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Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat

International Toxicology Consultants, LLC, 2000 L Street NW, Suite 200, Washington, District of Columbia 20036-4924, USA; INSERM U26, Université Paris 7, Hôpital Fernand Widal, 200 rue du Fg St Denis, Paris 75475, France; Department of Emergency Medicine, George Washington University School of Medicine, 2140 Pennsylvania Avenue, Washington, District of Columbia 20037, USA; sborron{at}intoxicon.com

C Monier

P Risède

F J Baud

INSERM U26, Université Paris 7, Hôpital Fernand Widal, 200 rue du Fg St Denis, Paris 75475, France

Opiates and substitution products are frequently abused, alone and in association with benzodiazepines. While this combination may result in severe respiratory depression and death, the quantitative relationship remains uncertain. We performed randomized, blinded intravenous median lethal dose (MLD) studies in Sprague–Dawley rats of morphine, buprenorphine, and methadone, alone and in combination with intraperitoneal flunitrazepam pretreatment. We employed the up-and-down method, performed in quadruplicate, comparing time to death following opioid injection. Results are expressed as median of four series (extremes). The MLDs of morphine, buprenorphine, and methadone alone were 64.0 (33.6:79.5), 234.6 (168.6:284.4), and 22.5 (19.3:24.1) mg/kg, respectively, and 60.6 (35.2:88.2), 38.4 (30.6:54.0), and 13.0 (9.7:13.8) mg/kg, respectively, after pretreatment with 40 mg/kg flunitrazepam. Times to death for morphine, buprenorphine, and methadone alone were 2.5 (0.8:24), 0.02 (0.0:24), and 2.0 (0.0:24) hours, respectively, and 13.5 (0.0:144), 24.0 (0.0:120), and 0.0 (0.0:24) hours, respectively, after pretreatment with flunitrazepam 40 mg/kg, ip. Flunitrazepam significantly altered methadone (P=0.02) and buprenorphine (P=0.02) but not morphine lethality (P=0.77). Flunitrazepam significantly prolonged time to death only for buprenorphine (P<0.01). Flunitrazepam–opioid drug–drug interactions are more complex than is generally believed. Mechanistic studies of flunitrazepam–opioid lethal interactions are needed.

Key Words: benzodiazepines • drug interactions • lethality • opioids

Human & Experimental Toxicology, Vol. 21, No. 11, 599-605 (2002)
DOI: 10.1191/0960327102ht303oa


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