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

Abstract

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.

Keywords

benzodiazepines drug interactions lethality opioids

References

Risser D , Schneider B . Drug-related deaths between 1985 and 1992 examined at the Institute of Forensic Medicine in Vienna, Austria . Addiction 1994; 89: 851–857 .

Steentoft A , et al. Fatal poisonings in young drug addicts in the Nordic countries: a comparison between 1984–1985 and 1991 . Forensic Sci Int 1996; 78: 29–37 .

Sporer KA . Acute heroin overdose . Ann Intern Med 1999; 130: 584–590 .

O’Connor PG , Fiellin DA . Pharmacologic treatment of heroin-dependent patients . Ann Intern Med 2000; 133: 40–54 .

Gowing L , Ali R , White J . Buprenorphine for the management of opioid withdrawal . Cochrane Database Syst Rev 2000; 3: CD002025-CD002025 .

Clark JC , Milroy CM , Forrest ARW . Deaths from methadone overdose . J Clin Forensic Med 1995; 2: 143–144 .

Drummer OH , et al. Methadone toxicity causing death in ten subjects starting on a methadone maintenance program . Am J Forensic Med Pathol 1992; 13: 346–350 .

Hammersley R , Cassidy MT , Oliver J . Drugs associated with drug-related deaths in Edinburgh and Glasgow, November 1990 to October 1992 . Addiction 1995; 90: 959–965 .

Neeleman J , Farrell M . Fatal methadone and heroin overdoses: time trends in England and Wales . J Epidemiol Community Health 1997; 51: 435–437 .

10.

Walsh SL , et al. Acute administration of buprenorphine in humans: partial agonist and blockade effects . J Pharmacol Exp Ther 1995; 274: 361–372 .

11.

Tracqui A , Kintz P , Ludes B . Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities . J Anal Toxicol 1998; 22: 430–434 .

12.

Zador D , Sunjic S , Darke S . Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances . Med J Aust 1996; 164: 204–207 .

13.

Steentoft A , et al. Drugs in blood samples from unconscious drug addicts after the intake of an overdose . Int J Legal Med 1996; 108: 248–251 .

14.

Gutierrez-Cebollada J , et al. Psychotropic drug consumption and other factors associated with heroin overdose . Drug Alcohol Depend 1994; 35: 169–174 .

15.

Darke SG , Ross JE , Hall WD . Benzodiazepine use among injecting heroin users . Med J Aust 1995; 162: 645–647 .

16.

Navaratnam V , Foong K . Opiate dependence–the role of benzodiazepines . Curr Med Res Opin 1990; 11: 620–630 .

17.

Dixon WJ . Staircase bioassay: the up-and-down method . Neurosci Biobehav Rev 1991; 15: 47–50 .

18.

Bruce RD . A confirmatory study of the up-and-down method for acute oral toxicity testing . Fundam Appl Toxicol 1987; 8: 97–100 .

19.

OECD . OECD guideline for testing of chemicals. Guideline 425: acute oral toxicity–up and down Procedure. Paris, France: OECD , 1998.

20.

Dixon WJ , Mood AM . A method for obtaining and analyzing sensitivity data . J Am Stat Assoc 1948; 43: 109–126 .

21.

Henry JA . Fatal opioid toxicity–a clinical perspective . Addiction 1999; 94: 974–975 .

22.

McCormick GY , et al. Effects of diazepam on arterial blood gas concentrations and pH of adult rats acutely and chronically exposed to methadone . J Pharmacol Exp Ther 1984; 230: 353–359 .

23.

Gueye PN , et al. Buprenorphine and midazolam act in combination to depress respiration in rats . Toxicol Sci 2002; 65: 107–114 .

24.

Gueye PN , et al. Lack of effect of single high doses of buprenorphine on arterial blood gases in the rat . Toxicol Sci 2001; 62: 148–154 .

25.

Reisine T , Pasternak GW . Opioid analgesics and antagonists. In Hardman JG , et al. eds. Goodman and Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill , 1996.

26.

White JM , Irvine RJ . Mechanisms of fatal opioid overdose . Addiction 1999; 94: 961–972 .

27.

Gong QL , et al. Antinociceptive and ventilatory effects of the morphine metabolites: morphine-6-glucuronide and morphine-3-glucuronide . Eur J Pharmacol 1991; 193: 47–56 .

28.

Ohtani M , et al. Kinetics of respiratory depression in rats induced by buprenorphine and its metabolite, norbuprenorphine . J Pharmacol Exp Ther 1997; 281: 428–433 .

29.

Becherucci C , Palmi M , Segre G . Pharmacokinetics of flunitrazepam in rats studied by a radioreceptor assay . Pharmacol Res Commun 1985; 17: 733–747 .

30.

Gopal S , Tzeng TB , Cowan A . Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine . Eur J Pharmacol Sci 2002; 15: 287–293 .

31.

Cowan A , Doxey JC , Harry EJ . The animal pharmacology of buprenorphine, an oripavine analgesic agent . Br J Pharmacol 1977; 60: 547–554 .

32.

Pasternak GW . Pharmacological mechanisms of opioid analgesics . Clin Neuropharmacol 1993; 16: 1–18 .

33.

Morin-Surun MP , et al. Different effects of mu and delta opiate agonists on respiration . Eur J Pharmacol 1984; 98: 235–240 .

34.

Dosaka-Akita K , et al. The kappa opioid agonist U50,488H antagonizes respiratory effects of mu opioid receptor agonists in conscious rats . J Pharmacol Exp Ther 1993; 264: 631–637 .

35.

Villiger JW , Taylor KM . Buprenorphine: characteristics of binding sites in the rat central nervous system . Life Sci 1981; 29: 2699–2708 .

36.

Negus SS , Picker MJ , Dykstra LA . Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats . Psychopharmacology (Berlin) 1989; 98: 141–143 .

37.

Kazemi H , Hoop B . Glutamic acid and gamma-aminobutyric acid neurotransmitters in central control of breathing . J Appl Physiol 1991; 70: 1–7 .

38.

Brady LS , et al. Reversal of the antinociceptive effects of centrally-administered morphine by the benzodiazepine receptor antagonist Ro 15-1788 . Life Sci 1984; 35: 2593–2600 .

39.

Rodgers RJ , Randall J , Kelway B . Naloxone potentiates the depressant effect of chlordiazepoxide on spontaneous activity in mice . Neurosci Lett 1985; 58: 97–100 .

40.

Upton N , Gonzalez JP , Sewell RD . Characterization of a kappa-agonist-like antinociceptive action of tifluadom . Neuropharmacology 1983; 22: 1241–1242 .

41.

Cox RF , Collins MA . The effects of benzodiazepines on human opioid receptor binding and function . Anesth Analg 2001; 93: 354–358 (353rd contents page).

42.

Sasaki K , et al. The interaction of morphine and gamma-aminobutyric acid (GABA)ergic systems in anxiolytic behavior: using mu-opioid receptor knockout mice . Brain Res Bull 2002; 57: 689–694 .

43.

Auletta CS . Acute, subchronic, and chronic toxicology. In Derelanko MJ , Hollinger MA eds. CRC handbook of toxicology. Boca Raton, FL: CRC Press , 1995.