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Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. Due to an undesirable adverse event profile when used as an anesthetic it had widely fallen out of human use in favor of more modern agents. However, it has recently been explored for several other indications such as treatment resistant depression and chronic pain. Several recent studies and case reports compiled here show that ketamine is an effective analgesic in chronic pain conditions including cancer-related neuropathic pain. Of special interest is ketamine's opioid sparing ability by counteracting the central nervous system sensitization seen in opioid induced hyperalgesia. Furthermore, at the sub-anesthetic concentrations used for analgesia ketamine's safety and adverse event profiles are much improved. In this article, we review both the basic science and clinical evidence regarding ketamine's utility in chronic pain conditions as well as potential adverse events.
Learn More >Fibromyalgia (FM), a disease of unknown etiology characterized by chronic generalized pain, is partly recapitulated in an animal model induced by repeated acid saline injections into the gastrocnemius muscle. Here, we attempted to investigate the sex difference in pain hypersensitivity (mechanical allodynia and hypersensitivity to electrical stimulation) in the repeated acid saline-induced FM-like generalized pain (AcGP) model. The first unilateral acid injection into gastrocnemius muscle at day 0/D0 and second injection at D5 (post day 0, P0) induced transient and long-lasting mechanical allodynia, respectively, on both sides of male and female mice. The pretreatment with gonadectomy did not affect the first injection-induced allodynia in both sexes, but gradually reversed the second injection-induced allodynia in male but not female mice. Moreover, the AcGP in male mice was abolished by intracerebroventricular minocycline treatments during D4-P4 or P5-P11, but not by early treatments during D0-D5 in male but not female mice, suggesting that brain microglia are required for AcGP in late-onset and sex-dependent manners. We also found that the intravenous treatments of splenocytes derived from male but not female mice treated with AcGP caused allodynia in naive mice. In addition, the purified CD4 T cells derived from splenocytes of acid-treated male mice retained the ability to cause allodynia in naive mice. These findings suggest that FM-like AcGP has multiple sexual dimorphic mechanisms.
Learn More >Primary dysmenorrhea (PD; menstrual pain without an identified organic cause) has been proposed as a possible risk factor for the development of chronic pelvic pain, but the mechanism through which this process occurs is unknown. One possible mechanism is central sensitization – alterations in the central nervous system that increase responsiveness to pain leading to hypersensitivity. Repeated episodes of pain, such as those experienced over time with PD, may alter how the brain processes pain. Ecological momentary assessment (EMA; collection of data in real time in participants' natural environments) is a novel data collection method that may help elucidate pain occurring during non-menstrual cycle phases.
Learn More >Previous studies have proved that observational learning can induce placebo analgesia, but the factors that influence observationally induced placebo analgesia have not yet been extensively examined. The primary goal of this study was to investigate the effect of information about the role that the observed person (model) plays in the experiment on the magnitude of the observationally induced placebo effect. This study also examined the contribution of the observer's empathy, conformity and fear of pain to the placebo analgesia induced by observational learning. The effects induced in two experimental groups and one control group were compared. Participants in the experimental groups observed a model introduced as either another participant taking part in the study or a coworker of the experimenter. The model rated the intensity of pain induced by electrocutaneous stimuli preceded by color stimuli. One-half of all participants watched a model rating pain stimuli preceded by the color orange as higher than stimuli preceded by the color blue; for the other half, the ratings were the opposite. There was no observation in the control group. Subsequently, all participants received pain stimuli of the same intensity preceded by orange and blue stimuli and rated the intensity of the experienced pain. Placebo analgesia was found in both experimental groups. However, the way the observed model was introduced to participants did not affect the magnitude of placebo analgesia. Thus, the study showed that the role played by the model is not crucial for observationally induced placebo analgesia. The examined observer's individual characteristics did not predict the magnitude of placebo effect.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
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