Benzodiazepines have a relatively high therapeutic index. Death after admission is rare and due to respiratory depression with aspiration of gastric contents. Over 10 years in the United Kingdom, however, 1512 fatal poisonings have been attributed to benzodiazepines with or without alcohol. These were compared with prescription data to establish a fatal toxicity index (deaths per million prescriptions) for each benzodiazepine. Similar indices have been derived for antidepressants and barbiturates. There were clear differences between benzodiazepines. Of drugs frequently prescribed, temazepam by far had the highest number of deaths per million prescriptions at 11.9 (95% confidence interval 10.9 to 12.; above that of some tricyclic antidepressants. In contrast, oxazepam had an index of 2.3 (1.2 to 3.4 ), and the average index for all benzodiazepines combined was 5.7.
Although there are potential sources of error in these studies, a bias that would lead to differences between compounds was not identified. Clinical studies can adjust for potential confounders which studies that use coronial data are unable to take into account. If differences between the benzodiazepines are supported by data from clinical studies this also adds credence to the fatal toxicity index which first noted these findings.
The aim was therefore to determine if temazepam caused more sedation and oxazepam less sedation than other benzodiazepines.
During 1991-3, 542 patients with benzodiazepine poisoning presented to the hospital, 239 of these patients, however, had ingested either more than one benzodiazepine or co-ingested other sedating drugs. The drugs ingested by the remainder were temazepam (64 ), oxazepam (45 ), diazepam (113), clonazepam (24 ), flunitrazepam (21 ), nitrazepam (1, others (1.
Details of coma scores and odds ratios of the benzodiazepines ingested showed that temazepam was significantly more toxic than most other benzodiazepines. Two out of the 45 subjects (4 who ingested oxazepam were stuporous or comatose, 38 out of the 194 subjects (19 who ingested other benzodiazepines (clonazepam, diazepam, flunitrazepam, nitrazepam and others) were stuporous or comatose, while 16 out of the 64 subjects (25 who ingested temazepam were stuporous or comatose. None of the oxazepam subjects were comatose, 16 out of the 194 subjects (8 who ingested other benzodiazepines were fully comatose, and 9 out of 64 subjects (14 who ingested temazepam were fully comatose.
The results show that there are differences between temazepam, oxazepam, and other benzodiazepines in the degree of sedation they cause in overdose, and the observed differences are not due to confounding by age, sex, dose ingested, co-ingestion of alcohol, chronic benzodiazepine use, or history of drug or alcohol abuse. This provides a plausible explanation why temazepam and oxazepam have different fatal toxicity indices from other benzodiazepines.
The sedation produced by benzodiazepines in therapeutic doses and overdose has a poor correlation with measured drug concentration but is increased with rapid absorption. Temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than other benzodiazepines. Further research is required to determine if the rate of absorption is different in overdose and is sufficient to explain the differences in sedation. Slowing the rate of absorption may reduce toxicity, but this would also reduce their sedative effect in therapeutic doses. Drug regulatory authorities should be aware that changes in formulation of benzodiazepines may affect toxicity in overdose.
Pharmacodynamic factors such as benzodiazepine receptor affinity and potency may also be important. Because of the wide variations in half life, adjustments for dose by conversion into defined daily doses or diazepam equivalents is imperfect. These are designed to compare use rather than potency. Though they correlate reasonably well with sizes of prescriptions and tablets, they may not account for potency per tablet taken in overdose.
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