ABSTRACT
BACKGROUND AND OBJECTIVES: The primary objective was to compare the serum pharmacokinetic profile of a single dose of extended-release epidural morphine (EREM) administered alone versus 15 to 60 mins after an analgesic epidural dose of bupivacaine. METHODS: This multicenter study enrolled 144 patients, 18 years or older, with scheduled lower abdominal surgery under general anesthesia. Patients were randomly assigned to a single 15-mg dose of EREM; the same dose administered 15, 30, or 60 mins after epidural bupivacaine (20 mL 0.25%); or epidural placebo (normal saline) administered 15, 30, or 60 mins after bupivacaine. Postoperatively, fentanyl patient-controlled analgesia was offered for breakthrough pain. Multiple serum samples were analyzed for morphine and morphine metabolites. Safety and efficacy were assessed. RESULTS: The mean maximum serum concentration and area under the concentration-time curve for morphine and metabolites were not significantly different when EREM was administered alone versus 15, 30, or 60 mins after bupivacaine. Median time to maximum serum concentration and median apparent terminal elimination half-life were also comparable. Total fentanyl patient-controlled analgesia consumption was comparable among all EREM groups (with/without prior bupivacaine) but significantly (P < 0.05) lower compared with the bupivacaine + placebo group. Nausea, vomiting, and dizziness were consistently more frequent in groups receiving EREM after bupivacaine versus EREM alone. CONCLUSIONS: The pharmacokinetic and efficacy profiles of a single 15-mg dose of EREM were not significantly altered when administered 15, 30, or 60 mins after an analgesic epidural dose of bupivacaine.
Subject(s)
Analgesics, Opioid/pharmacokinetics , Morphine/pharmacokinetics , Pain, Postoperative/prevention & control , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/blood , Analysis of Variance , Anesthesia, General , Area Under Curve , Bupivacaine/administration & dosage , Bupivacaine/pharmacokinetics , Colectomy , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Drug Administration Schedule , Female , Humans , Hysterectomy , Injections, Epidural , Male , Middle Aged , Morphine/administration & dosage , Morphine/blood , ProstatectomyABSTRACT
PURPOSE: A pooled analysis of six clinical studies was conducted to describe the pharmacokinetics of extended-release epidural morphine sulfate. METHODS: Data from six clinical studies evaluating extended-release epidural morphine sulfate in volunteers and abdominal or hip surgery patients were pooled and analyzed. Participants age 18 years or older received extended-release epidural morphine sulfate (2.5-40 mg) within 30 minutes of surgery initiation. Most participants received a test dose of 1.5% lidocaine with 1:200,000 epinephrine for epidural space identification 15 minutes before study drug administration. Blood samples were generally collected at 0.5, 2, 4, 8, 12, 18, 24, and 48 hours postinjection. RESULTS: Standard epidural morphine sulfate exhibited a spike in drug release, producing higher peak concentrations (C(max)) than 5-mg extended-release epidural morphine sulfate, which produced more prolonged serum morphine concentrations. Using labeled doses of extended-release epidural morphine sulfate (10-20 mg), the C(max) was comparable to that for 5-mg standard epidural morphine sulfate, whereas the apparent terminal elimination half-life and area under the serum concentration-time curve were twofold to fourfold greater and consistent with dose-proportional exposure. The mean dose-normalized C(max) for extended-release epidural morphine sulfate was 25% higher for women versus men. Administering extended-release epidural morphine sulfate 15 minutes after the test dose mitigated any pharmacokinetic interaction. Extended-release epidural morphine sulfate demonstrated dose- related reductions in postoperative fentanyl consumption and pain intensity. CONCLUSION: A pooled analysis of six studies revealed that extended-release epidural morphine sulfate provided a more prolonged release of morphine compared with standard epidural morphine sulfate. Extended-release epidural morphine sulfate displayed a consistent pharmacokinetic profile among adults, with only slight variability between men and women in C(max), which appeared to be mainly caused by differences in body weight.
