Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption.

BACKGROUND: The interleukin-1 receptor antagonist (IL-1Ra) is the principal determinant of IL-1ß bioactivity within the IL-1 gene cluster, regulating IL-1α and IL-1ß release. This study was designed to determine whether polymorphisms of the IL-1Ra gene (IL1RN) produce clinically measurable differences in serum IL-1Ra concentrations and opioid consumption in the postoperative period. METHODS: Opioid consumption and pain scores were evaluated in 96 patients undergoing a nephrectomy. DNA was extracted from all patients, and the genotypes of IL1RN were determined by polymerase chain reaction amplification of the variable number of tandem repeats of 86 base pairs in intron 2 of IL1RN. The concentrations of serum IL-1Ra concentrations at baseline and at 24 h postoperatively in 58 subjects were measured. RESULTS: Differences in opioid consumption among the three genotype groups (IL1RN*1 homozygotes and *2 and *3 carriers) were statistically significant in the first and second 12-h postoperative periods (P = 0.010). The IL1RN*2 carrier group consumed 43% (95% CI, 38-48%) less opioids in the first 24 h after surgery than the IL1RN*1 homozygote group (P = 0.003). Differences in the serum IL-1Ra concentration among the three genotype groups were statistically significant at 24 h postoperatively (P = 0.003), with IL1RN*2 carriers having the highest serum IL-1Ra concentrations. CONCLUSIONS: The variable number of tandem repeats in intron 2 of IL1RN may contribute to interindividual variations in opioid consumption in the first 24 h after surgery. Patients homozygous for the IL1RN*1 allele have lower concentrations of IL-1Ra and require higher doses of opioids postoperatively than patients carrying at least one IL1RN*2 allele.

The impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption.

BACKGROUND: Endogenous morphine-like compounds have been identified in humans and are released in response to stress. Human monocytes and granulocytes express the micro opiate receptor, micro3, which is morphine selective but opiate peptide insensitive. Recent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. We theorized that ultrarapid (UM) CYP2D6 metabolizers may have an enhancement of their endogenous pain modulating mechanisms. METHODS: After institutional review board approval, a previously developed surgical patient database was evaluated for information concerning CYP2D6 genotypes and morphine consumption. One hundred forty-two patients were found to have adequate information to be included in this current analysis. The study group was divided, based on morphine consumption, into two subgroups: low morphine consumers (LMC) (< or =10 mg/4 h, N = 80) and high morphine consumers (HMC) (>10 mg/4 h, N = 62). DNA was extracted from blood in all patients and was genotyped by the Amplichip (Roche, Pleasanton, CA) to determine the specific CYP2D6 genotypes. RESULTS: CYP2D6 UM were found to occur more frequently in the LMC group than in the HMC group (8/80 vs 0/62, P = 0.0091). No significant differences were noted for the poor, intermediate, or extensive metabolizers. CONCLUSIONS: Our current results suggest that CYP2D6 UM appear to require less morphine in the acute postoperative period compared with other CYP2D6 metabolizer groups. One possible mechanism for this observation is that CYP2D6 UM may have higher efficiency in synthesizing endogenous morphine compared with other metabolizers, thus increasing endogenous pain modulation and reducing the need for exogenous morphine.