Am J Psychiatry. 1984 Dec;141(12):1606-7.
Seizures induced by abrupt discontinuation of alprazolam.
Two patients had grand mal seizures following abrupt discontinuation of short-term treatment with alprazolam. Alprazolam’s pharmacokinetic and clinical properties are discussed in relation to withdrawal reactions.
J Clin Psychiatry. 1984 Jan;45(1):38-9.
Delirium and seizures due to abrupt alprazolam withdrawal: case report.
A case is reported of delirium and seizures due to the abrupt withdrawal from the benzodiazepine alprazolam. Because of their short half-life, agents such as alprazolam may present a greater risk of withdrawal reactions than longer acting agents.
- [PubMed – indexed for MEDLINE]
Clin Neuropharmacol. 1998 May-Jun;21(3):201-2.
Alprazolam withdrawal delirium: a case report.
Geha Psychiatric Hospital, Petah Tikva, Israel.
Benzodiazepine withdrawal delirium is thought to be uncommon. Only two clear reports of alprazolam withdrawal appear in the literature, but the use of this drug is expected to increase because of its recent approval for the treatment of panic disorder. We report on a patient with severe alprazolam withdrawal delirium that developed immediately after an accidental reduction of the dose. This case demonstrates importance of clinician awareness of the previous use of alprazolam in individual patients, especially in hospital settings where free patient use of drugs is prohibited.
- [PubMed – indexed for MEDLINE]
Am J Forensic Med Pathol. 2009 Jun;30(2):177-9.
A fatal case of benzodiazepine withdrawal.
Department of Pathology, University of Colorado Denver, Aurora, 80045, USA. firstname.lastname@example.org
Medical examiners often receive cases with limited medical history. Sometimes the medical history received is slightly skewed, or even incorrect. Here we describe a case which was initially referred to the Bexar County Medical Examiner’s Office from a large community hospital as a case of zolpidem overdose. The deceased presented to the hospital with hypertension, elevated temperature, worsening bizarre behavior, and movement irregularities. While in the hospital, the decedent developed seizure-like activity and died approximately 15 hours after admission. A complete autopsy was performed and yielded no significant gross or histologic abnormalities. A full toxicologic analysis revealed therapeutic levels of citalopram and phenytoin. Zolpidem was not present. Further review of the decedent’s medical history as well as information provided by the next of kin revealed that the deceased had been taking diazepam for several years but had recently been switched to alprazolam. The decedent had abruptly stopped taking the alprazolam approximately 4 days before admission when she ran out of the medication, after taking approximately 200 mg in a 6-day period. Given the inconsistent clinical presentation and the findings at autopsy, we suspect that she suffered from benzodiazepine withdrawal and not an overdose as initially reported. Although it is possible that the zolpidem, reportedly taken in the 12 hours before admission, masked the initial symptoms of withdrawal, the constellation of symptoms and signs at presentation are more consistent with benzodiazepine withdrawal than of zolpidem overdose. In this report, we emphasize to the forensic community that one must maintain a high index of suspicion for alternative explanations if the initial report does not seem to fit the presentation or autopsy findings. This case illustrates that although it may take some extra time and effort, further investigation into clinical history can prove crucial to obtaining the correct cause of death and manner of death. This is only the second case within the English literature of death because of benzodiazepine withdrawal.
Br J Clin Pharmacol. 2004 Jul;58(1):88-95.
Alprazolam is relatively more toxic than other benzodiazepines in overdose.
Discipline of Clinical Pharmacology, University of Newcastle, Newcastle, Australia. email@example.com
To describe alprazolam poisoning and the relative toxicity of alprazolam compared with other benzodiazepines.
A database of consecutive poisoning admissions to a regional toxicology service was searched to identify consecutive benzodiazepine deliberate self poisonings, which were coded as alprazolam, diazepam or other benzodiazepine. Major outcomes used were length of stay (LOS), intensive care (ICU) admission, coma (GCS < 9), flumazenil administration and requirement for mechanical ventilation. Prescription data were obtained for benzodiazepines for the study period.
There were 2063 single benzodiazepine overdose admissions: 131 alprazolam overdoses, 823 diazepam overdoses and 1109 other benzodiazepine overdoses. The median LOS for alprazolam overdoses was 19 h which was 1.27 (95% CI 1.04, 1.54) times longer compared with other benzodiazepines by multiple linear regression. For patients with alprazolam overdoses, 22% were admitted to ICU which was 2.06 (95% CI 1.27, 3.33) times more likely compared with other benzodiazepines after multivariate analysis adjusting for age, dose, gender, time to ingestion and co-ingested drugs. Flumazenil was administered to 14% of alprazolam patients and 16% were ventilated, which was significantly more than for other benzodiazepine overdoses (8% and 11%, respectively). Twelve percent of alprazolam overdoses had a GCS < 9 compared with 10% for other benzodiazepines. From benzodiazepine prescription data, total alprazolam prescriptions in Australia increased from 0.13 million in 1992 to 0.41 million in 2001. Eighty five percent of prescriptions were for panic disorder, anxiety, depression or mixed anxiety/depression.
Alprazolam was significantly more toxic than other benzodiazepines. The increased prescription of alprazolam to groups with an increased risk of deliberate self poisoning is concerning and needs review.
Am J Psychiatry. 1989 Feb;146(2):276.
Dangerously aggressive behavior as a side effect of alprazolam.
- [PubMed – indexed for MEDLINE]
Eur J Clin Pharmacol. 2011 Nov;67(11):1189-98. Epub 2011 Jun 8.
Prescribed drugs and violence: a case/noncase study in the French PharmacoVigilance Database.
Rouve N, Bagheri H, Telmon N, Pathak A, Franchitto N, Schmitt L, Rougé D, Lapeyre-Mestre M, Montastruc JL; French Association of Regional PharmacoVigilance Centres.
Service de Pharmacologie Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d’Information sur les Médicaments, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
Our aim was to identify prescribed drugs associated with violent behaviours using the French PharmacoVigilance Database (FPVD).
All reports of adverse drug reactions (ADR) recorded in the FPVD between 1 January 1985 and 31 July 2008 and including the terms aggressiveness or violence were selected. We compared proportion of exposure to different drugs between cases (reports with violence) and noncases (other reports in the database).
Among 537 cases, 56 were included (48 men, mean age 46 years). Misuse was observed in ten cases (18%). In 25 cases (44.6%), a previous psychiatric history was documented. Main drugs involved were nervous system (63.6%) followed by respiratory (7.8%), alimentary tract and metabolism (7.8%), dermatological (5.2%) and anti-infective (5.2%) agents. Case/noncase analysis found an association with dopaminergic agonists (pergolide, pramipexole, bromocriptine, piribedil), benzodiazepines (alprazolam, bromazepam) and serotoninergic antidepressants (taken as a whole), but not antipsychotics or antiepileptics. Association was also found with varenicline, isotretinoin, interferon alpha-2b, rimonabant, benfluorex, topiramate and antiviral drugs (ribavirin, efavirenz).
Dopaminergic agonists, benzodiazepines and serotoninergic antidepressants are the main pharmacological classes able to induce aggressive behaviour. This study also emphasises the putative role of other drugs less known to be involved in such ADR.
Encephale. 2003 Nov-Dec;29(6):479-85.
[Benzodiazepines and forensic aspects].
[Article in French]
Praticien Hospitalier, Chef de Service – SMPR, EPS Charcot, 30, avenue Marc-Laurent, BP 20, 78373 Plaisir cedex. firstname.lastname@example.org
Adverse effects of benzodiazepines are well known since the first one was used in 1958 (chlordiazepoxide). The literature collects study-cases or rarely controlled studies concerning side effects or paradoxical reactions to benzodiazepines. They mostly described drowsiness and behavioral disinhibition, including increased well-being feeling but also hostility, rage access with feeling of invulnerability, serious crimes and sometimes homicides. Delusional, manic, confusional or depressive states are also pointed out. Rate for aggressive behaviour is 0.3 to 0.7% but distinction should be done between accidental or “idiosyncratic” reaction and voluntary sought disinhibition, clearly more frequent. No benzodiazepine has any specificity for these adverse effects but pharmacology, doses, associated drugs (or alcohol) and psychopathology interact to produce hazardous psychic states. Pharmacology: GABA induces a decrease in serotonin compound and vigilance. Pharmacokinetic: first dose effect or over-dose effect, short half-life, lipophily, affinity, digestive absorption, active metabolites interact. Psychopathology: age, alcohol association, psychological status (high initial level of hostility, impulsivity, frustration, personality disorder and depressive status). External conditions: chronic illness, affective and professional frustrations, physical or psychic exhaustion contribute also. Some benzodiazepines (flunitrazepam, diazepam, clorazepate, triazolam, alprazolam, lorazepam, for example) are more often concerned for pharmacokinetics characteristics but also prescription habits. Forensic aspects should be considered in case of homicide. Especially, reality of benzodiazepines consumption and awareness of the potential paradoxical reaction should be precisely evaluated. Special focus on voluntary induced disinhibition has to be done for forensic considerations. Relationship but also crime facilitations are sometimes consciously sought. Some benzodiazepines have already been identified for this use: flunitrazepam, clorazepate but also triazolam and temazepam in UK, alprazolam in USA. Flunitrazepam is prohibited in USA and considered as narcotics in France. A Swedish study showed that violent acts were more frequent and serious in juvenile offenders taking flunitrazepam/alcohol than other young offenders staying in the same correctional institution. They recommended classification of flunitrazepam as narcotic. A study from Belgium with drug addicts concluded in the same way and asked for an increased information of professionals and a more efficient control of the delivery. Before concluding to idiosyncratic effect, and then possibly to penal irresponsibility, the forensic approach should consider: firstly the reality of the benzodiazepines absorption and implication in committing violence (urine test, chronology, amnesia); secondly, the association of unusual behaviour and converging circumstances (pharmacological, pharmacokinetic, psychopathology, external conditions); thirdly the consumer’s knowledge of the disinhibition effect. In our prison practice, we have to be particularly cautious as population frequently associates personality disorder, drug addiction and high level of frustration related to penitential context. Special information should be given to inmates when benzodiazepines are prescribed, but more extensively, a preventive strategy should be adopted in general population.
J Clin Psychopharmacol. 1997 Aug;17(4):328; author reply 329.
Reevaluation of “Alprazolam and suicidal ideation: a meta-analysis of controlled trials in the treatment of depression”.
- [PubMed – indexed for MEDLINE]
Toxicol Ind Health. 2008 Feb-Mar;24(1-2):53-60.
An evaluation of data for 10 children born to mothers who attempted suicide by taking large doses of alprazolam during pregnancy.
Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary.
FDA has identified alprazolam, a new type of benzodiazepine, as pregnancy category D. The objective of this study was to evaluate the effects on fetal development of very large doses of alprazolam that were used for suicide attempts during pregnancy. Pregnant women were identified among the patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, who were admitted as self-poisoned subjects from a total population of the three million people of Budapest and its surrounding region. Rates of congenital abnormalities, intrauterine fetal development, and cognitive-behavioral status were compared between children born to mothers who attempted suicide during pregnancy using alprazolam alone or in combination with other drugs and in their sib controls. Between 1984 and 1993, 559 pregnant women attempted suicide during pregnancy with drugs: 30 of these women self-poisoned with alprazolam, 10 delivered live-born infants who were examined. Doses of alprazolam used were between 7.5 and 100 mg, with a mean of 30 mg. Six of the 10 exposed children were born to mothers who attempted suicide between the 6th and 12th postconceptional weeks. Of the 10 exposed children, two had congenital abnormalities. One had a multiple congenital abnormality that included atypical gastroschisis and minor anomalies; an association of this defect and the 30 mg alprazolam used for self-poisoning in the 14th postconceptional week cannot be excluded. Another exposed child had mild pectus excavatum, but the times of the suicide attempt and the critical period for producing this defect did not overlap. Of 12 sibs, one had a multiple congenital abnormality. Thus, the rate of congenital abnormalities did not significantly differ between exposed children and their sibs. Mean birth weight was higher for babies born to mothers who attempted suicide by alprazolam during pregnancy than in their sib controls. Cognitive status and behavioral scale of the exposed children did not indicate fetotoxic effects, including neurotoxic effects, of large doses of alprazolam. The large doses of alprazolam used for self-poisoning during pregnancy did not result in a significantly higher rate of congenital abnormalities; however, there were only 10 self-poisoned pregnant women, and an association of one multiple congenital abnormality with a large dose of alprazolam cannot be excluded. The findings in this study did not identify fetotoxicity, including neurotoxicity, of very large doses of alprazolam. Our study shows that the self-poisoning model is feasible and provides beneficial information for use in estimating human teratogenic and fetotoxic risks of drugs.
- [PubMed – indexed for MEDLINE]