Aligning New Approaches to Accelerate the Development of Non-opioid Analgesic Therapies.
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ABSTRACT:
SUBMITTER: Sang CN
PROVIDER: S-EPMC7609808 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNon-opioid analgesics are prescribed in combination with opioids among patients with long bone fracture to reduce opioid prescribing needs, yet evidence is limited on whether they reduce the risk of serious opioid-related events (SOREs). We compared the risk of SOREs among hospitalized patients with long bone fracture discharged with filled opioid prescriptions, with and without non-opioid analgesics.DesignWe identified a retrospective cohort of analgesic-naïve adult patients with a long bone fracture hospitalization using the Merative MarketScan Commercial Database (2013-2020). The exposure was opioid and non-opioid analgesic (gabapentinoids, muscle relaxants, non-steroidal anti-inflammatory drugs, acetaminophen) prescriptions filled in the 3 days before through 42 days after discharge. The outcome was the development of new persistent opioid use or opioid use disorder during follow-up (day 43 through day 408 after discharge). We used Cox proportional hazards regression with inverse probability of treatment weighting with overlap trimming to compare outcomes among those that filled an opioid and a non-opioid analgesic to those that filled only an opioid analgesic. In secondary analyses, we used separate models to compare those that filled a prescription for each specific non-opioid analgesic type with opioids to those that filled only opioids.ResultsOf 29 489 patients, most filled an opioid prescription alone (58.4%) or an opioid and non-opioid (22.0%). In the weighted proportional hazards regression model accounting for relevant covariates and total MME, filling both a non-opioid analgesic and an opioid analgesic was associated with 1.63 times increased risk of SOREs compared with filling an opioid analgesic only (95% CI 1.41 to 1.89). Filling a gabapentin prescription in combination with an opioid was associated with an increased risk of SOREs compared with those that filled an opioid only (adjusted HR: 1.84 (95% CI1.48 to 2.27)).ConclusionsFilling a non-opioid analgesic in combination with an opioid was associated with an increased risk of SOREs after long bone fracture.Level of evidenceLevel III, prognostic/epidemiological.Study typeRetrospective cohort study.
| S-EPMC11253739 | biostudies-literature
Project description:Venom-derived compounds are of broad interest in neuropharmacology and drug development. α-Conotoxins are small disulfide-containing peptides from Conus snails that target nicotinic acetylcholine receptors (nAChRs) and are in clinical development for non-opioid-based treatment of intractable pain. Although refined by evolution for interaction with target prey receptors, enhancements of pharmacological properties are needed for use in mammalian systems. Therefore, we synthesized analogues of α-conotoxin RgIA using a combination of selective penicillamine substitutions together with natural and non-natural amino acid replacements. This approach resulted in a peptide with 9000-fold increased potency on the human α9α10 nAChR and improved resistance to disulfide shuffling compared to the native peptide. The lead analogue, RgIA-5474, potently blocked α9α10 nAChRs, but not opioid- or other pain-related targets. In addition, RgIA-5474 effectively reversed chemotherapy-induced neuropathic pain.
| S-EPMC8360267 | biostudies-literature
Project description:Pain management is the pillar of caring for patients with traumatic rib fractures. Intravenous lidocaine (IVL) is a well-established non-opioid analgesic for post-operative pain, yet its efficacy has yet to be investigated in trauma patients. We hypothesized that IVL is associated with decreased inpatient opioid requirements among patients with rib fractures. We retrospectively evaluated adult patients presenting to our Level 1 trauma center with isolated chest wall injuries. After 1:1 propensity score matching patients who received vs did not receive IVL, we compared the two groups' average daily opioid use, opioid use in the last 24 hours of admission, and pain scores during admissions hours 24-48. We performed multivariable linear regression for these outcomes (with sensitivity analysis for the opioid use outcomes), adjusting for age as a moderating factor and controlling for hospital length of stay and injury severity. We identified 534 patients, among whom 226 received IVL. Those who received IVL were older and had more serious injury. Compared to propensity-score matched patients who did not receive IVL, patients who received IVL had similar average daily opioid use and pain scores, but 40% lower opioid use during the last 24 hours of admission (p = 0.002). Multivariable regression-with and without sensitivity analysis-did not show an effect of IVL on any outcomes. IVL was crudely associated with decreased opioid requirements in the last 24 hours of admission, the time period associated with opioid use at 90 days post-discharge. However, we did not observe beneficial effects of IVL on multivariable adjusted analyses; we are conducting a randomized control trial to further evaluate IVL's opioid-sparing effects for patients with rib fractures.
| S-EPMC7521689 | biostudies-literature
Project description:Background and purposeOpioids are effective painkillers. However, their risk-benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required, but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the μ opioid receptor triggers both the antinociceptive and adverse effects of opioids.Experimental approachThe TREK1 potassium channel is activated downstream of μ receptor and involved in the antinociceptive activity of morphine but not in its adverse effects. Bypassing the μ opioid receptor to directly activate TREK1 could therefore be a safer analgesic strategy.Key resultsWe developed a selective TREK1 activator, RNE28, with antinociceptive activity in naive rodents and in models of inflammatory and neuropathic pain. This activity was lost in TREK1 knockout mice or wild-type mice treated with the TREK1 blocker spadin, showing that TREK1 is required for the antinociceptive activity of RNE28. RNE28 did not induce respiratory depression, constipation, rewarding effects, or sedation at the analgesic doses tested.Conclusion and implicationsThis proof-of-concept study shows that TREK1 activators could constitute a novel class of painkillers, inspired by the mechanism of action of opioids but devoid of their adverse effects.
| S-EPMC7520446 | biostudies-literature
Project description:Objective:Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design:This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting:Inpatient clinical research site. Subjects:Forty-two randomized subjects (73.8% male, 81% white, mean age?=?25 years). Methods:The primary objective was to evaluate single orally administered 100, 200, and 400?mg NKTR-181 doses in solution compared with 40?mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous system mu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design. Results:NKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P?<?0.0001). Drug Liking scores for oxycodone increased rapidly within 15?minutes and peaked at approximately one hour postdose, whereas Drug Liking (and most secondary abuse potential measures) for all doses of NKTR-181 were comparable with placebo for at least the first hour. Only the 400?mg Drug Liking scores were minimally differentiated vs placebo from one and a half to four hours, but remained significantly lower than oxycodone (P?<?0.003). NKTR-181 treatment-related adverse effects were mild and occurred at a lower rate compared with oxycodone. Conclusions:NKTR-181 demonstrated delayed onset of CNS effects and significantly lower abuse potential scores compared with oxycodone in recreational opioid users.
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Project description:There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or de novo donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.
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Project description:Parkinson disease (PD) treatment options have conventionally focused on dopamine replacement and provision of symptomatic relief. Current treatments cause undesirable adverse effects, and a large unmet clinical need remains for treatments that offer disease modification and that address symptoms resistant to levodopa. Advances in high-throughput drug screening methods for small molecules, developments in disease modelling and improvements in analytical technologies have collectively contributed to the emergence of novel compounds, repurposed drugs and new technologies. In this Review, we focus on disease-modifying and symptomatic therapies under development for PD. We review cellular therapies and repurposed drugs, such as nilotinib, inosine, isradipine, iron chelators and anti-inflammatories, and discuss how their success in preclinical models has paved the way for clinical trials. We provide an update on immunotherapies and vaccines. In addition, we review non-pharmacological interventions targeting motor symptoms, including gene therapy, adaptive deep brain stimulation (DBS) and optogenetically inspired DBS. Given the many clinical phenotypes of PD, individualization of therapy and precision of treatment are likely to become important in the future.
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Project description:Bronchopulmonary dysplasia (BPD) remains the most prevalent long-term morbidity of surviving extremely preterm infants and is associated with significant health care utilization in infancy and beyond. Recent advances in neonatal care have resulted in improved survival of extremely low birth weight (ELBW) infants; however, the incidence of BPD has not been substantially impacted by novel interventions in this vulnerable population. The multifactorial cause of BPD requires a multi-pronged approach for prevention and treatment. New approaches in assisted ventilation, optimal nutrition, and pharmacologic interventions are currently being evaluated. The focus of this review is the current state of the evidence for pharmacotherapy in BPD. Promising future approaches in need of further study will also be reviewed.
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Project description: Not available
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Project description:Kappa opioid receptors have exceptional potential as an analgesic target, seemingly devoid of many problematic Mu receptor side-effects. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side-effects limit clinical translation. We modify endogenous dynorphin peptides to improve drug-likeness and develop safer KOP receptor agonists for clinical use. Using rational, iterative design, we developed a series of potent, selective, and metabolically stable peptides from dynorphin 1-7. Peptides were assessed for in vitro cAMP-modulation against three opioid receptors, metabolic stability, KOP receptor selectivity, desensitisation and pERK-signalling capability. Lead peptides were evaluated for in vivo efficacy in a rat model of inflammatory nociception. A library of peptides was synthesised and assessed for pharmacological and metabolic stability. Promising peptide candidates showed low nanomolar KOP receptor selectivity in cAMP assay, and improved plasma and trypsin stability. Selected peptides showed bias towards cAMP signalling over pERK activity, also demonstrating reduced desensitisation. In vivo, two peptides showed significant opioid-like antinociception comparable to morphine and U50844H. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are somewhat biased peptide Kappa agonists they may lack many significant side-effects, such as tolerance, addiction, sedation, and euphoria/dysphoria, common to opioid analgesics.
| S-EPMC10020352 | biostudies-literature