Overdosing on Alprazolam

Ham-milton said:

Well, just Alprazolam, no alcohol or opiates (especially no opiates), and she'll be fine, but that's a horrible road to start going down.

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burn out said:

i can't believe people are saying she'll be fine. 500 mgs of alprazolam to someone with almost no benzo tolerance? i know it's ridiculously hard to overdose on benzos alone but the LD50s have never been tested on humans, not to mention what kind of affects this type of overdose could have on the nervous system.

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Morphinator said:

Ham-milton,

I can't say anything of alprazolam (for the simple reason that I haven't read studies or heard of overdose cases involving alprazolam alone), but I have read some disturbing things about OD situations with only a single benzo being responsible. I will show some examples when I dig them up for you.

Nitrazepam, temazepam, and flunitrazepam have all been involved in many overdose deaths without the consumption of alcohol, narcotics, or any other drug. Cases involving other benzodiazepines which have caused death from an overdose (without the consumption of any other drugs) include triazolam and flurazepam.

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Ham-milton said:

And what do those benzos have in common? They're all hypnotics and extremely amnesic.

The first three also have inherent toxicity that makes even normal doses potentially dangerous for some people. Temazepam is the worst, as I recall. I forget the specifics of their toxicity, and it's 3:30am here, but I'll look it up in the morning.

I don't know why, but for some reason I also seem to remember them having the lowest therapeutic ratios (ED50/LD50)

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Benzodiazepines have a relatively high therapeutic index.[46] Death after admission is rare and due to respiratory depression with aspiration of gastric contents.[47] Over 10 years in the United Kingdom, however, 1512 fatal poisonings have been attributed to benzodiazepines with or without alcohol.[48] 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[49] and barbiturates.[50] 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 12.8); 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,[51] a bias that would lead to differences between compounds was not identified.[52] 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 (18), others (18).

Details of coma scores and odds ratios of the benzodiazepines ingested showed that temazepam was significantly more toxic than most other benzodiazepines.[53] 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.[54]

The sedation produced by benzodiazepines in therapeutic doses and overdose has a poor correlation with measured drug concentration but is increased with rapid absorption.[55][56][57][58] Temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than other benzodiazepines.[59][60][61][62][63] 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.[64] 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.[65] 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.[66]

SOURCES:

Gaudreault P, Guay J, Thivierge RL, Verdy I (1991). "Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment". Drug Saf 6 (4): 247–65. PMID 1888441.

Höjer J, Baehrendtz S, Gustafsson L (1989). "Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period". J. Intern. Med 226 (2): 117–22. PMID 2769176.

Serfaty M, Masterton G (1993). "Fatal poisonings attributed to benzodiazepines in Britain during the 1980s". Br J Psychiatry 163: 386–93. PMID 8104653.

Cassidy S, Henry J (1987). "Fatal toxicity of antidepressant drugs in overdose". Br Med J (Clin Res Ed) 295 (6605): 1021–4. PMID 3690249.

Johns MW (1977). "Self-poisoning with barbiturates in England and Wales during 1959-74". Br Med J 1 (6069): 1128–30. PMID 861497.

Dwyer PS, Jones IF (1984). "Fatal self-poisoning in the UK and the paracetamol/dextropropoxyphene combination". Hum Toxicol 3 Suppl: 145S–174S.

Serfaty M, Masterton G (1993). "Fatal poisonings attributed to benzodiazepines in Britain during the 1980s". Br J Psychiatry 163: 386–93.

Buckley NA, Dawson AH, Whyte IM, O'Connell DL (1995). "Relative toxicity of benzodiazepines in overdose". BMJ 310 (6974): 219–21.

Serfaty M, Masterton G (1993). "Fatal poisonings attributed to benzodiazepines in Britain during the 1980s". Br J Psychiatry 163: 386–93.

Gaudreault P, Guay J, Thivierge RL, Verdy I (1991). "Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment". Drug Saf 6 (4): 247–65.

Busto U, Kaplan HL, Sellers EM (1980). "Benzodiazepine-associated emergencies in Toronto". Am J Psychiatry 137 (2): 224–7.

Fuccella LM, Bolcioni G, Tamassia V, Ferrario L, Tognoni G (1977). "Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules". Eur. J. Clin. Pharmacol 12 (5): 383–6.

Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI (1989). "Pharmacokinetic determinants of dynamic differences among three benzodiazepine hypnotics. Flurazepam, temazepam, and triazolam". Arch. Gen. Psychiatry 46 (4): 326–32.

Gaudreault P, Guay J, Thivierge RL, Verdy I (1991). "Benzodiazepine poisoning. Clinical and pharmacological considerations and treatment". Drug Saf 6 (4): 247–65.

Busto U, Kaplan HL, Sellers EM (1980). "Benzodiazepine-associated emergencies in Toronto". Am J Psychiatry 137 (2): 224–7.

Fuccella LM, Bolcioni G, Tamassia V, Ferrario L, Tognoni G (1977). "Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules". Eur. J. Clin. Pharmacol 12 (5): 383–6.
Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI (1989). "Pharmacokinetic determinants of dynamic differences among three benzodiazepine hypnotics. Flurazepam, temazepam, and triazolam". Arch. Gen. Psychiatry 46 (4): 326–32.

Mitler MM (1981). "Evaluation of temazepam as a hypnotic". Pharmacotherapy 1 (1): 3–13.
Fuccella LM, Bolcioni G, Tamassia V, Ferrario L, Tognoni G (1977). "Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules". Eur. J. Clin. Pharmacol 12 (5): 383–6.

Alexander B, Perry PJ (1991). "Detoxification from temazepam: schedules and strategies". J Subst Abuse Treat 8 (1-2): 9–17.

Serfaty M, Masterton G (1993). "Fatal poisonings attributed to temazepam in Britain during the 1980s". Br J Psychiatry 163: 386–93.

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smokester said:

^The nitro-containing compounds form superoxide free radicals. The downside of clonazepam is also its neurotoxicity. Alprazolam at least isnt, much like diazepam.

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]Withdrawal from certain hypnotic benzodiazepines are often more problematic and are often difficult to manage. Some hypnotics include nitrazepam (Mogadon®), temazepam (Restoril®), flurazepam (Dalmane®), triazolam (Halcion®), flunitrazepam (Rohypnol®), flutoprazepam (Restas®), and nimetazepam (Ermin®).

Neuropsychological function can be permanently affected by abuse of certain hypnotic benzodiazepines (temazepam, nitrazepam, flunitrazepam, flutoprazepam, and nimetazepam were found to be particularly toxic), with brain damage similar to alcoholic brain damage, as was shown in a 4– to 6-year follow-up study of hypnotic abusers by Borg and others of the Karolinska Institute. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics, hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in hypnotic benzodiazepine abusers, it is often permanent.[5] An earlier study by Borg et al. found evidence of cerebral disorder in those that exclusively abused hypnotic benzodiazepines, suggesting that cerebral disorder was not the result of other substances of abuse. Anxiolytic benzodiazepines, such as diazepam, clonazepam, alprazolam, bromazepam and lorazepam were not found to have the same toxic properties of most of the hypnotics.[6]

The brain damage associated with chronic hypnotic benzodiazepine abuse and withdrawal is an effect rarely, if ever reported among anxiolytic benzodiazepines such as alprazolam (Xanax®), diazepam (Valium®), clonazepam (Rivotril®; Klonopin®) and other similar anxiolytics. There are reports in the medical literature of at least six psychotic states developing after abrupt withdrawal from temazepam including delirium, paranoia, and suicide ideation after abrupt withdrawal of only 30 mg of temazepam and in other cases, auditory and visual hallucinations and visual cognitive disorder developed after abrupt withdrawal from 10 mg of temazepam, 5 mg of nitrazepam and 0.5 mg of triazolam. Two psychotic states developing after abrupt withdrawal from nitrazepam has also been reported in medical literature. Chronic high dose abuse of flutoprazepam and nitrazepam have been linked to speech disorders such as stuttering and cluttering. Besides being linked to the development of speech or communication disorders, they have also been linked to cognition problems and balance disorders. Several studies have shown that moderate to high dose abuse of temazepam, nimetazepam, flutoprazepam, and flunitrazepam cause aphasia, dysnomia, delusional disorders, severe memory problems, motor coordination damage, and neurological problems. Depersonalisation has also been reported as a benzodiazepine withdrawal effect from doses as low as 5 mg temazepam, 7.5 mg flurazepam, and 2.5 mg nitrazepam.[7] The studies conducted by Borg et al. on chronic abusers of diazepam, alprazolam, bromazepam, lorazepam, and clonazepam never produced any kind of abnormalities in brain function, severe deterioration of memory, and speech and communication disorders. Depersonalisation was a withdrawal effect from 20 mg diazepam, 1.7 mg alprazolam, 1.8 mg clonazepam, 14 mg bromazepam, and 4.2 mg lorazepam. These findings suggest that depersonalisation occurs with temazepam, flurazepam, and nitrazepam at doses much lower than their therapeutic doses, whereas the anxiolytics required doses higher than their therapeutic doses to produce a depersonalisation withdrawal effect.

Abrupt withdrawal from very high doses is even more likely to cause severe withdrawal effects. Many well documented cases of withdrawal from high dose abuse of temazepam have caused severe hypoperfusion of the whole brain with diffuse slow activity on EEG. After withdrawal, abnormalities in hypofrontal brain wave patterns persist beyond the withdrawal syndrome and organic brain damage occurs from chronic high dose abuse of temazepam. Widespread abuse of temazepam has provided doctors, pharmacologists, and scientists with plenty of case studies, and as a result, temazepam withdrawal has been well known to cause a sudden and often violent death.[8] High dose abuse of nitrazepam, flunitrazepam, flutoprazepam, triazolam, nimetazepam, flurazepam, and a few other hypnotic benzodiazepines have also been known to cause abnormalities in brain function, including severe hypoperfusion of the whole brain with diffuse slow activity on EEG. Just like temazepam, abnormalities in hypofrontal brain wave patterns persist well beyond the withdrawal syndrome and brain damage occurs. However, cases are not as well documented in medical literature for most of the aforementioned hypnotics as is with temazepam.

Besides the well documented cases of chronic high dose abuse of temazepam and the life threatening withdrawal syndrome associated with it, flutoprazepam, nitrazepam, and triazolam have also been known to cause sudden and violent deaths during withdrawal.


SOURCES:

Borg S; Bergman H, Engelbrektson K, Vikander B. (1989). "Dependence on hypnotic benzodiazepines: neuropsychological impairment, field dependence and clinical course in a 5-year follow-up study.". British journal of addiction. 84 (5): 547-53.

Borg S; Bergman H, Holm L. (Feb 1980). "Neuropsychological impairment and exclusive abuse of hypnotics.". The American journal of psychiatry. 137 (2): 215-7.

Terao T, Yoshimura R, Terao M, Abe K (1992). "Depersonalization following nitrazepam, flurazepam, and temazepam withdrawal". Biol. Psychiatry 31 (2): 212–3

Kitabayashi Y, Ueda H, Narumoto J, et al (2001). "Chronic high-dose temazepam dependence 123I-IMP SPECT and EEG studies". Addict Biol 6 (3): 257–261.

Borg S. Sedative hypnotic dependence: neuropsychological changes and clinical course. Nord Pskiatr Tidsskr 1987; 41: Suppl 15: 17-19.[

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