One of the main scientific objectives of Dr.Chidambaran’s ongoing project is to identify and characterize determinants of morphine induced respiratory depression (MIRD) in children undergoing surgery. The central hypothesis is that the risk of MIRD is determined by interacting clinical and identifiable genetic factors responsible for variations in response. The hypothesis is being tested by evaluating predictors of clinical (defined as respiratory rate < 8 per minute for > 3 minutes) over the first two postoperative days, and experimental respiratory depression outcomes in 300 children (aged 10-18 years) undergoing spine surgery.
Experimental MIRD entails using hypercapnia (rebreathing 5% carbon dioxide) to measure baseline minute ventilation response and depression in the response after morphine dose. The first aim is to test the hypothesis that Caucasian race (genetically defined using ancestry information markers using a Genome Wide Association Study array) and female sex contribute to MIRD risk. The second aim addresses the contribution of specific genetic variants and their interactions ( ATP binding cassette ABCB1, Fatty Acid Amide Hydrolase/FAAH and Mu-opioid receptor /OPRM1) to inter-patient variability in MIRD. Analysis is done using logistic regression after population stratification using known clinical predictors like morphine doses, hyperoxemia, pain scores, co-administration of sedatives and significant variables from Aim 1 as covariates. Furthermore, this project explores associations with MIRD for variants in select genes involved in the opioid-MIRD and morphine pharmacokinetic (PK) pathway using a discordant phenotype approach to maximize identification of associations. Morphine concentration data is analyzed using non-linear modeling to evaluate genetic effects on PK/PD.
We reported association for μ1 opioid receptor OPRM1 A118G SNP and clinical respiratory depression in our population. This variant results in decreased μ-receptor binding potential in the brain and increases morphine requirement. Multivariable logistic regression showed that the risk of MIRD in patients with AA genotype was significantly higher (odds ratio 5.6, 95% CI: 1.4–37.2, P=0.030). Presence of G allele was associated with higher pain scores (effect size 0.73, P=0.045). (attached figure). We also published our findings of associations of ABCC3 variants with postoperative MIRD and morphine pharmacokinetics in children. The ATP binding Cassette gene ABCC3 which is a hepatic efflux transporter of morphine metabolites, was found to affect morphine 3 and 6 glucuronide formation clearances. This supports findings in a tonsillectomy population which is under study at our institution, where ABCC3 variant is associated with MIRD. This is the first study to report association of ABCC3 variants with opioid-related RD, and morphine metabolite formation (in two independent surgical cohorts). Moreover, we identified a region of FAAH variants in the region +/- 5kb of the FAAH gene with regulatory function, associated with depression of the hypercarbic response after morphine administration, and post-operative vomiting. Patients with clinical respiratory depression also had depressed hypercarbic responses, which indicated our genetic associations can identify subclinical respiratory depression. This manuscript is under preparation. These findings bring us closer to my goal of understanding predictors of MIRD in children, and personalization of opioid analgesia to improve opioid safety.