Opioid-induced Respiratory Depression Research Articles

Naloxone Dispensing in Patients at Risk for Opioid Overdose After Total Knee Arthroplasty Within the Veterans Health Administration.

Naloxone prescribing among patients undergoing surgery is not well described. This cohort study was designed to examine patients' risk factors for opioid overdose and their association with naloxone prescribing among veterans undergoing total knee arthroplasty (TKA) after a systemwide Overdose Education and Naloxone Distribution (OEND) initiative. A retrospective analysis of Veterans Health Administration (VHA) records was performed and consisted of 38,011 veterans undergoing primary TKA from 2013 to 2016. Patient overdose risk was determined using a validated risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) based on patient diagnoses, health care utilization, and prescription drug use. Naloxone dispensing was examined from the year before surgery until 7 days after discharge. These rates were examined the year prior to implementation of a national OEND initiative (2013), the year of implementation (2014), and 2 years following implementation (2015-2016). In 2013, 3.3% of patients presenting for TKA had moderate or high risk for overdose and none were prescribed naloxone. By 2016, after OEND implementation, 2.2% of patients presenting for TKA had moderate or high risk for overdose, but only 10.9% of the moderate-risk and 12.7% of the high-risk patients were prescribed naloxone. Patients presenting for TKA routinely have risk factors for opioid overdose and significant proportions are at moderate or high risk for overdose. Despite this, most patients at moderate and high risk do not receive perioperative naloxone. Risk mitigation strategies using validated tools such as RIOSORD may help identify surgical patients at greatest risk for opioid overdose who could benefit from OEND.

Contribution of the caudal medullary raphe to opioid induced respiratory depression

BackgroundOpioid-induced respiratory depression can be partially antagonized in the preBötzinger Complex and Parabrachial Nucleus/Kölliker-Fuse Complex. We hypothesized that additional opioid antagonism in the caudal medullary raphe completely reverses the opioid effect. MethodsIn adult ventilated, vagotomized, decerebrate rabbits, we administrated remifentanil intravenously at “analgesic”, “apneic”, and “very high” doses and determined the reversal with sequential naloxone microinjections into the bilateral Parabrachial Nucleus/Kölliker-Fuse Complex, preBötzinger Complex, and caudal medullary raphe. In separate animals, we injected opioid antagonists into the raphe without intravenous remifentanil. ResultsSequential naloxone microinjections completely reversed respiratory rate depression from “analgesic” and “apneic” remifentanil, but not “very high” remifentanil concentrations. Antagonist injection into the caudal medullary raphe without remifentanil independently increased respiratory rate. ConclusionsOpioid-induced respiratory depression results from a combined effect on the respiratory rhythm generator and respiratory drive. The effect in the caudal medullary raphe is complex as we also observed local antagonism of endogenous opioid receptor activation, which has not been described before.

Applying molecular dynamics to elucidate binding interactions for developing opioid overdose therapeutics

Opioid overdose kills 128 people every day in the United States. While there are treatments for opioid overdose, there are currently no therapeutic tools to prevent it. Moreover, these treatments are limited to emergency scenarios, most notably due to induction of withdrawal and loss of analgesia. Fatal opioid overdoses are primarily attributed to opioid-induced respiratory depression (OIRD). As part of an ongoing collaboration, a class of cysteine esters have been identified that reverse OIRD without blocking the analgesic effects of the opioid or inducing withdrawal.

Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the “TS + fentanyl” and “saline + fentanyl” group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.

Current research in pathophysiology of opioid-induced respiratory depression, neonatal opioid withdrawal syndrome, and neonatal antidepressant exposure syndrome

Respiratory depression (RD) is the primary cause of death due to opioids. Opioids bind to mu (µ)-opioid receptors (MORs) encoded by the MOR gene Oprm1, widely expressed in the central and peripheral nervous systems including centers that modulate breathing. Respiratory centers are located throughout the brainstem. Experiments with Oprm1-deleted knockout (KO) mice undertaken to determine which sites are necessary for the induction of opioid-induced respiratory depression (OIRD) showed that the pre-Bötzinger complex (preBötC) and the pontine Kölliker-Fuse nucleus (KF) contribute equally to OIRD but RD was not totally eliminated. Morphine showed a differential influence on preBötC and KF neurons – low doses attenuated RD following deletion of MORs from preBötC neurons and an increase in apneas after high doses whereas deletion of MORs from KF neurons but not the preBötC attenuated RD at both high and low doses. In other KO mice studies, morphine administration after deletion of Oprm1 from both the preBötC and the KF/PBN neurons, led to the conclusion that both respiratory centres contribute to OIRD but the preBötC predominates. MOR-mediated post-synaptic activation of GIRK potassium channels has been implicated as a cause of OIRD. A complementary mechanism in the preBötC involving KCNQ potassium channels independent of MOR signaling has been described. Recent experiments in rats showing that morphine depresses normal, but not gasping breathing, cast doubt on the belief that eupnea, sighs, and gasps, are under the control of preBötC neurons. Methadone, administered to alleviate symptoms of neonatal opioid withdrawal syndrome (NOWS), desensitized rats to OIRD. Protection lost between postnatal days 1 and 2 coincides with the preBötC becoming the dominant generator of respiratory rhythm. Neonatal antidepressant exposure syndrome (NADES) and serotonin toxicity (ST) show similarities including RD. Enzyme CYP2D6 involved in opioid detoxification is polymorphic. Individuals of different CYP2D6 genotype may show increased, decreased, or no enzyme activity, contributing to the variability of patient responses to different opioids and OIRD.

Chapter 12 - The pathophysiology of opioid-induced respiratory depression

Opiates, such as morphine, and synthetic opioids, such as fentanyl, constitute a class of drugs acting on opioid receptors which have been used therapeutically and recreationally for centuries. Opioid drugs have strong analgesic properties and are used to treat moderate to severe pain, but also present side effects including opioid dependence, tolerance, addiction, and respiratory depression, which can lead to lethal overdose if not treated. This chapter explores the pathophysiology, the neural circuits, and the cellular mechanisms underlying opioid-induced respiratory depression and provides a translational perspective of the most recent research. The pathophysiology discussed includes the effects of opioid drugs on the respiratory system in patients, as well as the animal models used to identify underlying mechanisms. Using a combination of gene editing and pharmacology, the neural circuits and molecular pathways mediating neuronal inhibition by opioids are examined. By using pharmacology and neuroscience approaches, new therapies to prevent or reverse respiratory depression by opioid drugs have been identified and are currently being developed. Considering the health and economic burden associated with the current opioid epidemic, innovative research is needed to better understand the side effects of opioid drugs and to discover new therapeutic solutions to reduce the incidence of lethal overdoses.

Pharmacological Features, Therapeutic Efficacy and Side Effects of Nalbuphine: A Review

Introduction: Opioids can provide effective analgesia and routinely utilized to treat mild severe pain. Problems related with mu- agonist opioids like nausea, emesis, bowel and bladder disturbances, respiratory depression, pruritus and developing tolerance and dependence. This article will review about the utilization of Nalbuphine, which is a mixed opioid agonist- antagonist that FDA has indicated in moderate to severe pain treatment when an opioid drug is essential and alternative treatment methods have failed. The incidence of the common opioid side effects are low in case of Nalbuphine. Non-FDA approved uses of nalbuphine are in labor analgesia, pruritus associated with opioid, opioid-induced urinary retention and respiratory depression. It can be administered with the regularly utilized mu- opioid agonists like morphine, fentanyl etc. as a combination, giving better analgesia along with abating the incidence as well as the severity of side effects caused by mu-agonist.&#x0D; Methodology: This review article was prepared after a thorough study of the literature using data search engines such as ‘Scopus’,’ PubMed’, ‘Web of Science’, and ‘Google Scholar’. This article referred to prior Nalbuphine observational studies and case reports.&#x0D; Review Findings: After learning the pharmacology, uses, contraindications of Nalbuphine and reviewing the previous observational studies and case reports about Nalbuphine, the drug can be used for treating moderate to severe pain when an opioid drug is essential and reserve treatment methods have failed. Nalbuphine finds its use also in labor analgesia. The incidence of the usual side effects due to opioids are low in case of Nalbuphine. It can be administered with the regularly utilized mu- opioid agonists like morphine, fentanyl etc. as a combination , giving better analgesia along with abating the incidence as well as the severity of side effects caused by mu-agonist.&#x0D; Conclusion: Nalbuphine can be utilized for treating moderate to severe pain, as an adjuvant to balanced anesthesia for pre-operative / post-operative pain relief, for labor analgesia and to treat/ reduce the opioid induced side effects.

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity.

Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

Knowledge of opioid-induced respiratory depression among Chinese health care professionals: A cross-sectional study

ObjectiveThe purposes of this study were to measure knowledge about opioid-induced respiratory depression (OIRD) among Chinese health care professionals and explore the associated factors that influence Chinese health care professionals’ knowledge. MethodsA cross-sectional survey was conducted. A convenience sample of 900 Chinese health care professionals from 21 provinces, four municipalities, and four autonomous regions was used. The OIRD knowledge questionnaire, which is a self-designed questionnaire based on evidence, was used to judge the degree of knowledge among Chinese health care professionals according to the accuracy rate. The questionnaire included questions on six dimensions of knowledge. Sociodemographic characteristics were also measured by a multi-item questionnaire. ResultsThe overall accuracy rate on the OIRD knowledge questionnaire for all participants were 64.5% ±10.0% (mean ± SD) with a range from 20% to 100%. According to univariate analysis, Chinese health care professionals’ OIRD knowledge was positively correlated with age, region, profession, hospital level, type of hospitals and departments, education level, years of clinical working, and clinical practice of chronic cancer pain (CP) management. Multiple linear regression analysis showed differences in professions and regions (all P ​< ​0.05). ConclusionsMost Chinese health care professionals had misconceptions about OIRD and lacked relevant knowledge. We should assign importance to developing targeted training programs and exploring feasible and effective training methods.

A Retrospective Review of Opioid Prescribing Practices for At-Risk Pediatric Populations Undergoing Ambulatory Surgery.

Pediatric patients with sleep-disordered breathing (SDB) and obesity are at risk for opioid-induced respiratory depression. Although monitoring in the inpatient setting allows for early recognition of opioid-related adverse events, there is far less vigilance after ambulatory surgery as patients are discharged home. Guidelines for proper opioid dosing in these pediatric subsets have not been established. We sought to determine if at-risk children were more likely to receive doses of opioids outside the recommended range. Baseline opioid prescribing data for all outpatient surgery patients receiving an opioid prescription between January 2019 and June 2020 were retrospectively reviewed. Patients with SDB or obesity were identified. To obtain more information about prescribing practices, we analyzed patient demographics, size descriptors used for calculations, and prescription characteristics (dose, duration, and prescribing surgical service). A total of 4674 patients received an opioid prescription after outpatient surgery. Of those, 173 patients had SDB and 128 were obese. Surgical subspecialties rendering most of the opioid prescriptions included otolaryngology and orthopedics. Obese patients were more likely (64%) to be prescribed opioids using ideal weight at higher mg/kg doses (>0.05 mg/kg; 83.3%; p < 0.0001). When providers used actual body weight, lower mg/kg doses were more likely to be used (53.7%; p < 0.0001). No prescriptions used lean body mass. Overweight/obese children were more likely to receive opioid doses outside the recommended range. Variability in prescribing patterns demonstrates the need for more detailed guidelines to minimize the risk of opioid-induced respiratory complications in vulnerable pediatric populations.

Abstract 14444: A Novel Role for the Hypothalamic Paraventricular Nucleus in Resuscitation From Opioid-Induced Respiratory Depression by Fentanyl in the Rat

Introduction: Opioid receptor antagonists, like naloxone, reverses opioid-induced respiratory depression (OIRD). We recently found that systemic oxytocin reverses fentanyl OIRD in rats. Naloxone triggers a surge in oxytocin release from the hypothalamic paraventricular nucleus (PVN) in anesthetized rats. Hypothesis: Given that naloxone induces PVN oxytocin release, we hypothesized that the PVN, an unrecognized brain region for opioid overdose reversal, is capable of respiratory resuscitation following fentanyl OIRD. Methods: Naloxone (5 mg/kg, i.v.) was given to conscious rats with indwelling venous cannulae. Blood samples were extracted at 5 min post-naloxone to measure plasma oxytocin by ELISA. Under anesthesia, phrenic nerve activity was recorded in vagotomized, paralyzed, and artificially ventilated rats to quantify inspiratory drive following fentanyl (60 nmol/kg, i.v.) and assess OIRD reversal potential following unilateral PVN nanoinjection of naloxone (3 nmol/kg, 50 nL) or vehicle (50 nL). In spontaneously breathing mice with channelrhodopsin expressed exclusively in oxytocin neurons, expired CO 2 was used to monitor rhythmic ventilation and to quantify bradypnea during OIRD. Following fentanyl, blue light (473 nm, 12 mW) pulses (10 ms, 20 Hz) or dummy pulses were delivered to the PVN using a 5 s On/1 s Off pattern for 3 min. Results: Systemic naloxone resulted in a surge in plasma oxytocin compared to vehicle in the conscious rat. Naloxone in PVN both reversed and prevented OIRD by systemic fentanyl in the rat. Photostimulation of PVN oxytocin neurons prevented lethal effects of fentanyl OIRD, whereas dummy pulses failed to prevent lethal respiratory arrest in the mouse. Conclusions: Here, we confirm that naloxone stimulates oxytocin neurons of the PVN and results in a surge of plasma oxytocin. PVN opioid receptor antagonism and photoactivation of PVN oxytocin neurons are individually capable of reversing OIRD. Findings also indicate that PVN oxytocin neurons, previously unrecognized in reversal of OIRD, are a novel target for resuscitation agents.

Nurses' Ability to Recognize and Prevent Opioid-Induced Respiratory Depression: An Evidenced-Based Practice Project.

Opioids are the primary therapy for acute postoperative pain, despite being associated with opioid-induced respiratory depression (OIRD). The purpose of this study was to improve nurses' knowledge, confidence, and ability to recognize, prevent, and treat OIRD in postoperative inpatients and evaluate the feasibility of using the Pasero Opioid-Induced Sedation Scale (POSS). Registered nurses completed three tools: (1) an Opioid Knowledge Self-Assessment, which was administered pre- and post-education; (2) a Confidence Scale, which was administered pre- and post-education; and (3) a POSS Perceptions and Usability Scale that was administered post-education. Nurses were educated on the POSS and then immediately following the training practiced by undertaking a patient assessment using the instrument. They then completed the POSS Perceptions and Usability Scale to rate their perception of the feasibility of using the POSS. Between preeducation and posteducation, participant knowledge increased in the following areas: recognizing opioid-induced side effects, dose selection, risk factors for oversedation, and information to make clinical decisions. However, there was a drop in scores when asked about knowledge of who is at risk for opioid-related side effects. These findings support our conclusion that OIRD education improves nursing confidence and knowledge. There was significant agreement between the nurse and subject matter experts POSS scores, indicating that this tool is easy to use.

Dynamic Rhythmogenic Network States Drive Differential Opioid Responses in the In Vitro Respiratory Network.

Death from opioid overdose is typically caused by opioid-induced respiratory depression (OIRD). A particularly dangerous characteristic of OIRD is its apparent unpredictability. The respiratory consequences of opioids can be surprisingly inconsistent, even within the same individual. Despite significant clinical implications, most studies have focused on average dose-r esponses rather than individual variation, and there remains little insight into the etiology of this apparent unpredictability. The preBötzinger complex (preBötC) in the ventral medulla is an important site for generating the respiratory rhythm and OIRD. Here, using male and female C57-Bl6 mice in vitro, we demonstrate that the preBötC can assume different network states depending on the excitability of the preBötC and the intrinsic membrane properties of preBötC neurons. These network states predict the functional consequences of opioids in the preBötC, and depending on network state, respiratory rhythmogenesis can be either stabilized or suppressed by opioids. We hypothesize that the dynamic nature of preBötC rhythmogenic properties, required to endow breathing with remarkable flexibility, also plays a key role in the dangerous unpredictability of OIRD.SIGNIFICANCE STATEMENT Opioids can cause unpredictable, life-threatening suppression of breathing. This apparent unpredictability makes clinical management of opioids difficult while also making it challenging to define the underlying mechanisms of OIRD. Here, we find in brainstem slices that the preBötC, an opioid-sensitive subregion of the brainstem, has an optimal configuration of cellular and network properties that results in a maximally stable breathing rhythm. These properties are dynamic, and the state of each individual preBötC network relative to the optimal configuration of the network predicts how vulnerable rhythmogenesis is to the effects of opioids. These insights establish a framework for understanding how endogenous and exogenous modulation of the rhythmogenic state of the preBötC can increase or decrease the risk of OIRD.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Incidence and Outcomes of Life-Threatening Events During Hospitalization: A Retrospective Study of Patients Treated with Naloxone.

We describe the clinical course of medical and surgical patients who received naloxone on general hospital wards for suspected opioid-induced respiratory depression (OIRD). From May 2018 through October 2020, patients who received naloxone on hospital wards were identified and their records reviewed for incidence and clinical course. There were 86,030 medical and 106,807 surgical admissions. Naloxone was administered to 99 (incidence 11.5 [95%confidence interval 9.4-14.0] per 10,000 admissions) medical and 63 (5.9 [95%confidence interval 4.5-7.5]) surgical patients (P < 0.001). Median oral morphine equivalents administered within 24 hours before naloxone were 32 [15, 64] and 60 [32, 88] mg for medical and surgical patients, respectively (P = 0.002). The rapid response team was activated in 69 (69.7%) vs 42 (66.7%) and critical care transfers in 51 (51.5%) vs 30 (47.6%) medical and surgical patients respectively. The number of in-hospital deaths was 21 (21.2%) vs two (3.2%) and the number of discharges to hospice 12 (12.1%) vs one (1.6%) for medical and surgical patients, respectively (P = 0.001). Naloxone did not reverse OIRD in 38 (23%) patients, and these patients had more transfers to the intensive care unit and a higher 30-day mortality rate. Medical inpatients are more likely to suffer OIRD than are surgical inpatients despite lower opioid doses. Definitive OIRD was confirmed in 77% of patients because of immediate naloxone response, whereas 23% of patients did not respond, and this subset was more likely to need a higher level of care and had a higher 30-day mortality rate. Careful monitoring of mental and respiratory variables is necessary when opiates are used in hospital.

Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent

BackgroundOne of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids.MethodsA series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay.ResultsA series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488.ConclusionsMethods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

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.

Preventing Postoperative Opioid-Induced Respiratory Depression Through Implementation of an Enhanced Monitoring Program.

Opioid-induced respiratory depression (OIRD) is a serious complication that can lead to negative outcomes. There are known risk factors for OIRD; however, a lack of national guidelines for the prevention and early detection of OIRD exists. An evidence-based practice study was conducted to create an enhanced monitoring (EM) program. The EM program consisted of risk stratification of surgical spine patients, including the use of STOP-BANG screening for obstructive sleep apnea, capnography monitoring, use of home positive airway pressure therapy, capnography alarm optimization, hospitalist consultation, nursing education, and patient education. Approximately 17% (N = 937/5,462) of surgical spine patients were enrolled in the EM program. Fifty-six percent of EM patients were monitored with capnography and had out of range end-tidal carbon dioxide levels 17% of the time. The rate of transfers to the intensive care unit (ICU) for OIRD decreased, though not statistically significant (p = .151). The EM program with risk stratification was found to reduce transfers to the ICU for OIRD. Although not statistically significant, the decreased number of transfers was clinically significant. Engagement of the interprofessional team and capnography alarm parameter optimization helped to reduce nonactionable alarms.

Safety evaluation of oliceridine for the management of postoperative moderate-to-severe acute pain

ABSTRACT Introduction Opioids for managing postoperative pain are associated with side effects including opioid-induced respiratory depression (OIRD) and gastrointestinal complications. Opioids induce analgesia via G-protein signaling, while adverse effects are mediated by the β-arrestin pathway. Oliceridine is a biased ligand that preferentially activates G-protein signaling over β-arrestin, theoretically reducing adverse effects. Oliceridine has been approved by the Food and Drug Administration to treat acute pain severe enough to require intravenous opioid analgesics. Areas covered Preclinical and clinical trials demonstrate the analgesic efficacy of oliceridine. Available evidence suggests that oliceridine may have a lower risk of OIRD and gastrointestinal complications compared to conventional opioids. Expert opinion The analgesic efficacy of oliceridine has been evaluated in several clinical trials. However, safety data were obtained from an open-label observational study and studies assessing adverse effects as secondary outcomes, as post-hoc analyses, or from retrospective studies. These may be affected by gaps in detecting adverse events, heterogeneity in the original studies, and the limitations of retrospective studies. Prospective trials examining the safety of oliceridine versus conventional opioids are needed. Studies are also needed to assess the safety and efficacy of oliceridine in obstetric and pediatric populations, and in the context of multimodal analgesia and Enhanced Recovery after Surgery protocols

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network.

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBötzinger Complex (preBötC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBötC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: (1) pre-inspiratory spiking is reduced and (2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.