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

Abstract

<jats:p> 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&lt;0.01). Flunitrazepam–opioid drug–drug interactions are more complex than is generally believed. Mechanistic studies of flunitrazepam–opioid lethal interactions are needed. </jats:p>

Cause of death and drug use pattern in deceased drug addicts in Sweden, 2002–2003

“…Poisoning was strongly indicated whenever morphine or fentanyl was detected. The importance of benzodiazepines is however uncertain in illicit drug intoxication cases [35] and in many of our cases the detection of benzodiazepines were probably incidental. Amphetamine seems to be the dominating psychostimulant in Sweden, commonly detected in postmortem analysis and the second most commonly illicit drug seized by police and customs following cannabis [21].…”

Comparison of Five Benzodiazepine-Receptor Agonists on Buprenorphine-Induced μ-Opioid Receptor Regulation

“…Actually, in spite of restrictions on its prescription status, FLZ remains largely abused and misused (22, 35 -37). Furthermore, FLZ has been shown to induce a six-fold decrease in the median lethal dose of BPN in rats (38).…”

Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal

“…Since 40 mg/kg is a relatively high dose of morphine in opiate-naïve animals, possibly leading to symptoms of morphine overdose, including respiratory depression (Hurwitz & Fischer 1984) and lethality (Borron et al 2002), we could not examine the effects of acute morphine treatment at 40 mg/kg. We followed the Principles of Laboratory Animal Care (NIH Publication No.…”