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This study investigated the safety and efficacy of mirogabalin, a novel, potent, selective ligand of the α2δ subunit of voltage-dependent Ca channels, for the treatment of postherpetic neuralgia (PHN). In this multicenter, double-blind, placebo-controlled phase 3 study, Asian patients ≥20 years with PHN were randomized 2:1:1:1 to placebo or mirogabalin 15, 20, or 30 mg/day for up to 14 weeks (NCT02318719). The primary efficacy endpoint was the change from baseline in average daily pain score at week 14, defined as a weekly average of daily pain (0 = "no pain" to 10 = "worst possible pain," for the last 24 hours). Of 765 patients randomized, 763 received ≥ 1 dose of the study drug and were included in the analysis; 303, 152, 153, and 155 received placebo, mirogabalin 15, 20, or 30 mg/day, respectively. A total of 671 (87.7%) patients completed the study. At week 14, the difference in average daily pain score least squares mean vs placebo was -0.41, -0.47, and -0.77, respectively; all mirogabalin groups showed statistical significance. The most common treatment-emergent adverse events were somnolence, nasopharyngitis, dizziness, weight increase, and edema, and all of them were mild or moderate in severity. Mirogabalin was superior to placebo in all groups for relieving PHN and appeared well tolerated.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >Management of bone cancer pain (BCP) is difficult because of its complex mechanisms, which has a major impact on the quality of patients' daily life. Recent studies have indicated that endoplasmic reticulum (ER) stress is involved in many neurological and inflammatory pathways associated with pain. However, the factors that contribute to ER stress and its causes in bone cancer pain are still unknown. In this study, we examined whether the ER stress response is involved in caspase signaling pathway-dependent apoptosis in neurons in the spinal dorsal horn of tumor-38 bearing rats and whether it thereby induces bone cancer pain.
Learn More >Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine.
Learn More >Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.
Learn More >Improved understanding of brain mechanisms regulating endogenous analgesia is important from a fundamental physiological perspective and for identification of novel therapeutic strategies for pain. The endocannabinoid system plays a key role in stress-induced analgesia, including fear-conditioned analgesia (FCA), a potent form of endogenous analgesia. Here we studied the role of the endocannabinoid 2-arachidonoyl glycerol (2-AG) within the anterior cingulate cortex (ACC; a brain region implicated in the affective component of pain) in FCA in rats.
Learn More >Systematic review of topical diclofenac for the treatment of acute and chronic musculoskeletal pain.
The objective was to systematically review the efficacy and safety of topically applied diclofenac in both acute and chronic musculoskeletal pain in adults. We used standard Cochrane methods. Searches were conducted in MEDLINE, EMBASE, and the Cochrane Register of Studies; the date of the final search was November 2018. Included studies had to be randomised and double blinded, with ten or more participants per treatment arm. Risk of bias was assessed. The primary outcome of "clinical success" was defined as participant-reported reduction in pain of at least 50%. Details of adverse events (AE) and numbers of withdrawals due to lack of efficacy (LoE) or AE were recorded. For acute pain, 23 studies (5170 participants) were included. All participants were treated for at least 5 days; most were treated for 7-14 days. Compared to placebo, number needed to treat (NNT) for different formulations were as follows: diclofenac flector plaster, 4.7 (95%CI 3.7-6.5); diclofenac plaster with heparin, 7.4 (95%CI 4.6-19); and diclofenac emulgel, 1.8 (95%CI 1.5-2.1).4.7% (65/1373) participants reported a systemic AE; 4.1% (78/1919) reported a local AE; and 1.3% (14/1063) withdrew due to an AE. Few participants withdrew due to LoE.For chronic pain, 21 studies (26 publications) with 5995 participants were included. The majority of studies focused on knee osteoarthritis pain. Formulations of diclofenac included gel, solution with or without DMSO, emulsion, and plaster. A clinical success rate of approximately 60% (NNT 9.5 [95%CI 7-14.7]) was achieved with a variety of diclofenac formulations. Local AEs (approximately 14%) were similar for both diclofenac and placebo. Event rate for systemic events was approximately 10%. Few serious events were reported, and between 0% and 17% of participants withdrew due to AEs. AEs were likely higher in the chronic group because participants were exposed to treatment for weeks rather than days. This large systematic review of over 11,000 participants demonstrates that topical diclofenac is effective for acute pain, such as sprains and strains, with minimal AEs. The effectiveness of topical diclofenac was also demonstrated in chronic musculoskeletal pain, such as osteoarthritis, but with a higher NNT (worse) compared with acute pain. Again, the incidence of AEs was low. Formulation does play a part in effectiveness, and studies are needed to investigate this further. Studies of chronic pain outside of osteoarthritis would also be helpful.
Learn More >The attrition of novel analgesic drugs in the clinic can be attributed in the main to two factors: failure of preclinical research findings translating into human pain conditions, and a drop-off of efficacy between proof-of-concept (i.e., Phase II trials) and pivotal, confirmatory (Phase III trials) testing. In order to enhance the efficiency of the clinical drug evaluation process and determine rapidly whether a potential therapeutic candidate gives pain relief, by modulating central pain neurobiology, we propose a 'pre-proof-of-concept' approach, in which an efficacy assessment is performed in a single individual (N-of-1) using subjective clinical pain assessments supported by objective validated functional neuroimaging measures. Using an N-of-1 + i methodology, clinical- and neuroimaging-based metrics can be quantified under conditions of drug versus placebo or drug versus current standard of care conditions.
Learn More >Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.
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