Studies were undertaken to determine the possible role of enteric bacteria in the postmortem bioconversion of the nitrobenzodiazepines flunitrazepam, clonazepam, and nitrazepam. Flunitrazepam, clonazepam, and nitrazepam were completely metabolized in blood in the presence of eight species of enteric bacteria to their respective 7-amino-metabolites. The rates of metabolism, at 37°C, ranged from 0.1 ng/mL/min for Streptococcus faecalis to 8.8 ng/mL/min for Clostridium perfringens. The rate of conversion was reduced to 87% by a combination of 0.7% (w/v) sodium fluoride and potassium oxalate, and almost completely inhibited (96%) by 1% (w/v) sodium fluoride. pH had variable effects on the rate of metabolic bioconversion of nitrobenzodiazepines, while increasing temperatures were found to generally increase the rate of nitrobenzodiazepine bioconversion. These data support the proposal that bacteria may mediate postmortem bioconversion of the nitrobenzodiazepines.

Objectives To estimate the effects of methadone programs in New South Wales on mortality. Design and cases Retrospective, cross‐sectional study of all 1994 New South Wales coronial cases in which methadone was detected in postmortem specimens taken from the deceased. Cases were people we identified as patients in NSW methadone maintenance programs or those whose deaths involved methadone syrup diverted from maintenance programs. Outcome measures Relative risks of fatal, accidental drug toxicity in the first two weeks of treatment and later; the number of lives lost as a result of maintenance treatment; preadmission risks and the number of lives saved by maintenance programs, calculated from data from a previous study. Results There was very close agreement between this study's classifications and official pathology reports of accidental drug toxicity. The relative risk (RR) of fatal accidental drug toxicity for patients in the first two weeks of methadone maintenance was 6.7 times that of heroin addicts not in treatment (95% Cl RR, 3.3‐13.9) and 97.8 times that of patients who had been in maintenance more than two weeks (95% Cl RR, 36.7‐260.5). Despite 10 people dying from iatrogenic methadone toxicity and diverted methadone syrup being involved in 26 fatalities. In 1994, NSW maintenance programs are estimated to have saved 68 lives (adjusted 95% Cl, 29‐128). Conclusions In 1994, untoward events associated with NSW methadone programs cost 36 lives in NSW. To reduce this mortality, doctors should carefully assess and closely monitor patients being admitted to methadone maintenance and limit the use of takeaway doses of methadone.

No abstract

Studies were undertaken to determine the stability of nitrobenzodiazepines and their 7-amino metabolites in water and blood. At 22°C nitrazepam and clonazepam were stable in sterile fresh blood containing preservative over 28 days, whereas 25% of flunitrazepam was degraded. At 37°C all three drugs were substantially lost over 9 h (29–51%). There was only a small loss observed for the 7-amino metabolites and no substantial amounts of parent drug and 7-amino metabolite were degraded in water under these conditions. In the absence of preservative substantial amounts (25–50%) of parent drugs were lost in fresh blood over 10 days at 22°C. In bacterially-contaminated postmortem blood all three drugs were completely degraded over 8 h at 22°C with almost all drug completely converted to the respective 7-amino metabolite. These metabolites were also partially degraded (10–20%) over 45 h at 22°C. All 3 nitrobenzodiazepines were stable in blood stored for up to 24 months at −20°C, or 4°C over 10 months. Their respective 7-amino metabolites were, however, relatively unstable at −20°C with a significant loss (29%) after 2 months. At 4°C a 21% loss occurred after 1 month. Freeze/thawing was found not to affect the concentration of nitrobenzodiazepine and 7-amino metabolites. These results show that the nitrobenzodiazepines and their metabolites are unstable chemically and metabolically in blood. We advise that blood collected for the purpose of nitrobenzodiazepine determinations should be preserved with sodium fluoride, stored at −20°C and assayed as soon as practicable, preferably within a week of collection.