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The purpose of this study is to define the impact of preoperative opioid use on post-operative opioid use, patient-reported outcomes and revision rates in a cohort of patients receiving arthroscopic shoulder surgery METHODS: Patients who underwent shoulder arthroscopy were identified from an institutional database. Inclusion criteria were completion of preoperative and postoperative patient reported outcome measures (PROMs) at one-year follow-up, in addition to a questionnaire on use of opioids and number of pills per day. Outcomes assessed included postoperative PROM scores, postoperative opioid use, persistent pain, and achievement of the patient acceptable symptomatic state (PASS). A matched-cohort analysis was performed to evaluate the impact of opioid use on achievement of postoperative outcomes while a multivariate regression was performed to determine additional risk factors. Receiver operating characteristic curves were used to establish threshold values in oral morphine equivalents (OME) that predicted each outcome.
Learn More >Calcitonin gene-related peptide (CGRP) has recently been implicated in the pathogenesis of post-traumatic headache (PTH), which raises the prospect for therapeutic use of monoclonal antibodies targeting CGRP or its receptor. Therefore, we decided to assess the efficacy, tolerability, and safety of erenumab for prevention of persistent PTH attributed to mild traumatic brain injury.
Learn More >Abrocitinib, an oral, once-daily Janus kinase 1 selective inhibitor, was effective and well tolerated in a phase 3 monotherapy trial of patients with moderate-to-severe atopic dermatitis (AD).
Learn More >The descending serotonergic pathway, from the brainstem to spinal cord, modulates various aspects of pain processing. The spinal 5-hydroxytryptamine (5-HT) and 5-HT receptors play pivotal roles in pain modulation. Perospirone is a novel atypical antipsychotic that serves as a 5-hydroxytryptamine (5-HT) receptor agonist, a 5-HT receptor antagonist, and a dopamine D receptor antagonist. Little is known about the effect of perospirone on pain transmission. Here, we explored whether perospirone attenuated neuropathic and inflammatory pain in the spinal cord. A chronic constriction injury to the sciatic nerve was induced in male Sprague-Dawley rats. We evaluated the effects of intrathecal administration of perospirone (10, 20, or 40 μg) on mechanical and cold hyperalgesia using the electronic von Frey and cold plate tests, respectively. Normal rats were assessed in terms of inflammatory nociception using the formalin test and for motor coordination employing the rotarod test. To define the mechanism underlying the action of perospirone, the effects of intrathecal pretreatment with the 5-HT receptor antagonist WAY-100635, the 5-HT receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (DOI), and the dopamine D receptor agonist sumanirole on perospirone action were examined using the electronic von Frey test and cold plate test. Perospirone dose-dependently alleviated mechanical and cold hyperalgesia, but not inflammatory nociception in the spinal cord, and affected motor coordination. WAY-100635 reversed the antihyperalgesic action of perospirone significantly, but neither DOI nor sumanirole exhibited such an effect. We conclude that perospirone attenuates mechanical and cold hyperalgesia principally via 5-HT receptor activation in the spinal cord, and the agent is a promising novel candidate for neuropathic pain relief.
Learn More >Chronic pruritus is a cardinal symptom of the inflammatory skin disease atopic dermatitis (AD). Pathogenic mechanisms in the periphery, spinal cord and the brain have been implicated in AD-related pruritus. Therefore, both systemic and topical administration of drugs could potentially provide relief. Despite efforts to elucidate the mechanisms behind AD-related pruritus and the relative contribution of peripheral nervous system and central nervous system (CNS), specific and successful treatment options have not yet been developed. Several small molecule drugs are currently being investigated to treat AD and AD-related pruritus. These small molecule drugs can be applied systemically but also topically, as they are able to penetrate into the skin due to their small size. Small molecule drugs specifically targeting peripheral itch transmission, e.g. peripherally selective κ-opioid receptors agonists and neurokinin 1 receptors antagonists, have so far been unable to improve AD-related pruritus when applied systemically, possibly because of the lack of CNS activity. Current evidence from clinical and preclinical trials with centrally acting or peripherally selective oral κ-opioid receptors agonists implies that CNS activity is required for an antipruritic effect. CNS activity is, however, directly associated with CNS-mediated side-effects. On the other hand, topical application of small molecules with anti-inflammatory activity such as Janus kinase inhibitors and phosphodiesterase 4 inhibitors, and also of κ-opioid receptor agonists, has shown promising results regarding their ability to reduce AD-related pruritus. In conclusion, topical application of anti-inflammatory compounds appears to be a highly promising strategy for the treatment of AD-related pruritus.
Learn More >In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, ~20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors (proenkephalin, prodynorphin, and proopiomelanocortin) by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides bind to all three of the opioid receptor types (mu, delta, kappa), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been utilized to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e. to excised tissue) or in vivo (in animals), using antagonists of specific opioid receptors to infer endogenous peptide activity, and using positron-emission tomography (PET) to detect a change in receptor availability, a sign of peptide release. While each of these approaches have weaknesses, certain observations have been consistent across modalities thereby adding to our current understanding of the function of endogenous opioids. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.
Learn More >Fast purinergic signaling is mediated by ATP and ATP-gated ionotropic P2X receptors (P2XRs), and it is implicated in pain-related behaviors. The properties exhibited by P2XRs vary between those expressed in heterologous cells and in vivo. Several modulators of ligand-gated ion channels have recently been identified, suggesting that there are P2XR functional modulators in vivo. Here, we establish a genome-wide open reading frame (ORF) collection and perform functional screening to identify modulators of P2XR activity. We identify TMEM163, which specifically modulates the channel properties and pharmacology of P2XRs. We also find that TMEM163 is required for full function of the neuronal P2XR and a pain-related ATP-evoked behavior. These results establish TMEM163 as a critical modulator of P2XRs in vivo and a potential target for the discovery of drugs for treating pain.
Learn More >Paclitaxel-induced peripheral neuropathy (PIPN) is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous system. Antihypertensive drug losartan, an angiotensin II receptor type 1 (AT1R) blocker, was shown to have anti-inflammatory and neuroprotective effects in disease models, predominantly via activation of peroxisome proliferator-activated receptor gamma (PPARγ). Here, the effect of systemic losartan treatment (100 mg/kg/d) on mechanical allodynia and neuroinflammation was evaluated in rat PIPN model. The expression of pro-inflammatory markers protein and mRNA levels in dorsal root ganglia (DRGs) and spinal cord dorsal horn (SCDH) were measured with Western blot, ELISA and qPCR 10 and 21 days after PIPN induction. Losartan treatment attenuated mechanical allodynia significantly. Paclitaxel induced overexpression of C-C motif chemokine ligand 2 (CCL2), tumour necrosis alpha (TNFα) and interleukin-6 (IL-6) in DRGs, where the presence of macrophages was demonstrated. Neuroinflammatory changes in DRGs were accompanied with glial activation and pro-nociceptive modulators production in SCDH. Losartan significantly attenuated paclitaxel-induced neuroinflammatory changes and induced expression of pro-resolving markers (Arginase 1 and IL-10) indicating a possible shift in macrophage polarization. Considering the safety profile of losartan, acting also as partial PPARγ agonist, it may be considered as a novel treatment strategy for PIPN patients.
Learn More >Treating persistent neuropathic pain remains a major clinical challenge. Current conventional treatment approaches carry a substantial risk of toxicity and provide only transient pain relief. In this work, we show that the activity and expression of the inflammatory mediator secretory phospholipase-A (sPLA) enzyme increases in the spinal cord after painful nerve root compression. We then develop phospholipid micelle-based nanoparticles that release their payload in response to sPLA activity. Using a rodent model of neuropathic pain, phospholipid micelles loaded with the sPLA inhibitor, thioetheramide-PC (TEA-PC), are administered either locally or intravenously at the time of painful injury or 1-2 days afterwards. Local micelle administration immediately after compression prevents pain for up to 7 days. Delayed intravenous administration of the micelles attenuates existing pain. These findings suggest that sPLA inhibitor-loaded micelles can be a promising anti-inflammatory nanotherapeutic for neuropathic pain treatment.
Learn More >Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.
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