Neural basis of opioid-induced respiratory depression and its rescue.
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ABSTRACT:
SUBMITTER: Liu S
PROVIDER: S-EPMC8201770 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014. The diversion and misuse of prescription opioids along with increased use of drugs like heroin and fentanyl, has led to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically determined. We first tested the hypothesis that genetic variation in inbred strains of mice influences the innate variability in opioid-induced responses in respiratory depression, recovery time and survival time. Using the founders of the advanced, high-diversity mouse population, the Diversity Outbred (DO), we found substantial sex and genetic effects on respiratory sensitivity and opiate lethality. We used DO mice treated with morphine to map quantitative trait loci for respiratory depression, recovery time and survival time. Trait mapping and integrative functional genomic analysis in GeneWeaver has allowed us to implicate Galnt11, an N-acetylgalactosaminyltransferase, as a gene that regulates OIRD.
| S-EPMC7486296 | biostudies-literature
Project description:Strong opioid analgesics are the mainstay of therapy for the relief of moderate to severe acute nociceptive pain that may occur post-operatively or following major trauma, as well as for the management of chronic cancer-related pain. Opioid-related adverse effects include nausea and vomiting, sedation, respiratory depression, constipation, tolerance, and addiction/abuse liability. Of these, respiratory depression is of the most concern to clinicians owing to the potential for fatal consequences. In the broader community, opioid overdose due to either prescription or illicit opioids or co-administration with central nervous system depressants may evoke respiratory depression. To address this problem, there is ongoing interest in the identification of non-opioid respiratory stimulants to reverse opioid-induced respiratory depression but without reversing opioid analgesia. Promising compound classes evaluated to date include those that act on a diverse array of receptors including 5-hydroxytryptamine, D 1-dopamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) receptor antagonists, and nicotinic acetylcholine as well as phosphodiesterase inhibitors and molecules that act on potassium channels on oxygen-sensing cells in the carotid body. The aim of this article is to review recent advances in the development potential of these compounds for countering opioid-induced respiratory depression.
| S-EPMC7008602 | biostudies-literature
Project description:Background: Respiratory depression is a clinically and economically important but preventable complication of opioids. Genetic factors can help identify patients with high risk for respiratory depression. Methods: In this prospective genotype blinded clinical study, we evaluated the effect of a panel of variants in candidate genes on opioid-related respiratory depression in 347 children following tonsillectomy. Results: Using unsupervised hierarchical clustering and a combination of candidate genotypes and clinical variables, we identified several distinct clusters of patients at high risk (36-38%) and low risk (10-17%) of respiratory depression; the relative risk of respiratory depression for high versus low risk clusters was 2.1-3.8 (p = 0.003). Conclusion: Genetic risk predictions (genetic signatures) along with clinical risk factors effectively identify children at higher and lower risks of opioid-induced respiratory depression. Genetic signatures of respiratory depression offer strategies for improved clinical decision support to guide clinicians to balance the risks of opioid adverse effects with analgesia. Original submitted 9 July 2014; Revision submitted 19 September 2014.
| S-EPMC4287371 | biostudies-literature
Project description:BackgroundSafe postoperative pain relief with opioids is an unmet critical medical need in children. There is a lack of objective, noninvasive bedside tool to assess central nervous system (CNS) effects of intraoperative opioids. Proactive identification of children at risk for postoperative respiratory depression (RD) will help tailor analgesic therapy and significantly improve the safety of opioids in children. Quantitative pupillometry (QP) is a noninvasive, objective, and real-time tool for monitoring CNS effect-time relationship of opioids. This exploratory study aimed to determine the association of QP measures with postoperative RD, as well as to identify the best intraoperative QP measures predictive of postoperative RD in children.MethodsAfter approval from the institutional review board and informed parental consent, in this prospective, observational study of 220 children undergoing tonsillectomy, QP measures were collected at 5 time points: awake preoperative baseline before anesthesia induction (at the time of enrollment [T1]), immediately after anesthesia induction before morphine administration (T2), 3 minutes after intraoperative morphine administration (T3), at the end of surgery (T4), and postoperatively when awake in postanesthesia recovery unit (PACU) (T5). Intraoperative use of opioid and incidence of postoperative RD were collected. Analyses were aimed at exploring correlations of QP measures with the incidence of RD and, if found significant, to develop a predictive model for postoperative RD.ResultsPerioperative QP measures of percentage pupil constriction (CONQ, P = .027), minimum pupillary diameter (MIN, P = .027), and maximum pupillary diameter (MAX, P = .034) differed significantly among children with and without postoperative RD. A predictive model including the minimum pupillary diameter 3 minutes after morphine administration (MIN3), minimum pupillary diameter normalized to baseline (MIN31), and percentage pupillary constriction after surgery (T4) standardized to baseline (T1) (CONQ41), along with the weight-based morphine dose performed the best to predict postoperative RD in children (area under the curve [AUC], 0.76).ConclusionsA model based on pre- and intraoperative pupillometry measures including CONQ, MIN, along with weight-based morphine dose-predicted postoperative RD in our cohort of children undergoing tonsillectomy. More studies with a larger sample size are required to validate this finding.
| S-EPMC8446291 | biostudies-literature
Project description: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.
| S-EPMC8390004 | biostudies-literature
Project description:IntroductionWhole-body plethysmography (WBP) in unrestrained, non-anesthetized rodents is a preclinical method to assess the respiratory depressant effects of opioids, the leading cause of opioid overdose death in humans. However, low baseline respiration rates under normocapnic conditions (i.e., "floor" effect) can render the measurement of respiratory decreases challenging. We assessed hypercapnia-induced increases in respiration as a strategy to assess opioid-induced decreases in respiration in rats.MethodsWBP was used to assess respiration frequency, tidal volume and minute volume in the presence of normocapnic and hypercapnic (8% CO2) conditions in rats during the rat diurnal period of the light cycle. The mu-opioid receptor agonist fentanyl was administered intravenously, and the hot plate test was used to assess acute antinociception.Results and discussionHypercapnia-induced increases in respiratory parameters (frequency, minute volume, and tidal volume) were decreased by fentanyl at doses that did not decrease the same parameters under the normocapnic conditions. These findings show that hypercapnia increases sensitivity to respiratory depressant effects of fentanyl, as compared with assessments during the rat diurnal period when activity and breathing rate are generally low, i.e., there is a floor effect. The current approach is highly sensitive to opioid-induced respiratory depression, and therefore provides a useful method for assessment in a pre-clinical setting.
| S-EPMC8494486 | biostudies-literature
Project description:On August 6th, 2019, a two-day trans-agency scientific meeting was convened by the United States (U.S.) National Institute of Allergy and Infectious Diseases (NIAID/NIH) on the research and development of medical countermeasures (MCMs) and treatment strategies to mitigate synthetic opioid-induced toxicities. This trans-agency meeting was an initiative of the Chemical Countermeasures Research Program (CCRP) and organized by the NIAID in collaboration with the National Institute of Drug Abuse (NIDA), the Biomedical Advanced Research and Development Authority (BARDA), the Food and Drug Administration (FDA), and the Defense Threat Reduction Agency (DTRA). The CCRP is part of the larger NIH biodefense research program coordinated by NIAID, which also includes MCM research and development programs against biological, radiological, and nuclear threats. Its overarching goal is to integrate cutting-edge research and technological advances in science and medicine to enhance the nation's medical response capabilities during and after a public health emergency involving the deliberate or accidental release of toxic chemicals. The potential of a mass casualty public health event involving synthetic opioids is a rapidly growing concern. As such, the overall goals of this trans-agency meeting are to better understand opioid-induced toxicities and advance the development of MCMs to mitigate and reverse opioid-induced respiratory depression (OIRD) to prevent consequential mortality. The primary objectives of the meeting were (1) highlight the latest research on mechanisms of OIRD and related toxicities, animal models, diagnostics, delivery technologies, and emerging new treatment options to prevent lethality; (2) identify current knowledge gaps to advance medical countermeasure development; (3) hear from the U.S. FDA on regulatory considerations to support new technology and treatment approaches; and (4) provide a forum for networking and collaborative partnerships. To accomplish this, a diverse group of almost 200 US domestic and international subject matter experts spanning fundamental and translational research from academia, industry, and government came together in-person to share their collective expertise and experience in this important field. This report briefly summarizes the information presented throughout the meeting, which was also webcast live in its entirety to registered remote attendees.
| S-EPMC6942061 | biostudies-literature
Project description:Background: Opioids are commonly prescribed to hospitalized adults to promote adequate pain relief, yet they can cause potentially fatal respiratory depression. Aim: The aim of this study was to examine the risk factors for the development of severe opioid-induced respiratory depression (OIRD) in hospitalized adults to ensure adequate monitoring of high-risk patients. Methods: A retrospective case-control study was conducted using data from the medical records of a university-affiliated hospital in Canada. Cases were eligible if they were adults (≥18 years old) and received opioid analgesia within 24 h of naloxone administration for respiratory depression. Controls had the same eligibility criteria, except for respiratory depression and naloxone administration. The case-control ratio was 1:1, and they were matched based on sex, type of unit, opioid molecule and the presence/absence of medication errors. Results: A total of 133 cases and 133 controls were included. Following cumulative risk factor analysis, renal failure (odds ratio [OR] = 2.176, 95% confidence interval [CI], 1.021-4.640, P = 0.044), the first 24 h of opioid administration (OR = 1.899, 95% CI, 1.090-3.309, P = 0.024), concomitant central nervous system (CNS) depressants (OR = 1.785, 95% CI, 1.023-3.113, P = 0.041), and increasing age (OR = 1.019, 95% CI, 1.002-1.035, P = 0.028) were positively associated with severe OIRD. Conclusions: Some adult hospitalized patients were at higher risk of experiencing severe OIRD, such as those with renal failure, those in their first 24 h of opioid administration, those receiving CNS depressants in addition to opioids, and those with an advanced age. These results will assist with the screening of patients at higher risk for severe OIRD, which is key to implementing appropriate monitoring and enhancing the safety of opioid use in hospital settings.
| S-EPMC7951145 | biostudies-literature
Project description:OBJECTIVE:This systematic review and meta-analysis aim to evaluate the risk factors associated with postoperative opioid-induced respiratory depression (OIRD). DESIGN:Systematic review and meta-analysis. DATA SOURCES:PubMed-MEDLINE, MEDLINE in-process, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed and Clinicaltrials.gov (January 1946 to November 2017). ELIGIBILITY CRITERIA:The inclusion criteria were: (1) adult patients 18 years or older who were administered opioids after surgery and developed postoperative OIRD (OIRD group); (2) all studies which reported both OIRD events and associated risk factors; (3) all studies with reported data for each risk factor on patients with no OIRD (control group) and (4) published articles in English language. DATA ANALYSIS:We used a random effects inverse variance analysis to evaluate the existing evidence of risk factors associated with OIRD. Newcastle-Ottawa scale scoring system was used to assess quality of study. RESULTS:Twelve observational studies were included from 8690 citations. The incidence of postoperative OIRD was 5.0 cases per 1000 anaesthetics administered (95%?CI: 4.8 to 5.1; total patients: 841 424; OIRD: 4194). Eighty-five per cent of OIRD occurred within the first 24?hours postoperatively. Increased risk for OIRD was associated with pre-existing cardiac disease (OIRD vs control: 42.8% vs 29.6%; OR: 1.7; 95%?CI: 1.2 to 2.5; I2: 0%; p<0.002), pulmonary disease (OIRD vs control: 17.8% vs 10.3%; OR: 2.2; 95%?CI: 1.3 to 3.6; I2: 0%; p<0.001) and obstructive sleep apnoea (OIRD vs control: 17.9% vs 16.5%; OR: 1.4; 95%?CI: 1.2 to 1.7; I2: 31%; p=0.0003). The morphine equivalent daily dose of the postoperative opioids was higher in the OIRD group than in the control; (24.7±14?mg vs 18.9±13.0?mg; mean difference: 2.8; 95%?CI: 0.4 to 5.3; I2: 98%; p=0.02). There was no significant association between OIRD and age, gender, body mass index or American Society of Anesthesiologists physical status. CONCLUSION:Patients with cardiac, respiratory disease and/or obstructive sleep apnoea were at increased risk for OIRD. Patients with postoperative OIRD received higher doses of morphine equivalent daily dose.
| S-EPMC6303633 | biostudies-literature
Project description:Overdoses caused by the opioid agonist fentanyl have increased exponentially in recent years. Identifying mechanisms to counter progression to fatal respiratory apnea during opioid overdose is desirable, but difficult to study in vivo. The pontine Kölliker-Fuse/Parabrachial complex (KF/PB) provides respiratory drive and contains opioid-sensitive neurons. The contribution of the KF/PB complex to fentanyl-induced apnea was investigated using the in situ arterially perfused preparation of rat. Systemic application of fentanyl resulted in concentration-dependent respiratory disturbances. At low concentrations, respiratory rate slowed and subsequently transitioned to an apneustic-like, 2-phase pattern. Higher concentrations caused prolonged apnea, interrupted by occasional apneustic-like bursts. Application of CTAP, a selective mu opioid receptor antagonist, directly into the KF/PB complex reversed and prevented fentanyl-induced apnea by increasing the frequency of apneustic-like bursting. These results demonstrate that countering opioid effects in the KF/PB complex is sufficient to restore phasic respiratory output at a rate similar to pre-fentanyl conditions, which could be beneficial in opioid overdose.
| S-EPMC7050369 | biostudies-literature