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The Effect of Naltrexone and Acamprosate on Cue-Induced

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The Effect of Naltrexone and Acamprosate on Cue-Induced European Neuropsychopharmacology (2007) 17, 558–566 www.elsevier.com/locate/euroneuro The effect of naltrexone and acamprosate on cue-induced craving, autonomic nervous system and neuroendocrine reactions to alcohol-related cues in alcoholics☆ Wendy Ooteman a,b,⁎, Maarten W.J. Koeter a,b, Roel Verheul c,d, Gerard M. Schippers a,b, Wim van den Brink a,b a Amsterdam Institute for Addiction Research, Amsterdam, The Netherlands b Department of Psychiatry, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands c Viersprong Institute for Studies on Personality Disorders (VISPD), Halsteren, The Netherlands d Department of Clinical Psychology, University of Amsterdam, Amsterdam, The Netherlands Received 22 March 2006; received in revised form 1 February 2007; accepted 13 February 2007 KEYWORDS Abstract Alcoholism; Naltrexone; Introduction: Acamprosate and naltrexone have been shown to be effective in relapse prevention of Acamprosate; alcoholism. It is hypothesized that naltrexone exerts its effects primarily on cue-induced craving Efficacy; and neuroendocrine cue reactivity, whereas acamprosate exerts its effect primarily on autonomic Craving; nervous system reactions to alcohol-related cues. Cue reactivity Experimental procedures: In a randomized double-blind experiment, 131 abstinent alcoholics received either acamprosate (n=56), naltrexone (n=52) or placebo (n=23) for three weeks and participated in two cue-exposure sessions: the first the day before and the second at the last day of medication. Results: Consistent with the hypotheses, naltrexone reduced craving more than acamprosate, and acamprosate reduced heart rate more than naltrexone. No medication effect was found on cue- induced cortisol. Discussion: The findings provide some evidence for differential effects of naltrexone and acamprosate: naltrexone may exert its effect, at least partly, by the reduction of cue-induced craving, whereas acamprosate may exert its effect, at least partly, by the reduction of autonomic nervous system reactions to alcohol-related cues. © 2007 Elsevier B.V. and ECNP. All rights reserved. ☆ The study in this article was conducted as part of the ‘Addiction’ programme granted by the Netherlands Organization for Health Research and Development (NWO/ZonMW). ⁎ Corresponding author. Academic Medical Center, Psychiatric Center, Tafelbergweg 25, 1105 BC, Amsterdam, The Netherlands. Tel.: +31 20 5667288; fax: +31 20 4087862. E-mail addresses: [email protected] (W. Ooteman), [email protected] (W. van den Brink). 0924-977X/$ - see front matter © 2007 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2007.02.012 Downloaded from ClinicalKey.com at Inova Fairfax Hospital - JCon January 08, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. Effect of naltrexone and acamprosate 559 1. Introduction alcohol-related cues in alcoholics is even smaller. Monti et al. (1999) did not find an effect of naltrexone treatment on Relapse prevention is among the most important treatments measures of autonomic nervous system reactions to alcohol- for alcohol dependence. Over the last 20 years, the role of related cues (blood pressure and heart rate) in alcoholics. In pharmacotherapy in relapse prevention has become increas- fact, they found a smaller decrease in blood pressure after ingly evident. There are two relatively new compounds that naltrexone treatment than after placebo treatment. Others are proven effective (Kranzler, 2000) which are approved in hypothesized that naltrexone's effect on craving may be both the United States and Europe, i.e. naltrexone and related in part to naltrexone's ability to stimulate the HPA axis acamprosate. However, the effect size of these medications and to normalize its suppressed basal activity and blunted is moderate at best and their mechanism of action is not fully response to a number of functional tests (Adinoff et al., 2005; understood. The current study is the first randomized, Kiefer et al., 2002; O'Malley et al., 2002). double-blind, placebo-controlled study testing the main hy- Acamprosate or calcium-acetyl-homotaurinate is a gluta- potheses regarding the assumed different mechanisms of mate-antagonist and possible GABA-agonist. In general, action of the two compounds. acamprosate is believed to maintain abstinence primarily by Naltrexone is an opioid antagonist that mainly acts at the reducing craving. Some investigators hypothesize that acam- mu opioid receptor (Littleton and Zieglgansberger, 2003). It is prosate specifically acts on craving that is mediated through hypothesized to prevent relapse by attenuating the self- glutamatergic and GABA-ergic dysregulations of stress, anxiety reported urge for alcohol's stimulating or rewarding properties or withdrawal systems (relief craving), and is thus accompa- (reward craving) in patients characterized by an opioidergic nied by autonomic nervous system reactions (Littleton, 1995; dysregulation and a reward seeking personality style (Verheul Koob and Le Moal, 2001, 2005; Verheul et al., 1999). et al., 1999; Koob and Le Moal, 2001, 2005). Several studies Since its approval, several trials have been performed have shown that naltrexone is most effective in patients with investigating acamprosate's efficacy. In most clinical trials, strong self-reported baseline craving (Jaffe et al., 1996), and continuous abstinence rather than relapse or craving has been that craving can be reduced by naltrexone (e.g. Chick et al., the primary outcome measure, with a beneficial effect of 2000a; Anton et al., 1999; Volpicelli et al., 1992). It is generally acamprosate on continuous abstinence rates with a modest believed that naltrexone reduces craving by blocking opioid effect size (see for a review: Mann, 2004; see for a meta- receptors, which in turn leads to an attenuation of the analysis: Mann et al., 2004). The effects of acamprosate on rewarding effect of alcohol (Volpicelli et al., 1995). craving are less consistent. Several trials showed a significant Since its approval, several trials have been performed reduction of craving compared to placebo (e.g. Chick et al., investigating naltrexone's efficacy in relapse prevention. 2000b; Pelc et al., 1997; Paille et al., 1995), but other studies However, the data are somewhat inconsistent and effect did not (Roussaux et al., 1996; Tempesta et al., 2000). Only few sizes are modest at best (see for review studies: Mann, 2004; studies included cue-induced craving and/or autonomic Srisurapanont and Jarusuraisin, 2005a,b; Roozen et al., 2006). nervous system reactions to alcohol-related cues as outcome The most consistent finding has been an increase in time to measures. Weinstein et al. (2003) presented some preliminary first relapse, although not in all trials, including the largest results of an uncontrolled pilot study suggesting that acam- with 627 veterans (Krystal et al., 2001). Negative findings may prosate does alter cue-induced self-reported craving and be accounted for by inadequate samples sizes, poor medica- reaction time to an alcohol-related stimulus. In addition, tion compliance (Mann, 2004) or inadequate patient treatment Agelink et al. (1998) showed improved autonomic neurocardial matching (Ooteman et al., 2005). balance in abstinent alcoholics treated with acamprosate, i.e. Many studies have examined the effect of naltrexone on following treatment with acamprosate patients showed less craving in non-experimental settings (see for reviews: Srisur- disturbances in neurocardiac vagal function. apanont and Jarusuraisin, 2005a; Roozen et al., 2006). In summary, it seems that acamprosate and naltrexone However, only a limited number of studies have included exert their effect on relapse via different mechanisms and cue-induced craving or measures of autonomic nervous system relate to different aspects of drinking behaviour. However, reactions to alcohol-related cues in the laboratory as outcome until now, the literature lacks sufficient empirical evidence measures. Alcohol-related cues (e.g. negative mood, the sight on the differential effect of naltrexone and acamprosate on and smell of alcohol) are generally believed to act as triggers both cue-induced craving and autonomic nervous system and for craving and/or autonomic nervous system reactions to neuroendocrine reactions to alcohol-related cues. The aim of alcohol-related cues (e.g. Cooney et al., 1997; Kaplan et al., the current study is, therefore, to investigate possible mech- 1985; Niaura et al., 1988). Therefore, cue-induced craving and anisms of action on craving of naltrexone and acamprosate. autonomic nervous system reactions to alcohol-related cues The primary hypothesis is that naltrexone and acamprosate may be important intermediate outcome measures for exert their effect through different mechanisms: naltrexone naltrexone's efficacy as well. With respect to the effect of will primarily exert its effect on cue-induced craving and naltrexone on cue-induced craving, the limited number of endocrinological cue-reactivity measures of the HPA axis studies showed inconsistent results. Some studies (Rohsenow (cortisol), whereas acamprosate will primarily exert its et al., 2000; O'Malley et al., 2002; Palfai et al., 1999)founda effect on cue-induced autonomic nervous system para- reduction in the level of cue-induced craving after naltrexone meters associated with withdrawal symptoms or anxiety treatment, whereas other studies (Modesto-Lowe et al., 1997; (heart rate,
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