The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial

Malcolm, Robert; Myrick, Hugh; Roberts, James S.; Wang, W.; Anton, Raymond F.; Ballenger, James C.

doi:10.1007/s11606-002-0038-1

Cited by 114 publications

(39 citation statements)

References 43 publications

(21 reference statements)

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“…Benzodiazepines are commonly used to ameliorate the symptoms of acute withdrawal from alcohol, however there is an increasing trend to instead use anti-convulsants such as carbamezepine that are more effective in preventing rebound withdrawal symptoms and reducing post-treatment drinking than BZs (Malcolm et al, 2002;Mueller et al, 1997). The sedative-anticonvulsant chlomethiazole that may act at the anesthetic binding site on GABA A receptors (Usala et al, 2003) is widely used in Europe in acute withdrawal.…”

Section: Gaba a Receptors As Therapeutic Targets For Alcoholismmentioning

confidence: 99%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

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Section: Gaba a Receptors As Therapeutic Targets For Alcoholismmentioning

confidence: 99%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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“…Therefore, future basic and clinical investigations should identify the best strategy for opiate antagonist treatment of alcoholism. Finally, a priority should be given to translation of preclinical to clinical research to identify means to minimize the persistent adaptive changes induced by sustained alcohol abuse (Heinz et al 2003a,b;Longo et al 2002;Malcolm et al 2001Malcolm et al , 2002. Repeated alcohol sensitization of withdrawal-induced anxiety-like behavior.…”

Section: Future Directionsmentioning

confidence: 99%

Conceptual framework for the etiology of alcoholism: a ?kindling?/stress hypothesis

2004

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Rationale-The rationale for proposing the "kindling"/stress hypothesis is to provide a conceptual basis for the insidious development and maintenance of alcohol abuse.Objective and results-An objective of the hypothesis is to emphasize how continued alcohol abuse is linked to progressive neural adaptation. Work has shown that repeated withdrawals from chronic low levels of alcohol sensitize ("kindle") anxiety-like behavior ("anxiety") in rats, a finding consistent with multiple withdrawal kindling of seizure activity. Additionally, stress substitutes for initial cycles of the multiple withdrawal protocol to sensitize withdrawal-induced anxiety, which is indicative that stress is capable of facilitating neuroadaptive processes related to withdrawal. The persistence of adaptation caused by stress and multiple withdrawals is revealed by the appearance of withdrawal-induced anxiety following a future re-exposure to a single 5-day period of alcohol. This persisting adaptation also permits stress to induce anxiety during a period of abstinence-a response not observed in animals without previous exposure to alcohol. Furthermore, stress interacts with repeated withdrawals to enhance voluntary alcohol drinking. Results of other preclinical and clinical studies reported in the literature are integrated with these investigations in support of the proposed hypothesis.Conclusions-The "kindling"/stress hypothesis is based on the premise that repeated withdrawals from cycles of chronic alcohol exposure contribute to a progressive development of persisting adaptive change that sensitizes withdrawal-induced anxiety and allows stress to evoke symptoms associated with negative affect during abstinence. Thus, these consequences of repeated withdrawals account for the evolution of major characteristics of alcoholism, which include worsened acute withdrawal symptoms and increased stress-induced negative affect during abstinence, both of which enhance the likelihood of relapse-and with relapse an inability to limit an abusive pattern of alcohol intake. The "kindling"/stress hypothesis provides a clear strategy for future studies to explore the advancing neural adaptation proposed to contribute to the pathogenesis of alcoholism.

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“…Carbamazepine also has good support by medical evidence and was included as an option. 13,14 We incorporated the requirement for sobriety before referral for admission. This was based on our experience with inebriated patients referred for inpatient detoxification, with a substantial number leaving AMA several hours later when sober.…”

Section: Protocol Developmentmentioning

confidence: 99%