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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.

SUBMITTER: Sadhasivam S

PROVIDER: S-EPMC4492912 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Sadhasivam S S Zhang X X Chidambaran V V Mavi J J Pilipenko V V Mersha T B TB Meller J J Kaufman K M KM Martin L J LJ McAuliffe J J

The pharmacogenomics journal 20150106 5

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 o ...[more]

PMID: 25558980

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Project description:AimLarge interindividual variability in morphine pharmacokinetics (PK) could contribute to variability in morphine analgesia and adverse events. Respiratory depression (RD) and postoperative nausea and vomiting (PONV) are significant adverse drug response of intravenous morphine in the perioperative setting limiting its efficacy in achieving adequate surgical pain relief. OCT1 is a transporter in the liver that transports morphine from the bloodstream into hepatocytes. Earlier we reported association of genetic polymorphisms in OCT1 with morphine PK, and lower morphine clearance in Caucasian children as compared with African-American (AA) children. The aim of this study is to identify the association between common OCT1 genotypes affecting morphine's PK and clinically important postoperative morphine-related adverse outcomes.MethodsAfter obtaining institutional review board (IRB) approval and informed consents, 311 children ages 6-15 years, American Society of Anesthesiologists' physical status 1 or 2 scheduled for tonsillectomy who received standard anesthetic, surgical and postoperative care were recruited. Clinical data collected included postoperative pain scores, total opioid use, incidence of PONV and RD. Four nonsynonymous SNPs of the OCT1 gene (rs12208357, rs34130495, rs72552763 and rs34059508) in each patient were genotyped using commercially available TaqMan assays. We investigated the genetic association of OCT1 with incidences of postoperative RD and PONV.ResultsCaucasian and AA children differed significantly in the incidence of obstructive sleep apnea (p < 0.001) and total morphine use (p = 0.028). There were incidences of prolonged post anesthesia care unit stay in 7% of Caucasian children, while no such incidences were observed for AA children (p = 0.05). OCT1 polymorphism rs12208357 was associated with high incidences of PONV and PONV leading to prolonged post anesthesia care unit stay (p < 0.05). A significant association was also found between rs72552763 GAT deletion and high incidence of RD (p = 0.007).ConclusionChildren with certain OCT1 genotypes are associated with higher risk for RD and PONV following morphine administration leading to prolonged hospital stay. The OCT1 transporters' effects on morphine's PK could explain this association.

Project description:AbstractDespite the dramatic advancement of cancer chemotherapy and immunotherapy, the insufficient progress has been made in basic or translational research on personalization of opioid therapy. Predicting the effectiveness of opioid analgesic therapy and the risk of adverse effects prior to therapy are expected to enable safer and more appropriate opioid therapy for cancer patients. In this study, we compared the incidence of opioid-induced adverse effects between patients with different variants of the genes related to responsiveness to opioid analgesics.Participants were 88 patients with lung cancer who provided general consent for exome sequencing and were treated with morphine or oxycodone at Shizuoka Cancer Center Hospital between April 2014 and August 2018. Incidence rates for 6 adverse effects of opioid therapy (somnolence, nausea, constipation, delirium, urinary retention, and pruritus) were determined and the influence of single nucleotide polymorphisms in coding regions of the opioid μ receptor 1 (OPRM1) (rs1799971), opioid δ receptor 1 (rs2234918), opioid κ receptor 1 (rs1051660), catechol-O-methyltransferase (COMT) (rs4680), dopamine receptor D2 (rs6275), adenosine triphosphate binding cassette B1 (rs1045642), G-protein regulated inward rectifier potassium channel 2 (rs2070995), and fatty acid amide hydrolase (rs324420) genes on those adverse effects were analyzed.Analysis of OPRM1 gene variant status (Asn133Asp A > G) showed that G/G homozygotes were at significantly lower risk of somnolence compared with A allele carriers (0% vs 28.4%; Fisher exact test, P = .005; OR, 0; 95% CI, 0-0.6), and analysis of COMT gene variant status (Val158Met, G > A) showed that G/G homozygotes were at significantly higher risk of somnolence compared with A allele carriers (35.0% vs 10.4%; Fisher exact test, P = .008; OR, 4.5; 95% CI, 1.4-18.1). No relationship between variant status and adverse effects was found for the other genes.These findings demonstrate that OPRM1 and COMT gene variants influence the risk of somnolence as an adverse effect of opioid analgesic therapy.

Project description:BACKGROUND:Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due to the pleiotropic effects of related phenotypes, we tested six of these obesity-related genetic variants for their association with physical activity: fat mass and obesity-associated (FTO)(rs9939609)T>A, potassium channel tetramerization domain containing (KCTD15) (rs11084753)G>A, melanocortin receptor4 (MC4R)(rs17782313)T>C, neuronal growth regulator 1 (NEGR1)(rs2815752)A>G, SH2B adapter protein 1 (SH2B1)(rs7498665)A>G, and transmembrane protein18 (TMEM18)(rs6548238)C>T. METHOD:European-American women (n = 263) and men (n = 229) (23.5 ± 0.3 years, 24.6 ± 0.2 kg/m2) were genotyped and completed the Paffenbarger physical activity Questionnaire. Physical activity volume in metabolic energy equivalents [MET]-hour/week was derived from the summed time spent (hour/week) times the given MET value for vigorous, moderate, and light intensity physical activity, and sitting and sleeping, respectively. Multivariable adjusted [(age, sex, and body mass index (BMI)] linear regression tested associations among genotype (dominant/recessive model) and the log of physical activity volume. RESULT:MC4R (rs17782313)T>C explained 1.1 % (p = 0.02), TMEM18(rs6548238)C>T 1.2 % (p = 0.01), and SH2B1 (rs7498665)A>G 0.6 % (p = 0.08) of the variability in physical activity volume. Subjects with the MC4R C allele spent 3.5 % less MET-hour/week than those with the TT genotype (p = 0.02). Subjects with the TMEM18 T allele spent 4.1 % less MET-hour/week than those with the CC genotype (p = 0.01). Finally, subjects with the SH2B1 GG genotype spent 3.6 % less MET-hour/week than A allele carriers (p = 0.08). CONCLUSION:Our findings suggest a shared genetic influence among some obesity-related gene loci and physical activity phenotypes that should be explored further. Physical activity volume differences by genotype have public health importance equating to 11-13 lb weight difference annually.

Project description:IntroductionPerioperative opioid use has been associated with adverse clinical outcomes. Additionally, opioid disposal carries significant costs, due to the waste of pharmaceutical products and the time needed by skilled labor to report the waste. In this study, we aimed to estimate costs and predict factors of opioid-associated intraoperative product waste, as well as to evaluate whether higher intraoperative opioid doses are associated with increased risk of adverse postoperative outcomes.MethodsWe included 170,607 patients undergoing general anesthesia and receiving intraoperative fentanyl, hydromorphone, or morphine at Beth Israel Deaconess Medical Center, Boston, MA, USA, between January 2010 and June 2020. We estimated product waste-associated costs based on various opioid syringe sizes and determined predictors of opioid waste. Further, we evaluated whether higher opioid doses were associated with postoperative adverse events according to the severity-indexed, incident report-based medication error-reporting program classification. The primary outcome included post-extubation desaturation, postoperative nausea or vomiting, or postoperative somnolence or sedation.ResultsThe use of the smallest syringe sizes (50 mcg for fentanyl, 0.2 mg for hydromorphone, and 2 mg for morphine) resulted in the lowest product waste-associated costs. The main predictor of opioid waste was the administration of more than one intraoperative opioid (adjusted odds ratio [aOR] = 7.64, 95% CI 7.40-7.89, P < 0.001). Intraoperative doses of fentanyl > 50-100 mcg (aOR = 1.17 [1.10-1.25], P < 0.001, adjusted risk difference [ARD] 2%) and > 100 mcg (aOR = 1.24 [1.16-1.33], P < 0.001, ARD 3%), hydromorphone > 1 mg (aOR = 1.13 [1.06-1.20], P < 0.001, ARD 2%), and morphine > 2-4 mg (aOR = 1.26 [1.02-1.56], P = 0.04, ARD 3%) and > 4 mg (aOR = 1.45 [1.18-1.77], P < 0.001, ARD 5%) were associated with higher risk of the primary outcome.ConclusionSmaller syringe sizes of intraoperative opioids may help to reduce product waste and associated costs, as well postoperative adverse events through utilization of lower intraoperative opioid doses.

Project description:BackgroundMethylphenidate is the most prescribed stimulant to treat attention deficit-hyperactivity disorder (ADHD). Despite its widespread usage, a fair proportion of children are classified as non-responders to the medication. Variability in response and occurrence of adverse events with methylphenidate use may be due to several factors, including drug-drug interactions as well as pharmacogenetic differences resulting in pharmacokinetic and/or pharmacodynamic variances within the general population. The objective of this study was to analyze the effect of carboxylesterase 1 (CES1) variants on the frequency of adverse effects and dosing requirements of methylphenidate in children with ADHD.MethodsThis was a retrospective cohort study of children and adolescents who met the inclusion criteria and had a routine visit during the enrollment period were invited to participate. Inclusion criteria included: ADHD diagnosis by a healthcare provider, between 6 and 16 years of age at the time of permission/assent, had not previously been prescribed methylphenidate, and treatment with any methylphenidate formulation for at least three consecutive months. Three months of records were reviewed in order to assess changes in dose and frequency of discontinuing methylphenidate. Participants' ADHD symptoms, medication response, adverse effects, select vitals, and dose were extracted from the electronic health record. Saliva samples were collected by trained study coordinators. Haplotypes were assigned based on copy number in different portions of the CES1 gene. Due to limited numbers, diplotypes (combinations of two haplotypes) were grouped for analysis as CES1A1/CES1A1, CES1A1/CES1A1c and CES1A1c/CES1A1c.ResultsA total of 99 participants (n = 30 female; n = 69 male) had both clinical data and CES1 sequencing data, with an average age of 7.7 years old (range 3-15 years). The final weight-based dose in all individuals was 0.79 mg/kg/day. The most common adverse effects reported were decreased appetite (n = 47), weight loss (n = 24), and sleep problems (n = 19). The mean final weight-based dose by haplotype was 0.92 mg/kg for CES1A2/CES1A2, 0.81 mg/kg for CES1A2/CES1P1, and 0.78 mg/kg for CES1P1/CES1P1. After correction for multiple hypothesis testing, only one SNV, rs114119971, was significantly associated with weight-based dosing in two individuals. The individuals with the rs114119971 SNV had a significantly lower weight-based dose (0.42 mg/kg) as compared to those without (0.88 mg/kg; p < 0.001).DiscussionVariation in CES1 activity may impact dose requirements in children who are prescribed methylphenidate, as well as other CES1 substrates. Although intriguing, this study is limited by the retrospective nature and relatively small sample size.

Dataset Information

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

Publications

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

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