[Abuse of alcohol and benzodiazepine during substitution therapy in heroin addicts: a review of the literature]. / Abus d'alcool et de benzodiazépines lors des traitements de substitution chez l'héroïnomane : une revue de la littérature.

INTRODUCTION: In spite of its seriousness, dependence on alcohol and benzodiazepines during substitution treatment are poorly documented. Its frequency is nonetheless significant. According to studies, between one and two thirds of patients are affected. This consumption is under verbalized by patients and underestimated by carers. In one study, where the average diazepam doses were from 40 to 45 mg per day, 30% of the patients were taking 70 to 300 mg per day, two thirds having experimented with a fixed dose of 100mg. Benzodiazepines, especially diazepam and flunitrazepam, were studied versus placebo. Thus, 10 to 20mg of diazepam gave rise to euphoria, a sensation of being drugged, sedation and lessening of cognitive performance. The aim of this consumption is to potentiate the euphoria induced by opioids, a "boost" effect during the hour after taking it, or the calming of the outward signs of withdrawal. The most sought after molecules are the most sedative, those with pronounced plasmatic peaks, and the most accessible. LITERATURE FINDINGS: In multidependant subjects, opioid dependence had been earlier in adolescence, with a number of therapeutic failures. They had been faced with repetitive rejection and separation during childhood, medicolegal and social problems. Somatization, depression, anxiety and psychotic disorders are frequent in this subgroup. Heavy drinkers under methadone treatment are highly vulnerable to cocaine. Their behaviour is at risk, with exchange of syringes; their survival rate is 10 years less than that of moderate consumers of alcohol. Most are single, with a previous prison, psychiatric or addictive cursus and they present significant psychological vulnerability. For some authors, benzodiazepines indicate a psychiatric comorbidity. Methadone significantly reduces the consumption of alcohol by nonalcoholic heroin addicts. Although alcohol is an enzymatic inductor of methadone catabolism, with bell-shaped methadone plasma curves over 24 hours, a substitution treatment is recommended. It has a minimum impact on care, in spite of efficiency and retention in therapeutical programs, allowing the subject's inclusion in the framework of a more regular and sustained medical follow-up. Treatment of benzodiazepine dependence by a progressive regression of doses has little efficacy in subjects which cannot control how much medication they are taking. Certain authors have suggested maintenance treatments of clonezepam. The most appropriate therapeutic propositions are: (1) maintenance of therapeutic links though a framework of deliverance from flexible substitution treatment; (2) prevention by cautious prescribing and control of dispensing medication; (3) parallel treatment of psychiatric comorbidities and related personality disorders; (4) individual psychiatric treatment, either institutional or in consistent networks.

[Benzodiazepine poisoning in a neonate: clinical and toxicokinetic evaluation following enterodialysis with activated charcoal]. / Intoxication par les benzodiazépines chez un nouveau-né: évaluation clinique et toxicocinétique de l'entérodizlyse par le charbon activé.

CASE REPORT: A pregnant woman who was a regular user of anxiolytics was admitted to the maternity ward at 38 weeks and 4 days amenorrhea after a massive overdose of clorazepate dipotassium, a benzodiazepine. The exact quantity ingested was undetermined. The infant, born at 39 weeks, presented no spontaneous breathing and tracheal intubation was necessary in the delivery room. The neonatal blood concentrations of the clorazepate metabolites were very high at delivery (26 mg/l nordiazepam and 3.5 mg/l oxazepam) and showed little change over the next 5 days (16 mg/l nordiazepam and 2.1 mg/l oxazepam, with an apparent half-life of 168 h for nordiazepam and 160 h for oxazepam). By day 6, the infant was still dependent on ventilator support and enterodialysis was begun with repeated doses of activated charcoal (1 g/kg every 6 h by gastric tube). Treatment was continued for 5 days and a spectacular diminution in the serum concentrations of the two metabolites was noted on day 11: 1.5 mg/l nordiazepam and less than 0.1 mg/l oxazepam. The nordiazepam and oxazepam half-lifes were reduced to 42 h and 30 h respectively. The concomitant clinical improvement authorized the weaning from ventilation on day 12. CONCLUSION: This is the first report of the use of enterodialysis to treat severe benzodiazepine poisoning in a neonate. Depuration of the toxin was accelerated and the duration of intensive care was shortened thanks to this technique.

Prolonged sedation requiring mechanical ventilation and continuous flumazenil infusion after routine doses of clorazepam for alcohol withdrawal syndrome.

We report the cases of two patients who developed prolonged sedation after routine doses of clorazepam for alcohol withdrawal syndrome. They required prolonged mechanical ventilation (10 days for both patients) followed by continuous flumazenil infusion (16 days for one patient and 3 days for the other) to avoid reintubation. In the two patients, nordazepam accumulation (main active metabolite of clorazepam) was demonstrated as the cause of the coma. This accumulation could be attributed, in one case, to impaired hepatic cytochrome P 450 3A4 activity. Caution is required when prescribing benzodiazepines to alcoholic patients and the use of benzodiazepine which do not undergo hepatic oxidation by cytochrome P 450 such as oxazepam or lorazepam is suggested.

Potentially toxic serum concentrations of desipramine after discontinuation of valproic acid.

Pharmacological interventions in the treatment of various cognitive, behavioural and neurological problems after brain injury often may involve combinations of medications from various drug classes. This carries the implication of potentially new or previously underreported drug interactions. A case report is presented in which a commonly used anticonvulsant drug, valproic acid, and a commonly used antidepressant, desipramine, interacted in such a manner as to cause potentially toxic serum concentrations of desipramine. This case demonstrates the important point that it is not simply the addition of one drug to another that may cause interaction, but the withdrawal of a particular drug which may then adversely impact the remaining drug regimen.

Disposition of clorazepate in dogs after single- and multiple-dose oral administration.

Clorazepate dipotassium was administered orally to 8 healthy dogs at a dosage of 2 mg/kg of body weight, q 12 h, for 21 days. Serum disposition of nordiazepam, the principle metabolite of clorazepate, was determined after the first and last dose of clorazepate. Disposition variables were analyzed by use of model-independent pharmacokinetics by the predictive equations method and the trapezoidal rule method. Complete blood counts, serum chemical analyses, and urinalyses were performed before administration of clorazepate and at 10 and 21 days after administration of clorazepate. Maximal nordiazepam concentrations ranged from 446 to 1,542 ng/ml (814 +/- 334 ng/ml), at 59 to 180 minutes (97.9 +/- 42.0 minutes) after a single oral dose of clorazepate. Maximal nordiazepam concentrations ranged from 927 to 1,460 ng/ml (1,308 +/- 187.6 ng/ml), at 120 to 239 minutes (153 +/- 57.9 minutes) after multiple oral doses of clorazepate. Serum disposition was significantly altered after multiple doses of clorazepate. Using data determined by the predictive equations method, the mean residence time after multiple doses (712 +/- 214 minutes) was longer (P less than 0.05) than after a single dose (527 +/- 95.8 minutes). Oral volume of distribution after multiple doses of clorazepate (1.76 +/- 0.647 L/kg) was smaller (P less than 0.02) than after a single dose (3.18 +/- 1.52 L/kg). Oral clearance after multiple doses of clorazepate (3.09 +/- 0.726 ml/min/kg) was less (P less than 0.001) than after a single dose (6.54 +/- 2.15 ml/min/kg). Absorption half-life after multiple doses (72 minutes) was longer (P less than 0.01) than after a single dose (33 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Clorazepate, correlation between metabolism and anticonvulsant activity.

The metabolism and the anticonvulsant effect of clorazepate were followed for 2 h after its i.v. administration to mice. The ED50 of the drug was 12 mg/kg at 1 min against pentetrazole-induced convulsions (45 mg/kg i.v.), it reached a minimum at 1 h (2.0 mg/kg) and rose to 2.7 mg/kg at 2 h. The concentrations of unchanged clorazepate and its metabolites, desmethyldiazepam and oxazepam, were determined in plasma and brain after administration of the respective ED50s. Unchanged clorazepate could be detected in plasma for the first hour but never in brain, so it can be considered as inactive pro-drug. The brain concentrations of desmethyldiazepam and oxazepam after the respective ED50s of clorazepate were considerably higher at 1 and 15 min than after longer time intervals. This may be explained by a time lag needed to reach and bind to the benzodiazepine receptor.

Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam.

After single 10-mg intravenous (IV) doses of desmethyldiazepam (DMDZ) to 12 healthy human volunteers, (mean age, 62 years) blood samples were obtained over the next 14 or more days. Mean kinetic variables were volume of distribution (Vd), 90 liters; elimination half-life (t1/2), 93 hours; and clearance, 12.3 mL/min. Vd was significantly correlated with body weight (r = .73, P less than .01) and with percent ideal body weight (r = .91, P less than .001). Eleven of the same subjects also received 5- to 15-mg doses of IV diazepam (DZ). Mean kinetic variables were Vd, 180 liters; t1/2, 83 hours; and clearance, 28 mL/min. Clearances of DZ and DMDZ were significantly correlated (r = .73, P less than .02). Based on area analysis, the extent of conversion of DZ to systemic DMDZ averaged 53%. After oral administration of DMDZ in tablet form (10 mg), or of clorazepate dipotassium in capsule form (15 mg), systemic availability of DMDZ from each of the oral dosage forms was not significantly different from 100%.

Clorazepate and lorazepam: clinical improvement and rebound anxiety.

Sixty-two anxious patients were treated under double-blind conditions for 4 weeks with either clorazepate or lorazepam. Two-thirds of each treatment group were then switched abruptly to placebo for 2 weeks, while one-third continued to receive active medication. Two major findings were obtained. About 70% of the patients maintained improvement during the 2-week placebo period. Some patients, however, experienced rebound anxiety, which appeared to be more intense and occurred earlier when placebo was substituted for a benzodiazepine with a short half-life (lorazepam) than for one with a long half-life (clorazepate). The clinical relevance of these findings is discussed.