Analgesic Effects Of Opioids Research Articles

Development and validation of a risk-score model for opioid overdose using a national claims database

Opioid overdose can be serious adverse effects of opioid analgesics. Thus, several strategies to mitigate risk and reduce the harm of opioid overdose have been developed. However, despite a marked increase in opioid analgesic consumption in Korea, there have been no tools predicting the risk of opioid overdose in the Korean population. Using the national claims database of the Korean population, we identified patients who were incidentally prescribed non-injectable opioid analgesic (NIOA) at least once from 2017 to 2018 (N = 1,752,380). Among them, 866 cases of opioid overdose occurred, and per case, four controls were selected. Patients were randomly allocated to the development (80%) and validation (20%) cohort. Thirteen predictive variables were selected via logistic regression modelling, and a risk-score was assigned for each predictor. Our model showed good performance with c-statistics of 0.84 in the validation cohort. The developed risk score model is the first tool to identify high-risk patients for opioid overdose in Korea. It is expected to be applicable in the clinical setting and useful as a national level surveillance tool due to the easily calculable and identifiable predictors available from the claims database.

Rational Design, Chemical Syntheses, and Biological Evaluations of Peripherally Selective Mu Opioid Receptor Ligands as Potential Opioid Induced Constipation Treatment.

Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting μ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6β-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound 19 (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.

Immunomodulatory effects of pharmaceutical opioids and antipyretic analgesics: Mechanisms and relevance to infection.

Understanding how pharmaceutical opioids and antipyretic analgesics interact with the immune system potentially has major clinical implications for management of patients with infectious diseases and surgical and critical care patients. An electronic search was carried out on MEDLINE, EMBASE, PsycINFO, CENTRAL and the Cochrane library to identify reports describing the immunomodulatory effects of opioid analgesics and antipyretic analgesics, and their effects in infectious diseases. In adaptive immunity, nonsteroidal anti-inflammatory drugs have divergent effects: augmenting cell-mediated immunity but inhibiting humoral immunity. Nonsteroidal anti-inflammatory drugs have demonstrated a beneficial role in Mycobacterium tuberculosis infection and histoplasmosis in animals, and may be plausible adjuvants to antimicrobial agents in these diseases. There is a need to evaluate these findings rigorously in human clinical trials. There is preliminary evidence demonstrating antiviral effects of indomethacin in SARS CoV-2 in vitro; however, uncertainty regarding its clinical benefit in humans needs to be resolved in large clinical trials. Certain opioid analgesics are associated with immunosuppressive effects, with a developing understanding that fentanyl, morphine, methadone and buprenorphine suppress innate immunity, whilst having diverse effects on adaptive immunity. Morphine suppresses key cells of the innate immunity and is associated with greater risk of infection in the postsurgical setting. Efforts are needed to achieve adequate analgesia whilst avoiding suppression of the innate immunity in the immediate postoperative period caused by certain opioids, particularly in cancer surgery.

Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation.

Chronic pain is a complex sensory, cognitive, and emotional experience that imposes a great personal, psychological, and socioeconomic burden on patients. An estimated 1.5 billion people worldwide are afflicted with chronic pain, which is often difficult to treat and may be resistant to the potent pain-relieving effects of opioid analgesics. Attention has therefore focused on advancing new pain therapies directed at the cannabinoid system because of its key role in pain modulation. Endocannabinoids and exogenous cannabinoids exert their actions primarily through Gi/o-protein coupled cannabinoid CB1 and CB2 receptors expressed throughout the nervous system. CB1 receptors are found at key nodes along the pain pathway and their activity gates both the sensory and affective components of pain. CB2 receptors are typically expressed at low levels on microglia, astrocytes, and peripheral immune cells. In chronic pain states, there is a marked increase in CB2 expression which modulates the activity of these central and peripheral immune cells with important consequences for the surrounding pain circuitry. Growing evidence indicate that interventions targeting CB1 or CB2 receptors improve pain outcomes in a variety of preclinical pain models. In this mini-review, we will highlight recent advances in understanding how cannabinoids modulate microglia function and its implications for cannabinoid-mediated analgesia, focusing on microglia-neuron interactions within the spinal nociceptive circuitry.

Less Well-Known Consequences of the Long-Term Use of Opioid Analgesics: A Comprehensive Literature Review.

BackgroundThe adverse effects of short-term opioid analgesics are well known and acknowledged; however, the spectrum of the sequelae of long-term use seems less clear. Some effects may remain undetected but still have the potential to cause harm and reduce patients’ quality of life.ObjectiveTo review the literature on the adverse effects of long-term opioid therapy.MethodsWe performed a quasi-systematic search, analyzing articles published in the MEDLINE database between January 2000 and March 2021 that identified adverse effects of opioids used for chronic pain treatment.ResultsGrowing evidence indicates that there are multiple serious adverse effects of opioid treatment. Long-term opioid use may have significant effects on the endocrine, immune, cardiovascular, respiratory, gastrointestinal, and neural systems. Studies show that long-term opioid treatment increases the risk of fractures, infections, cardiovascular complications, sleep-disordered breathing, bowel dysfunction, overdose, and mortality. Opioids may potentially affect cancer development. Most consequences of the long-term use of opioids have been identified in studies of patients with non-malignant pain.ConclusionStudies indicate that long-term use of opioids increases the risk of drug-related events in a significant number of patients. Clinicians should be aware of these complications associated with prescribing opioids, discuss them with patients, prevent complications, if possible, and diagnose them early and manage adequately. More human studies are needed to assess the risk, including trials with individual opioids, because they have different adverse effect profiles.

Contribution of G-Protein α-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine.

While opioids produce both analgesia and side effects by action at μ-opioid receptors (MORs), at spinal and supraspinal sites, the potency of different opioids to produce these effects varies. While it has been suggested that these differences might be because of bias for signaling via β-arrestin versus G-protein α-subunits (Gα), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of Gα subunits, we evaluated the role of Gαi/o subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gαi2, Gαi3, and Gαo markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for Gαi1, as well as Gαi2 and Gαi3, but not Gαo, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gαi1 and Gαi2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while Gαi1 AS-ODN markedly reduced AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E2-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gαi3 and Gαo AS-ODN-treated rats, respectively. In contrast, none of the Gαi/o AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gαi/o subunits is necessary for the analgesia and side effects of two of the most clinically used opioid analgesics. The design of opioid analgesics that demonstrate selectivity for individual Gαi/o may produce a more limited range of side effects and enhanced analgesia.SIGNIFICANCE STATEMENT Biased μ-opioid receptor (MOR) agonists that preferentially signal through G-protein α-subunits over β-arrestins have been developed as an approach to mitigate opioid side effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense to different Gαi/o subunits play a role in hyperalgesia and analgesia induced by subanalgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G-protein α-subunits.

COMET – effectiveness and tolerability of methocarbamol versus oral opioid-analgesics as add-on measure in patients with non-specific low back pain refractory to recommended 1st line treatments. A retrospective analysis of depersonalized propensity score matched open-label real-world 4-week data from the German Pain e-Registry

Background To compare the 4-week effectiveness and tolerability of an add-on treatment with oral high dose methocarbamol (MET) vs long-acting oral opioid analgesics (LAO) in patients with non-specific low back pain (nsLBP) poorly responsive to recommended 1st line treatments. Methods Analysis of anonymized, propensity score-matched real-world data from the German Pain e-Registry, using a sequential non-inferiority superiority approach, for adult outpatients with nsLBP who had initiated treatment with MET or LAO between 1st January 2018 and 31st December 2019 (EUPAS identifier: 38484). The primary effectiveness variable was the absolute change of the average 24-h. pain intensity index (PIX). Safety was assessed by incidence of physician-confirmed drug-related adverse events (DRAEs), and DRAEs leading to discontinuation. Results Propensity score-matched data were analyzed for 374 patients treated with MET and 374 patients treated with LAO. Mean ± SD (median) MET dose over the 4-week evaluation period was 2390.4 ± 1980 (3000) mg and 69.6 ± 25.9 (60) mg morphine equivalent for LAO. With 25.8 ± 11.4 (median 26, 95%CI: 24.5–27.1) vs. 11.4 ± 6.8 (median 11; 95%CI: 10.6–12.2) mm VAS, absolute 4-week improvement vs. baseline was superior for MET vs. LAO [p < .001; effect size 1.6; least square mean difference 14.4 (95%CI: 13.4–15.3)]. Percentages of patients with a PIX improvement ≥ MCID was 81.8 vs. 24.6% [p < .001; OR: 13.8 (9.7–19.6), RR: 4.0 (3.2–5.0), NNT: 1.7]. A significantly lower number of patients treated with MET vs. LAO reported DRAEs in response to study medication: 36 (9.6%) vs. 139 (37.2%; p < .001; NNT 4), and 9 patients treated with MET (2.4%) vs. 86 (23.0%) treated with LAO discontinued treatment in response to these DRAEs (p < .001; NNT: 5). Conclusion 4-week add-on treatment with MET in patients with nsLBP who showed an inadequate response to recommended 1st line treatments is superior effective to LAO and significantly better tolerated. KEY MESSAGES Low back pain is the most common musculoskeletal problem worldwide. In the majority of patients, LBP does not have a specific cause and the most prevalently coded form is mechanical, non-specific (ns) LBP associated with muscular tension, restrictions in mobility, and static malposition. Current treatment recommendations for nsLBP are largely “non-specific” as well, limited to symptomatic pain-relieving measures. In our propensity score-matched two cohort analyses of depersonalized real-world data from the German Pain e-Registry, a 4-week treatment with the muscle relaxant methocarbamol proved superior effective and significantly better tolerated than treatment with oral long-acting opioid analgesics in patients who poorly responded to recommended 1st line treatments.

Opioids for procedural pain in neonates

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To determine the effects of opioid analgesics in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non‐pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route.

N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance

Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine’s antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3–30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance.

Effect of adjuvant drugs on the analgesic activity of opioid morphine analgesics and compound RU-1205

Introduction: Adjuvant medications can be used to increase the analgesic effect of opioid analgesics, reduce the manifestation of side effects, and also for premedication. This paper provides information on the effect of clonidine, haloperidol, metocloparmide, diazepam, midazolam on opioid analgesics: - morphine and the selective kappa-opioid agonist compound RU-1205.&#x0D; Materials and methods: A probable interaction between RU-1205, morphine and adjuvant drugs in pain behaviors was carried out on the model of somatogenic pain. 95 male mice received either RU-1205 (5 mg/kg, i.p.) and morphine (1 mg/kg, i.p.) separately or in combination with haloperidol (0.45 mg/kg, i.p.); midazolam (0.3 mg/kg, i.p.); diazepam (1 mg/kg, i.p.); metoclopramide (5 mg/kg, i.p.), and clonidine (1 mg/kg, i.p.). The analgesic effect was assessed by tail flick test. Registration of the latent period of the reaction was carried out 30, 60 and 90 minutes after the adjuvant drug administration.&#x0D; Results: When studying the interaction with morphine, it was found that clonidine, haloperidol and metoclopramide enhanced the effects; diazepam offset them, and midazolam had no affect on the analgesic properties. In the course of the studies, RU-1205 showed an increase in analgesic activity when combined with clonidine, a slight increase with midazolam, and a decrease when co-administered with diazepam. Haloperidol had no influence on the effect of RU-1205, while metoclopramide both potentiated and reduced the analgesic effect.&#x0D; Discussion: Pharmacodynamic and pharmacokinetic interactions of RU-1205 with an α2AR agonist, benzodiazepine receptor agonists, D2P antagonist, and σ-receptor blocker were established.&#x0D; Conclusion: The presented data make it possible to more accurately formulate ideas about the localization and action mechanism of the kappa-agonist of opioid receptors, the compound RU-1205.

Effectiveness, Safety, and Tolerability of Nabiximols Oromucosal Spray vs Typical Oral Long-Acting Opioid Analgesics in Patients with Severe Neuropathic Back Pain: Analysis of 6-Month Real-World Data from the German Pain e-Registry.

ObjectiveTo compare the effectiveness, safety, and tolerability of add-on nabiximols (NBX) oromucosal spray vs typical oral long-acting opioid (LAO) analgesics in patients with severe (± chronic) peripheral neuropathic back pain poorly responsive to other treatments.MethodsRetrospective analysis of anonymized, propensity score–matched data from the German Pain e-Registry of adult outpatients who initiated NBX or LAO between March 2017 and March 2020.ResultsData were analyzed from propensity score–matched patients treated with NBX (n = 655) or LAO (n = 655): mean age ≈51 years; 57% female; mean pain duration ≈2.6 years; chronic pain 61%; severe dysfunctional pain 93%. At 6 months, NBX was noninferior to LAO for overall symptom relief, based on the least-squares mean difference between cohorts in change from baseline in patient-reported, pain-related aggregated nine-item scale scores (−27.84%; 95% confidence interval [CI] −29.71 to −25.96; P < 0.001) and individual pain-related scale scores. Subsequent prespecified superiority analysis of the primary endpoint showed that NBX was superior to LAO: all secondary endpoints measuring symptoms of pain and physical function improved significantly with NBX and LAO, with between-group differences favoring NBX (all P < 0.001). Fewer patients treated with NBX than LAO experienced treatment-related adverse events (25.5% vs 76.0%; P < 0.001) or discontinued treatment because of treatment-related adverse events (7.9% vs 29.3%; P < 0.001).ConclusionWithin study limitations (e.g., observational design, all potential biases), add-on NBX was superior to and better tolerated than add-on treatment with typical oral LAO analgesics in patients with neuropathic back pain inadequately controlled by recommended/established systemic therapies.

Evaluation of G protein bias and β-arrestin 2 signaling in opioid-induced respiratory depression

Respiratory depression is a potentially fatal side effect of opioid analgesics and a major limitation to their use. G protein-biased opioid agonists have been proposed as "safer" analgesics with less respiratory depression. These agonists are biased to activate G proteins rather than β-arrestin signaling. Respiratory depression has been shown to correlate with both G protein bias and intrinsic efficacy, and recent work has refuted the role of β-arrestin signaling in opioid-induced respiratory depression. In addition, there is substantial evidence that G proteins do, in fact, mediate respiratory depression by actions in respiratory-controlling brainstem neurons. Based on these studies, we provide the perspective that protection from respiratory depression displayed by newly developed G protein-biased agonists is due to factors other than G protein versus arrestin bias.

Perioperative gabapentinoid use lowers short-term opioid consumption following lower limb arthroplasty: Systematic review and meta-analysis.

The management of post-operative pain and high levels of acute and chronic opioid use following total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain challenges to the perioperative team. We performed a system-atic review and meta-analysis to determine the opioid sparing effects, analgesic effects, and safety profile of perioperative gabapentinoid usage in lower limb arthroplasty. We searched multiple databases from inception until May 2019 and included randomized controlled trials (RCT) on perioperative gabapentinoids in lower limb arthroplasty. The primary outcome was cumulative opioid con-sumption (oral morphine equivalents) at 24 and 48 hours, and the secondary outcomes were pain scores, time to hospi-tal discharge, and adverse events including nausea, vomiting, pruritus, and sedation. Methodological quality was as-sessed using the Cochrane tool. The grading of recommendations assessment, development, and evaluation method-ology for the certainty of evidence was also used. We included 19 RCT involving 2,455 patients undergoing lower limb arthroplasty. The overall methodological quality of included studies was good. Gabapentinoid use was associated with a significant reduction in opioid consump-tion at 24 hour (mean difference (MD) 22.81 mg [95 percent Confidence Interval (CI) 13.64-31.98]) and 48 hour (MD 44.03 mg [95 percent CI 16.92-71.14]). We found no meaningful difference in pain scores at rest between gabapenti-noid and placebo groups at 24 or 48 hours. Gabapentinoid use reduced the risk of post-operative nausea (risk ratio (RR) 0.69 [95 percent CI 0.57-0.82]), vomiting (RR 0.65 [95 percent CI 0.47-0.91]), and pruritus (RR 0.60 [0.37-0.98]), but not sedation (RR 1.25 [0.76-2.06]). There was no effect on time to discharge from hospital (MD-0.05 days [95 per-cent CI -0.31 to 0.20]. The addition of gabapentinoids to perioperative multimodal analgesia decreases opioid consumption fol-lowing lower limb arthroplasty, while also lowering rates of nausea, vomiting, and pruritus. Further study is required to evaluate the effect of gabapentinoid use on long-term opioid use and dependence.

Adverse effects of opioid analgesics from the central nervous system

Opioid analgesic drugs are widely used in the treatment of moderate to severe pain as well as symptomatic treatment of dyspnoea. However, the use of opioids may cause central adverse effects, such as delirium, cognitive impairment, sedation, hallucinations, myocloni, seizures, hyperalgesia, sleep and mood disorders. The ability to diagnose and properly manage the above adverse effects is important for the proper treatment of patients receiving opioid analgesics.

Improvements on a chemically contiguous hapten for a vaccine to address fentanyl-contaminated heroin

Unintentional overdose deaths related to opioids and psychostimulants have increased in prevalence due to the adulteration of these drugs with fentanyl. Synergistic effects between illicit compounds and fentanyl cause aggravated respiratory depression, leading to inadvertent fatalities. Traditional small-molecule therapies implemented in the expanding opioid epidemic present numerous problems since they interact with the same opioid receptors in the brain as the abused drugs. In this study, we report an optimized dual hapten for use as an immunopharmacotherapeutic tool in order to develop antibodies capable of binding to fentanyl-contaminated heroin in the periphery, thus impeding the drugs’ psychoactive effects on the central nervous system. This vaccine produced antibodies with nanomolar affinities and effectively blocked opioid analgesic effects elicited by adulterated heroin. These findings provide further insight into the development of chemically contiguous haptens for broad-spectrum immunopharmacotherapies against opioid use disorders.

Phenotypes of remodeling in respiratory physiology due to chronic opioid use

Deaths related to synthetic opioids have increased six-fold over the past 20 years. In comparison to the expansive foundation of literature investigating circuit and cellular level mechanisms involved with acute opioid induced respiratory depression (OIRD), very little is known about how chronic opioid use remodels respiration. Similarly, the understanding of tolerance to the euphoric and analgesic effects of opioids has been well studied, yet tolerance to the respiratory side effects of chronic opioid use has been largely ignored. One reason that this gap in knowledge may exist is that the rates of tolerance to the analgesic and euphoric effects of opioids appear to emerge faster than respiratory tolerance to opioids. The goal of this ongoing work is to investigate the mechanisms by which chronic fentanyl use influences the control of breathing and the development of tolerance to its depressive respiratory effects. Here, we introduce an adult mouse model of chronic opioid use. In this model, the synthetic opioid, fentanyl (0.7 mg/kg) was administered for up to ten days. Breathing was assessed prior to, during and after OIRD using unrestrained whole body plethysmography. Our preliminary findings indicate that after five days of fentanyl administration, the magnitude of OIRD is approximately 50% less (n=5) as compared to ORID during the first day of fentanyl. Moreover, assessing the hypoxic chemoreflex after five days of chronic fentanyl treatment reveals that the hypoxic ventilatory response (outside of the window of OIRD). In 2 of 5 subjects, pronounced periodic breathing emerged during baseline conditions after the fifth day of fentanyl administration. These results are consistent with phenotypes observed in individuals who chronically use opioids and/or receive treatment for chronic opioid use and suggest that chronic fentanyl use perturbs respiratory control outside of the immediate window of OIRD. Thus, our model can be used to examine the mechanisms that that drive pharmacodynamic changes to opioids and promote respiratory-related morbidities associated with chronic fentanyl use.

Optogenetic activation of preBötzinger Complex cells alleviates respiratory depression by opioids

Rationale Opioids are extensively used for their analgesic properties but present a variety of unwanted side effects, including tolerance, dependence and respiratory depression. The analgesic effect of opioids is due to activation of µ-opioid receptors (MOR) in the central nervous system and no treatments are currently available to prevent respiratory depression without reducing their analgesic properties. The neural circuits and mechanisms regulating respiratory depression, sedation, and analgesia by opioids often overlap, therefore making challenging the identification of the mechanisms regulating respiratory depression. Neurons expressing tachykinin precursor 1 peptide (TAC1) located in the preBötzinger Complex (preBötC) also co-express neurokinin-1 receptors (NK1R) and MORs. NK1R neurons are preferentially inhibited by opioids and play an essential role in mediating opioid-induced respiratory depression. Objective Here, we tested the hypothesis that optogenetic activation of TAC1-expressing preBötC cells will prevent or reverse respiratory rate depression by opioids. Methods Using a Cre-loxP recombination approach, we injected, in TAC1 Cre recombinase mice the adeno-associated virus containing the gene cassette of the excitatory channelrhodopsin-2 ChETA flanked between loxP sites. After a four weeks period to allow ChETA expression in targeted cells, a 200 µm optical fiber was positioned above the preBötC for laser stimulation with blue light (wavelength: 480 nm). Respiratory rate was measured in anesthetized mice with electromyographic recordings of thediaphragm and genioglossus muscles activity. Once breathing was stable (>20 min), the clinically-relevant µ-opioid drug fentanyl (1mg/kg) was administered by intramuscular injection. About 5 minutes after fentanyl injection, targeted preBötC cells were stimulated using laser stimulations (frequency: 30Hz, duration of stimulation: 330ms). Results Data show that fentanyl depressed respiratory rate by about 40% in 5 minutes and stimulation of TAC1-expressing preBötC cells increased breathing rate back to baseline level when the laser was on; an effect that was reversible. Conclusion TAC1-expressing preBötC may constitute cell targets to prevent respiratory rate depression by opioids. These results may help identify the cells mediating respiratory depression by opioids, an essential step toward the development of therapeutic targets to reduce the risk of opioids overdose and associated mortality.

Deciphering the Novel Role of Gαz in Mu Opioid Receptor Signaling

A better understanding of mu opioid receptor (MOR) signaling is necessary to combat the negative side effects of opioid analgesics. The MOR is a G protein coupled receptor that couples to the Gαi/o class of proteins; however, it is common to downplay the diversity within this class. Gαz is an often-overlooked member of this class, yet its prevalent expression in similar regions of the brain as opioid receptors suggests it may serve a distinct role in MOR signaling. Using a bioluminescence resonance energy transfer (BRET) sensor, we investigated the potential of Gαz and its regulator of G protein signaling counterpart, RGSZ, as a means to control both efficacy and potency of MOR agonists. To avoid hindering the MOR•Gαz interaction, Gα signaling was correlated to the interaction of Venus-tagged Gβγ with a non-functional, C-terminal fragment of its effector, G protein-coupled receptor kinase 3 (GRK3ct). As a result, agonist binding to MOR resulted in an increase in BRET due to G-protein dissociation. The full agonists DAMGO, β-endorphin, methadone, and fentanyl were more potent when MOR signaled through Gαz compared to other Gαi/o subunits tested. For example, the EC50 value was 3-fold greater when the MOR signaled through Gαi1 compared to Gαz. Interestingly, fentanyl was equally efficacious with similar Emax values with both Gα subunits. Additionally, partial agonists such as morphine, (-)pentazocine, and (-)cyclazocine were both more potent and more efficacious when the MOR signaled through Gαz compared to the other Gαi/o subunits. In the case of (-)pentazocine, when MOR signaled through Gαz, the EC50 value was 2-fold lower compared to when MOR signaled through Gαi1. Moreover, the Emax value was also 2-fold higher when the MOR signaled through Gαz compared to Gαi1. Next, RGSZ was transfected and again the BRET assay was used to determine potency and efficacy. When RGSZ was present in the system, the concentration-response curve of DAMGO had a significant rightward shift. Taken together, Gαz can enhance opioid potency and efficacy downstream of receptor binding.

A Highly Efficacious Carfentanil Vaccine That Blunts Opioid-Induced Antinociception and Respiratory Depression

The opioid epidemic remains a dire public health crisis with millions of people currently suffering from opioid use disorder (OUD) and tens of thousands dying each year. Synthetic opioids are most responsible for the crisis because of their extreme potency and ease of manufacture. Carfentanil for example has an estimated potency 10,000 times greater than morphine and thus is highly dangerous for human use. Herein, we report two synthetic opioid vaccines that elicited high-affinity antibodies against carfentanil and fentanyl with cross-reactivity to other synthetic opioids in mice and offered protection against opioid-induced respiratory depression, the primary cause of overdose deaths. These vaccines also successfully diminished drug biodistribution to the brain and shielded against opioid analgesic effects. Collectively, these findings provide new insights into the development of immunotherapeutic strategies aimed at opioid abuse and overdose.

Differences in Need for Opioids After Sinonasal Surgery at Day of Surgery and in the Postoperative Period.

In the last years, the use of opioid analgesics has increased, as well as their morbidity and mortality, especially in the United States. Most patients after sinonasal surgery receive opioid analgesics, although up to 90% have leftover opioid pills. Around 70% of these patients keep the opioid analgesics, which could possibly lead to improper use. The objective of the following study was the investigation of the need for, use of, timing and side effects of opioid and non-opioid analgesics after sinonasal surgery. This was a retrospective study of (n = 280) patients who underwent sinonasal surgery in the Otolaryngology Department of the University Erlangen-Nürnberg between January and December 2018. The postoperative pain (3-5 days after surgery) using the numeric rating scale and the postoperative need for on-demand opioids and non-opioid analgesics in relation to demographic and surgical parameters were evaluated. Of total, 59.64% of all patients received opioid analgesics postoperatively on the day of surgery. On the first postoperative day (POD1), the mean pain score yielded the highest values; however, only 0.71% of the patients needed opioid analgesics, and pain was sufficiently controlled with non-opioids or no pain medication at all. There was a significant reduction of the pain score from POD2 to 5 (P = .01; P < .01, respectively). Only 1.8% of the patients needed an opioid analgesic from POD1-5. Of total, 2.1% of the patients presented with a postoperative bleeding complication, and only 1 (0.4%) patient needed endoscopic coagulation. Our results indicate that the majority of patients need opioid analgesics almost exclusively on the day of surgery. There were no major complications in patients taking either opioid or non-opioids. Our results indicate that the postoperative pain regimen from POD1 should initially be started using non-opioid analgesics and be further escalated to opioid analgesics in individual cases.