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Genetic variation regulates opioid-induced respiratory depression in mice.

ABSTRACT: 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.

SUBMITTER: Bubier JA

PROVIDER: S-EPMC7486296 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Genetic variation regulates opioid-induced respiratory depression in mice.

Bubier Jason A JA He Hao H Philip Vivek M VM Roy Tyler T Hernandez Christian Monroy CM Bernat Rebecca R Donohue Kevin D KD O'Hara Bruce F BF Chesler Elissa J EJ

Scientific reports 20200911 1

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 region ...[more]

PMID: 32917924

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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.

Project description:Iron overload causes inhibition of hepatic uroporphyrinogen decarboxylase (UROD) and uroporphyria in C57BL/10ScSn but not DBA/2 mice [Smith, Cabral, Carthew, Francis and Manson (1989) Int. J. Cancer 43, 492-496]. We have investigated the induction of uroporphyria in 12 inbred strains of mice 25 weeks after iron treatment (600 mg/kg) to determine if there was any correlation with the Ah locus. Under these conditions, inhibition of UROD occurred to varying degrees in Ahd mice (SWR and AKR) as well as nominally Ahb-1 (C57BL/6J, C57BL/10ScSn and C57BL/10-cc) and Ahb-2 strains (BALB/c and C3H/HeJ). Five other Ahb or Ahd strains (C57BL/Ks, A/J, CBA/J, LP and DBA/2) were unaffected. Thus there appeared to be no correlation with the Ah phenotype and this illustrated that some other variable inherited factors are involved. Comparisons between another susceptible strain, A2G, and the congenic A2G-hr/+strain (carrying the recessive hr gene) showed a modulating influence associated with the hr locus. In contrast with individual mice of inbred strains, which showed consistent responses to iron, those of the outbred MF1 strain showed a spectrum of sensitivities as might be expected for a heterogeneic stock. The rate of porphyria development was accelerated by administration of 5-aminolaevulinic acid (5-ALA) in the drinking water, but this did not overcome strain differences. Among four strains the order of susceptibility was SWR > C57BL/10ScSn > C57B1/6J > DBA/2 (the last strain was completely resistant). With degrees of iron loading greater than 600 mg of Fe/kg (1200-1800 mg of Fe/kg) C57BL/10ScSn mice (after 20 weeks) and SWR mice (after 5 weeks which included 4 weeks of 5-ALA treatment) had less inhibition of UROD and a lower uroporphyric response, showing that there was an optimum level of liver iron concentration. Studies on selected microsomal enzyme activities associated with cytochrome P-450 showed no correlation with the propensities of strains to develop porphyria. These activities included the NADPH-dependent oxidation of uroporphyrinogen I to uroporphyrin I.

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.

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Genetic variation regulates opioid-induced respiratory depression in mice.

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Genetic variation regulates opioid-induced respiratory depression in mice.

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