Amnesic trace locked into the benzodiazepine state of memory

Rats were trained in a food-rewarded lever-pressing task until they could complete an FR10 requirement within the first 120 s of the session, and were tested for the retention of this response requirement after having reached this criterion. The pharmacological treatment instituted at the time of tests was either the same as or different from that used during acquisition. In this state-dependency (StD) procedure, saline-to-drug as well as drug-to-saline state changes produced robust failures to transfer with chlordiazepoxide (CDP) and also with yohimbine. Diazepam substituted for, while Ro 15-1788 antagonised, CDP; none of several non-benzodiazepine compounds substituted for CDP. Neither food deprivation nor extensive overtraining after CDP prevented the failure of transfer when animals were tested for drug-to-saline transfer. Another series of experiments evaluated the effects of CDP and diazepam in a rat conflict procedure. The doses at which CDP and diazepam produced anti-conflict effects were similar to those at which failure to transfer occurred in saline-to-drug state changes, and higher than those at which such failure occurred in drug-to-saline state changes. With benzodiazepines, StD of memory retrieval conceivably constitutes a parsimonious explanation of the anxiolytic and untoward (amnesic, drug dependence) actions of these drugs.     

Long-term benzodiazepine treatment: Is it ever justified?

Long-term benzodiazepine treatment is still used for various indications. It is now accepted that benzodiazepines can cause dependence even in normal therapeutic doses in long-term use. Is long-term use therefore ever justified? This review marshals the evidence for and against the effectiveness of benzodiazepines in long-term use and their side-effects, especially psychological deficits. The topic of dependence is then addressed. It is concluded that although short-term use is justified in view of the effectiveness and safety of the benzodiazepines, long-term benzodiazepine use is much more problematic. In the absence of comprehensive long-term efficacy and safety data, constant vigilance is necessary to prevent unplanned long-term use.     

Single- and multiple-dose kinetics of estazolam,a triazolo benzodiazepine

The pharmacokinetic properties of estazolam, a triazolo benzodiazepine hypnotic agent, were assessed in a series of healthy volunteers following single and multiple doses. After single oral doses of 2–16 mg, peak plasma concentrations were reached within 6 h. Values of elimination half-life ranged from 8.3–31.2 h (mean 17.0 h) and did not vary significantly with dose. During 3 weeks of therapy, steady-state plasma concentrations increased approximately in proportion to increasing doses, and accumulation was essentially complete within 3 days of each dose change. The mean observed accumulation ratio was 1.84, which was slightly larger than the predicted ratio of 1.53. Exposure to multiple-dose estazolam therapy had no significant influence on the kinetics of a single dose of antipyrine, suggesting that estazolam neither stimulates nor inhibits enzyme activity in humans. Thus the accumulation and elimination kinetics of estazolam can be classified as intermediate to those of the short-acting (such as oxazepam) and the long-acting (such as diazepam) benzodiazepine derivatives.     

Discriminative stimulus properties of the benzodiazepine receptor antagonist flumazenil

Rats were trained to discriminate the stimulus properties of the benzodiazepine (BZ) receptor antagonist flumazenil using a conditioned taste aversion procedure. On drug trials, fluid-restricted rats were injected with flumazenil (32 mg/kg), given access to a 0.25% saccharin solution for 30 min, and injected with LiCl (1.8 mEq/kg IP). On saline trials, injections of saline bracketed the period of saccharin consumption. Acquisition of the discriminated taste aversion, as measured by differential effects of drinking between saline and drug trials, developed after only five pairings of flumazenil with the LiCl injections. Flumazenil did not alter saccharin consumption in unconditioned controls (N=9) that never received LiCl. The discrimination was also measured by flumazenil's ability to reduce the preference for saccharin over tap water using two-bottle choice tests. Flumazenil demonstrated dose-dependent generalization upon decreasing the training dose as low as 1 mg/kg. Two other BZ receptor antagonists of different chemical structure, CGS 8216 and ZK 93426, substituted completely for the flumazenil stimulus. Partial generalization was exhibited to the partial inverse agonists FG 7142 and beta-CCE, while the full inverse agonists DMCM and PTZ failed to substitute for the flumazenil stimulus. The BZ receptor agonists diazepam and alprazolam failed to substitute for the flumazenil stimulus, although partial generalization was shown with CDP. The results suggest that the BZ receptor antagonist flumazenil may produce intrinsic discriminative stimulus effects that are independent from those of BZ receptor agonists or inverse agonists.     

Effects of alcohol on speaking in isolated humans

Drugs of abuse often increase human social interaction, as is suggested in our cultural drug use practices and has been demonstrated in controlled laboratory studies. The environmental and pharmacological mechanisms controlling these effects remain unclear. The present study examined the importance of a social context for obtaining drug-produced increases in human speech by examining the acute effects of alcohol (0, 22, 45, 67 g) on the amount of speech emitted by six normal volunteers who were producing speech monologues in an isolated context. A withinsubject repeated-measures experimental design was used. Alcohol produced a significant dose-dependent increase in total speech. Conversely, response rates on a nonverbal behavioral task (circular-lights device) decreased as an orderly function of alcohol dose. These results suggest that a social context is not a necessary condition for alcohol to increase rates of human speech. Moreover, the decreases in response rates observed in the nonverbal task rule out the possibility that alcohol affected total speech via a generalized increase in overall activity levels.     

Take a walk around the octagon — Looking for a model to replace the disease concept

The disease concept of drug misuse is considered to have been superseded. An eight-faceted model is presented to replace it, the facets representing the injurious agent; genetic vulnerability; physical and mental complications; the psychiatric perspective; the behavioural family dynamic model; the moral perspective; the social perspective; and the political economic perspective. A holistic approach to understanding drug misuse is called for, encompassing the various perspectives.     

Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence

Introduction: Both alcohol and benzodiazepine dependence (AD, BD) are severe and chronic conditions with devastating physical and mental health effects. The relative scarcity and controversial evidential status of available pharmacological interventions for the treatment of patients' acute withdrawal syndrome and/or relapse prevention call for the clinical investigation of novel safe and efficacious agents.

Areas covered: We review published studies of pregabalin as monotherapy in the treatment of AD and BD in more than 450 patients. Available evidence includes four RCTs, two in AD with active comparator drugs (naltrexone, tiapride, and lorazepam) and one placebo-controlled, and one placebo-controlled in BD. We also review other available studies on pregabalin's potential to reduce benzodiazepine consumption, its side effects, especially cognitive, as well as extant reports on its liability for abuse.

Expert opinion: Available evidence suggests that monotherapy with pregabalin, within the dosage range of 150 – 600 mg/d, is a promising “novel” option for the safe and efficacious relapse prevention of both AD and BD. However, its efficacy as monotherapy in the acute treatment of AD withdrawal syndrome is still controversial. Clinicians should be cautious in prescribing pregabalin to patients with a history of multiple substance recreational use, and monitor its effects on cognition at dosages above 450 mg/d. Further, well-designed clinical research is still needed for the eventual consolidation of pregabalin's place in the treatment of AD and BD.     

A clinical validation of the National Survey on Drug Use and Health assessment of substance use disorders

Alcohol and illicit drug abuse and dependence continue to be of great national concern in the United States, as is true in other nations. The National Survey on Drug Use and Health (NSDUH) provides national annual estimates of substance use and abuse/dependence among the U.S. civilian, noninstitutionalized population aged 12 years or older. We conducted a clinical validation study of the substance use disorder questions of the NSDUH instrument using a sample of 288 adults and adolescents recruited from the community and outpatient substance abuse treatment programs in North Carolina. Using the Structured Clinical Interview for DSM-IV (SCID-IV) for adults and the Pittsburgh Adolescent Alcohol Research Center's Structured Clinical Interview (PAARC-SCID) for adolescents, we computed the psychometric properties of the NSDUH questions. We found the level of agreement between the NSDUH and the SCID/PAARC-SCID interviews to be fair to moderate overall. There was somewhat better agreement for dependence than for abuse and for adults than for adolescents.     

Self-injection of barbiturates,benzodiazepines and other sedative-anxiolytics in baboons

Self-injection of 12 sedative-anxiolytics was examined in baboons. Intravenous injections and initiation of a 3-h time-out were dependent upon completion of a fixed-ratio schedule requirement, permitting eight injections per day. Before testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. At some doses, all five of the benzodiazepines examined (alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam) maintained rates (number of injections per day) of drug self-injection above vehicle control in each of the baboons tested. Maximum rates of benzodiazepine self-injection were generally submaximal. Of the benzodiazepines examined, triazolam maintained the highest rates of self-injection. Among the three barbiturates tested, methohexital generally maintained high rates of self-injection in contrast to hexobarbital and phenobarbital, which only maintained low rates. Of the four non-benzodiazepine non-barbiturate sedatives examined, both chloral hydrate and methyprylon occasionally maintained high rates of self-injection. Although there were differences within and across animals, baclofen maintained intermediate rates of self-injection. The novel anxiolytic buspirone maintained only low rates of self-injection that were not different from vehicle. This study further validates the self-injection methodology for assessing sedative-anxiolytic abuse liability and provides new information about drug elimination rate as a determinant of drug self-administration.     

Governing images and self-control: A comment on Drew's “Beyond the disease concept of addiction”

Critical reconsiderations of the policy implications of the disease concept of addictions have been produced over the last twenty-five years. One widely adopted approach, drawing on psychiatric traditions, has been that of the alcohol dependence syndrome. Other approaches have substituted new governing images, such as Drew's 'way of life leading to predicaments' model, which gives primacy to individual free will. This model is morally based and consistent with much current treatment practice, which is based on the premise that the addict is responsible for his behaviour. By retaining faith in the usefulness of treatment, the model presents a potential contradiction, namely that self control can be learnt by external control. Policy implications and broader cultural considerations of the model need to be canvassed.     

Beyond the disease concept of addiction: Towards an integration of the moral and scientific perspectives

This article examines governing images of drug use. It is proposed that there are preferable alternatives to the classical disease concept and its modifications (typified by the psycho-bio-social model of drug use). The characteristics of addictions, issues in treatment, and the elements of effective treatment approaches are described. Criticisms of the disease concept are reviewed. A new governing image must be able to accommodate the insights of science, the advances of technology, the wisdom of tradition and the reality of the moral dimension of living. The 'way of life leading to predicaments' model of drug use is described.     

MDMA use and neurocognition: a meta-analytic review

Rationale To determine the association between MDMA misuse and neurocognition using meta-analysis.Objective Separate analyses were conducted based on two sets of inclusion/exclusion criteria. A relatively stringent set required that the subjects be matched on important moderator variables, whereas the other did not. The study participants’ performance in the following neurocognitive domains was reviewed: attention/concentration, verbal and nonverbal learning and memory, psychomotor speed and executive systems functioning.Results In the 11 studies meeting the relatively stringent inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Similarly, in the 23 studies meeting the relatively lenient inclusion/exclusion criteria for this review, MDMA use was associated with neurocognitive deficits in each domain. Small to medium effect sizes were generally observed. A comparison of the effect sizes across the two sets of analyses did not reveal significant differences.Conclusions The findings from this review reveal that MDMA use is associated with neurocognitive deficits. The implications of these findings are discussed.These data were presented at the annual meeting of the Society for Neuroscience, San Diego, CA held last November 2004. This research was supported in part by grants from the National Institute of Health (DA50038, DA00388, DA07272 and P51-RR000165).     

Behavioral effects of nicotine exposure from secondhand tobacco smoke among bar and restaurant workers

This study explores the behavioral effects of nicotine exposure from secondhand tobacco smoke (SHS) on bar and restaurant workers. Baseline data were obtained from a longitudinal study of 105 bar and restaurant workers. Hair nicotine, self-reported SHS exposure, smoking status, symptoms of nicotine exposure after being exposed to a smoky environment, and nicotine dependence were assessed. Nonsmokers reporting four or more symptoms of nicotine exposure had higher hair nicotine levels than those reporting less than four symptoms. Nonsmokers with higher hair nicotine levels were 2.2 times more likely to report 4 or more behavioral symptoms. Self-reported secondhand tobacco smoke exposure and hair nicotine were not predictive of nicotine dependence among smokers. Nicotine exposure from secondhand tobacco smoke may have important behavioral outcomes in nonsmokers. This study provides further evidence for the importance of prohibiting smoking in hospitality venues to protect the health of workers.     

Lack of preference for flurazepam in normal volunteers

The reinforcing efficacy of flurazepam (15 and 30 mg) in humans was assessed using an experimental choice procedure. Twelve healthy volunteers were tested in two 3-week choice experiments, in which each dose of the drug was compared to placebo. Subjective effects of the drug (and placebo) were monitored using the Profile of Mood States and a 49-item version of the Addiction Research Center Inventory. The lower dose of flurazepam was chosen equally as often as placebo and produced no significant subjective effects. The higher dose (30 mg) was chosen significantly less often than chance, and produced typical tranquilizer-like effects (e.g., sedation). These results are consistent with previous results using other benzodiazepines such as diazepam and lorazepam, and suggest that the reinforcing efficacy of these drugs in normal volunteers is low.     

Behavioral effects of a novel kappa opioid analgesic,U-50488, in rats and rhesus monkeys

U-50488 [trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)-benzeneacetamide] is a structurally novel analgesic reported to have specific kappa opioid receptor agonist properties. Potent antinociceptive activity was demonstrated in rhesus monkeys and the effect was reversed by naloxone. The overt behavioral effects of U-50488 at supra-analgesic doses more closely resembled those of ethylketocyclazocine (EKC) than morphine. In monkeys trained to discriminate a 10-g/kg dose of EKC from saline, the stimulus effects generalized completely to U-50488 and other kappa agonists (e.g., bremazocine, cyclazocine), but not to the pure mu agonists. Like the other kappa agonists, U-50488 produced diuresis in monkeys by a naloxone-sensitive mechanism. In drug-naive rats offered continuous opportunity to self-administer drugs IV, most rats self-administered morphine or EKC, but none of the rats self-administered U-50488 at a rate above that of a group offered saline. Rats with continuous IV infusion of U-50488 for 3 weeks exhibited few abstinence signs and no weight loss when challenged with an injection of naloxone or after abrupt cessation of drug infusion. These experimental results support the previous reports in mice that U-50488 is a very selective kappa opioid agonist in rats and rhesus monkeys.     

Animal models of drug withdrawal symptoms

There have been few attempts to model subjective symptoms of drug withdrawal using animals as subjects. Two approaches for developing such models are reviewed. First, using drug discrimination methodology, it may be possible to train animals to detect the effects of withdrawal. This method has two difficulties: 1) the only discriminations trained to date involve precipitated withdrawal, and 2) the stimulus controlling behavior is difficult to specify. Second, withdrawal from many drugs of abuse produces the symptom of anxiety, and it seems likely that animal models of anxiety could be useful for studying drug withdrawal. This hypothesis has been explored most fully using subjects trained to detect the discriminative stimulus properties of the putative anxiogenic drug pentylenetetrazole (PTZ). Withdrawal from benzodiazepines or ethanol substitutes fully for PTZ, and withdrawal from cocaine, morphine, and nicotine substitutes partially for PTZ. Emerging data suggest that other animal models of anxiety may also be useful for detecting drug withdrawal. The final portion of this review examines a behavioral test that is very sensitive for detecting physical signs of withdrawal in animals. In subjects maintained on an operant baseline using food as a reinforcer, withdrawal from a drug of dependence frequently is associated with disruption of that operant behavior. For example, tetrahydrocannabinol and cocaine, drugs that are not traditionally seen as having significant withdrawal signs, produce disruption of operant responding when high-dose administration is terminated, and their readministration reverses this behavioral disruption. Based on the observation that withdrawal is associated with anxiogenic stimuli, we suggest a method to determine if disruption of operant behavior may be related to these stimuli.     

Caffeine physical dependence: a review of human and laboratory animal studies

Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been poorly characterized in laboratory animals and only moderately well characterized in humans. In humans, a review of 37 clinical reports and experimental studies dating back to 1833 shows that headache and fatigue are the most frequent withdrawal symptoms, with a wide variety of other signs and symptoms occurring at lower frequency (e.g. anxiety, impaired psychomotor performance, nausea/vomiting and craving). When caffeine withdrawal occurs, severity can vary from mild to extreme (i.e. incapacitating). The withdrawal syndrome has an onset at 12–24 h, peak at 20–48 h, and duration of about 1 week. The pharmacological specificity of caffeine withdrawal has been established. The proportion of heavy caffeine users who will experience withdrawal symptoms has been estimated from experimental studies to range from 25% to 100%. Withdrawal symptoms have been documented after relatively short-term exposure to high doses of caffeine (i.e. 6–15 days of 600 mg/day). Although animal and human studies suggest that physical dependence may potentiate the reinforcing effects of caffeine, human studies also demonstrate that a history of substantial caffeine intake is not a necessary condition for caffeine to function as a reinforcer. The similarities and differences between caffeine and classic drugs of abuse are discussed.     

A cotwin-control analysis of drug use and abuse/dependence risk associated with early-onset cannabis use

We assessed whether, after controlling for genetic and shared environmental influences, early cannabis use remains a significant predictor of other drug use, abuse, and dependence, and whether the risk for early-users is greater than that for later cannabis users. Data from a 1992 telephone diagnostic interview of 8169 male twins (M = 42.0 years at interview) who served in the U.S. military during the Vietnam-era were used to identify a subsample of 293 monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for early cannabis use (before age 18). Using cotwin-control analyses, outcomes assessed were: lifetime illegal drug use (stimulant/cocaine, sedative, opiate, and hallucinogen/PCP), lifetime DSM-III-R illegal drug abuse/dependence, and lifetime DSM-III-R alcohol dependence. After controlling for covariates, early cannabis users were at greater risk than their later/never-using cotwins for 8 of 9 substance-related comparisons, including: using other illegal drugs (ORs: 2.71–4.09), having illegal drug abuse/dependence (ORs: 2.02–2.13), and developing alcohol dependence (OR = 2.36). When analyses were limited to pairs in which the cotwin used cannabis later, early and later-users only differed significantly on sedative, opiate, and hallucinogen use. After familial influences on early cannabis use were controlled for, cannabis use—regardless of the age of initiation—still conferred increased risk of other illegal drug use, drug abuse/dependence, and alcohol dependence. In contrast to previous research, there is limited evidence for increased risk associated with early-onset use in this sample of Vietnam-era veterans.     

Clobazam maintenance among methadone maintenance patients with problematic benzodiazepine use: five case studies

The aim of this pilot study was to determine the potential of maintenance with clobazamin patients on methadone who were also benzodiazepine dependent. Five individuals were recruited and four were maintained on clobazam for a minimum of 3 months prior to reduction. Three subjects were abstinent from other benzodiazepines at 3 months. Clobazam was given as a single daily dose and was reported by the clients as less sedating than diazepam. There is potential for clobazam to be used as a maintenance benzodiazepine. [Wickes WA, Darke S, Ross J. Clobazam maintenance among methadone maintenance patients with problematic benzodiazepine use: five case studies. Drug Alcohol Rev 2000;19:401-405]