The concept of combined analgesia during the postoperative period is now well documented and widely used. Its principle is based upon the administration in combination of analgesics of different classes that do not share the same mechanism of action. The objective is to reduce the dose of each of the combined medicines, leading to fewer adverse effects for the same level of analgesia .
Nefopam is an analgesic proposed for several years. Its main characteristic is an analgesic effect with a mechanism of action different from that of opiates and non-steroidal anti-inflammatory drugs. Its morphine-sparing effect is well admitted but has been associated with adverse effects in earlier studies using intermittent intramuscular (i.m.)  or intravenous (i.v.)  injections of nefopam. We, therefore, undertook a prospective randomized double-blind controlled trial to evaluate the morphine-sparing effect of nefopam when used as a continuous i.v. infusion.
After ethical committee approval and informed consent, 64 patients undergoing scheduled surgery under general anaesthesia were assigned to one of two postoperative analgesia protocol groups. Inclusion criteria were ASA Grades I-III, adult age, male or female gender, and supra- or sub-mesocolic abdominal surgery via laparotomy under general anaesthesia. Exclusion criteria were ineffective or unsuitable analgesia not relieving the patient and requiring a change of treatment, further surgery and postoperative complications requiring discontinuation or change of the analgesic treatment.
Preoperative premedication was with midazolam. The anaesthesia protocol was standardized, with induction using a combination of thiopental, remifentanil and rocuronium to facilitate endotracheal intubation, followed by maintenance anaesthesia using isoflurane, remifentanil and rocuronium. Postoperative analgesia for all patients was with propacetamol (the prodrug of acetaminophen (paracetamol)) 2 g by slow i.v. injection 40 min before the remifentanil was stopped, and an i.v. injection of morphine 0.15 mg kg−1 20 min before the remifentanil was stopped.
Morphine titration (3 mg 10 min−1 until a visual analogue score (VAS) of 3/10 was obtained) was started immediately after extubation in the postoperative recovery room, followed by random assignment between two groups to the nefopam group (continuous infusion of Acupan® 80 mg i.v. day−1 during 2 days) or the placebo group (continuous infusion of physiological saline for 2 days). Treatment was other-wise the same in both groups, i.e. patient-controlled i.v. morphine (100 mg PCA cassette, concentration 1 mg mL−1, bolus 1 mg, refractory period 7 min, maximum dose 20 mg 4 h−1) administered for 48 h and i.v. propacetamol 2 g every 6 h.
The primary end-point was the cumulative dose of self-administered morphine during the first 48 postoperative hours. Other parameters of interest were pain scores (VAS) at rest, evaluated in postoperative recovery room at 10, 20, 30 min, 1, 2 h after extubation, and on the ward every 4 h. We also recorded haemodynamic and respiratory variables. Particular attention was paid to adverse effects: sweating, nausea, tachycardia, palpitations, vertigo, agitation, irritability, hallucinations, convulsions, respiratory depression and pruritus.
Results are expressed as mean ± SD. Patient characteristics data were compared using a χ2 test for qualitative data and t-test for quantitative data. Cumulative doses of morphine were compared using a t-test. Pain scores (VAS) and haemodynamic variables were compared by analysis of variance with repeated measurement in time and a Tukey test when analysis of variance showed significance. The incidence of adverse events was compared using a χ2 test.
Two of the 64 patients were excluded: one in the placebo group because of bradypnoea requiring interruption of the administration of morphine and the other in the nefopam group since he had accidentally received i.v. ketoprofen in the recovery room. Hence, data from 62 patients were analysed. The two groups were similar regarding patient characteristics data (age, gender, weight and height) and type of surgery (Table 1).
At the end of the 48 h observation period, cumulative morphine consumption was 58 ± 28 mg in the placebo group and was 39 ± 28 mg in the nefopam group (P < 0.01). There was no evidence of any statistical difference in analgesic efficacy throughout the 48 h of postoperative period (Fig. 1). There was no significant difference in the incidence of adverse effects (Table 2). Other secondary end-points, i.e. heart rate, systolic and diastolic arterial pressure, oxygen saturation and respiratory rate were equivalent.
Up to now, there have been few studies quantifying the morphine-sparing effect of nefopam given by continuous i.v. administration, and none studied the analgesic effect of this drug after laparoscopic supraor sub-mesocolic surgery. A recent study  showed the analgesic efficacy of nefopam given by intermittent i.v. injections of 20 mg 4 h−1 compared with i.v. propacetamol and placebo in combination with morphine-PCA after liver resection. In the nefopam group, the morphinesparing was 50% at 24 h after operation compared with the control group, and analgesia was improved. However, there was more frequent sweating, and patient satisfaction was not impaired. Other studies, all with intermittent administration protocols, have confirmed this analgesic efficacy [2,4-6]. This study quantified a marked 33% morphine-sparing effect of nefopam, proving its analgesic efficacy by continuous i.v. administration for a period of 48 h after various types of laparoscopic abdominal surgery. The absence of adverse effects, in particular sweating or nausea, is probably due to continuous i.v. administration, avoiding the peaks associated with periodic administration as used in earlier study protocols. Analgesic quality evaluated by VAS scores was similar in both groups despite a lower morphine consumption in the nefopam group, proving its analgesic efficacy.
In conclusion, we found that the continuous i.v. administration of nefopam resulted in a morphine-sparing effect of about 33% during the first 48 h after supra- or sub-mesocolic abdominal surgery via laparotomy. The combination of morphine and nonmorphine analgesics by continuous administration could provide adequate postoperative analgesia without increasing the risk of adverse drug reactions.
J. P. Viale
Department of Anaesthesia; Hôpital de la Croix-Rousse; Lyon, France
Hôpital Fleyriat; Bourg en Bresse, France
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