title: 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 because of opioid-induced respiratory depression (RD) 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 in which 259 healthy children between 6 and 15 years of age who 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, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold 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. The 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 RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sadhasivam
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: V
authors.identifier: http://orcid.org/0000-0001-7913-1932
authors.initials: V
authors.lastname: Chidambaran
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mavi
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: V
authors.initials: V
authors.lastname: Pilipenko
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Mersha
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Bioinformatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Meller
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Cincinnati VA Medical Center, Cincinnati, OH, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: McAuliffe
mesh_terms: D000293:Adolescent; D000581:Amidohydrolases / Q000235:genetics*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000009:adverse effects; D002186:Cannabinoids / Q000819:agonists; D002648:Child; D055030:Drug Users; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics / Q000473:pathology; D063388:Endocannabinoids / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D056726:Genetic Association Studies; D060148:HapMap Project; D006801:Humans; D008297:Male; D009293:Opioid-Related Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000009:adverse effects; D014068:Tonsillectomy / Q000009:adverse effects*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000701:Analgesics, Opioid; D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide