not only reflect the complexity and heterogeneity of pain types, but also our lack of understanding of the underlying mechanisms. Sensory neurons within the dorsal root ganglia (DRG) have emerged as viable targets for effective chronic pain therapy. However, DRG's contain different classes of primary sensory neurons including pain-associated nociceptive neurons, non-nociceptive temperature sensing, mechanosensory and chemoreceptive neurons, as well as multiple types of immune and endothelial cells. This cell-population heterogeneity makes investigations of individual subgroups of DRG neurons, such as nociceptors, difficult. In attempts to overcome some of these difficulties, a limited number of immortalized DRG-derived cell lines have been generated over the past few decades. experiments using DRG-derived cell lines have been useful in understanding sensory neuron function. In addition to retaining phenotypic similarities to primary cultured DRG neurons, these cells offer greater suitability for high throughput assays due to ease of culture, maintenance, growth efficiency and cost-effectiveness. For accurate interpretation and translation of results it is critical, however, that phenotypic similarities and differences of DRG-derived cells lines are methodically compared to native neurons. Published reports to date show notable variability in how these DRG-derived cells are maintained and differentiated. Understanding the cellular and molecular differences stemming from different culture methods, is essential to validate past and future experiments, and enable these cells to be used to their full potential. This review describes currently available DRG-derived cell lines, their known sensory and nociceptor specific molecular profiles, and summarize their morphological features related to differentiation and neurite outgrowth.