Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics

Abstract

Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood-brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1-10.8, P=0.0002).

Fatty Acid Amide Hydrolase–morphine Interaction Influences Ventilatory Response to Hypercapnia and Postoperative Opioid Outcomes in Children

“…Twin studies have revealed significant heritability (30%) for RD from opioids [62]; contributing nongenetic risk factors like female sex and medical comorbidities have been described [63][64][65]. Our study strengthens the evidence for FAAH associations with morphine outcomes in children, adds to the genetic risk factors reported previously -OPRM1 [66] and ABCB1 [67] and expands the knowledge base toward identifying genetic risk signatures for RD in children [68]. FAAH inhibitors have been explored for treatment of pain and nausea [69,70]; our findings spur further investigation of these agents to alter risk of opioid RD.…”

Neonatal pain management: still in search for the Holy Grail

“…The authors hereby documented a maturational expression in P-gp to reach adult levels beyond 3 months of age. This ontogenic pattern fits quite well with the observations that P-gp polymorphisms (ABCB1 polymorphism rs9282564) were associated with a higher risk of opioid-related respiratory depression in children, but not anymore in adults, and not yet in neonates [57]. Adding one copy of the minor allele increased the odds of prolonged stay to the respiratory depression 4.7 fold.…”

Genetic Risk Signatures of Opioid-Induced Respiratory Depression Following Pediatric Tonsillectomy

“…Variations in ABCB1 efflux pump P-gp transporter at the blood brain barrier can significantly alter cerebral pharmacokinetics and respiratory depressive effects of opioids [11,48]. Additional associations with RD are independently observed for SNPs in the ABCB1 gene, which encodes a key transporter involved in opioids’ (including morphine) central analgesic and adverse effects [49]. …”