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Osteoarthritis (OA) is a common cause of joint disease and activity limitation in adults. Common therapies to treat OA-related pain are oral and topical non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular (IA) corticosteroids. However, prolonged courses of oral NSAIDs are associated with systemic adverse effects and repeat IA corticosteroid injections may cause cartilage degeneration. IA NSAIDs may be an alternative therapy possibly minimizing systemic side effects while maintaining efficacy. Therefore, we sought to summarize the pharmacokinetics, safety and efficacy of IA NSAIDs to help providers make a more informed decision on the use of IA NSAIDs.
Learn More >Migraine is responsible for significant disability and societal burden. Recently, drugs targeting the calcitonin gene-related peptide (CGRP) pathway raised new hopes. CGRP, a potent vasodilator, plays a key role in the pathogenesis of migraine attacks. The deficiency of CGRP is involved in Raynaud's phenomenon, which consists of abnormal vasoconstriction of the digits. We aimed to assess the potential association of Raynaud's phenomenon with CGRP-targeting drugs, analyzing real-world data from the World Health Organization (VigiBase®).
Learn More >Multi-receptor targeting has been proposed as a promising strategy for the development of opioid analgesics with fewer side effects. Cebranopadol and AT-121 are prototypical bifunctional ligands targeting the nociceptin/orphanin FQ peptide receptor (NOP) and µ-opioid receptor (MOP) that elicit potent analgesia in humans and nonhuman primates, respectively. Cebranopadol was reported to produce typical MOP-related side effects such as respiratory depression and reward, whereas AT-121 appeared to be devoid of these liabilities. However, the molecular basis underlying different side effect profiles in opioid analgesics remains unknown. Here, we examine agonist-induced receptor phosphorylation and G protein signaling profiles of a series of chemically diverse mixed MOP/NOP agonists, including cebranopadol and AT-121. We found that these compounds produce strikingly different MOP phosphorylation profiles. Cebranopadol, AT-034 and AT-324 stimulated extensive MOP phosphorylation, whereas AT-201 induced selective phosphorylation at S375 only. AT-121, on the other hand, did not promote any detectable MOP phosphorylation. Conversely, none of these compounds was able to elicit strong NOP phosphorylation and low NOP receptor phosphorylation correlated with partial agonism in a GIRK-channel assay. Our results suggest a close correlation between MOP receptor phosphorylation and side effect profile. Thus, bifunctional MOP/NOP opioid ligands combining low efficacy G protein signaling at both NOP and MOP with no detectable receptor phosphorylation appear to be devoid of side-effects such as respiratory depression, abuse liability or tolerance development, as with AT-121.
Learn More >Existing guidelines advocate an updated therapeutic algorithm for chronic neuropathic pain (NeP), but pharmacotherapeutic management should be individualized to pain phenotypes to achieve higher efficacy. This study was aimed to evaluate the efficacy of medications, based on NeP phenotypes, and to propose symptom-based pharmacotherapy. This retrospective study was enrolled 265 outpatients with chronic NeP related to spinal disorders. The patients were classified into three groups: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients, and from clinical information. The proportions of patients with ≥ 30% and ≥ 50% reduction in NPSI score for each pain subtype (spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia) and drugs were evaluated. The pain reduction rate was significantly lower in patients with spinal cord-related pain, especially for paresthesia/dysesthesia. For spinal cord-related pain, duloxetine and neurotropin had insufficient analgesic effects, whereas mirogabalin was the most effective. Pregabalin or mirogabalin for radicular pain and duloxetine for cauda equina syndrome are recommended in cases of insufficient analgesic effects with neurotropin. The findings could contribute to better strategies for symptom-based pharmacotherapeutic management.
Learn More >We estimate the probability of successful development and duration of clinical trials for medications to treat neuropathic and nociceptive pain. We also consider the effect of the perceived abuse potential of the medication on these variables.
Learn More >Lumbar spinal stenosis is a prevalent and disabling cause of low back and leg pain in older persons, affecting an estimated 103 million persons worldwide. Most are treated nonoperatively. Approximately 600 000 surgical procedures are performed in the US each year for lumbar spinal stenosis.
Learn More >This review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence.
Learn More >Moderate-to-severe atopic dermatitis (AD) often requires long-term management with systemic therapies.
Learn More >Converging evidence shows that patients with fibromyalgia syndrome have signs of small fibre impairment, possibly leading to pain and autonomic symptoms, with a frequency that has not yet been systematically evaluated. To fill this gap, our review aims to define the frequency of somatic and autonomic small fibre damage in patients with fibromyalgia syndrome, as assessed by objective small fibre-related testing. We found 360 articles on somatic and autonomic small fibre assessment in patients with fibromyalgia. Out of the 88 articles assessed for eligibility, 20 were included in the meta-analysis, involving 903 patients with fibromyalgia. The estimated prevalence of somatic small fibre impairment, as assessed with skin biopsy, corneal confocal microscopy, and microneurography, was 49% (95% confidence interval (CI): 39-60%, I = 89%), whereas the estimated prevalence of autonomic small fibre impairment, as assessed with heart rate variability, sympathetic skin response, skin conductance, and tilt testing, was 45% (95% CI: 25-65%, I = 91%). Our study shows that a considerable proportion of patients with fibromyalgia have somatic and autonomic small fibre impairment, as assessed by extensive small fibre-related testing. Nevertheless, the heterogeneity and inconsistencies across studies challenge the exact role of small fibre impairment in fibromyalgia symptoms.
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