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This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines (CBM) for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are: 1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; 2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and 3) to identify important directions for future research. In service of these goals, this review a) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; b) describes pharmacokinetics of cannabinoids in rodents and humans; and c) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
Learn More >We report a systematic review and meta-analysis of studies which assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference (SMD) effect size for each comparison and performed a random effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86 %). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective CB1, CB2, non-selective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol; THC), and PPAR-alpha agonists (predominantly palmitoylethanolamide; PEA) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MGL) inhibitors and cannabidiol (CBD) significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low, therefore the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.
Learn More >A scarcity of studies on the role of resilience resources (RRs) and vulnerability risk (VR) in children and adolescents with primary headache hampers the development of a risk-resilience model for pediatric headaches.
Learn More >Osteopathic manipulative treatment (OMT) is frequently offered to people with nonspecific low back pain (LBP) but never compared with sham OMT for reducing LBP-specific activity limitations.
Learn More >An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish () is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.
Learn More >The COVID-19 pandemic has affected the entire world and catapulted the United States into one of the deepest recessions in history. While this pandemic rages, the opioid crisis worsens. During this period, the pandemic has resulted in the decimation of most conventional medical services, including those of chronic pain management, with the exception of virtual care and telehealth. Many chronic pain patients have been impacted in numerous ways, with increases in cardiovascular disease, mental health problems, cognitive dysfunction, and early death. The epidemic has also resulted in severe economic and physiological consequences for providers. Drug deaths in America, which fell for the first time in 25 years in 2018, rose to record numbers in 2019 and are continuing to climb, worsened by the coronavirus pandemic. The opioid epidemic was already resurfacing with a 5% increase in overall deaths from 2018; however, the preliminary data show that prescription opioid deaths continued to decline, while at the same time deaths due to fentanyl, methamphetamine, and cocaine climbed, with some reductions in heroin deaths. The health tracker data also showed that along with an almost 88% decline in elective surgeries, pain-related prescriptions declined 15.1%. Despite increases in telehealth, outpatient services declined and only began returning towards normal at an extremely slow pace, accompanied by reduced productivity and increased practice costs. This review, therefore, emphasizes the devastating consequences of concurrent epidemics on chronic pain management and the need to develop best practice efforts to preserve access to treatment for chronic pain.
Learn More >Inflammatory Bowel Disease (IBD) is a life-long disorder that often begins between the ages of 15 and 30. Anecdotal reports suggest cannabinoids may be an effective treatment. This study sought to determine whether home cage wheel running is an effective method to assess IBD, and whether THC, the primary psychoactive compound in cannabis, can restore wheel running depressed by IBD. Adolescent and adult female Sprague-Dawley rats were individually housed in a cage with a running wheel. Rats were injected with trinitrobenzene sulphonic acid (TNBS) into the rectum to induce IBD-like symptoms. One day later, both vehicle and TNBS treated rats were injected with a low dose of THC (0.32 mg/kg, s.c.) or vehicle. Administration of TNBS depressed wheel running in adolescent and adult rats. No antinociceptive effect of THC was evident when administered 1 day after TNBS. In fact, administration of THC prolonged TNBS-induced depression of wheel running for over 5 days in adolescent and adult rats. These results show that home cage wheel running is affected by TNBS-induced IBD, making it a useful tool to evaluate the behavioral consequences of IBD, and that administration of THC, instead of producing antinociception, exacerbates TNBS-induced IBD. Perspective This article advances research on inflammatory bowel disease in two important ways: 1) Home cage wheel running is a new and sensitive tool to assess the behavioral consequences of IBD in adolescent and adult rats; and 2) Administration of the cannabinoid THC exacerbates the negative behavioral effects of IBD.
Learn More >While patient perceptions of burden to caregivers is of recognized clinical significance among people with chronic pain, perceived burden to treating physicians has not been studied. This study examined how people with chronic pain perceived levels of medical evidence (low vs high) and pain severity (4,6,8/10) to influence physician burden and how burden then mediated expected clinical judgments. 476 people with chronic pain read vignettes describing a hypothetical patient with varying levels of medical evidence and pain severity from the perspective of a treating physician, rated the burden that patient care would pose, and made a range of clinical judgments. The effect of pain severity on clinical judgments was expected to interact with medical evidence and be conditionally mediated by burden. Although no associations with burden were found for the pain severity x medical evidence interaction or for pain severity alone, low levels of supporting medical evidence yielded higher burden ratings. Burden significantly mediated medical evidence effects on judgments of symptom credibility, clinical improvement, and psychosocial dysfunction. Results indicate that perceived physician burden negatively influenced judgments of patients with chronic pain, beyond the direct effects of medical evidence. Implications are discussed for clinical practice, as well as future research. Perspective People with chronic pain expect physicians to view the care of patients without supporting medical evidence as burdensome. Higher burden is associated with less symptom credibility, more psychosocial dysfunction, and less treatment benefit. Perceived physician burden appears to impact how patients approach treatment, with potentially adverse implications for clinical practice.
Learn More >Cisplatin plays an essential role in the treatment of various cancers. Cisplatin exhibits high efficacy, but it often leads to severe neurotoxic side effects, such as chemotherapy-induced polyneuropathy (CIPN). The pathophysiology of CIPN is not fully understood. There is increasing evidence for damage to satellite glial cells (SGC) and dorsal root ganglion (DRG) neurons. We investigated the influence of cisplatin on the function of SGCs and the direct influence on DRGs. Satellite glial cells were isolated from DRG and exposed to 0.1, 1, 10, or 100 μM cisplatin for 2 h, 4 h, and 24 h. Using immunocytochemical staining and Western blot analysis, the expression of the glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), and inward rectifier potassium channel 4.1 (K) was determined. An increase in the immune reactivity (IR) and protein levels of GFAP and ROS was measured, and a reduction of IR and protein level of K was detected. A decrease in these channels' current density was observed using the whole-cell patch-clamp recording. The interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) release of SGCs increased after cisplatin exposure as measured using ELISA, and interleukin-1β (IL-1β) decreased. The SGC-secreted factors in the supernatant after cisplatin treatment led to a modulation of cultured DRG neurons' excitability. Taken together, the modulation and function of different SGC proteins could be linked to a direct impact of cisplatin. Further, SGC-secreted factors influenced the excitability of sensory neurons. Overall, SGCs could be a potential target in preventing and treating chemotherapy-induced neuropathic pain.
Learn More >To explore small fiber somatosensory and sympathetic function in PD and MSA.
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