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

The Pharmacogenomics Journal volume 15, pages 436–442 (2015)Cite this article

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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.

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Acknowledgements

This work was supported in part by USPHS Grant #UL1 RR026314 from the National Center for Research Resources and Electronic Medical Records and Genomics (eMERGE) network U01 grant #U01HG006828, NIH and with the Place Outcomes Research Award (PI: SS) and Translational Research Award (PIs: JMA and SS), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. Additional research funding support was provided by the Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. No financial support except departmental salary support for the authors. All authors listed in this manuscript have no conflicts of interest relevant to this article to disclose. This pharmacogenetic study was designed and undertaken by the authors. The sponsor of this study, the Cincinnati Children’s Hospital Medical Center (CCHMC), provided funding support for the genetic analyses and supported salary of the research team. The authors directed and had access to all the analyses and the full clinical and genetic database, wrote all drafts of the report, decided to publish the results, and attest for the accuracy and completeness of the data.

Trial Registration. This clinical trial reflects a portion of a larger study, Personalizing Perioperative Morphine Analgesia in Children, NCT01140724, registered at clinicaltrials.gov.

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Authors and Affiliations

  1. Department of Anesthesia,

    S Sadhasivam, V Chidambaran, J Mavi & J McAuliffe

  2. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    S Sadhasivam, V Chidambaran, J Mavi & J McAuliffe

  3. Department of Pediatrics,

    S Sadhasivam, X Zhang, V Chidambaran, J Mavi, V Pilipenko, T B Mersha, J Meller, K M Kaufman, L J Martin & J McAuliffe

  4. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    S Sadhasivam, X Zhang, V Chidambaran, J Mavi, V Pilipenko, T B Mersha, J Meller, K M Kaufman, L J Martin & J McAuliffe

  5. Division of Human Genetics,

    X Zhang, V Pilipenko & L J Martin

  6. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    X Zhang, V Pilipenko & L J Martin

  7. Division of Asthma Research,

    T B Mersha

  8. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    T B Mersha

  9. Division of Bioinformatics,

    J Meller

  10. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    J Meller

  11. Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    K M Kaufman

  12. Cincinnati VA Medical Center, Cincinnati, OH, USA

    K M Kaufman

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  1. S Sadhasivam
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Correspondence to S Sadhasivam.

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Sadhasivam, S., Zhang, X., Chidambaran, V. et al. Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects. Pharmacogenomics J 15, 436–442 (2015). https://doi.org/10.1038/tpj.2014.79

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