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The Median Effective Dose of Nefopam and Morphine Administered Intravenously for Postoperative Pain After Minor Surgery: A Prospective Randomized Double-Blinded Isobolographic Study of Their Analgesic Action

The aim of this study was to characterize the nature of analgesic interaction between nefopam and morphine administered IV for postoperative pain after minor surgery. To do so, we defined the median effective analgesic dose (ED50) for each drug and also the median ED50 of their combination and compared them using the isobolographic method. Determination of median effective doses was performed by the up-and-down sequential drug administration in a two-stage study. First, in a prospective, randomized, double-blinded study, we enrolled 60 patients with mild to moderate pain after minor surgery; this was followed by an open study enrolling 30 patients. The end-point was a pain score less than 3 on a Numerical Pain Scale (0–10). Initial doses were 16 mg in group N, 5 mg in group M, and 7.5 mg of N combined with 2.5 mg of M in group N+M. The testing interval was 2 mg in group N, 1 mg in group M, and 1.5 mg of N combined with 0.5 mg of M in group N+M. ED50 (95% confidence interval) was 5 mg (4–6 mg) for morphine, 18 mg (16–18 mg) for nefopam, and 4 mg (3.5–4.5 mg) with 12 mg (10.5–13.5 mg) for the combination of morphine and nefopam administered at a 3:1 dose ratio. Isobolographic analysis demonstrated a significant infra-additive interaction. The incidence of side effects did not differ significantly among morphine, nefopam, and their combination. These findings suggest that the combination of nefopam and morphine does not offer any advantage compared to each drug administered IV or alone after minor surgery. This study is the first to define the ED50 of nefopam and morphine in postoperative patients. In conclusion, the addition of nefopam has a morphine-sparing effect, but the combination is infra-additive.