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PubMed2003

Testing for benzodiazepine inebriation--relationship between benzodiazepine concentration and simple clinical tests for impairment in a sample of drugged drivers.

OBJECTIVE: To study how the various 25 subtests and observations of the Norwegian clinical test for impairment related to the blood benzodiazepine concentrations of apprehended drivers suspected of driving under the influence of benzodiazepines. The impact of single-dose intake in non-daily users of benzodiazepines on the clinical picture of inebriation was also studied. METHODS: Included in the study were 818 drivers suspected of driving under the influence of non-alcoholic drugs with blood samples containing only one benzodiazepine. We determined which of the 25 subtests and observations of the clinical test for impairment related significantly to the blood benzodiazepine concentrations. RESULTS: Significantly related to blood benzodiazepine concentrations were 13 subtests and observations. Of these, 9 withstood adjustment for a variety of background variables. Single dose intake in non-daily users only influenced 3 subtests and observations after adjustment for blood benzodiazepine concentration and background variables. Romberg's test, 1 observation concerning alertness (oriented for time and place), 4 tests on motor and coordination (walk and turn on line, finger-to-nose and finger-to-finger tests), 2 observations on speech (articulation and content) and 1 observation regarding appearance (general conduct) were related to blood benzodiazepine concentrations. CONCLUSION: Many of these simple clinical tests are included in the standardized field sobriety test and are of value in revealing benzodiazepine impairment. The present study offered some possible additions. Combinations of these robust tests can also be used to reveal benzodiazepine inebriation in other contexts.

Automobile Driving↗
PubMed1987

Endogenous benzodiazepine-like molecules in the human, rat and bovine brains studied with a monoclonal antibody to benzodiazepines.

The anti-benzodiazepine monoclonal antibody 21-7F9 has been used for the identification and study of endogenous benzodiazepine-like molecules in the human, rat and bovine brains. A sandwich radioimmunoassay has been designed for the quantification of the membrane-bound endogenous benzodiazepine-like molecules. The localization of these molecules is not restricted to the brain tissue. They are also present in kidney, liver and spleen as well as in the neuroblastoma X glioma NG108-15 hybrid cell line. Immunoblots show benzodiazepine-like immunoreactivity in the membrane proteins of all of these tissues. The membrane-bound benzodiazepine-like molecules are resistant to limited proteolysis of the membranes. Moreover, this treatment increases the binding of the monoclonal antibody 21-7F9 to the membranes, probably by exposing sites that normally are not accessible to the antibody. Immunocytochemistry experiments show that benzodiazepine-like molecules are also present in samples of human cerebella that have been stored in paraffin since 1940, 15 years before the first chemical synthesis of benzodiazepines. The results indicate that the cerebellar benzodiazepine-like molecules recognized by the antibody are the product of biological (not chemical) synthesis. Benzodiazepine-like immunoreactivity has also been detected in NG108-15 cells that have been cultured for 3 months in serum-free medium. These results suggest that the cells could biosynthesize benzodiazepine-like molecules.

Animals↗
PubMed2003

The impact of attitudes and beliefs on length of benzodiazepine use: a study among inexperienced and experienced benzodiazepine users.

Prolonged benzodiazepine use is a widespread phenomenon in medical practice. In the present article, we argue that psychological models may contribute to our understanding of benzodiazepine use. This study examined variables derived from the theory of planned behaviour and the health belief model in relation to the length of benzodiazepine use. Data were collected from a sample of all benzodiazepine users with a request for this medicine in the only pharmacy in a Dutch community (N=467). Determinants of the length of benzodiazepine use were analysed separately for inexperienced and experienced users using structural equation modelling (SEM) analyses. For both groups, results showed that the intention to use benzodiazepines was a predictor of length of use. Attitudes towards benzodiazepine use had an indirect influence on length of use, through intentions. Furthermore, a positive attitude toward using benzodiazepines was related to the perceived norm of the prescriber. Experienced users were more inclined to consume benzodiazepines when they had less control over drug taking. In this group, the belief that benzodiazepine use leads to dependence was associated with less control over drug taking and a high intention to use the drug. In addition, older experienced users reported a higher intention to use the drug. For inexperienced users, the perceived attitude of the prescriber towards use of the medicine was a strong determinant. Finally, results of SEM-analyses showed that the model accounted for far more variance in behaviour for experienced users (67%), than for inexperienced users (18%).

Adult↗
PubMed1990

Clinical experience with the benzodiazepine antagonist flumazenil in suspected benzodiazepine or ethanol poisoning.

The clinical efficacy of different doses of the specific benzodiazepine antagonist flumazenil was studied in a total of 72 patients with benzodiazepine or ethanol overdose. In a randomized double-blind study, 18 patients (group 1) and eight patients (group 2) with suspected benzodiazepine overdose received 5 mg (group 1) or 1 mg (group 2) flumazenil or placebo, respectively. The stage of coma, heart rate, blood pressure and respiratory rate were monitored within the following 15 min. If no change in the stage of coma was observed, 5 mg (group 1) or 1 mg (group 2) flumazenil were given, and the stage of coma, heart rate and blood pressure were again monitored. In a similar way, the effect of 5 and 1 mg flumazenil was investigated in 13 patients (group 3) and four patients (group 4) with ethanol intoxication. In an open trial, the clinical efficacy of flumazenil for the diagnosis of benzodiazepine or ethanol overdose was studied in 29 patients (group 5). In all patients, a toxicological screening confirmed benzodiazepine or ethanol overdose. None of the patients receiving placebo showed effects on stage of coma, heart rate, blood pressure or respiratory rate. Patients with benzodiazepine overdose who received 5 mg flumazenil regained consciousness about 1-2 min after the end of injection. The effect of 1 mg flumazenil (group 2) on benzodiazepine-induced coma was less pronounced. In patients with ethanol overdose (group 3), ethanol-induced coma was reversed after 5 mg flumazenil more slowly than in patients of group 1. No effect of flumazenil on ethanol-induced coma was observed in group 4. In group 5, flumazenil proved to be useful for diagnosing benzodiazepine or ethanol intoxication. In one patient with coma due to carbamazepine overdose, flumazenil was also found to be effective. Additionally, a possible analytical interference of flumazenil and its metabolites with the identification of other benzodiazepines by a toxicological screening procedure was studied. Even after an oral dose of 200 mg flumazenil, no interference with immunological benzodiazepine assays (EMIT, TDX, and RIA) was found. A metabolite and an artifact of flumazenil could be identified in urine by gas chromatography/mass spectrometry.

Adolescent↗
PubMed2000

Prior benzodiazepine exposure and benzodiazepine treatment outcome.

BACKGROUND: We examined discontinuation symptoms following brief benzodiazepine therapy (8 weeks) and intermittent benzodiazepine therapy (2 weeks with at least 2 weeks without drug) and associations with prior benzodiazepine use. The hypothesis was that prior benzodiazepine use would predispose patients to more severe discontinuation symptoms. METHOD: Data were drawn from 3 double-blind, randomized, placebo-controlled, published treatment trials: alprazolam for patients with premenstrual syndrome (PMS) and diazepam and lorazepam for patients with generalized anxiety disorder (GAD). The PMS group provided prospective daily symptom ratings, which allowed ongoing investigation of effects of prior treatment. In the GAD groups, taper outcome was examined after 8 weeks of benzodiazepine therapy as a function of prior benzodiazepine use and as a function of time since last prior benzodiazepine use. Symptom scores were analyzed using t statistics in the PMS group and analysis of covariance with 8-week scores as the covariate in the GAD groups. RESULTS: The PMS subjects reported no increase in symptom scores and no significant difference from placebo-treated subjects during taper and discontinuation of alprazolam in the follicular phase of each treatment cycle. In the GAD trials, the results of treatment discontinuation did not differ significantly as a function of presence or absence of prior benzodiazepine use or as a function of time since last benzodiazepine use. CONCLUSION: These preliminary data fail to support the hypothesis that prior benzodiazepine use predisposes patients to more severe discontinuation symptoms when treatment is brief and doses are low.

Alprazolam↗
PubMed2005

The absence of benzodiazepine craving in a general practice benzodiazepine discontinuation trial.

This study aimed to assess benzodiazepine craving longitudinally and to describe its time course by means of the Benzodiazepine Craving Questionnaire (BCQ). Subjects were long-term benzodiazepine users participating in a two-part treatment intervention aimed to reduce long-term benzodiazepine use in general practice in The Netherlands. Four repeated measurements of benzodiazepine craving were taken over a 21-month follow-up period. Results indicated that (1) benzodiazepine craving severity decreased over time, (2) patients still using benzodiazepines experienced significantly more severe craving than patients who had quit their use after one of the two interventions, and (3) the way in which patients had attempted to quit did not influence the experienced craving severity over time, however, (4) patients who had received additional tapering off, on average, reported significantly more severe craving than patients who had only received a letter as an incentive to quit. Although benzodiazepine craving is prevalent among (former) long-term benzodiazepine users during and after discontinuation, craving severity decreases over time to negligible proportions. Self-reported craving can be longitudinally monitored and quantified by means of the BCQ.

Aged↗
PubMed2006

Comparison of urine and oral fluid as matrices for screening of thirty-three benzodiazepines and benzodiazepine-like substances using immunoassay and LC-MS(-MS).

Benzodiazepines are the most frequently detected medicinal drugs in drivers. The use of benzodiazepines is associated with an increased road accident risk. In this study, the presence of benzodiazepines detected by liquid chromatography-(tandem) mass spectrometry [LC-MS(-MS)] in oral fluid and urine samples obtained from drivers stopped during a roadside survey was compared. In addition, the sensitivity and selectivity of enzyme multiplied immunoassay technique (EMIT II Plus) relative to LC-MS(-MS) was determined for both matrices. A total number of 1,011 urine samples were collected and screened for benzodiazepines using immunoassay (IA) (EMIT II Plus; cutoff 300 ng/mL). In the IA-positive (n = 25) and a group of randomly selected negative urine samples (n = 79), the presence or absence of benzodiazepines was confirmed by LC-MS-MS after deglucuronidation. The corresponding oral fluid samples (n = 101, 3 samples omitted), were analyzed by LC-MS(-MS) and IA (EMIT II Plus; cutoff 10 ng/mL). The presence of benzodiazepines was demonstrated by LC-MS-(MS) in all IA-positive urine samples, but in only four corresponding oral fluid samples. Concentrations in oral fluid were, one substance excepted, lower than in urine. The sensitivity and specificity of EMIT II Plus were better by using urine as matrix for screening of benzodiazepines than by using oral fluid. The results show that benzodiazepines are detectable in oral fluid. More research has to be done to determine the pharmacokinetic profile of the different benzodiazepines in oral fluid and to study the relationship between dose, concentration (in oral fluid and blood), and impairment.

Benzodiazepines↗
PubMed2006

Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program.

OBJECTIVE: To identify predictors of resumed benzodiazepine use after participation in a benzodiazepine discontinuation trial. METHOD: We performed multiple Cox regression analyses to predict the long-term outcome of a 3-condition, randomized, controlled benzodiazepine discontinuation trial in general practice. RESULTS: Of 180 patients, we completed follow-up for 170 (94%). Of these, 50 (29%) achieved long-term success, defined as no use of benzodiazepines during follow-up. Independent predictors of success were as follows: offering a taper-off program with group therapy (hazard ratio [HR] 2.4; 95% confidence interval [CI], 1.5 to 3.9) or without group therapy (HR 2.9; 95% CI, 1.8 to 4.8); a lower daily benzodiazepine dosage at the start of tapering off (HR 1.5; 95% CI, 1.2 to 1.9); a substantial dosage reduction by patients themselves just before the start of tapering off (HR 2.1; 95% CI, 1.4 to 3.3); less severe benzodiazepine dependence, as measured by the Benzodiazepine Dependence Self-Report Questionnaire Lack of Compliance subscale (HR 2.4; 95%CI, 1.1 to 5.2); and no use of alcohol (HR 1.7; 95% CI, 1.2 to 2.5). Patients who used over 10 mg of diazepam equivalent, who had a score of 3 or more on the Lack of Compliance subscale, or who drank more than 2 units of alcohol daily failed to achieve long-term abstinence. CONCLUSIONS: Benzodiazepine dependence severity affects long-term taper outcome independent of treatment modality, benzodiazepine dosage, psychopathology, and personality characteristics. An identifiable subgroup needs referral to specialized care.

Aged↗
PubMedDate not supplied

Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group.

Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.

Adolescent↗
PubMedDate not supplied

Mapping of benzodiazepine-like immunoreactivity in the rat brain as revealed by a monoclonal antibody to benzodiazepines.

A monoclonal antibody against benzodiazepines (21-7F9) was used to study the distribution of benzodiazepine-like immunoreactivity in the rat brain. Immunodensitometry in combination with image analysis were used for quantification. The results showed a ubiquitous distribution of benzodiazepine-like immunoreactivity throughout the brain. Very high levels of benzodiazepine-like immunoreactivity were found in the Purkinje cell layer of the cerebellum, in the primary olfactory cortex, in the stratum pyramidale of the hippocampus and in the mitral cell layer of the olfactory bulb. High densities of benzodiazepine-like immunoreactivity were found in the granule cell layer of the cerebellum, the pyramidal cell layer of the olfactory tubercle, the granule layer of the dentate gyrus, the arcuate nucleus of the hypothalamus, the mammillary bodies, the interstitial nucleus of Cajal and superficial grey layer of superior colliculus. The substantia nigra pars compacta, the islands of Calleja and layers II, III, V and VI of the cerebral cortex had moderate levels of benzodiazepine-like immunoreactivity. Lower densities were found in the internal granular layer and the external plexiform layer of the olfactory bulb, in the molecular layer of the dentate gyrus, in layers I and IV of the cerebral cortex, in the nucleus caudate-putamen and most of the thalamic nuclei. The lowest density of immunoreactivity was found in the globus pallidus, and the strata radiatum, oriens and lacunosum-moleculare of the hippocampus. The distribution of endogenous benzodiazepine-like immunoreactivity was compared with the distribution of the GABA/benzodiazepine receptor by using both immunocytochemistry and receptor autoradiography. Our studies have shown a clear mismatch between the localization of the benzodiazepine-like immunoreactivity and the GABA/benzodiazepine receptors.

Animals↗
PubMed2002

Clinical impairment of benzodiazepines--relation between benzodiazepine concentrations and impairment in apprehended drivers.

BACKGROUND: Acute intake of benzodiazepines is followed by concentration-dependent deterioration of performance in controlled experimental studies. Whether this is true in a population of benzodiazepine users is uncertain. We studied the relationship in a population of suspected drugged drivers. METHODS: In Norway physicians examine and take blood samples from nearly all suspected drivers. Our material comprised 818 samples containing only one benzodiazepine and our reference group consisted of 10,759 cases containing only alcohol. RESULTS: 159 drivers (19%) were considered as not impaired and 659 (81%) as impaired. None of the background factors, e.g. gender, age or time of day when apprehended, related significantly to either the physician's conclusion or to blood levels of benzodiazepines. Impaired subjects had significantly higher blood levels of diazepam (n=411) (P<0.001), oxazepam (n=73) (P<0.05) and flunitrazepam (n=211) (P<0.05) than those not impaired. The risk of being assessed as impaired did rise with increasing benzodiazepine blood level, with odds ratios (ORs) for being assessed as impaired of 1.61, 3.65 and 4.11 for the three supratherapeutic drug levels. The corresponding OR found for different elevated blood-alcohol concentrations were 1.49, 2.94 and 10.49. CONCLUSION: The blood concentration of benzodiazepines was the only characteristic which was related to impairment. This indicated a drug-concentration related effect of benzodiazepines on performance and paves the way for a discussion on legal limits for benzodiazepines in relation to driving.

Adult↗
PubMed1986

Purification of a benzodiazepine from bovine brain and detection of benzodiazepine-like immunoreactivity in human brain.

An endogenous brain substance that binds to the central-type benzodiazepine receptors with agonist properties is present in both rat and bovine brains. This substance has been purified to homogeneity from bovine brain by immunoaffinity chromatography on immobilized monoclonal anti-benzodiazepine antibody followed by gel filtration on Sephadex G-25 and two reversed-phase HPLC steps. The purified substance was characterized as the benzodiazepine N-desmethyldiazepam (nordiazepam). The techniques used for the identification were mass spectrometry, HPLC, spectrophotometry, benzodiazepine receptor binding, and immunological techniques. Benzodiazepine-like immunoreactivity was also found in all the human brains tested, including six brains that had been stored in paraffin since 1940, fifteen years before the first synthesis of benzodiazepines. These results show that benzodiazepine-like molecules of natural origin--and possibly benzodiazepines themselves--are present in human and other mammalian brains.

Animals↗
PubMed1999

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders.

Despite decades of relevant basic and clinical research, active debate continues about the appropriate extent and duration of benzodiazepine use in the treatment of anxiety and related disorders. The primary basis of the controversy seems to be concern among clinicians, regulators, and the public about the dependence potential and the abuse liability of benzodiazepines. This article reports systematically elicited judgments on these issues by a representative panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depressive disorders, a panel which was constituted by a multistage process of peer nomination. The criterion for inclusion at each stage was the nomination by at least two peers as one of the "professionally most respected physicians of the world with extensive experience and knowledge in the pharmacotherapy of anxiety and depressive disorders." Sixty-six respondents (90%) completed a comprehensive questionnaire covering a wide range of topics relevant to the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. Overall, the expert panel judged that benzodiazepines pose a higher risk of dependence and abuse than most potential substitutes but a lower risk than older sedatives and recognized drugs of abuse. There was little consensus about the relative risk of dependence and abuse among the benzodiazepines. Differences between benzodiazepines with shorter and longer half-lives in inducing withdrawal symptoms are much less clear during tapered than during abrupt discontinuation. There was little agreement about the most important factors contributing to withdrawal symptoms and failure to discontinue benzodiazepines. The pharmacologic properties of the medication may be the most important contributors to withdrawal symptoms. In contrast, the clinical characteristics of the patient may be the most important contributors to failure to discontinue medication. The experts' judgment seems to support the widespread use of benzodiazepines for the treatment of bona fide anxiety disorders, even over long periods. The experts generally viewed dependence and abuse liability as clinical issues amenable to appropriate management, as for other adverse events related to therapy. However, more definitive clinical research on the remaining controversial issues is urgently needed to promote optimal patient care.

Anti-Anxiety Agents↗
PubMed1990

Effects of benzodiazepines on passive avoidance response and latent learning in mice: relationship to benzodiazepine receptors and the cholinergic neuronal system.

The effects of benzodiazepines on learning and memory were investigated, using passive avoidance and latent learning tasks, with particular attention being paid to the possible involvement of benzodiazepine receptors and the cholinergic neuronal system. Benzodiazepines such as diazepam, nitrazepam and chlordiazepoxide (CDP) impaired the passive avoidance response when administered before training, but not when administered immediately after training or before the retention test. CDP also impaired latent learning in the water finding task. State-dependent learning was not observed with CDP at the dose used. A benzodiazepine inverse agonist, Ro 15-4513, and a benzodiazepine antagonist, Ro 15-1788, completely and partially reversed, respectively, the disruptive effects of CDP on learning and memory at the doses which did not enhance learning and memory. The disruptive effects of CDP on learning and memory were partially antagonized by a choline esterase inhibitor, physostigmine, and by a blocker for muscarinic acetylcholine receptors, scopolamine, at the doses which increase acetylcholine release. These results suggest that benzodiazepines induce disruptive effects on learning and memory through benzodiazepine receptors, and that benzodiazepine-induced impairment of learning and memory is, at least in part, the result of the dysfunction of the cholinergic neuronal system.

Animals↗
PubMed1997

The Mr 18,000 subunit of the peripheral-type benzodiazepine receptor exhibits both benzodiazepine and isoquinoline carboxamide binding sites in the absence of the voltage-dependent anion channel or of the adenine nucleotide carrier.

The peripheral type benzodiazepine receptor (PBR) binds benzodiazepines such as RO5-4864 and isoquinoline carboxamide derivatives such as PK11195. This receptor includes an Mr 18,000 isoquinoline-binding subunit predominantly located in mitochondrial mem- branes. This protein has been found to copurify with two other mitochondrial proteins, namely the outer membrane voltage-dependent anion channel (VDAC), also known as mitochondrial porin, and the inner membrane adenine nucleotide carrier. In vitro reconstitution experiments suggested that the PBR was a multimeric complex in which the isoquinoline binding site was on the Mr 18,000 subunit, denoted pk18, whereas the benzodiazepine binding site required the association of this subunit with VDAC to be expressed. Untransformed cells of the yeast Saccharomyces cerevisiae are devoid of specific binding sites for isoquinolines and benzodiazepines, whereas yeast cells transformed with a pk18-expressing vector exhibit RO5-4864 and PK11195 binding sites that are pharmacologically identical to those of the PBR. To clarify the role of VDAC and of the adenine nucleotide carrier, if any, in the constitution of the benzodiazepine binding site, yeast host strains were constructed in which the corresponding genes had been knocked out. Mitochondria prepared from pk18-producing cells devoid of either VDAC or adenine nucleotide carrier exhibit both benzodiazepine and isoquinoline carboxamide binding sites with little or no change in the Kd values as compared with the wild-type background. These results rule out the contention that VDAC is indispensable for establishing the benzodiazepine binding site and are in agreement with the hypothesis that the Mr 18,000 subunit carries both the isoquinoline carboxamide and benzodiazepine binding domains.

Adenine Nucleotides↗
PubMed1990

Benzodiazepine dependency discontinuation: focus on the chemical dependency detoxification setting and benzodiazepine-polydrug abuse.

Benzodiazepines are commonly encountered in both psychiatric and chemical dependency treatment settings. However, in the chemical dependency setting, benzodiazepines are most frequently used as secondary drugs of abuse, and are most often found within a polydrug use pattern. Benzodiazepine use by the drug-abusing population consists of the combined use of benzodiazepines with other psychoactive drugs. They are used to medicate cocaine toxicity, as a secondary or tertiary drug to boost the effects of alcohol or heroin, and by those who have developed tolerance and dependence to sedative-hypnotic drugs. The presence of an anxiety disorder, a family history of addiction, or benzodiazepine polydrug use will significantly affect the type of withdrawal a patient will experience and its treatment course. Medical procedures accepted for benzodiazepine discontinuation include (1) graded reduction; (2) substitution of a long-acting benzodiazepine; and (3) phenobarbital substitution.

Anti-Anxiety Agents↗