title: 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.
abstract: The aim of this study was to characterize the nature of analgesic interaction between nefopam and morphine administered i.v. for postoperative pain after minor surgery. To do so, we defined the median effective analgesic dose (ED(50)) for each drug and also the median ED(50) 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. ED(50) (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 i.v. or alone after minor surgery. This study is the first to define the ED(50) of nefopam and morphine in postoperative patients. In conclusion, the addition of nefopam has a morphine-sparing effect, but the combination is infra-additive.
  
  
  CONCLUSIONS
  Pharmacologic interaction between nefopam and morphine shows infra-additivity but their combination may be clinically useful as morphine consumption is decreased in postoperative patients.
authors.affiliation: From the Department of Anesthesiology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris and the Anesthesia Laboratory UPRES EA 3540, Faculté de Médecine du Kremlin-Bicêtre Université de Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Beloeil
authors.forename: Noémie
authors.initials: N
authors.lastname: Delage
authors.forename: Isabelle
authors.initials: I
authors.lastname: Nègre
authors.forename: Jean-Xavier
authors.initials: JX
authors.lastname: Mazoit
authors.forename: Dan
authors.initials: D
authors.lastname: Benhamou
mesh_terms: D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009340:Nefopam / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D010149:Postoperative Pain / Q000188:drug therapy*; D011446:Prospective Studies
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D009340:Nefopam; D009020:Morphine; D010100:Oxygen