The Effect of Naltrexone and Acamprosate on Cue-Induced

European Neuropsychopharmacology (2007) 17, 558–566

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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).

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, skin conductance). The secondary hypothesis is Monti et al., 1999) did not. It should be noted, however, that that both naltrexone and acamprosate result in a larger Monti et al. (1999) did find an effect on the number of patients reduction of cue-induced craving and/or autonomic nervous reporting cue-induced craving. The number of studies about system and neuroendocrine reactions to alcohol-related naltrexone's effect on autonomic nervous system reactions to cues than placebo.

2. Experimental procedures glass in front of the subject. While the pre-recorded mood induction script was played over the headphone for 5 min, the subject was 2.1. Participants instructed to sniff the beverage four times (one time at the start of the script and three times at the end of the script). During exposure, craving was assessed four times on a VAS scale ranging from 0 to 10 The study population consisted of both treatment-seeking and non- (at the 1st, 3rd, 4th and 5th minute). At the end, a self-report treatment-seeking alcoholics, that were recruited either at the craving questionnaire (JACQ-now; Ooteman et al., 2006a) was filled Jellinek addiction treatment center in Amsterdam or through adver- out and a final assessment with the VAS scale was taken before tisement in newspapers and radio-interviews. bringing the participant back to a relaxed state. Inclusion criteria were: primary DSM-IV diagnosis of alcohol dependence; minimum age of 18; and no heavy drinking days (≥5 units) for a minimum of one week and a maximum of six months. Exclusion 2.4. Subjective outcome measures criteria were: co-morbid cocaine or heroine dependence; cocaine or heroine use in the last 30 days before intake; current use of naltrexone, At baseline and during cue exposure, craving was measured on a 10- ‘ ’ ‘ acamprosate or disulfiram; severe cognitive deficits; insufficient point VAS scale that measured craving right now (VASa) ( How strong is ’ demand of the Dutch language; disturbed renal function your urge or need to drink right now? ). Immediately after cue exposure, (creatinineN120 μmol/l); acute hepatitis (ASAT/ALAT≥3×normal subjects were retrospectively asked to give a rating of their craving ‘ value); severe liver insufficiency; hypersensitivity for acamprosate during the session on a 10-point VAS scale (VASb) ( How strong was your ’ and/or naltrexone; pregnancy; lactation; expected medical interven- strongest urge or need to drink alcohol during the session? ). In addition, tions including pain relief with opioids; severe medical illnesses; active they were asked to administer the 24-item Jellinek Alcohol Craving psychosis; current use of anti psychotic medication; and suicidality. Questionnaire (JACQ-now; Ooteman et al., 2006a), a questionnaire with four subscales that measure the core aspects of craving. After the second cue-exposure session, an evaluation form was filled out and 2.2. General design medication compliance (defined as the percentage of pills taken by the subject) was retrospectively assessed by self-report. All clients filled out self-report questionnaires on demographics, immediately after inclusion in the study. To assess the severity of their 2.5. Autonomic nervous system and neuroendocrine alcohol problems all participants self-administered the Alcohol Use Disorders Identification Test (AUDIT; Babor et al., 1992). All partici- outcome measures pants were instructed to quit drinking one week before start of the medication period. They were then prepared for a cue-exposure 2.5.1. Autonomic nervous system reaction to alcohol-related challenge. Based on a Drinking Triggers Interview (Monti et al., 1993a), cues outcome measures individualized audio-taped mood induction scripts were prepared The following physiological measures were continuously recorded (Cooney et al., 1997). The aim of the script was to induce the mood in during both cue-exposure challenges: (1) heart rate (HR); (2) skin which the subject was most likely to experience craving. conductance level (SCL); (3) skin conductance response (SCR). Based One day before the start of the medication period, every subject on these assessments, mean values of HR, SCL and SCR as well as Δ was exposed to a cue-exposure challenge, in which craving and peak values (see statistical analysis) were calculated, since subjects autonomic nervous system reaction to alcohol-related cues were may peak at different moments in time in which case mean values measured. All subjects then participated in a randomized, double- may mask the cue-exposure (and medication) effect. blind, placebo-controlled protocol: 40% of the subjects received For HR assessment, ECG electrodes were placed on either side of acamprosate, 40% naltrexone and 20% placebo for 21 days, under the participant's chest. A Contact Precision Instruments analogue– supervision of a physician. The placebo group was smaller than the digital converter (ADC) sampled the ECG signal at a rate of 300 Hz medication groups because the effect of naltrexone and acampro- and calculated the number of interbeat intervals (IBI's) during 10-s sate compared to placebo was not the main focus of this study, but sampling periods (range 2 mV, High Pass 10 Hz, Low Pass 200 Hz). part of our secondary research question. The dosages of naltrexone For the assessment of SCL and SCR, electrodes were taped to the and acamprosate were given according to current treatment middle phalanx of the forefinger and the middle finger of the recommendations. For acamprosate, 2.0 g/day was given to patients participant's non-dominant hand. The skin conductance signal was with bodyweight N60 kg, and 1.3 g/day in patients with bodyweight amplified by a Contact Precision Instruments skin conductance b60 kg. The recommended dose of naltrexone is 50 mg/day. All coupler, sampled at a fixed 40 Hz. SCL and SCR count were averaged tablets (placebo, naltrexone and acamprosate) were identical in across a 10-s sampling period. The response criterion for SCR was an appearance. Based on data about the pharmacokinetics of the increase of 0.0015625 μS. compounds, 21 days of administration should be sufficient to exclude the possibility that no effect is detected due to a potential latency 2.5.2. Neuroendocrine cue-reactivity outcome measure period for the effect of acamprosate (Wilde and Wagstaff, 1997)or Cortisol production was measured in saliva and sampled ten times naltrexone (Mason et al., 2002; Yuen et al., 1999). during the cue-exposure session. The first baseline sample was taken After three weeks of placebo or medication, all subjects were directly following the resting period, and a second baseline sample was exposed to a second cue-exposure session according to exactly the same taken 5 min after the resting the period. A further eight samples were protocol as the first session, with an additional retrospective assessment taken 15, 20, 25, 30, 35, 40, 45, and 50 min after start of the cue of medication compliance of the past three weeks. After debriefing and exposure. Saliva was collected using Sarstedt salivettes with a dental unblinding, a treatment advice was given by the physician. All subjects cotton roll, frozen at −20°C and cortisol analyses were performed at received three vouchers with a total value of 35 Euro. the Department of Psychology, TU Dresden, Germany, (Laboratory Dr. Kirschbaum) using a commercial immunoassay with chemilumines- 2.3. Procedure cence detection. The lower sensitivity of the assays is 0.44 nmol/l, intra-assay and inter-assay coefficients of variation are less than 10%. The cue-exposure paradigm was based on procedures developed by Cooney et al. (1997) and Monti et al. (1993b). First, subjects were 2.6. Statistical analysis screened for alcohol use by a breathalyzer, connected to electrodes and acclimatized for 30 min. Each subject was then asked to relax Despite some drop-outs after randomization, there were no signif- for 4 min. The subject's favourite beverage was then poured in the icant (pb0.05) differences in baseline characteristics between the

Figure 1 Subject progress through study phases. three groups, with the exception of more years of education in the of the baseline-period from the maximum value during the 5-min placebo condition. However, in order to improve the power of the lasting cue-exposure period. Cortisol Δ peak scores were calculated by study and to prevent residual confounding, AUDIT (Alcohol Use Dis- subtracting the mean of two baseline values (sample 1a and 1b were orders Identification Test) scores, gender and benzodiazepine use regarded as baseline values since it takes approximately 15–25 min will be used as covariates in all analyses. before the cortisol reaction becomes apparent following the cue) from Responses at each cue-exposure session on the autonomic ner- the highest cortisol value after cue exposure. vous system and endocrinological measures were operationalized as The effect of naltrexone and acamprosate for each of the auto- Δ peak values. For craving, two different Δ peak scores were cal- nomic nervous system and neuroendocrinological measures was culated: the first by subtracting the baseline VAS score from the estimated using univariate ANCOVA (General Linear Model module, highest VAS score filled out during cue exposure (Δ peak VASa), the SPSS 12), with the difference score in Δ peak value between the first second by subtracting the baseline VAS score from the retrospective and second cue exposure as dependent variable, medication con- VAS score ‘how strong was your strongest urge?’ filled out im- dition (naltrexone, acamprosate and placebo) as independent var- mediately after cue exposure (Δ peak VASb). For HR, SCL and SCR, Δ iable and Δ peak of the first cue-exposure session, baseline AUDIT peaks were calculated by subtracting the average of the last minute scores, benzodiazepine use and gender as covariates.

Table 1 Sample characteristics and alcohol-related variables Placebo (n=23) Naltrexone (n=52) Acamprosate (n=56) p-value Subject characteristics Mean age in years (SD) 45.3 (9.6) 47.2 (10.1) 48.1 (9.8) 0.52 % men 78.3 78.8 66.1 0.27 % Dutch ethnicity 87.0 88.5 76.8 0.23 % inpatients 17.4 32.7 25.0 0.36 % in treatment 73.9 69.2 64.3 0.68 % higher education 50.0 28.0 38.9 0.18 Mean years education (SD) 15.8 (5.0) 13.6 (4.3) 13.4 (3.9) 0.07 % employed 54.5 58.0 57.4 0.96 % married 22.7 32.0 16.7 0.18

Alcohol-related variables Mean AUDIT score (SD) 20.5 (4.2) 21.3 (5.1) 20.8 (5.4) 0.78 Mean age of onset (SD) 32.8 (8.2) 35.9 (10.3) 35.2 (9.7) 0.45

Other substance use % using benzodiazepines 27.3 12.0 13.0 0.21 % using cannabis 18.2 8.0 18.5 0.26 % using nicotine 86.4 84.0 92.6 0.39 % using anti-depressives 40.9 26.0 31.5 0.45

Physiological baseline values of HR and SCL at T1 HR (SD) 78.8 (22.2) 78.9 (26.3) 73.9 (11.9) 0.41 SCL (SD) 2.8 (1.2) 2.1 (1.2) 3.1 (4.2) 0.23 Abbreviations: SD = standard deviation, AUDIT = Alcohol Use Disorders Identification Test, HR = heart rate, SCL = skin conductance level.

Standardized effect sizes are presented as Cohen's d values. For sessions in the naltrexone group were significantly larger the primary research question, relatively large samples were in- than the reductions in Δ peak craving scores between the cluded to compare the acamprosate and naltrexone group. For both sessions in the acamprosate group for VASb [p b0.05, research questions, significance was tested at the 0.05 level. How- d=0.29]. No significant effects were found for the other ever, given the relatively small sample size of the placebo group, craving indicators (VASa and the (sub)scales of the JACQ). In p-values smaller than 0.1 were regarded as trends for the second- Δ ary research question. contrast to our expectations, reductions in peak craving scores between the sessions in both the acamprosate and naltrexone group were not significantly larger than in the 3. Results placebo group (see Fig. 2).

3.1. Study population

A total of 524 subjects were screened (see Fig. 1). Of these, 188 subjects refused to participate at intake and 139 subjects had to be excluded (most important reasons for exclusion: various medical conditions and current use of anti-craving compounds). Of the remaining 197 subjects, 41 subjects filled out baseline questionnaires, but refused further participation before randomization leaving 156 subjects for the current study. Of these 156 subjects, 25 subjects (16%) (7 in the acamprosate group, 11 inthenaltrexonegroup,and7intheplacebogroup)droppedout after the first cue-exposure session, leaving 131 subjects (84%) who completed the entire study: 56 in the acamprosate group, 52 in the natrexone group, 23 in the placebo group.

3.2. Baseline characteristics

Table 1 shows that most study participants were Dutch, male, unemployed, unmarried and with low education. In the total group, 26.7% of the participants were inpatients, 41.2% were outpatients and 32.1% was currently non-treatment-seeking. Most subjects had moderate to severe levels of alcohol dependence. With the exception of the mean years of education, there were no significant (pb0.20) differences between the groups in baseline characteristics; mean years of education was higher in the placebo than in the active medication conditions.Withrespecttothebaselinevaluesofthesubjective craving scores or the autonomic nervous system parameters during the first cue-exposure session, there were no significant differences between the medication conditions (see Table 1 for the baseline data of heart rate and skin conductance level; baseline data for skin conductance response, cortisol and subjective craving are not shown).

3.3. Medication compliance

Self-reported medication compliance in study completers was good. The mean percentage of taken pills was 98.1% in the placebo group, 99.1% in the naltrexone group, and 96.5% in the acamprosate group. These findings were confirmed by data on medication (metabolites) in randomly taken urine samples: 95% of the patients were urine positive for naltrexone or acamprosate at the second test session.

3.4. Effect of naltrexone and acamprosate on craving Figure 2 Cue-induced craving scores before and after three weeks of medication. Left bar represents cue-exposure session 1, For all craving measures, and for each active medication right bar cue-exposure session 2. Abbreviations: Δ peak VASa = group, a significant increase in Δ peak value was found during highest VAS during cue exposure – baseline VAS. Δ peak VASb = both cue-exposure sessions (pb0.05). In line with our expec- retrospective VAS ‘strongest craving’–baseline VAS. JACQ = tations, the reductions in Δ peak craving scores between the Jellinek Alcohol Craving Questionnaire.

Figure 3 Physiological cue-reactivity measures before and after three weeks of medication. Left bar represents cue-exposure session 1, right bar cue-exposure session 2. Abbreviations: HR = heart rate, SCL = skin conductance level, SCR = skin conductance response.

3.5. Effect of naltrexone and acamprosate on tions in Δ peak cortisol levels were observed. In addition, no autonomic nervous system reactions to alcohol- significant differences between placebo and active medica- related cues tions were found in basal cortisol levels or in cortisol Δ peaks (see Fig. 3d). For all physiological parameters, and for each medication group, a significant increase in Δ peak value was observed 4. Discussion during both cue-exposure sessions (pb0.05). In line with our Δ expectations, the decrease in peak HR in the acamprosate In summary, the effect of naltrexone on cue-induced craving Δ was significantly larger than the decrease in peak HR in the was significantly larger than the effect of acamprosate b naltrexone group [p 0.05, d=0.15]. However, in contrast to [pb0.05; d=0.29], although this effect was not statistically our expectations, no significant medication effect was found significant for the comparison of naltrexone with placebo. Δ in the reduction of peak SCL between the sessions and a With respect to autonomic nervous system reaction to trend was found for a smaller reduction between the sessions alcohol-related cues, a small but significant effect was seen for both active medications compared to the placebo group for acamprosate versus naltrexone [pb0.05; d=0.15], and a Δ on peak SCR [p=0.08, d=0.06 for acamprosate; p=0.05, trend for a moderate reduction in Δ peak HR was found in the Δ d=0.27 for naltrexone]. In addition, reductions in peak acamprosate group compared to placebo [p=0.07; d=0.40]. on all physiological measures between the sessions in the No significant medication effects were observed with regard naltrexone group were not significantly larger than in the to cortisol responses to cue exposure. placebo group. However, a trend was found for a larger First, it seems that naltrexone has a moderate effect on Δ decrease in peak HR in the acamprosate group compared to cue-induced craving compared to acamprosate. This was the placebo group [p=0.07, d=0.40] (see Fig. 3). most strongly present on the VASb-scale [pb0.05, d=0.29]. The VASb scale may therefore be the most sensitive scale in 3.6. Effect of naltrexone and acamprosate on the current study to detect a reduction in cue-induced endocrinological cue reactivity craving. An explanation for this may be that the VASb scale is administered directly following the experience of cue- No significant cue-induced cortisol Δ peak values were found induced craving, combining the advantages that a) the crav- at the first and second cue-exposure session in each ing experience is very recent, and that b) it concerns the medication group. In contrast to our expectations, no highest craving score of the entire cue-exposure period and significant effects of naltrexone and acamprosate on reduc- therefore reduces the risk that the highest score is missed.

Since the effect of naltrexone on cue-induced craving is only naltrexone on the HPA-axis in the regulation of craving and moderate, it is questionable whether naltrexone exerts its relapse is warranted. main therapeutic effect on relapse through the reduction of Our findings raise the question whether acamprosate and cue-induced craving. This would be in line with studies naltrexone are highly effective in the reduction of cue- showing low correlations between craving and relapse induced craving and autonomic nervous system reactions to (Rohsenow and Monti, 1999). Although we did not find an alcohol-related cues in the short term. In summary, it seems effect of acamprosate on cue-induced craving at three weeks that naltrexone may only moderately reduce cue-induced of medication, acamprosate may exert its effects on cue- craving (specifically when measured by use of a VAS scale) induced craving after more than three weeks of medication. and that acamprosate may only moderately reduce arousal of Second, in line with our prediction, a small but significant the sympathetic nervous system (specifically heart rate). effect on Δ peak HR was seen for acamprosate versus Cue-reactivity measures may not be sensitive enough to naltrexone [pb0.05; d=0.15]. In addition, although it did elucidate pharmacologic mechanisms of action, or alterna- not reach statistical significance, acamprosate showed a tively, naltrexone and acamprosate may exert their effect by trend for a moderate effect on one of the physiological mea- acting on other brain systems. Finally, it is possible that the sures (heart rate) compared to placebo [p=0.07, d=0.40], observed moderate effects on cue-induced parameters may whereas naltrexone did not. Sympathetic autonomic nervous reflect the moderate clinical effects on relapse. system reactions to alcohol-related cues may therefore be a The moderate effect sizes in this and other studies on the sensitive parameter for acamprosate's mechanism of action. efficacy of acamprosate and naltrexone are most likely a This is in line with our hypothesis that acamprosate is dif- consequence of inefficient patient–treatment matching, re- ferentially effective in reducing physiological reactions that sulting in subgroups of non-responders who mask the effect are medicated through glutamatergic and GABA-ergic dysre- of the medication (Verheul et al., 1999; Ooteman et al., gulations of stress, anxiety or withdrawal systems (Littleton, 2005). In line with this post-hoc explanation, we found large 1995; Verheul et al., 1999; Koob and Le Moal, 2001, 2005). It is standard deviations of the mean group values for all outcome also in line with a study showing improved neurocardial measures. Subgroups of alcoholics may differentially respond balance (Agelink et al., 1998) and a pilot study showing an to acamprosate or naltrexone. One part of the patients may effect of acamprosate on another cue-reactivity measure benefit with reasonably large effect sizes, whereas another (reaction time) (Weinstein et al., 2003). However, despite of part may even show an effect in the opposite direction. More a moderate effect size for acamprosate compared to placebo research is needed on the characteristics of these responders [d=0.31], we did not find a significant medication effect on and non-responders at the phenotypic level (e.g. clinical SCL. Moreover, in sharp contrast to our predictions, we found characteristics), the endophenotypic level (e.g. brain func- a trend for smaller reductions in cue-induced SCR in both tioning) as well as at the genetic level (e.g. gene poly- medication groups compared to the placebo group [pb0.1; morphisms) (see also: Gottesman and Gould, 2003; Ooteman d=0.06 for acamprosate and d=0.27 for naltrexone]. It may et al., 2005). be that not all sympathetic outcome measures in our study Despite the various strengths of the current study (e.g. are sensitive to the dampening effect of acamprosate. In the explicit hypothesis driven approach; inclusion of two com- current study, naltrexone did not significantly decrease any petitive medications; cue-induced craving and autonomic physiological indicators of cue reactivity. This is partly in line nervous system reaction to alcohol-related cues as the with Monti's study, showing a smaller decrease of cue-induced outcome measures), the current study also has several limi- arterial pressure in the naltrexone group compared to tations. First, the study has a relatively small placebo group, placebo (Monti et al., 1999). Our finding, however, is not in which may have masked existing effects of acamprosate and line with McCaul's study in heavy drinkers, showing alcohol- naltrexone when compared to placebo. Second, our study induced heart rate reductions after naltrexone (McCaul focussed on effects after only three weeks of medication. et al., 2001). This discrepancy may result from the fact that Long-term medication challenges may show different results. in McCaul's study alcohol was actually consumed and heavy For example, in Weinstein's pilot study a reduction in cue drinkers instead of alcohol dependent subjects were studied. reactivity was found after six weeks of treatment (Weinstein Third, no significant effects of naltrexone on baseline et al., 2003). Perhaps, acamprosate's immediate effect on cortisol and Δ peak cortisol after cue exposure were ob- autonomic nervous system reactions to alcohol-related cues is served. Our findings, therefore, do not support the hypoth- followed by a delayed effect on cue-induced craving. Third, esis that naltrexone exerts its therapeutic effect by restoring since exactly the same cue-exposure protocol was repeated at the blunted basal activity and reactivity of the HPA system in the second session, it cannot be excluded that habituation alcohol dependent subjects. Our finding is not in line with masked existing differences in cue-reactivity measures be- the study of O'Malley et al. (2002) showing a stimulating tween groups. Fourth, although the participants were effect of naltrexone on cortisol (O'Malley et al., 2002). How- instructed not to drink during the medication period, some ever, in that particular study subjects were exposed to real of the patients may have been drinking alcohol. Although this alcohol (elevating cortisol levels) and cortisol was measured may account for the non-responders only, drinking itself has by an invasive method (in serum), which may explain the also been hypothesized to affect specifically naltrexone's discrepancies with the current study. Another explanation mechanism of action (see for a review: Sinclair,2001). Fifth, in why we did not find an effect of naltrexone on cortisol might the current study, the reductions in sympathetic arousal are be the poor temporal resolution of the cortisol reaction and hypothesized to be related to withdrawal and anxiety. subsequently the difficulty of attributing cortisol responses However, sympathetic indices are conservatively interpreted to the cue-exposure period. Since the literature is scarce and as general measures of arousal. For example, cue-reactivity not very consistent, further investigation of the effect of theorists have suggested that sympathetic arousal can reflect

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