Objective: The primary objective was to evaluate the serum pharmacokinetic profile of a single 15-mg dose of extended-release epidural morphine (EREM) administered at the lower thoracic epidural space alone or following a lidocaine-epinephrine test dose in patients undergoing major upper abdominal surgery.
Materials and methods: This randomized, open-label study recruited men and women > or = 18 years of age scheduled for major upper abdominal surgery. Patients were randomly assigned to 1 of 5 treatment groups and were administered a single 15-mg dose of EREM or EREM preceded by a 3 ml lidocaine (1.5%)/epinephrine (1 : 200,000) test dose with or without a saline flush: EREM alone; test dose + flush + 3-minute wait + EREM; test dose + flush + 10-minute wait + EREM; test dose + flush + 15-minute wait + EREM; or test dose + 3-minute wait + EREM. EREM was administered at the lower thoracic epidural intervertebral space (T8 - T12) approximately 30 minutes before the surgical incision. Noncompartmental pharmacokinetic parameters were determined based on the serum concentration-time profiles of morphine and morphine metabolites. Effectiveness and safety were also assessed.
Results: The intent-to-treat and safety populations included 39 patients; the pharmacokinetic population included 37 patients. Administration of EREM 3 minutes after a lidocaine-epinephrine test dose, with or without a flush, resulted in an increased mean maximum serum concentration of morphine (Cmax; flush, 30.2 +/- 8.5 ng/ml; no flush, 25.6 +/- 10.1 ng/ml; EREM alone, 11.5 +/- 7.3 ng/ml) and a decreased median time to Cmax (tmax; flush, 0.2 h; no flush, 0.2 h; EREM alone, 2.0 h) compared with administration of EREM alone, without affecting relative morphine bioavailability. Flushing the catheter and waiting 15 minutes normalized the Cmax (11.4 +/- 6.4 ng/ml) but not the median tmax (0.5 h). There were no significant group differences in safety, tolerability, or analgesic effectiveness.
Conclusions: The interaction between EREM and a lidocaine-epinephrine test dose administered at T8 - T12 can be minimized by waiting 15 minutes after test dose administration. The overall safety and effectiveness of 15 mg EREM administered at the lower thoracic epidural intervertebral space in patients undergoing major upper abdominal surgery appears similar to that observed in previous studies assessing lumbar administration. ClinicalTrials.gov Identifier: NCT00728832.