Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure

Mintzer, Miriam Z.; Griffiths, Roland R.

doi:10.1007/s00213-004-2009-1

Cited by 18 publications

(13 citation statements)

References 33 publications

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“…Using this approach, discontinuation of benzodiazepine treatment was shown to substitute for the discriminative stimulus effects of flumazenil, evidenced by a time-related switch in responding from the vehicle to the flumazenil lever (Gerak and France 1999). The results of drug discrimination studies, therefore, are consistent with clinical reports that flumazenil-induced withdrawal is qualitatively similar to withdrawal emerging upon discontinuation of benzodiazepine treatment (Mintzer and Griffiths 2005).…”

Section: Introductionsupporting

confidence: 75%

Changes in relative potency among positive GABAA receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys

McMahon

Javors

2007

Psychopharmacology

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These results suggest that positive GABA(A) receptor modulators acting at different sites attenuate withdrawal induced by discontinuation of benzodiazepine treatment, consistent with previous studies suggesting that the same compounds attenuate flumazenil-precipitated withdrawal. Differences in the relative potency of positive modulators as a function of acute versus chronic benzodiazepine treatment suggest that neuroactive steroids, in particular, are especially potent in benzodiazepine-dependent animals.

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Section: Introductionsupporting

confidence: 75%

Changes in relative potency among positive GABAA receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys

McMahon

Javors

2007

Psychopharmacology

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“…Benzodiazepine withdrawal is characterized by many signs that are opposite to the therapeutic effects of benzodiazepines (e.g. anxiety, insomnia) and, in more severe cases, patients may experience seizures (70,120,134). Comprehensive reviews discussing the evidence of physical dependence to benzodiazepines, as well as the factors that may influence the development of physical dependence to chronic benzodiazepine treatment can be found elsewhere (70,207,208).…”

Section: Physical Dependence Following Chronic Treatment With Benzodimentioning

confidence: 99%

“…Controlled studies examining patients who use low therapeutic doses of benzodiazepines chronically have demonstrated that flumazenil can precipitate withdrawal symptoms (18,19,74,121). Likewise, precipitated withdrawal also has been observed in healthy human volunteers following daily exposure to a relatively high therapeutic dose of a benzodiazepine (120). In preclinical studies, the severity of withdrawal has been shown to be dose-dependent in non-human primates (111) and dogs (170).…”

Section: Physical Dependence Following Chronic Treatment With Benzodimentioning

confidence: 99%

Abuse and dependence liability of benzodiazepine-type drugs: GABAA receptor modulation and beyond

Licata

Rowlett

2008

Pharmacology Biochemistry and Behavior

174

127

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Over the past several decades, benzodiazepines and the newer non-benzodiazepines have become the anxiolytic/hypnotics of choice over the more readily abused barbiturates. While all drugs from this class act at the GABA(A) receptor, benzodiazepine-type drugs offer the clear advantage of being safer and better tolerated. However, there is still potential for these drugs to be abused, and significant evidence exists to suggest that this is a growing problem. This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs. Moreover, the pharmacological and putative biochemical basis of the abuse-related behavior is discussed.

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“…Similarly, when neuronal functions are disturbed by the actions of drugs, adaptive changes occur that are usually opposite to those induced by the initial action of the drug, and thus tend to overcome the drug effect, producing an ‘acute tolerance’[8,9]. If the drug is then removed suddenly, as by the application of a receptor blocker, the adaptive changes are unmasked and become the basis of an acute withdrawal reaction [10–12].…”

Section: Intracellular Signalling Systemsmentioning

confidence: 99%

What neurobiology cannot tell us about addiction

Kalant

2010

Addiction

109

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Molecular neurobiological studies have yielded enormous amounts of valuable information about neuronal response mechanisms and their adaptive changes. However, in relation to addiction this information is of limited value because almost every cell function appears to be involved. Thus it tells us only that neurons adapt to 'addictive drugs' as they do to all sorts of other functional disturbances. This information may be of limited help in the development of potential auxiliary agents for treatment of addiction. However, a reductionist approach which attempts to analyse addiction at ever finer levels of structure and function, is inherently incapable of explaining what causes these mechanisms to be brought into play in some cases and not in others, or by self-administration of a drug but not by passive exposure. There is abundant evidence that psychological, social, economic and specific situational factors play important roles in initiating addiction, in addition to genetic and other biological factors. Therefore, if we hope to be able to make predictions at any but a statistical level, or to develop effective means of prevention, it is necessary to devise appropriate integrative approaches to the study of addiction, rather than pursue an ever-finer reductive approach which leads steadily farther away from the complex interaction of drug, user, environment and specific situations that characterizes the problem in humans.

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Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure

Abstract: These findings support previous human research studies indicating that flumazenil precipitates withdrawal after short chronic exposure to benzodiazepines and suggests that duration of exposure does not influence the intensity of withdrawal beyond the first week of exposure.

Cited by 18 publications

References 33 publications

Changes in relative potency among positive GABAA receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys

Changes in relative potency among positive GABAA receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys

Abuse and dependence liability of benzodiazepine-type drugs: GABAA receptor modulation and beyond

What neurobiology cannot tell us about addiction

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