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Opioids have been used to treat pain and invoke pleasure for centuries. Modern scientific advancements have led to more potent, synthetic opioids. While certainly more effective in treating pain, they can also be much more addictive. Over the years the scientific community has developed a clearer understanding of the role opioid receptors play in causing and treating opioid use disorders (OUD) and we now know that OUD can develop in individuals taking opioids for "legitimate" pain. Current guidelines suggest that all prescribers (especially those prescribing opioids) be capable treating OUD. Pharmacological advances have led to a wide array of safe and effective treatment options to address OUDs. This paper will discuss the history of opioid development, what is known about the transition from analgesic uses to addiction and modern evidenced based treatment strategies to address OUDs.
Learn More >Chronic non-cancer pain (CNCP) among patients with substance use disorder (SUD) poses a risk for worse treatment outcomes. Understanding the association of CNCP with SUD is important for informing the need and potential benefits of pain assessment/management among those with SUDs.
Learn More >The role of immune mediators, including pro-inflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel up-regulated IL-20 via dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.
Learn More >A cognitive task, the n-back task, was used to interrogate the cognitive dimension of pain in patients with implanted dorsal root ganglion stimulators (DRGS). Magnetoencephalography (MEG) signals from thirteen patients with implanted DRGS were recorded at rest and while performing the n-back task at three increasing working memory loads with DRGS-OFF and the task repeated with DRGS-ON. MEG recordings were pre-processed, then power spectral analysis and source localization were conducted. DRGS resulted in a significant reduction in reported pain scores (mean 23%, = 0.001) and gamma oscillatory activity ( = 0.036) during task performance. DRGS-induced pain relief also resulted in a significantly reduced reaction time during high working memory load ( = 0.011). A significant increase in average gamma power was observed during task performance compared to the resting state. However, patients who reported exacerbations of pain demonstrated a significantly elevated gamma power (F(3,80) = 65.011612, < 0.001, adjusted -value = 0.01), compared to those who reported pain relief during the task. Our findings demonstrate that gamma oscillatory activity is differentially modulated by cognitive load in the presence of pain, and this activity is predominantly localized to the prefrontal and anterior cingulate cortices in a chronic pain cohort.
Learn More >To employ systems biology-based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain.
Learn More >Atopic dermatitis (AD), a chronic, highly pruritic skin disorder, impairs quality of life (QoL). Janus kinase inhibitors suppress inflammatory and pruritus-associated cytokine signaling in AD.
Learn More >Dipyrone is an analgesic pro-drug used clinically to control moderate pain with a high analgesic efficacy and low toxicity. Dipyrone is hydrolyzed to 4-methylaminoantipyrine (4-MAA), which is metabolized to 4-aminoantipyrine (4-AA). Here, were investigate the involvement of peripheral cannabinoid CB and opioid receptor activation in the local antihyperalgesic effect of dipyrone and 4-MAA. The inflammatory agent, carrageenan was administered to the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test. Dipyrone or 4-MAA were locally administered 2.5 h after carrageenan. Following dipyrone injection, hindpaw tissue was harvested and its hydrolysis to 4-MAA was analyzed by mass spectrometry (MS). The selective CB receptor antagonist (AM630), naloxone (a non-selective opioid receptor antagonist), nor-BNI (a selective kappa-opioid receptor), CTOP (a selective mu-opioid receptor), or naltrindole (a selective delta-opioid receptor) was administered 30 min prior to 4-MAA. The results demonstrate that carrageenan-induced mechanical hyperalgesia was inhibited by dipyrone or 4-MAA in a dose-dependent manner. Dipyrone administered to the hindpaw was completely hydrolyzed to 4-MAA. The antihyperalgesic effect of 4-MAA was completely reversed by AM630, naloxone and nor-BNI, but not by CTOP or naltrindole. These data suggest that the local analgesic effect of dipyrone is mediated by its hydrolyzed bioactive form, 4-MAA and, at least in part, depends on CB receptor and kappa-opioid receptor activation. In conclusion, the analgesic effect of dipyrone may involve a possible interaction between the cannabinoid and opioid system in peripheral tissue.
Learn More >Chronic non-cancer pain (CNCP) is a significant health burden among adults. Standard behavioral therapies typically focus on targeting negative affect (NA) and yield only modest treatment effects. The aims of this study were to systematically review and investigate the association between positive affect (PA) and pain severity among adults with CNCP. Databases search included MEDLINE (PubMed), PsycINFO, CINAHL, ProQuest Dissertations and Theses, OLASTER, Open Grey, and PsyArXiv (inception to July 23, 2019). We analyzed studies that: (1) employed observational, experimental, or intervention study designs; (2) enrolled individuals with CNCP (pain ≥ 12 weeks); and (3) reported full quantitative results on outcomes. Two researchers independently screened articles, extracted data, and assessed the risk of bias. The main meta-analysis was followed by subgroup analyses. All analyses were performed using random-effects models. Formal tests for heterogeneity (Q-statistic; I) and publication bias (p-curve and p-uniform*) were performed. We meta-analyzed 29 studies with 3521 participants. Results demonstrated that PA inversely impacts pain severity in people with CNCP (r = -0.23). Subgroup analyses showed a significant effect for gender and marginally significant effects for age in studies that adjusted for NA. On average, effect sizes for observational studies were larger in studies with a higher proportion of female respondents and in studies that did not adjust for NA. Finally, larger effect sizes were found in intervention studies with older compared with younger samples.
Learn More >Chronic pain is a highly prevalent and complex health problem that is associated with a heavy symptom burden, substantial economic and social impact, and also, very few highly effective treatments. This review examines evidence for the efficacy and safety of magnesium in chronic pain. The previously published protocol for this review was registered in International Prospective Register of Systematic Reviews (PROSPERO), MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched until September 2018. We included randomized controlled trials (RCTs) comparing magnesium (at any dose, frequency, or route of administration) with placebo using participant-reported pain measures. A total of 9 RCTs containing 418 participants were included. Three studies examined neuropathic pain (62 participants), 3 examined migraines (190 participants), 2 examined complex regional pain syndrome (86 participants), and 1 examined low back pain with a neuropathic component (80 participants). Heterogeneity of included studies precluded any meta-analyses. No judgement could be made about safety because adverse events were inconsistently reported in the included studies. Evidence of analgesic efficacy from included studies was equivocal. However, reported efficacy signals in some of the included trials provide a rationale for more definitive studies. Future, larger-sized trials with good assay sensitivity and better safety assessment and reporting, as well as careful attention to formulations with optimal bioavailability, will serve to better define the role of magnesium in the management of chronic pain.
Learn More >There is a high prevalence of painful diabetic polyneuropathy (pDPN) with around one-third of all patients with diabetes suffering from pDPN. pDPN has debilitating consequences, with a major impact on morbidity and quality of life. Unfortunately, there is no globally licenced pharmacotherapy that modulates the underlying disease mechanisms to prevent or halt the progression of diabetic neuropathy. The cornerstone of treatment therefore remains optimising glycaemic control and cardiovascular risk factors, and symptom control. Evidence from placebo-controlled studies has shown that antidepressants and anticonvulsants are effective for alleviating pDPN. Current clinical guidelines recommend the treatment of pDPN through the use of amitriptyline (tricyclic antidepressant), duloxetine (serotonin norepinephrine reuptake inhibitor), gabapentin and pregabalin (α2-δ ligands), tramadol and tapentadol (μ receptor agonists and norepinephrine reuptake inhibitors) and topical agents such as capsaicin (transient receptor potential V1 receptor desensitizer), although the latter is known to cause degeneration of small nerve fibers. pDPN can be difficult to treat, which frustrates healthcare providers, patients and caregivers. There is an additional need for clinical trials of novel therapeutic agents and optimal combinations for the management of pDPN. This article reviews the pharmacological management of pDPN, emerging therapies, the difficulties of placebo response in clinical trials and novel proposed biomarkers of treatment response.
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