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2/18/98 Bibliography- Sedative Hypnotics American Psychiatric Association Task Force on Benzodiazepine Dependence. (1990). Benzodiazepine dependence, toxicity and abuse. NO ABSTRACT
Ciraulo, D. A., Sands, B. F. and Shader, R. I. (1988). Critical review of liability for benzodiazepine abuse among alcoholics. Am J Psychiatry 145(12), 1501-1506. ABSTRACT The authors critically reviewed the literature on benzodiazepine use
among alcoholics, psychiatric patients, and the general population to determine
whether alcoholics have a greater liability for benzodiazepine abuse. Data
suggest that the prevalence of benzodiazepine use among alcoholics is greater
than in the general population but comparable to the prevalence in psychiatric
patients. The liability for abuse may also be greater for alcoholics, but
the substantial methodologic deficiencies of existing studies preclude
such a conclusion. Given the frequency of anxiety disorders and benzodiazepine
use among alcoholics, their potential for benzodiazepine abuse is an important
issue. The authors discuss clinical guidelines and strategies for future
research.
deWit, H. and Griffiths, R. R. (1991). Testing the abuse liability of anxiolytic and hypnotic drugs in humans. Drug Alcohol Depend 28(1), 83-111. ABSTRACT This paper represents a comprehensive review of laboratory studies investigating
the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective
effects of these drugs, most of which are either barbiturates or benzodiazepines,
have been measured using various self-report questionnaires and their reinforcing
effects have been studied using self-administration and choice procedures.
Studies using both subjective and reinforcing effects reveal orderly relations
between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates
are associated with higher abuse liability than benzodiazepines), between
different doses of the drugs (e.g. higher doses are usually associated
with higher abuse liability) and among different compounds within a class.
The subjective and reinforcing effects of barbiturates and benzodiazepines
depend critically upon the subject populations that are tested and it is
argued that individuals with histories of drug abuse provide a more sensitive
indicator of abuse liability than healthy volunteers. Several principles
of abuse liability testing are discussed, including the selection of an
appropriate subject population, the use of blind drug administration procedures,
the comparison of a test compound to an appropriate standard, the inclusion
of a placebo and a wide range of doses of the test drug and the use of
multiple measures of likelihood of abuse.
Eickelberg, S. J. (1998). Management of sedative-hypnotic intoxication and withdrawal. In Principles of Addiction Medicine, ed. A.W. Graham and T.K. Schultz. 441-456. 2nd ed., Chevy Chase, MD: American Society of Addiction Medicine. NO ABSTRACT
Evans, S. M., Funderburk, F. R. and Griffiths, R. R. (1990). Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability. J Pharmacol Exp Ther 255(3), 1246-1255. ABSTRACT Zolpidem, which is currently marketed in Europe as a hypnotic, is a short-duration imidazopyridine whose actions are mediated at the gamma- aminobutyric acid benzodiazepine receptor complex. However, zolpidem produces a variety of biochemical differences from classic benzodiazepine agonists including showing selectivity for the central BZ1 (omega 1) receptor subtype as well as showing a different pattern of distribution of binding sites. This study compared zolpidem to the benzodiazepine hypnotic triazolam in 15 healthy male volunteers with histories of sedative drug abuse. Placebo, zolpidem (15, 30 and 45 mg) and triazolam (0.25, 0.5 and 0.75 mg) were administered p.o. in a mixed sequence in a double-blind, cross-over design. The onset time with zolpidem was faster than with triazolam, with peak effects of both drugs occurring at 1 to 2 hr after administration. Both zolpidem and triazolam produced dose-related decrements in performance on various performance tasks including circular lights, reaction time, balance, number recall and the digit symbol substitution test. Both drugs also produced similar dose-related changes on various observer ratings including overall strength of drug effect. Triazolam, but not zolpidem, increased subject- and observer-rated sleepiness and produced greater impairment on a picture memory task. Zolpidem, but not triazolam, produced increases in subject ratings of various somatic symptoms (e.g., dizzy, anxious and queasy) and there were 9 days on which subjects vomited after zolpidem, but none after triazolam. Although the highest dose of both drugs was identified by subjects as being active, the highest dose of triazolam was identified as being barbiturate, benzodiazepine or alcohol, almost twice as often as the highest dose of zolpidem. Overall, this study shows that although zolpidem produces many effects in common with triazolam, it also has a unique profile of effects distinguishable from classic benzodiazepine agonists. The mechanism(s) underlying these differences is unclear, but may be related to the atypical biochemical profile of zolpidem. (6) Griffiths, R. R. and Sannerud, C. A. (1987). Abuse and dependence on benzodiazepines and other anxiolytic/sedative drugs. In Psychopharmacology: The third generation of progress, ed. Y. Herbert, Meltzer, and J.T. Coyle. 1535-1541. 2nd ed., New York: Raven Press. NO ABSTRACT
(7) Griffiths, R. R. and Wolf, B. (1990). Relative abuse liability of different benzodiazepines in drug abusers. Journal of Clinical Psychopharmacology 10,237-243. ABSTRACT There is a convergence of data from various sources suggesting that
there are meaningful differences among the benzodiazepines with respect
to their attractiveness as drugs of abuse for drug abusers. Laboratory
studies of subjective and reinforcing effects in drug abusers, interviews
with drug abusers, clinical judgment of medical professionals, and epidemiological
studies all indicate that diazepam, in particular, has a greater abuse
liability than many of the other benzodiazepines. Some of the available
data also suggest that lorazepam and alprazolam are more diazepam-like
in having relatively high abuse liability, while oxazepam, halazepam, and
possibly chlordiazepoxide, are relatively low in this regard. These differences
in abuse liability among benzodiazepines are analogous to the widely recognized
differences in abuse liability within the barbiturate class that have proved
to be important in helping guide clinicians' drug prescribing practices.
(8) Griffiths, R. R., Sannerud, C. A., Ator, N. A. and Brady, J. V. (1992). Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal. J Pharmacol Exp Ther 260(3), 1199-1208. ABSTRACT This study examined in baboons various behavioral effects of
zolpidem,
a short-acting imidazopyridine hypnotic which has selectivity for subtypes
of the benzodiazepine receptor. Intravenous drug self-injection was studied
under a fixed-ratio 80- or 160-response schedule with a 3-hr timeout after
each injection. Maximal rates of self-injection maintained by zolpidem
(0.01-1 mg/kg) were consistently higher than those maintained by vehicle
and the benzodiazepine hypnotic triazolam. Substitution of vehicle after
about 2 weeks of zolpidem self-injection (7-8 mg/kg/day) resulted in a
time-limited suppression of food pellet intake, indicating a drug withdrawal
effect. In a drug discrimination study, baboons were trained to discriminate
either lorazepam (1.8 mg/kg p.o.) or pentobarbital (10 mg/kg p.o.) from
the no-drug condition. Zolpidem (0.1-18 mg/kg p.o.) occasioned both lorazepam-
and pentobarbital-appropriate responding (greater than 80%) in a dose-dependent
manner. In a final experiment, zolpidem (3.2 or 5.6 mg/kg i.m.) produced
ataxia and sedation that progressively decreased over 7 consecutive days
of administration. The withdrawal, discriminative stimulus effects and
tolerance shown with zolpidem were similar to those shown previously with
benzodiazepines under similar conditions. The rates of self-injection of
zolpidem were similar to those maintained by intermediate duration barbiturates
(e.g., pentobarbital) and higher than those maintained by 11 benzodiazepines
studied previously under similar conditions. Further research on the reinforcing
effects of zolpidem may provide useful insights into mechanisms underlying
the maintenance of behavior by compounds acting through the benzodiazepine
receptor.
(9) Hobbs, W. R., Rall, T. W. and Verdoom, T. A. (1996). Hypnotics and sedatives: Ethanol. In Pharmacological basis of therapeutics, ed. Goodman & Gilman. 361-396. 9th ed., New York: McGraw-Hill. NO ABSTRACT
(10) Jackson, A. H. and Shader, R. I. (1973). Phenobarb conversion: Guidelines for the withdrawal of narcotic and general depressant drugs. Dis Nerv Syst 34,162. NO ABSTRACT No match
Juergens, S. M. and Cowley, D. R. (1998). The pharmacology of sedative-hypnotics. In Principles of Addiction Medicine, ed. A.W. Graham and T.K. Schultz. 117-130. 2nd ed., Chevy Chase, MD: American Society of Addiction Medicine. NO ABSTRACT
Mueller, T. I., Goldenberg, I. M., Gordon, A. L., Keller, M. B. and Warshaw, M. G. (1996). Benzodiazepine use in anxiety disordered patients with and without a history of alcoholism. J Clin Psychiatry 57(2), 83-89. BACKGROUND: People with a history of alcohol use disorders are thought to be at risk for misusing prescribed benzodiazepines. We examine the use of prescribed benzodiazepines in anxiety disordered subjects with and without a history of alcohol dependence or abuse. METHOD: A group of 343 subjects in the Harvard/Brown Anxiety Disorders Research Program (HARP) who were taking benzodiazepines at the time of entry into a prospective study of anxiety disorders serve as the study group. Subjects with (N=99) and without (N=244) a history of alcohol use or dependence (DSM- III-R) are examined for their reported total daily dose, p.r.n. use, or continued use of benzodiazepines. RESULTS: There is no significant difference in maximum daily dose or continued use of benzodiazepines over 12 months of follow- up. There is a clinically small but statistically significant difference in median daily dose during the second but not the first 6 months of follow-up for the alcohol history positive versus alcohol history negative groups. Additionally, there was significantly less reported use of p.r.n. benzodiazepines in the alcohol history positive versus alcohol history negative subjects during the second 6 months, but not the first 6 months, of follow-up. CONCLUSION: The presence or absence of a history of alcohol use disorders is not
a strong predictor of the use of benzodiazepines in subjects with anxiety
disorders over 12 months of prospective follow-up.
Noyes, R., Jr., Garvey, M. J., Cook, B. L. and Perry, P. J. (1988). Benzodiazepine withdrawal: a review of the evidence. J Clin Psychiatry 49(10), 382-389. ABSTRACT In a recent series of controlled studies, investigators looked at what
happened when benzodiazepines were discontinued. Despite methodological
problems, these studies showed that rebound anxiety occurred in a substantial
minority of patients after several weeks of drug use. Also, a withdrawal
syndrome developed in nearly half of patients who used benzodiazepines
for more than a year. In these studies, risk factors included dose, duration
of use, elimination rate of the drug, and abruptness of discontinuation.
Patients who are physically dependent on benzodiazepines may need help
in stopping these agents. Physicians should advise gradual discontinuation
and, along with emotional support, should consider the use of alternative
medications for the control of symptoms.
Pedersen, W. and Lavik, N. J. (1991). Adolescents and benzodiazepines: Prescribed use, self-medication and intoxication. Acta Psychiatry Scand 84(1), 94-98. ABSTRACT In a longitudinal study of 1230 people aged 13-18 years from the Greater
Oslo Area, the past-year prevalence of anxiolytic or hypnotic use was 10%,
which is higher than previously reported. The majority gave therapeutic
reasons as a motive for using these drugs. However, most of the use was
unprescribed. The parents, and especially the mother, were the most important
suppliers. A minority gave intoxication as a motive for using these drugs.
In this group, the suppliers were mainly peers and the illegal market.
Neither the unprescribed nor the prescribed therapeutic use show any association
with use of drugs such as alcohol and cannabis. There is, however, a strong
association between the unprescribed use of benzodiazepines by young people
and by their parents. This suggests a pattern of learning and role modelling,
which must be regarded as problematic for public health policy. Those who
use the drugs to become intoxicated have particularly poor mental health,
and they use many other drugs as well. This group probably runs a special
risk of developing more serious drug abuse.
Rickels, K., Schweizer, E., Case, G. W. and Garcia-Espana, F. (1988). Benzodiazepine dependence, withdrawal severity, and clinical outcome: Effects of personality. Psychopharmacol bull 24,415-420. NO ABSTRACT
Schwartz, H. I. and Blank, K. (1991). Regulation of benzodiazepine prescribing practices: Clinical implications. Gen Hosp Psychiatry 13(4), 219-224. ABSTRACT In an effort to control prescription abuse of
benzodiazepines, the New
York State Department of Health (DOH) enacted a regulation requiring the
use of triplicate prescriptions for these medications. DOH predicted that
this regulation would reduce the overall abuse of benzodiazepines and eliminate
widescale organized fraud and abuse without any negative impact or reduced
availability to patients. Following implementation of the regulation, the
authors reviewed all psychiatric emergency room cases and outpatient clinic
walk-in evaluations over a 3-month period in an urban medical center and
identified 59 cases in which the use of benzodiazepines was a significant
presenting problem. Of these, 24 (41%) were judged to be directly related
to the new triplicate regulation. In all but one of these cases the patient
presented because of symptoms or concerns directly stemming from the refusal
by a clinician to continue prescribing a benzodiazepine in a previously
established pattern. Typically, abrupt discontinuation of benzodiazepine
treatment led to a withdrawal syndrome and/or the unmasking of a previously
treated anxiety disorder. In attempting to redress what are essentially
criminal substance abuse problems through the regulation of legitimate
clinical practice, regulatory agencies may ultimately deprive patients
of appropriate, legitimate, and efficacious treatments.
Sellers, E. M., Schneiderman, J. F., Romach, M. K., Kaplan, H. L. and Somer, G. R. (1992). Comparative drug effects and abuse liability of lorazepam, buspirone, and secobarbital in nondependent subjects. J Clin Psychopharmacol 12(2), 79-85. ABSTRACT The pharmacologic effects of lorazepam (2 mg), buspirone (20 mg, 10
mg), secobarbital (100 mg), and placebo were compared in 15 male, experienced,
intermittent nontherapeutic drug users. All drugs produced a "drug effect,"
however, buspirone 20 mg was significantly less liked than were lorazepam,
secobarbital, or buspirone 10 mg (p less than .05) but not placebo. Lorazepam
was liked better than were other drugs only at 1 hour and only compared
with buspirone 20 and placebo. Compared with other drugs, lorazepam drug
effects were greater and resulted in more prolonged impairment of a motor
tracking task, standing steadiness, and memory. Buspirone 20 mg significantly
impaired memory at 1 hour compared with placebo. Subjects were more likely
to identify buspirone as unfamiliar. Because buspirone 20 mg was less liked
than were other drugs, dose escalation as part of drug abuse is not likely
to occur. Lorazepam also was not particularly liked and was not different
from placebo on most subjective abuse-relevant measures.
Shader, R. L. and Greenblatt, D. J. (1993). Use of benzodiazepines in anxiety disorders. N Engl J Med 328(19), 1398-1405. NO ABSTRACT
Smith, D. E. and Wesson, D. R. (1995). Benzodiazepines and other sedative-hypnotics. In American psychiatric press textbook of substance abuse treatment, ed. M. Galanter and H. Kleber. 1st ed., Washington, DC: American Psychiatric Press. NO ABSTRACT
Volkow, N. D., Wang, G. J., Begleiter, H., Hitzemann, R., Pappas, N., Burr, G. et al. (1995). Regional brain metabolic response to lorazepam in subjects at risk for alcoholism. Alcohol Clin Exp Res 19(2), 510-516. ABSTRACT The mechanisms underlying the blunted response to alcohol administration observed in subjects at risk for alcoholism are poorly understood and may involve GABA-benzodiazepine receptors. The purpose of this study was to investigate if subjects at risk for alcoholism had abnormalities in brain GABA-benzodiazepine receptor function. This study measured the effects of 30 micrograms/kg (i.v.) of lorazepam, on regional brain glucose metabolism using positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose in subjects with a positive family history for alcoholism (FP) (n = 12) and compared their response with that of subjects with a negative family history for alcoholism (FN) (n = 21). At baseline, FP subjects showed lower cerebellar metabolism than FN. Lorazepam decreased whole-brain glucose metabolism, and FP subjects showed a similar response to FN in cortical and subcortical regions, but FP showed a blunted response in cerebellum. Lorazepam-induced changes in cerebellar metabolism correlated with its motor effects. The decreased cerebellar baseline metabolism in FP as well as the blunted cerebellar response to lorazepam challenge may reflect disrupted activity of benzodiazepine-GABA receptors in cerebellum. These changes could account for the decreased sensitivity to the motor effects of alcohol and benzodiazepines in FP subjects. |