AnesthesiaWeb - Lit Reviews- Maximum Tolerated Dose of Nalmefene in Patients Receiving Epidural Fentanyl and Dilute Bupivacaine for Postoperative Analgesia

July 2000

Maximum Tolerated Dose of Nalmefene in Patients Receiving Epidural Fentanyl and Dilute Bupivacaine for Postoperative Analgesia.
Dougherty TB, Porche VH, Thall PF. Anesthesiology 2000; 92:1010-1016

Commentary by Richard W. Rosenquist, M.D.

[see abstract below]

Patients receiving epidural opiates, either alone or in combination with local anesthetics frequently experience side effects, including nausea and pruritus. Treatment regimens for these side effects have included antihistamines, such as diphenhydramine, agonist/ antagonist drugs, such as nalbuphine, and antinausea agents, such as Reglan, droperidol or Ondansetron. Despite the use of these medications, in some patients these side effects remain difficult to relieve and it is necessary to reverse some of the effects of the opiate. This has been variously accomplished with intravenous naloxone, oral naltrexone and more recently intravenous nalmefene. The authors of this study set out to determine the maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia. They set out to determine the dose of nalmefene that could be administered without reversing the analgesic effect of the epidural infusion.

Before induction of general anesthesia, each patient had an indwelling epidural catheter for postoperative pain control inserted at a segmental level appropriate for the proposed surgery. Subarachnoid or intravenous placement of the epidural catheter was ruled out by testing it with lidocaine 1.5% with epinephrine. Patients received a general anesthetic and antiemetics were not administered during the anesthetic. One hour before completion of surgery, fentanyl 100-150 mg was administered to the epidural catheter. A continuous infusion of fentanyl 10 mg/ml in 0.075% bupivacaine was initiated at 5-10 ml/hour with a patient-controlled epidural anesthesia pump. The demand dosing was set for 0.5 ml every 15 minutes. In the recovery room, each patient's pain intensity was brought to a VAS score of 3 or lower by administering boluses through the epidural or adjusting the basal infusion rate. Patients were removed from the study if the investigators were unable to reduce the VAS score to 3 or less without the aid of intravenous opiates. Patients eligible to receive the study drug were able to adequately assess their pain and the VAS score was maintained at 3 or lower for a minimum of 30 minutes. After the patient's baseline VAS score was recorded, the patient received a single intravenous injection of one of four doses of nalmefene: 0.25, 0.5, 0.75 or 1 mg/kg given over two minutes. The patient was unaware of the dose given. Pain intensity was assessed at least hourly for four hours and once again at eight hours. Reversal of anesthesia was defined as an increase in the VAS score of two or greater above the patient's baseline score after administration of nalmefene. This increase could occur at any time during the eight-hour observation period. The patients were treated in cohorts of one starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (i.e., 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20.

The modified continual reassessment method repeatedly updated the PROA of each dose level as success of patients who were observed for the presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.5 mg/kg (final mean PROA = 0.18). The 1 mg/kg dose was never tried because its projected PROA was far above 0.20.

The authors conclude that the modified continual reassessment method facilitated determination of the maximum tolerated dose of nalmefene. Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

The treatment of side effects associated with the use of epidural opiates remains challenging. The authors have provided a valuable service by outlining doses at which potential reversal of analgesia could occur with the administration of nalmefene. Nalmefene, a long acting opiate antagonist, has been investigated by other authors for reversal of opiate related side effects for epidural or intrathecal opiate administration. Dosing regimens have not been well characterized and this drug has not been widely incorporated into common treatment protocols for the reversal of opiate induced side effects. Further information, such as that provided by this study, may help practitioners to develop side effect treatment protocols that allow the use of a pure opiate antagonists with confidence that they not reverse analgesia rather than using the drugs that do not address the cause of side effects directly or may cause additional sedation.