Naltrexone in the Treatment of Alcohol Dependence

Krystal, John H.; Cramer, Joyce A.; Król, W; Kirk, Gail; Rosenheck, Robert A.

doi:10.1056/nejmoa011127

Cited by 569 publications

(303 citation statements)

References 25 publications

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“…MOR blockade in the ventral tegmental area inhibits dopamine release following alcohol intake and opioid antagonists reduce alcohol intake in rodents (Mitchell et al 2009). Consistent with this preclinical literature, naltrexone has been shown to have a small‐to‐moderate effect size in reducing alcohol use in some (Garbutt et al 1999; Bouza et al 2004) but not all studies (Krystal et al 2001). In heroin dependence, naltrexone blocks the physiological and psychological effects of heroin (Navaratnam et al 1994; Brewer 2002; Brewer & Streel 2010), preventing relapse, particularly in the early detoxification phase (Foster, Brewer, & Steele 2003).…”

Section: Introductionmentioning

confidence: 64%

Naltrexone ameliorates functional network abnormalities in alcohol‐dependent individuals

et al. 2017

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Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50‐mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly‐drug‐dependent individuals compared with 36 healthy volunteers. Graph theoretic and network‐based statistical analysis of resting‐state functional magnetic resonance imaging (MRI) data revealed that alcohol‐dependent subjects had reduced functional connectivity of a dispersed network compared with both poly‐drug‐dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol‐dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly‐substance‐dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.

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Section: Introductionmentioning

confidence: 64%

Naltrexone ameliorates functional network abnormalities in alcohol‐dependent individuals

et al. 2017

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“…therapeutic efficacy of NTX in treating alcoholism (O'Malley et al, 1992(O'Malley et al, , 1996Volpicelli et al, 1992Volpicelli et al, , 1997Anton et al, 1999;Chick et al, 2000;Johnson and Ait-Daoud, 2000;Heinala et al, 2001;Krystal et al, 2001;Morris et al, 2001;Guardia et al, 2002), identifying factors that predict therapeutic response to NTX is a critical goal of alcoholism research. Although the cognitive effects of acute and chronic NTX may differ, recent data supports equivalent or greater efficacy of acute NTX dosing, relative to daily maintenance, in reducing excessive alcohol intake (Hernandez-Avila et al, 2006).…”

Section: Discussion Ntx Effects On Impulsive Choicementioning

confidence: 99%

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

Mitchell

Fields

et al. 2006

Neuropsychopharmacol

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The opioid receptor antagonist naltrexone (NTX) is one of few approved treatments for alcoholism, yet the mechanism by which it reduces drinking remains unclear. In rats, NTX reduces morphine-induced impulsive choice bias; however, nothing is known about the drug's effect on discrete aspects of impulsive behavior in humans, such as decision-making and inhibitory control. Here, we used a modified delay discounting procedure to investigate whether NTX improves decision-making or inhibitory control in humans. We measured the effect of acute NTX (50 mg) on choice between smaller sooner (SS) and larger later monetary rewards and on response errors (motor mismatch) in a high conflict condition in a group of abstinent alcoholics (AA) and healthy control subjects (CS). We previously reported that AA selected the SS option significantly more often than did CS in this paradigm. If the choice bias of AA is due to enhanced endogenous opioid signaling in response to potential reward, NTX should reduce such bias in the AA group. We found that NTX did not reliably reduce impulsive choice in the AA group; however, NTX's effect on choice bias across individuals was robustly predictable. NTX's effect on choice bias was significantly correlated with scores on Rotter's Locus of Control (LOC) scale; increasingly internal LOC scores predicted increasing likelihood of impulsive choices on NTX. In addition, we found that NTX significantly enhanced control of motor responses, particularly within the CS group. These results suggest that endogenous opioids may impair response selection during decision-making under conflict, and that NTX's effects on explicit decision-making are personality-dependent. Determining the biological basis of this dependence could have important implications for effective alcoholism treatment.

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“…In preclinical studies, opiate antagonists are capable of minimizing acute drinking of alcohol (Altshuler et al 1980;Badia-Elder et al 1999;Froehlich et al 1990;Heyser et al 2003;Hölter and Spanagel 1999;Hyytia and Sinclair 1993;Overstreet et al 1999;Samson and Doyle 1985), as well as reducing alcohol seeking by an alcohol conditioned stimulus (Liu and Weiss 2002a;Koob et al 2003). However, naltrexone's maintenance of abstinence in alcoholdependent patients was not remarkable in one study (Guardia et al 2002) and was absent in another (Krystal et al 2001). Chick et al (2000) provided disappointing effectiveness of acamprosate in their investigation.…”

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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Naltrexone in the Treatment of Alcohol Dependence

Abstract: Our findings do not support the use of naltrexone for the treatment of men with chronic, severe alcohol dependence.

Cited by 569 publications

References 25 publications

Naltrexone ameliorates functional network abnormalities in alcohol‐dependent individuals

Naltrexone ameliorates functional network abnormalities in alcohol‐dependent individuals

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

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

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