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To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients.
Learn More >Elucidation of epigenetic mechanisms correlating with neuropathic pain in humans is crucial for the prevention and treatment of this treatment-resistant pain state. In the present study, associations between neuropathic pain characteristics and DNA methylation of the transient receptor potential ankyrin 1 (TRPA1) gene were evaluated in chronic pain patients and preoperative patients. Pain and psychological states were prospectively assessed in patients who suffered chronic pain or were scheduled for thoracic surgery. Neuropathic characteristics were assessed using the Douleur Neuropathique 4 (DN4) questionnaire. DNA methylation levels of the CpG islands in the TRPA1 gene were examined using whole blood. Forty-eight adult patients were enrolled in this study. Increases in DNA methylation rates at CpG -51 showed positive correlations with increases in the DN4 score both in preoperative and chronic pain patients. Combined methylation rates at CpG -51 in these patients also significantly increased together with increase in DN4 scores. Neuropathic pain characteristics are likely associated with methylation rates at the promoter region of the TRPA1 gene in human peripheral blood.
Learn More >Our objective was to develop comprehensive national estimates of the total burden of HZ among US adults, including direct (ie, medical costs) and indirect (ie, productivity losses) costs, as well as its psychosocial impact (ie, quality of life losses).Using a patient-level microsimulation model, we projected health and economic outcomes among US adults aged 18 years and older using a 10-year time horizon. We conducted a comprehensive systematic literature review to generate parameter values and conducted simulation modeling to generate our outcomes, including numbers of cases of uncomplicated HZ, postherpetic neuralgia (PHN), and ocular complications, productivity losses, and losses in quality adjusted life years (QALYs). We used a societal perspective for outcomes; the costing year was 2015.Projected outcomes for an unvaccinated population included 1.1 million HZ cases, 114,000 PHN cases, and 43,000 ocular complications annually, resulting in approximately 67,000 QALYs lost. HZ and its complications would incur costs of $2.4 billion in direct medical costs and productivity losses annually.Projected QALY-losses were most sensitive to HZ and PHN health utility values in the model. Cost estimates were most sensitive to the probability of HZ and to the costs per episode of PHN.The national burden of direct, indirect, and psychosocial HZ costs is substantial. Our results can inform economic analyses for HZ vaccines. Comprehensive, national assessments of the total burden of other painful conditions would be very informative.
Learn More >Patients with advanced cancer face a life-limiting condition that brings a high symptom burden that often includes pain, fatigue, and psychological distress. Psychosocial interventions have promise for managing symptoms, but need additional tailoring for these patients' specific needs. Patients with advanced cancer in the community also face persistent barriers – availability of interventions in community clinics, financial and illness-related factors – to accessing psychosocial interventions.
Learn More >We recently demonstrated in rat spinal cord that a regimen of escalating doses of systemic morphine, analogous to regimens used clinically for chronic pain management, selectively upregulates the mu-opioid receptor (MOR) splice variants MOR-1B2 and MOR-1C1 mRNA and functional protein. The current study investigated the potential relevance of upregulating MOR-1B2 and MOR-1C1 to the ability of chronic morphine to shift MOR signaling from predominantly G /G inhibitory to G stimulatory. Specifically, we tested the hypotheses that chronic morphine induces phosphorylation of carboxyl terminal sites unique to MOR-1B2 and MOR-1C1, and that this phosphorylation is causally related to augmented association of these variants with G α. Hypotheses were validated by (1) abolition of the chronic morphine-induced increment in MOR-1C1 and MOR-1B2 association with G α by inhibitors of protein kinase A and Casein kinase 2, respectively; (2) failure of chronic morphine to augment MOR variant G α interactions in Chinese hamster ovary cells transiently transfected with either rat MOR-1C1 or MOR-1B2 in which targeted protein kinase A and Casein kinase 2 serine phosphorylation sites, respectively, were mutated to alanine; (3) abrogation of chronic morphine-induced augmented MOR G α association in spinal cord of male rats following intrathecal administration of dicer substrate small interfering RNAs targeting MOR-1B2/MOR-1C1 mRNA. The ability of chronic morphine to not only upregulate specific MOR variants but also their carboxyl terminal phosphorylation and consequent augmented association with G α may represent a novel component of opioid tolerance mechanisms, suggesting novel potential targets for tolerance abatement. This article is protected by copyright. All rights reserved.
Learn More >Despite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries.
Learn More >No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing.
Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain.
Learn More >Despite evidence of broad impact on daily functioning in adolescence, little is known regarding the life course effects of childhood chronic pain. This is the first nationally representative study to characterize the disruptive impact of chronic pain in adolescence on key educational, vocational, and social outcomes in young adulthood (12 years later). Data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) was used, including 3,174 youth with chronic pain and 11,610 without chronic pain. Multivariate regression analyses controlling for sociodemographic factors and adolescent depression found that chronic pain in adolescence was associated with long-term risk for a constellation of impairments indicative of socioeconomic disparities. Specifically, adolescent chronic pain was subsequently associated with reduced educational attainment (e.g., lower odds of attaining a high school diploma and bachelor's degree), poor vocational functioning (e.g., lower odds of receiving employer-provided benefits, higher odds of receiving public aid), and social impairments (e.g., early parenthood, lower self-reported romantic relationship quality) in young adulthood. These findings provide a window into the future of adolescents with chronic pain, contributing to the limited knowledge base of the scope of adverse long-term outcomes during the transition to adulthood. However, several questions remain. Increased research attention is needed to understand the life course impact of pediatric chronic pain, including early risk factors and underlying mechanisms that drive adverse outcomes as they unfold across the lifespan.
Learn More >: To evaluate the real-life effectiveness, safety, tolerability and patient-reported outcomes (PRO) of the sufentanil sublingual tablet system (SSTS) for postoperative pain management (POPM). : This prospective, multicenter, noninterventional, study included adults with acute moderate to severe postoperative pain who self-administered sufentanil using the SSTS. Main outcome measures were pain intensity at rest (numerical rating scale [NRS]: 0 [no pain] to 10 [most intense pain imaginable]); most intense pain intensity (0-10); 4-point patient assessment of the pain control method ("excellent", "good", "fair", "poor"); patient satisfaction with the pain control level and the method of administration of pain medication (6-point scale: "extremely satisfied", "very satisfied", "satisfied", "dissatisfied", "very dissatisfied", "extremely dissatisfied"). Adverse drug reactions were recorded. : The SSTS reduced resting pain intensity in patients (n = 341) from a mean ± SD NRS score of 5.2 ± 2.3 (at SSTS handover) to 1.8 ± 1.6 (3 day after handover). The proportion of patients with severe pain (for the PRO measure "most intense pain") decreased steadily during the 72 hours of treatment. Overall, 87.1% of patients reported the method of pain control to be "good" or "excellent"; 91.8% reported being "extremely/very satisfied" or "satisfied" with the level of pain control; and 95.9% were at least satisfied with the method of pain medication administration. SSTS safety and tolerability was typical for opioids and as described in the SSTS Summary of Product Characteristics. : The SSTS is a valuable option for real-life POPM and is effective in a wide range of surgical procedures. : European Union electronic Register of Post-Authorization Studies (EU PAS Register) number: EUPAS14689.
Learn More >Standard pharmacological treatment of migraine has many shortcomings. Acupuncture is becoming a more widely used therapy for the prevention and treatment of migraine, but its effectiveness is still in question when compared to the pharmacological treatments even though very few of these have Class A and B evidence for migraine prevention. This is a systematic review of data from existing randomized trials that compare the effectiveness of acupuncture treatment with conventional migraine preventative medications.
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