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Migraine is highly prevalent and associated with a large socio-economic burden in the United States. Current preventive medications have variable efficacy and their use is often limited by intolerable side effects. Calcitonin gene-related peptide (CGRP) has been identified as an integral part of migraine pathophysiology. There are currently seven CGRP antagonists under investigation, all of which are undergoing or have completed phase 3 clinical trials. Three of the investigated CGRP antagonists are approved for use within and outside of the United States. The trials have resulted in positive efficacy and safety data. The purpose of this review is to evaluate the seven CGRP antagonists and their future place in therapy.
Learn More >Central neuropathic pain (CNP) after spinal cord injury (SCI) is debilitating and immensely impacts the individual. CNP is relatively resistant to treatment administered after it develops, perhaps owing to irreversible pathological processes. Although preemptive treatment may overcome this shortcoming, its administration necessitates screening patients with clinically relevant biomarkers that could predict CNP early post-SCI. The aim was to search for such biomarkers by measuring pro-nociceptive and for the first time, anti-nociceptive indices early post-SCI.Participantswere 47 patients with acute SCI and 20 healthy controls (HC). Pain adaptation, conditioned pain modulation (CPM), pain temporal summation (TSP), windup pain, and allodynia were measured above, at, and below the injury level, at 1.5 months post-SCI. HC were tested at corresponding regions. SCI patients were monitored for CNP emergence and characteristics at 3-4, 6-7, and 24 months post-SCI.CNP prevalence was 57.4%. CNP severity, quality and aggravating factors but not location somewhat changed over 24 months. SCI patients who eventually developed CNP exhibited early, reduced at-level pain adaptation and CPM magnitudes than those who did not. The best predictor for CNP emergence at 3-4 and 7-8 months was at-level pain adaptation with odds ratios of 3.17 and 2.83, respectively (∼77% probability) and a cut-off value with 90% sensitivity. Allodynia and at-level CPM predicted CNP severity at 3-4 and 24 months, respectively.Reduced pain inhibition capacity precedes, and may lead to CNP. At-level pain adaptation is an early CNP biomarker with which individuals at risk can be identify to initiate preemptive treatment.
Learn More >Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve-injured mice.
Mu and delta opioid receptors (MOP, DOP) limit pain perception in physiological conditions, but their relative contribution to the manifestations of pathological pain is not completely understood. Here we used a genetic approach to investigate the opioid mechanisms modulating neuropathic pain and its comorbid manifestations.
Learn More >To report evidence of chronic physical illnesses, mental health disorders, and psychological features as potential risk factors for back pain in children, adolescents, and young adults.
Learn More >Oxaliplatin is a widely used chemotherapeutic drug and represents the cornerstone of colorectal cancer therapy, in combination with 5-fluorouracil and folinic acid. As with many chemotherapeutic agents, its use is associated with a number of side effects, ranging from hypersensitivity reactions to haematological dyscrasias. Oxaliplatin also induces acute and chronic peripheral neuropathy. While it is likely that the haematological side effects are associated with its anti-proliferative effects and with the ability to form DNA adducts, the molecular mechanisms underlying peripheral neuropathy and hypersensitivity reactions are poorly understood, and therefore the choice of adequate supportive therapies is largely empirical. Here we show that an acute low dose oxaliplatin application on DRG neurons is able to induce an increase in intracellular calcium that is dependent on the Histamine 1 receptor (H1). Oxaliplatin-induced intracellular calcium rises are blocked by two selective H1 antagonist, as well as by U73122, a PLC inhibitor, and by 2-APB, a non-specific IP receptor blocker. Moreover, expression of the H1 receptor on HEK293 t cells unmasks an oxaliplatin-induced Ca-rise. Last, activation of H1 via either histamine or oxaliplatin activates TRPV1 receptors, a mechanism that has been associated with itch. These data, together with literature data that has shown that anti-histamine agents reduce the incidence of oxaliplatin-induced hypersensitivity, may provide a molecular mechanism of this side effect in oncological patients.
Learn More >Disability in inflammatory bowel disease (IBD) is under-investigated. Models theorize that disability is the result of a disease and its related impairments, limitations, and restrictions. This disablement process can be affected by psychosocial factors. Pain, depression, catastrophizing, and social support are associated with IBD-disability outcomes, but no studies have examined these factors concurrently. This study examined the role of psychosocial factors in the process of IBD disablement within the context of pain. Depressive symptoms, pain catastrophizing, and perceived social support were proposed as mediators in the relationship between pain and pain-related disability in cross-sectional and longitudinal models. Cross-sectionally, the mediation effects of depressive symptoms and pain catastrophizing, but not perceived social support, were significant. Longitudinally, depression was a significant mediator. Depressive symptoms and pain catastrophizing have mechanistic roles in the relationship between IBD patients' pain and pain-related disability and should be targets for intervention.
Learn More >Pain is often the initial complaint for which patients seek medical care presenting both a diagnostic and therapeutic challenge to the primary care provider. The appreciation of pain is not merely the result of abnormal sensory stimulation causing an unpleasant sensation but rather a combination of the recognition of the somatic discomfort in association with an emotional response to that discomfort. The perception of pain and the extent of distress and disability can vary depending on previous experience, cultural background, situational factors, and comorbid psychiatric disease. While acute pain is usually the result of tissue damage, that is not always the case as evidenced by the primary headache disorders. Chronic pain may be the result of an injury, irreversible underlying disease or clinical conditions such as fibromyalgia for which the mechanism remains unclear. Treatment of the underlying cause will usually effect a resolution or improvement in the pain but when the discomfort persists a consultation with a neurologist or pain management specialist should be considered.
Learn More >Pain is a common complaint presented in healthcare, but most epidemiological pain research has focused either on single pain conditions or on the adult population. The aim of this study was to investigate the 2017 consultation prevalence of a wide range of pain conditions in the general population of young people.
Learn More >Tolerance to the antinociceptive effects of cannabinoids represents a significant limitation to their clinical use in managing chronic pain. Tolerance likely results from desensitization and down-regulation of the cannabinoid type 1 receptor (CBR), with CBR desensitization occurring via phosphorylation of CBRs by a G protein-coupled receptor kinase and subsequent association with an arrestin protein. Previous studies have shown that (1) desensitization-resistant S426A/S430A mice exhibit a modest delay in tolerance for Δ-THC and CP55,940 but a more pronounced disruption in tolerance for WIN 55,212-2 and (2) that c-Jun N-terminal kinase (JNK) signaling may selectively mediate antinociceptive tolerance to morphine compared to other opioid analgesics. In the current study, we found that pretreatment with the JNK inhibitor SP600125 (3 mg/kg) attenuates tolerance to the antinociceptive and anti-allodynic effects of Δ-THC (6 mg/kg) in wild-type mice using the formalin test and in mice with cisplatin-evoked neuropathic pain, respectively. We also find that SP600125 causes an especially robust reduction in tolerance to the antinociceptive effects of Δ-THC (30 mg/kg) but not WIN 55,212-2 (10 mg/kg) in the tail-flick assay using S426A/S430A mice. Interestingly, SP600125 pretreatment accelerated tolerance to the antinociceptive and anti-allodynic effects of CP55,940 (0.3 mg/kg) in mice with acute and neuropathic pain. These results demonstrate that inhibition of JNK signaling pathways delay tolerance to Δ-THC, but not to CP55,940 or WIN55,212-2, demonstrating that the mechanisms of cannabinoid tolerance are agonist-specific.
Learn More >Pain-related fear is typically associated with avoidance behavior and pain-related disability in youth with chronic pain. Youth with elevated pain-related fear have attenuated treatment responses, thus targeted treatment is highly warranted. Evidence supporting graded in-vivo exposure treatment (GET) for adults with chronic pain is considerable, but just emerging for youth. The current investigation represents the first sequential replicated and randomized single-case experimental phase design with multiple measures evaluating GET for youth with chronic pain, entitled GET Living. A cohort 27 youth (81% female) with mixed chronic pain completed GET Living. For each participant, a no-treatment randomized baseline period was compared with GET Living and 3- and 6-month follow-ups. Daily changes in primary outcomes fear and avoidance and secondary outcomes pain catastrophizing, pain intensity, and pain acceptance were assessed using electronic diaries and subjected to descriptive and model-based inference analyses (MLM). Based on individual effect size calculations, a third of participants significantly improved by the end of treatment on fear, avoidance, and pain acceptance. By follow-up over 80% of participants had improved across all primary and secondary outcomes. MLM results to examine the series of replicated cases were generally consistent. Improvements during GET Living was superior to the no-treatment randomized baseline period for avoidance, pain acceptance, and pain intensity, whereas fear and pain catastrophizing did not improve. All five outcomes emerged as significantly improved at 3- and 6-month follow-up. The results of this replicated SCED support the effectiveness of graded exposure for youth with chronic pain and elevated pain-related fear avoidance.
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