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There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus.
Learn More >The burden of chronic pain in the United States is staggering. Concurrently, the problems associated with use of opioids for treatment of chronic pain have been prominently scrutinized in recent years. Buprenorphine is an opioid that is available for treatment of both chronic pain and opioid use disorder. Its use for chronic pain has been hampered by various factors including complex and often misunderstood pharmacology, challenges to transition and induction to buprenorphine from other opioids, provider perceptions around the legality of prescribing sublingual buprenorphine for pain, and insurance coverage limitations. This article reviews the pharmacology and clinical effectiveness of buprenorphine in the context of chronic pain treatment.
Learn More >Medical marijuana is becoming widely available to patients in the U.S. and with recreational marijuana now legalized in many states, patient interest is on the rise. The endocannabinoid system plays an important role in skin homeostasis in addition to broader effects on neurogenic responses such as pruritus and nociception, inflammation, and immune reactions. There are numerous studies of in vitro and animal models that provide insight into the possible mechanisms of cannabinoid modulation on pruritus, with the most evidence behind neuronal modulation of both peripheral itch fibers and centrally-acting cannabinoid receptors. In addition, human studies, while limited due to differences in cannabinoids used, disease models, and delivery method, have consistently shown significant reductions in both scratching and symptomatology in chronic pruritus. Clinical studies that have shown reduction in pruritus in several dermatologic (atopic dermatitis, psoriasis, asteatotic eczema, prurigo nodularis, allergic contact dermatitis) and systemic (uremic pruritus, cholestatic pruritus) diseases. These preliminary human studies warrant controlled trials to confirm the benefit of cannabinoids for treatment of pruritus and to standardize treatment regimens and indications. In patients who have refractory chronic pruritus after standard therapies, cannabinoid formulations may be considered as an adjuvant therapy where it is legal.
Learn More >Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small-molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo-controlled phase I trials of ubrogepant, spray-dried oral compressed tablet (SD-OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100-400 mg) and multiple (40-400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well-tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was < 5% at all time points. No participant in either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant SD-OCT demonstrated linear PK appropriate for acute treatment of migraine, with rapid uptake (time of maximum plasma concentration (t ): 2-3 hours) and no accumulation with daily use. Overall, there was no evidence of ubrogepant-associated hepatotoxicity with daily doses up to 400 mg for 10 days or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful strategy for characterizing hepatic safety in early drug development.
Learn More >Extramedical opioid use has escalated in recent years. A better understanding of cause-specific mortality in this population is needed to inform comprehensive responses.
Learn More >Capsaicin, derived from the chilli pepper plant, is available in high concentration (8%) patches to provide topical therapy for neuropathic pain. Its analgesic effects relate to defunctionalisation and nerve terminal retraction of predominantly C fibres in the dermis and epidermis. Systematic reviews and meta-analysis support its use for the management of post-herpetic neuralgia and HIV neuropathy with some evidence for use in painful peripheral diabetic neuropathy. The article concludes with advice on the practicalities of running a topical 8% capsaicin clinic for peripheral neuropathic pain.
Learn More >Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4β2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam.
Learn More >The gabapentinoids are often recommended as first-line treatments for the management of neuropathic pain. The differing pharmacodynamic and pharmacokinetic profiles can have implications for clinical practice. This article has summarised these key differences. In addition to their use in managing neuropathic pain, gabapentinoids are increasingly being used for off-label conditions despite the lack of evidence. Prescription rates for off-label conditions have overtaken that for on-label use. Similarly, the use of gabapentinoids in the perioperative period is now embedded in clinical practice despite conflicting evidence. This article summarises the risks associated with this increasing use. There is increasing evidence of the potential to cause harm in vulnerable populations such as the elderly and increasing prevalence of abuse. The risk of respiratory depression in combination with opioids is of particular concern in the context of the current opioid crisis. This article describes the practical considerations involved that might help guide appropriate prescribing practices.
Learn More >Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive Phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations which were used to inform the Phase III dose-selection rationale, based on approximately 800 participants pooled across two Phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain endpoints (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one Phase II trial. A population PK model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from Phase II to Phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the Phase III clinical trials.
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