1 Surgical Technique or Genomics? Predictors of Post-operative Morphine Consumption Dr. Keith Candiotti Department of Anesthesiology University of Miami

2 Rationale Several studies investigating postoperative pain and convalescence have shown laparoscopy to be superior compared to open nephrectomy.Several studies investigating postoperative pain and convalescence have shown laparoscopy to be superior compared to open nephrectomy. Our recent study has shown that the Interleukin-1 receptor antagonist (IL-1Ra) polymorphism has a significant impact on postoperative morphine consumption.Our recent study has shown that the Interleukin-1 receptor antagonist (IL-1Ra) polymorphism has a significant impact on postoperative morphine consumption. This present study was designed to evaluate if genomics (IL-1) or surgical technique was a better predictor of postoperative morphine consumption.This present study was designed to evaluate if genomics (IL-1) or surgical technique was a better predictor of postoperative morphine consumption.

3 IL-1Ra Association with Morphine Use The cytokine interleukin-1 (IL-1) acts as a major initial inducer of a proinflammatory state.The cytokine interleukin-1 (IL-1) acts as a major initial inducer of a proinflammatory state. Two structurally different forms (IL- 1α and IL-1β) exist, both of which bind to the same receptor protein (IL-1R).Two structurally different forms (IL- 1α and IL-1β) exist, both of which bind to the same receptor protein (IL-1R). The IL-1-receptor antagonist (IL-1Ra) binds to this same receptor but does not initiate signal transduction, thus acting as an antagonist to both IL- 1α and IL-1βThe IL-1-receptor antagonist (IL-1Ra) binds to this same receptor but does not initiate signal transduction, thus acting as an antagonist to both IL- 1α and IL-1β

4 IL-1Ra Association with Morphine Use IL-1β mediated induction of cyclooxygenase-2 (COX-2) in the central nervous system elevates PGE 2 levels in the CSF and contributes to inflammatory pain hypersensitivity.IL-1β mediated induction of cyclooxygenase-2 (COX-2) in the central nervous system elevates PGE 2 levels in the CSF and contributes to inflammatory pain hypersensitivity. Additionally, it has been demonstrated that IL-1β induces substance P release from primary afferent neurons through the COX-2 system Additionally, it has been demonstrated that IL-1β induces substance P release from primary afferent neurons through the COX-2 system Recently, it has been demonstrated that the IL- 1Ra variants decrease the expression of IL-1β.Recently, it has been demonstrated that the IL- 1Ra variants decrease the expression of IL-1β.

5 IL-1Ra Association with Morphine Use The IL-1*1 genotype (wildtype) is associated with “regular” expression of IL-1  and thus proinflammatory.The IL-1*1 genotype (wildtype) is associated with “regular” expression of IL-1  and thus proinflammatory. IL-1*2 (probably *3) are associated with a down regulation of IL-1  and reduced inflammation.IL-1*2 (probably *3) are associated with a down regulation of IL-1  and reduced inflammation. Peak of IL-1  is at around 24 hours post-op.Peak of IL-1  is at around 24 hours post-op. Previous reports showed some association with opioid use but were not conclusive.Previous reports showed some association with opioid use but were not conclusive.

6 Study Design 80 patients undergoing nephrectomies were enrolled.80 patients undergoing nephrectomies were enrolled. Standardized anesthetic protocol was utilized.Standardized anesthetic protocol was utilized. Patients were followed for 72 hoursPatients were followed for 72 hours All patients were on Morphine PCA for at least 48 hours.All patients were on Morphine PCA for at least 48 hours. Patients reported VAS pain scores for 0-72 hours.Patients reported VAS pain scores for 0-72 hours. Data was separated based on surgery incision type.Data was separated based on surgery incision type.

7 Morphine Consumption at Each 12 Hours Postoperatively Postoperative Time (hrs) * ** * p=0.002; **p=0.002 between two groups ** *

8 Pain Scores Postoperatively Postoperative Time (hrs) * * P=0.010 *

9 24 H Morphine Consumption in the IL-1 Ra Polymorphism Morphine Consumption mg A vs. C p=.03 B vs. D p=.04 B vs. C p=.5 N=29

10 Conclusions Postoperative pain is multifactorial.Postoperative pain is multifactorial. Based on the current surgical literature incision type is a major predictor of postoperative pain.Based on the current surgical literature incision type is a major predictor of postoperative pain. Polymorphisms in certain genes have been linked with morphine consumption and postoperative pain (CYP2D6, IL-1, ABCB1, Mu-receptor variants.Polymorphisms in certain genes have been linked with morphine consumption and postoperative pain (CYP2D6, IL-1, ABCB1, Mu-receptor variants. Based on our preliminary data genomics (IL-1) MAY play as great a role in postoperative pain as surgical incision type.Based on our preliminary data genomics (IL-1) MAY play as great a role in postoperative pain as surgical incision type.