Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects

Abstract

Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year in due to opioid induced respiratory depression in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype blinded observational study 259 healthy children between 6 and 15 years that received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, respiratory depression (RD), postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (PACU) due to RD and PONV were analyzed. Five specific FAAH SNPs had significant associations with more than 2 fold increased risk for refractory PONV (adjusted p<0.0018), and nominal associations (p<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. FAAH SNP, rs324420 is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related respiratory depression, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

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

“…In our previous prospective genotype-blinded study in 259 white children aged 6-15 years, undergoing tonsillectomy, we reported that FAAH SNPs rs4141964, rs3766246, rs324420, rs2295632 and kgp12517369 increase the odds of PONV by more than twofold, and had nominal associations with RD and prolonged postanesthesia care unit stay [17]. The first four SNPs listed above are also associated with HCVR in the present study, providing further validation.…”

“…Hence, in patients receiving opioids like morphine, factors that increase anandamide levels, or decrease its hydrolysis would be expected to potentiate opioid effects, as would be expected with FAAH variants with reduced function affecting anandamide hydrolysis. We recently reported associations of FAAH variants with RD after outpatient tonsillectomy surgery [17]; in this study, we postulate that use of a sensitive measure of subclinical RD such as HCVR, would allow improved identification of FAAH genetic effects on opioid-related RD before they manifest clinically. To our knowledge, this has not been studied before.…”

OCT1 Genetic Variants are Associated with Postoperative Morphine-Related Adverse Effects in Children

“…Research Article Balyan, Zhang, Chidambaran et al our group, we reported that variants in certain genes in the morphine response pathway, namely, μ-opioid receptor (OPRM1), ATP-binding cassette ABCB1 and FAAH, affect morphine clinical outcomes including RD in children [6][7][8]. The efflux of morphine glucuronides from the hepatic cell is an ATP-dependent process mediated by the ATP-binding cassette transporters including ABCC3 [9,10].…”

“…Clinical RD was defined as a persistent (longer than 1 min) oxygen desaturation less than 90% or a respiratory rate less than eight breaths per minute or oxygen desaturation less than 94% in addition to respiratory rate less than ten per minute requiring supplemental oxygen to maintain SpO2 more than 94% in the absence of clinically obvious upper airway obstruction [16]. PONV is defined as occurrence of emesis or requirement of antiemetic administration due to self-reported experience of nausea.…”

“…Standard criteria to be met for PACU discharge were: level of consciousness arousable or awake, airway patent with adequate air exchange, core temperature ≥36.3°C, acceptable pain level, hemodynamically stable and surgical site without any bleeding or comp lications. More than 90 min stay in PACU due to RD or PONV were termed as prolonged RD and prolonged PONV, respectively [16]. The sum of morphine (mg/kg) administered intra operatively and during postoperative period at PACU was termed as 'total morphine dose.…”