Lack of effect of single high doses of buprenorphine on arterial blood gases in the rat.

High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD(50)) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD(50) using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD(50) determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6-176.5). The mean dose received by surviving animals was 96.9 +/- 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD(50), is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.

Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 1995-99.

AIMS: (1). To assess the trends in the number, mortality and the nature of severe opiate/opioid poisonings from 1995 to 1999 in north-east Paris and adjacent suburbs and (2). to examine the effects of the introduction of high-dose buprenorphine on these parameters. DESIGN: Retrospective, 5-year study with review of pre-hospital, hospital and post-mortem data. SETTING AND PARTICIPANTS: Eighty patients from the toxicological intensive care unit (TICU) in north-east Paris, 421 patients from the pre-hospital emergency medical service in a north-east suburb of Paris (SAMU 93) and 40 deaths from the coroner's office in Paris. MEASUREMENTS AND RESULTS: We found that the number of pre-hospital opiate/opioid poisonings and deaths decreased over 5 years. During the same time frame, opiate/opioid poisoning admissions to our TICU remained steady, but the number of deaths declined. From 1995 to 1999, the detection of buprenorphine among opiate/opioid-poisoned TICU patients increased from two to eight occurrences per year while detection of opiates diminished from 17 to 10 occurrences per year. Increased buprenorphine detection correlated directly with increasing sales over this time period. In spite of the increased use of buprenorphine, the mortality associated with opiate/opioid poisonings has diminished in the pre-hospital environment from 9% in 1995 to 0% in 1999, and in the TICU from 12% in 1995 to 0% in 1997 and thereafter. We found a high frequency of multiple opiate/opioid use in severe poisonings, as well as the frequent association of other psychoactive drugs including ethanol. CONCLUSIONS: The number and the mortality of opiate/opioid poisonings appear to be stable or decreasing in our region. The association of multiple opiates/ opioids appears nearly as common as the association with other psychoactive drugs. The introduction of high-dose buprenorphine coincides with a decrease in opiate/opioid poisoning mortality. Further study will be necessary to clarify this observation.

Empiric use of flumazenil in comatose patients: limited applicability of criteria to define low risk.

STUDY OBJECTIVE: To develop clinical rules for the safe and effective use of flumazenil in suspected benzodiazepine overdose. METHODS: We assembled a retrospective series of 35 consecutive comatose patients admitted between October 1992 and July 1993 to a toxicologic ICU with the presumptive diagnosis of drug overdose. These patients were divided into two groups. Group A (low-risk) patients had a clinical picture compatible with uncomplicated benzodiazepine intoxication (calm, without abnormalities in pulse or blood pressure, lateralizing signs, hypertonia, hyperreflexia, or myoclonus) in the absence of predefined electrocardiographic or clinical signs of tricyclic antidepressant or other proconvulsant overdose, and absence of an available history of long-term benzodiazepine treatment or an underlying seizure disorder. Group B ("non-low risk") comprised all other patients. Efficacy of flumazenil was categorized as complete awakening (with normal level of alertness), partial awakening, or no change in alertness level. The safety of flumazenil was defined on the basis of the absence of seizures or death. RESULTS: In group A (n=4), flumazenil was associated with complete awakening in three patients and partial awakening in one. No seizures were observed. In group B (n=31), flumazenil was associated with complete awakening in 4 patients, partial awakening in 5, and no response in 22. In group B, five seizures occurred. CONCLUSION: Comatose patients with clinical or ECG criteria thought to contraindicate the use of flumazenil have a reasonably high risk of seizures after administration of this drug. Low-risk patients may be able to receive flumazenil safely, but they may be only a small portion of comatose patients with suspected overdose.

Extrapyramidal syndrome as a delayed and reversible complication of acute dichlorvos organophosphate poisoning.

We describe 4 cases of delayed extrapyramidal disorder following acute dichlorvos poisonings. All patients were seriously poisoned since all exhibited profound coma and respiratory failure, and they were all tracheally intubated and mechanically ventilated. On admission, plasma cholinesterase activity was greaty decreased, < 10 micromol/ml/h at 37 C in all patients (< 10% of normal for our laboratory). Extrapyramidal symptoms occurred between 5 and 15 d and were characterized by dystonia of arms and legs, resting tremor, cogwheel rigidity, and hypereflexia. With bromocriptine therapy the features of extrapyramidal syndrome disappeared progressively with complete recovery in all patients. Our observations suggest a delayed extrapyramidal syndrome should be taken into account during the course of acute dichlorvos organophosphate poisonings.