A postmarketing study of relative abuse liability of hypnotic sedative drugs

Aims To demonstrate the utility of postmarketing studies using in‐treatment drug and alcohol abusers as informants for assessing the relative abuse liability of sedative–hypnotic drugs. Design A survey was conducted that ascertained exposure to a variety of drugs with hypnotic/sedative properties and elicited subjective evaluations indicative of abuse liability. Methods Complete data were obtained from 297 admissions (78% male) to three addiction treatment sites in the United Kingdom. Subjects were asked 15 questions about 12 different drugs, including five benzodiazepines, three antidepressants, two non‐benzodiazepine hypnotics and two antihistamines (plus one fictitious drug). Three of the benzodiazepines (diazepam, nitrazipam, temazepam) emerged as having substantially more abuse liability than any of the other drugs tested, as revealed by higher scores on abuse liability items (purchased on street, taken to get high, like drug, potential for addiction to drug). The antihistamines (chlorpheniramine, diphenhydramine) had lowest abuse liability profiles, while the antidepressants (amitriptyline, fluoxetine, trazadone) and non‐benzodiazepine hypnotics (zolpidem, zopiclone) had similar profiles. Conclusion This pilot study suggests that postmarketing information on hypnotic drug use obtained from drug addicts entering treatment produces data consistent with other measures of abuse liability. The data suggest that the risk of misuse of newer non‐benzodiazepine hypnotics may be less than that of benzodiazepine drugs, and similar to that of sedating antidepressants. The new methodology may serve to clarify or validate premarketing abuse liability data, and may help to inform the regulatory process and physician practice.     

Double-blind controlled trial of flumazenil in patients who underwent upper gastrointestinal endoscopy

The antisedative effect of flumazenil, a benzodiazepine antagonist, was studied in a double-blind placebo controlled trial in 61 patients who underwent upper gastrointestinal endoscopy and sedation with benzodiazepines. The efficacy of flumazenil in reversing the effect of both benzodiazepines, diazepam and midazolam, was significantly higher than placebo (p less than 0.0001). The effect of flumazenil was prompt and was clearly noticed at the first assessment, 5 min after its administration. In none of the patients was a relapse of the sedative effect of the benzodiazepines noticed. The administration of flumazenil was free of major side effects. Flumazenil administration permits an earlier discharge of patients following endoscopy. Its availability in the endoscopy suite may improve the outcome of serious but rare side effects related to benzodiazepines.     

Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates

Benzodiazepines exert their effects by binding to multiple subtypes of the GABAA receptor, the predominant subtypes in the brain being those that contain alpha1-, alpha2-, alpha3-, and alpha5-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABAA receptor subtype-preferring compounds in nonhuman primate models predictive of anxiolytic, sedative, motor, subjective, and reinforcing effects of benzodiazepine-type drugs. These compounds included zolpidem, which shows preferential binding to GABAA receptors containing alpha1-subunits (alpha1GABAA receptors); L-838,417, which shows functional selectivity for alpha2GABAA, alpha3GABAA, and alpha5GABAA receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that alpha1GABAA receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve alpha2GABAA, alpha3GABAA, and/or alpha5GABAA subtypes. Our results also suggest that the alpha1GABAA receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of alpha1GABAA receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.     

Benzodiazepine use and anxiolytic abuse and dependence in treated alcoholics

The prevalence and correlates of benzodiazepine use and anxiolytic abuse and dependence are examined in a sample of 427 patients in Toronto, Canada, who met lifetime DSM-III criteria for alcohol abuse or dependence. The patients were evaluated with the NIMH-DIS and other standard psychiatric and substance abuse rating scales. Forty per cent were recent users of benzodiazepines and 20% had abused or been dependent upon anxiolytics, including benzodiazepines, during their lifetime. Patients with antisocial personality disorder (ASPD) were at higher risk for an anxiolytic disorder as were women and the unemployed. Recent users of benzodiazepines showed more current psychological distress, depressive symptomatology and more severe substance abuse problems than other patients and were more likely to have a lifetime DSM-III anxiety disorder. Patients with anxiolytic disorders, even if ASPD was controlled for, showed more psychiatric impairment and drug abuse problems than the remaining patients. Of those with a positive urine screen, 46% did not report using benzodiazepines in the previous week. Nineteen per cent of the patients who did not report benzodiazepine use in the previous week had a positive urine screen and were more likely to be found in the detoxification unit.     

Double-Blind Study of Alprazolam, Diazepam, Clonidine, and Placebo in the Alcohol Withdrawal Syndrome: Preliminary Findings

Both a reduction in the inhibitory effects of GABA (disinhibition) and activation of the sympathetic nervous system are manifested during the alcohol withdrawal syndrome. This study was designed to explore the relative efficacy of medications that differentially affects these two biological systems: the benzodiazepines, which attenuate GABAergic disinhibition, and the α₂-adrenergic receptor agonists, which decrease sympathetic activation. The benzodiazepine diazepam ( n = 6), the α₂-receptor agonist clonidine ( n = 7), the benzodiazepine alprazolam (that is also purported to have α₂-receptor agonist properties) ( n = 6), and placebo ( n = 6) were evaluated in their effectiveness in decreasing signs and symptoms of alcohol withdrawal. Drug-free, alcohol-dependent patients were administered 1 of the 4 medications in a double-blind design until symptoms of withdrawal, as measured by the Clinical Instrument Withdrawal Assessment for Alcohol-Revised, were successfully treated. Alprazolam was significantly more efficacious than both clonidine and placebo in decreasing withdrawal symptoms. Diazepam was more effective than clonidine and placebo on some measures of withdrawal. Clonidine decreased systolic blood pressure significantly more than the other two active drugs and placebo, but was no more effective than placebo in decreasing other symptoms of withdrawal. Alprazolam did not significantly decrease blood pressure compared with diazepam or placebo. Despite the small sample size, these preliminary findings suggest that the efficacy of alprazolam in the treatment of alcohol withdrawal is related to its effect at the benzodiazepine receptor and not its α₂-receptor agonist properties.     

DEMONSTRATION TO MEDICAL STUDENTS OF PLACEBO RESPONSES AND NON-DRUG FACTORS

A class experiment for medical students Summary was devised to demonstrate the influence of the placebo effect and non-drug factors on response to drugs. The subjects were conditioned to expect sedative or stimulant effects, but all received placebo in one or two blue or pink capsules. Predictions about the size and nature of the placebo response and influence of the non-drug factors were made before the experiment and discussed afterwards. Four of six predictions were fully confirmed. Drug- associated changes were reported by 30% of the subjects and were severe in 1 or 2 individuals. Two capsules produced more noticeable changes than one, and blue capsules were associated with more sedative effects than pink capsules. Students rated the experiment highly both as a learning experience and for its relevance to their future practice of medicine.     

Long-Term Therapy With Benzodiazepines Despite Alcohol Dependence Disorder

The author describes the long-term administration of benzodiazepines to seven male patients (58–70 years old), each with at least a 25-year history of alcohol dependence. Benzodiazepines were prescribed for the treatment of an anxiety disorder or sleep disturbance. All seven patients maintained abstinence during benzodiazepine administration, except for a brief period of relapse in two patients. These patients comprised all of the subjects given benzodiazepines for more than 1 week in a Veterans Affairs substance abuse program over a 3-year period. These case reports suggest that the long-term administration of benzodiazepines to carefully selected alcohol-dependent patients is not necessarily incompatible with abstinence. Guidelines for the use of benzodiazepines in this patient population are reviewed.     

Trihexyphenidyl Abuse

Trihexyphenidyl, commonly used in neurological and psychiatric practice may be used by certain patients for its euphoriant and hallucinogenic effects. Apart from producing symptoms suggestive of a toxic psychosis due to overdosage, its chronic use may produce dependence. Two cases of Trihexyphenidyl abuse are described.     

Effects of stress and alcohol on subjective state in humans

BACKGROUND: There is increasing evidence that stress and hypothalamic-pituitary-adrenal axis activation interact with drugs of abuse and influence drug-taking behaviors. Both studies with laboratory animals and survey data with alcohol users suggest that acute or chronic stressful events increase alcohol intake. One mechanism for the increase in alcohol intake may be that stress alters the subjective effects produced by the drug in ways that enhance the reinforcing properties of alcohol. Therefore, in this study we determined whether an acute social stressor alters subjective responses to ethanol in humans. The stressor was a modified version of the Trier Social Stress Test, an arithmetic task that increases cortisol levels. METHODS: Twenty male volunteers participated in two laboratory sessions, in which they performed the Trier Social Stress Test on one session and no task on the other session, immediately before consuming a beverage that contained ethanol (0.8 g/kg in juice) or placebo (juice alone). Eleven subjects received ethanol on both sessions, and nine subjects received placebo on both sessions. Primary dependent measures were self-report questionnaires of mood states. Salivary levels of cortisol were obtained to confirm the effectiveness of the stress procedure. RESULTS: Stress alone produced stimulant-like subjective effects. In the group who received ethanol, stress increased sedative-like effects and decreased stimulant-like effects. CONCLUSIONS: At this relatively high dose of ethanol, stress increased sedative effects of alcohol and did not increase desire for more alcohol. It is possible that in some individuals, the increased sedative effects after stress may increase the likelihood of consuming more alcohol. The effects of stress on consumption at this, or lower, doses of alcohol remain to be determined.     

Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance abuse or dependence

In this article, the authors reevaluate the traditional position that benzodiazepines should be avoided in anxiety disorder patients with a history of substance abuse or dependence. The efficacy of benzodiazepines in each of the anxiety disorders is reviewed, as are their side effects and toxicity. The definitions of benzodiazepine abuse and dependence are discussed, and relevant animal, experimental, and clinical data are reviewed and analyzed. A manual and computerized (MEDLINE) search was performed from 1966 to the present to examine the English-language literature published on benzodiazepines, substance abuse, and each of the anxiety disorders listed in DSM-IV. The authors found that benzodiazepines have demonstrated efficacy in generalized anxiety disorder, panic disorder, and agoraphobia; they are promising agents in the treatment of social phobia and alcohol-induced anxiety disorders. They are generally well tolerated. There is much ambiguity over appropriate definitions for benzodiazepine abuse and dependence: although most benzodiazepine abusers concurrently abuse other substances, there is little evidence to indicate that a history of substance abuse is a major risk factor for future benzodiazepine abuse or dependence. Furthermore, benzodiazepines do not appear to induce relapse of substance abuse in these patients. The authors conclude that the position that benzodiazepines are contraindicated in former substance abusers appears to lack empirical justification. Benzodiazepines may be indicated in certain patients with anxiety disorders and a history of substance abuse or dependence.     

Buspirone: pharmacological and clinical properties of the first member of a new anxiolytic drug family

Buspirone is a new anxiolytic agent with an original chemical structure. Its activity in doses of 15 to 30 mg per day has been demonstrated in patients presenting with manifestations of generalized anxiety. Its mode of action is still imperfectly known; in animals, it influences several neuromediator systems but does not act on benzodiazepine receptors. Its main pharmacokinetic features are: complete absorption when given orally, short half-life (4 to 8 h), reduced plasma clearance in patients with hepatic cirrhosis or renal impairment and no major interaction with most of the other psychotropic drugs. Controlled clinical studies have provided evidence of its anxiolytic properties; against anxiety symptoms buspirone has proved more effective than placebo and as effective as several reference benzodiazepine derivatives, with a lesser incidence of sedative effects. However, it is not effective in the treatment of benzodiazepine withdrawal. Gastrointestinal disorders and moderate headache have been reported in less than 10 p. 100 of the patients treated. Administered acutely, buspirone does not seem to alter cognitive mechanisms. Unlike benzodiazepines, it does not potentiate the effects of alcohol and does not lead to drug-dependence. Its usefulness in panic disorders, anxious-depressive states and obsessional symptoms remains to be determined.     

Patterns of Benzodiazepine Abuse and Dependence

Patterns of benzodiazepine abuse and dependence are not well known. Data on drug use and other demographic and clinical characteristics were collected in 176 patients consecutively referred to the Addiction Research Foundation Clinical Institute for assessment and treatment of benzodiazepine abuse and/or dependence. Objective confirmation of benzodiazepine use was obtained in 95% of subjects screened. Two groups of subjects emerged: patients who used only benzodiazepines (median daily dose: 15 mg of diazepam or equivalent) for long periods of time (56%) and those who used benzodiazepines (median daily dose: 40 mg of diazepam or equivalent) in the context of multiple drug abuse (44%). Benzodiazepines were the primary drug of abuse in 23 (32%) of the multiple drug abusers. Patients using only benzodiazepines were significantly older, took lower daily doses and their life-time benzodiazepine exposure was lower. Diazepam was most frequently alleged in both groups, but relative preference for other benzodiazepines differed. The results have implications for recognition, assessment, management and treatment of benzodiazepine abuse and dependence.     

The subjective, rather than the disinhibiting, effects of alcohol are related to binge drinking

Background: Evidence suggests that alcohol‐related problems are associated with impulsivity and disinhibited behavior. Less certain is whether disinhibited behavior is due to an impulsive disposition or alcohol’s ability to disinhibit some people more than others. There are a range of disinhibited behaviors associated with alcohol, including excessive alcohol consumption, bingeing. The study tested whether nondependent alcohol bingers showed more disinhibition after placebo and/or alcohol relative to nonbingers and whether this was related to enhanced motivation to drink following a priming dose of alcohol. Methods: Twenty participants (10 bingers) attended the laboratory twice. Baseline measures included impulsivity, alcohol‐related cognitions, alcohol urge, and mood. Participants were preloaded with alcohol (male: 0.6 g/kg, female: 0.5 g/kg) and placebo (counterbalanced). After a 20‐minute rest, participants completed 2 impulsivity tasks (Two Choice & Time Estimation) separated by second urge and mood ratings. Results: Bingers did not show greater impulsivity characteristics but were more concerned about their drinking (p = 0.02) and ability to control drinking (p = 0.04). A priming effect was found: alcohol urge increased after alcohol but not placebo (p = 0.006). Bingers reported greater tolerance to the sedative (p = 0.05) and lightheaded (p = 0.04) effects of alcohol, relative to nonbingers. Binge status was not associated with impulsivity task performance, while preload type (alcohol/placebo) supported only marginal associations. Conclusions: Risk of binge drinking in nondependent individuals is not strongly affected by impulsive personality characteristics or alcohol’s ability to induce behavioral disinhibition. However, alcohol did lead to a priming effect and bingers were more tolerant to the sedative and lightheaded effects of alcohol relative to placebo. Risk of binge drinking is associated with the subjective effects of a priming dose of alcohol.     

Pergolide mesylate for cocaine abuse: a controlled preliminary trial.

A small, controlled study was conducted to assess whether pergolide mesylate has clinical promise as a treatment for cocaine abuse prior to embarking on a larger, randomized, double-blind, controlled trial. Fourteen individuals were placed on placebo for 2 weeks, followed by a 24-week single-blind study in which they were placed on pergolide for 12 weeks, followed by placebo for 12 weeks. Another 14 patients received single-blind placebo for two weeks and then were randomized into a 24-week double-blind, placebo-controlled, multiple baseline design. Initially, patients enrolled in the study were placed on risperidone (n = 9) or placebo (n = 5). During the first 12 weeks, retention was worse for those receiving pergolide compared to risperidone or placebo. Neither risperidone nor pergolide were more efficacious in reducing cocaine use than placebo. Although earlier open studies found pergolide to show promise as a treatment for cocaine abuse, this study did not support these earlier findings. Comparing an agent to both an active control and placebo group may better predict whether a promising new agent will have clinical utility compared to the standard open trial.     

Anxiolytics and sedative/hypnotics dependence

Anxiolytics and sedative/hypnotics are commonly used drugs. Benzodiazepines have largely replaced barbiturate and non-barbiturate anxiolytics and sedative/hypnotics as they are as effective and safer. Experiments in laboratory animals have shown that chronic administration of benzodiazepines tested to date can induce physical dependence. The severity of the withdrawal syndrome is clearly related to the dose, duration of administration and elimination rate of the drugs. It is now also clear that high doses of barbiturates and benzodiazepines can induce physical dependence in humans. In addition, a withdrawal syndrome after discontinuation of chronic benzodiazepine therapeutic treatment, with and without tolerance, has been well characterized. Symptoms may resemble those of anxiety or ‘rebound’ phenomena but some are typical of withdrawal. A relationship between benzodiazepine discontinuation and self-administration has been well documented. Negative reinforcement associated with a reduction of withdrawal symptoms may play a role supporting persistent benzodiazepine use.     

Electroencephalographically determined sedative effects (vigilosomnography) of the new Thienodiazepin-derivate clotiazepam (author's transl)

In a double blind, randomized clinical study eighteen volunteers received either placebo or 5 mg diazepam or 5 mg clotiazepam at three different times at an interval of one week. Beside other parameters which have been measured a 60-minute polygraphic EEG recording was made thirty minutes after administration of the drugs. The vigilosomnograms revealed clear and reliable differences between placebo and the two active substances and suggest a sedative effect of both substances at the dose level used. There was only a slight difference between the two active substances. 5 mg clotiazepam produced a slightly stronger sedation than 5 mg diazepam. However, the records of autonomic side effects and subjective statements regarding the patients' condition showed that clotiazepam is associated with less side effects than diazepam.     

Therapeutic rationale for low dose doxepin in insomnia patients

Histamine is an excitatory neurotransmitter in central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressant with sleep-promoting effects, for example, doxepin, promotes sleep not through a sedative action but through resynchronisation of circadian cycle. The stimulation of the H1 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the H1 receptor, making it a selective H1 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressant, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients. Doxepin is not designated as controlled substance/unscheduled drugs and thus may be of special advantage to use in patients with a history of substance abuse. Hence, well-documented therapeutic efficacy, tolerability and lack of important adverse effects make the low dose doxepin as a unique, rational drug for the treatment of insomnia in adult and elderly patients.     

Comparison of desipramine or carbamazepine to placebo for crack cocaine-dependent patients

The authors compared the effects of desipramine or carbamazepine to placebo in an intensive outpatient program for cocaine abuse. Subjects recruited from an urban drug treatment program were randomly assigned to a double-blind, placebo-controlled, eight-week trial of desipramine, carbamazepine, or placebo. Patient ratings, urine drug screens, and blood samples were obtained weekly. Using survival analysis, the three groups did not differ in time to drop out of treatment. While subjects improved over time on all self-ratings related to cocaine use, mood, and craving, only two items related to mood were significantly different over time as a function of treatment group. Subjects in the two treated groups reported significantly more improvement on self-ratings of depression and irritability. No treatment differences were noted for sustained abstinence or for proportion of positive urine drug screens. Desipramine subjects who attained a minimum blood level were retained in treatment significantly longer than placebo or other non-compliant treatment groups. This finding supports previous reports of a possible role for desipramine in cocaine abuse treatment.