Abstract ID: A29

Abstract Title: A Pharmacokinetic and Pharmacodynamic Study of a Single Dose of Epidural DepoDur Following Epidural Bupivacaine: A Randomized Controlled Trial in Patients Undergoing Lower Abdominal Surgery

Authors: Gambling D¹, Hughes T², Gould E³, Manvelian G⁴
Sharp Mary Birch Hospital for Wormen San Diego CA USA¹, Woodland Healthcare Hospital and Clinic Woodland CA USA², Endo Pharmaceuticals Inc. Chadds Ford PA USA³, SkyePharma Inc. San Diego CA USA⁴
Poster Type: Either

ABSTRACT BODY

Introduction: In contrast to standard epidural morphine, DepoDur® (morphine sulfate extended-release liposomal injection) is a single-dose perioperative epidural injection that releases morphine over an extended period to provide up to 48 hours of analgesia.(Gambling et al, 2005; Viscusi et al, 2005) No study has reported the use of DepoDur following prior injection of an epidural anesthetic. Therefore, we assessed the pharmacokinetics and pharmacodynamics of DepoDur in patients receiving epidural bupivacaine for lower abdominal surgery.

Materials and Methods: Patients were randomized to 1) epidural DepoDur (15 mg) alone, 2) epidural bupivacaine 0.25% with epidural DepoDur 15 mg, or 3) epidural bupivacaine 0.25% with epidural placebo. The time between epidural injections was 15, 30, or 60 minutes. Pharmacokinetic parameters included AUC0-last, Cmax, tmax, and t1/2. Pharmacodynamic assessments included efficacy (total amount of postoperative fentanyl or equivalent) and incidence of adverse events (AEs).

Results: 23 patients who received bupivacaine alone and 106 who received DepoDur were assessed for efficacy and safety. Ninety-one DepoDur-treated patients had sufficient data for the pharmacokinetic analysis of morphine. The administration and timing of bupivacaine did not significantly affect the concentration-vs-time curve (Figure), the mean AUC0-last (range, 122.7–171.2 h*ng/mL), the median Tmax (range, 0.25–0.5 h,) or the median t1/2 (range, 6.5–8.1 h) of morphine following DepoDur injection. Similar results were observed with morphine metabolites. Opioid AEs were similar between groups except that nausea and vomiting were more frequent with combined treatment (75% and 36.7%) than with DepoDur alone (59.3% and 18.5%). One patient treated with DepoDur alone and 6 receiving combined treatment experienced respiratory depression considered possibly/probably related to study medication and requiring naloxone treatment. Clinically significant reductions in the mean ± SD total amount of postoperative fentanyl equivalents administered through 48 hours were observed in patients receiving DepoDur alone (828.1±1049.5) or in combination with bupivacaine (range, 552.3±748.2 to 985.3±1333.1) vs placebo (3817.3±3843.8).

Discussion: Compared to treatment with DepoDur alone, a 15–60-minute interval between epidural doses of bupivacaine and DepoDur did not affect the pharmacokinetic parameters of morphine and its metabolites. Moreover, treatment with bupivacaine did not affect the clinical efficacy of DepoDur. The data are consistent with previously published studies supporting the efficacy and safety of a single perioperative dose of DepoDur without use of local anesthetic.

References
1. Gambling D, Hughes T, Martin G, Horton W, Manvelian G. A comparison of Depodur, a novel, single-dose extended-release epidural morphine, with standard epidural morphine for pain relief after lower abdominal surgery. Anesth Analg. 2005;100:1065-1074.

2. Viscusi ER, Martin G, Hartrick CT, Singla N, Manvelian G. 48 hours of postoperative pain relief following total hip arthroplasty with a novel, extended-release epidural morphine formulation. Anesthesiology. 2005;102:1014-1022.

Funding: Endo Pharmaceuticals Inc., PA, and SkyePharma Inc., CA.

ATTACHED FILES

A29_Gambling_ASRA-S 2006 Abstract Figure1.ppt

Reg Anesth Pain Med 2005; 30(3):A29