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

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

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.

Trial registration: ClinicalTrials.gov NCT01140724.

Conflict of interest statement

Conflict of Interests

None of the authors have any conflicts of interest to disclose.

Figures

Figure 1. The consort diagram
Figure 1. The consort diagram
illustrates the flow of study participants through this clinical trial. Eligible participants, reasons for exclusions, enrolled and analyzed patients are reported. IRB = institutional review board.
Figure 2. FAAH genotypes associated with Respiratory…
Figure 2. FAAH genotypes associated with Respiratory Depression, PONV and Morphine requirement
Figure 2a. They axis shows the −log10 P values and the x axis shows the chromosomal positions of the FAAH SNPs. Results are shown for whites (red dots) and blacks (blue dots) separately. P values of the genetic association of the 39 FAAH SNPs with PONV (top) and RD (bottom). The reference lines represent the thresholds of p=0.0018 (shot dash line) and p=0.05 (dotted line), respectively. PACU = Post Anesthesia Care Unit; RD = respiratory depression; PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase. Figure 2b. The y axis shows the −log10 P values and the x axis shows the chromosomal positions of the of the 11 FAAH SNPs between 46.86 to 46.89 Mb of Chromosome 1 with PONV (top panel) and RD (bottom panel). Results are shown for whites (red dots) and blacks (blue dots) separately. The reference lines represent the thresholds of p=0.0018 (shot dash line) and p=0.05 (dotted line), respectively. PACU = Post Anesthesia Care Unit; RD = respiratory depression; PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase.
Figure 2. FAAH genotypes associated with Respiratory…
Figure 2. FAAH genotypes associated with Respiratory Depression, PONV and Morphine requirement
Figure 2a. They axis shows the −log10 P values and the x axis shows the chromosomal positions of the FAAH SNPs. Results are shown for whites (red dots) and blacks (blue dots) separately. P values of the genetic association of the 39 FAAH SNPs with PONV (top) and RD (bottom). The reference lines represent the thresholds of p=0.0018 (shot dash line) and p=0.05 (dotted line), respectively. PACU = Post Anesthesia Care Unit; RD = respiratory depression; PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase. Figure 2b. The y axis shows the −log10 P values and the x axis shows the chromosomal positions of the of the 11 FAAH SNPs between 46.86 to 46.89 Mb of Chromosome 1 with PONV (top panel) and RD (bottom panel). Results are shown for whites (red dots) and blacks (blue dots) separately. The reference lines represent the thresholds of p=0.0018 (shot dash line) and p=0.05 (dotted line), respectively. PACU = Post Anesthesia Care Unit; RD = respiratory depression; PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase.
Figure 3. Missense FAAH SNP, rs324420 and…
Figure 3. Missense FAAH SNP, rs324420 and risk of Respiratory Depression and PONV
Compared to CA genotype of FAAH polymorphism, rs324420, children with AA genotype had higher risk of PONV [Odds ratio of 2.73 (1.58–4.73), p=0.0003] and RD [Odds ratio of 1.61 (1.01, 2.59), p=0.0473]; on the other hand relatively children with CC genotype had less risk of PONV and RD than children with CA and AA genotypes. PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase.

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