Flumazenil potentiation of postoperative morphine analgesia. (Tel‐Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel‐Aviv University, Tel‐Aviv) Clin J Pain 2000;16:193–199.
Authors: Weinbroum Avi A. , Weisenberg Marian , Rudick Valeri , Geller Eran , Niv: David 
Published: March 2003

The goal of this study was to test the effect of concomitant administration of flumazenil (FL) and morphine (MO) on immediate postoperative analgesia and the MO requirement to control pain in human beings. Thirty‐six patients undergoing inguinal hernioplasty under lidocaine epidural anesthesia were enrolled in this double‐blinded, randomized, controlled study. On the first complaint of pain, either MO (2 mg) only or MO (2mg) plus FL (0.2mg) was administered. Additional doses of the same medications administered via a patient‐controlled analgesia device with a 10‐min lockout period were available thereafter. The study continued 2 h after the loading doses of the medications were administered, with an additional 2‐h period of observation. Thirty‐two patients completed the study. Both groups reached a similar satisfactory equianalgesic state (2 in a 0‐10 visual analogue scale). The MO plus FL group consumed 9.5 ± 1.1 mg of MO versus 14.1 ± 1.1 mg of MO in the MO only group. The MO plus FL patients were subjectively more comfortable and less sedated than the MO patients. “Fine” coordination (using an electronic maze) and “coarse” coordination (measured by transferring a pen from one hand to another as rapidly as possible with both arms placed inside an 80‐cm metal frame) in the MO group were worse than in the MO plus FL group. End‐tidal CO2 increased and blood pressure decreased in the MO group. There were few and insignificant side effects in the MO group. None of these patients required an MO antagonist, and recovery was prolonged in none. Conclude that flumazenil afforded lower MO consumption during immediate postoperative period. Cognitive, hemodynamic, and respiratory functions were better after MO plus FL than after MO alone.

Comment by Tat‐Leang Lee, M.D. This interesting study is one of many studies that have advocated a multimodal approach to the management of postoperative pain. This approach utilizes drugs that act on different pathways, different receptors, or both. By combining flumazenil to morphine, the authors were able to retain the quality of analgesia afforded by opioids, yet reduced morphine requirements and consequently the adverse effects associated with it. Being the first study of flumazenil as an analgesic in humans, it is unfortunate that due to ethical concerns, the authors could not study a group of patients receiving flumazenil alone. This leaves unanswered the question as to whether the morphine‐sparing effect seen in the patients receiving flumazenil was caused by an intrinsic analgesic effect of flumazenil or as a potentiation of the effect of morphine. An obstacle to the clinical use of this approach is the relatively high price of flumazenil. In this study, the authors used a mean of 0.95 mg (2 vials) of flumazenil for each patient, which in the reviewer's institution would add US$64 to each patient's hospitalization cost.