Using cue reactivity to screen medications for cocaine abuse: A test of amantadine hydrochloride

Addictive Behaviors. Vol. 17, pp. 491--499, 1992

0306-4603/92 $5.1)0 + ,00 Copyright© 1992 Pergamon Press Ltd.

Printed in the USA. All rights reserved.

USING CUE REACTIVITY TO SCREEN MEDICATIONS FOR C O C A I N E ABUSE: A T E S T O F A M A N T A D I N E H Y D R O C H L O R I D E STEVEN J. ROBBINS, RONALD N. EHRMAN, ANNA ROSE CHILDRESS, and CHARLES P. O'BRIEN University of Pennsylvania Abstract - - The use of responding to drug-related stimuli as a dependent measure for studies ofanticraving medications was assessed. Cocaine-dependent subjects receiving either amantadine hydrochloride, a putative anticraving agent, or placebo were exposed to drug-related cues prior to and 7 days after the initiation ofthe medication. Measurements of heart rate, skin resistance. skin temperature, and self-reported craving were taken during each stimulus session. Amantadine increased physiological reactivity to the drug-related cues compared to the placebo while having no effect on craving. Although the results discourage the use of amantadine as an anticraving medication, they do suggest that responses elicited by drug-related stimuli provide a valuable set of dependent measures for use in future medication trials ofanticraving agents.

INTRODUCTION

Over the past several years, there has been much interest in the development of medications to aid in the treatment of cocaine dependence. A primary goal of many of these attempts is the reduction of cocaine craving, which is thought to motivate cocaine use (e.g., Gawin & Kleber, 1984; Dackis, Gold, Davies, & Sweeney, 1985; Tenant & Sagherian. 1987; Weiss, Pope, & Mirin, 1985). The effectiveness of these medications is typically assessed through self-reports of craving levels collected in the laboratory or clinical setting from patients receiving either the medication or a placebo. However, such subjective reports are faced with a number of methodological difficulties. First, self-reports collected outside the subjects' drug-use environment may underestimate the level of craving which subjects would ordinarily experience. A large body of work has accumulated in recent years to document that drug-related events (i.e., drug paraphernalia, the sight of other people using drugs, etc.) produce reliable increases in drug craving in cocaine, opiate, and alcohol abusers (see Childress, Ehrman, McLellan, & O'Brien, 1988; O'Brien, Ehrrnan, & Terries, 1986; Sherman, Jorenby, & Baker, 1988). Consequently, reports of craving obtained in the absence of these cues may be artificially low. In one recent example, Ehrman, Robbins, Childress, & O'Brien (1992) found that 14 of 15 cocaine-dependent inpatients reported no craving when queried in a laboratory environment. A second problem arises when subjects are asked to assess their level of craving over a period of time, such as the previous week (e.g., Gawin & Kleber, 1984). There is now a large literature documenting that people make a variety of errors in estimating the frequency or probability of past events (see Baron, 1988, for a review). For example, Tversky and Kahneman (1973) first coined the term availability heuristic to describe Requests for reprints should be sent to Steven J. Robbins, University of Pennsylvania, Treatment Research Center, 3900 Chestnut St., Philadelphia. PA 19104-6178. This work was supported by NIDA Grants DA05186 and DA03008 and the Department of Veteran's Affairs. 491

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the tendency of people to use salient individual examples as the basis for estimating the overall frequency or probability of an event. In this way, retrospective craving estimates could be inflated by the memory of a single craving episode. Alternatively, such estimates could be mistakenly reduced as the result of a salient memory of a single instance when the subject was free of drug-related thoughts. The availability heuristic and other memory biases introduce a source of variability to retrospective craving assessments that is absent when estimates of current craving levels are collected. What is needed to counter these difficulties is a means of asking subjects about craving in a standard situation which reproduces elements of the drug-use environment encountered outside the laboratory/clinic setting. Recent work in our laboratory on the role of classical conditioning in substance abuse has led to the development of laboratory stimuli ideally suited to this task. In one study, cocaine abusers listened to a taped discussion of the effects of cocaine, watched a videotape of simulated cocaine use, and handled cocaine paraphernalia. Subjects showed greater physiological arousal and reported greater craving for cocaine in the presence of the cocaine-related cues than during exposure to stimuli lacking drug content (Childress et al., 1988; O'Brien, Childress, McLellan, & Ehrman, 1990). More recently, Ehrman et al., (1992) demonstrated that cocaine users show larger increases in physiological arousal and reported greater withdrawal and craving when watching videotapes of cocaine use than when watching heroin-related or nondrug scenes. Such differential responses were not present in subjects lacking a history of drug abuse. Because cocaine-related cues consistently increase craving when shown to cocaine abuse patients, these stimuli could be used to create a standard craving assessment situation for medication studies. Presentations of drug stimuli should: (a) increase reports of craving in the laboratory, by better approximating the conditions in the drug-use environment, and (b) avoid the memory problems associated with retrospective craving reports. In support of point (a), Ehrman et al. (1992) found that 10 of the 14 cocainedependent subjects who reported no craving in a laboratory setting provided positive craving scores following exposure to cocaine-related cues. Presentations of cocainerelated stimuli also allow the measurement of physiological responses which appear to reflect an individual's past drug use in particular situations (Ehrman et al.. 1992). These responses could serve as an indication of a medication's ability to reduce arousal generated by drug-related situations outside the clinic. The present study was a preliminary attempt to examine the use of drug-cue responding to assess anticraving medications. Toward this end, we combined our drug-cue methodology with an ongoing, double-blind, placebo-controlled study of the effects of amantadine hydrochloride on cocaine craving and use in outpatient cocaine users. Amantadine was chosen for investigation at our center because of a recent report suggesting that it may reduce craving and promote abstinence in chronic cocaine users (e.g., Tenant & Sagherian. 1987), possibly through the enhancement of dopaminergic activity. Twenty subjects in the medication trial (10 amantadine, 10 placebo) were asked to participate in two cue-reactivity sessions. The first session occurred before subjects received their medication. The second session was scheduled 1 week after subjects began taking amantadine or placebo. During each session, subjects' heart rate, skin temperature, skin resistance, and reported craving were measured in the presence of cocaine-related stimuli. The stimuli used have previously been shown to elicit enhanced physiological and subjective reactivity in cocaine users (Childress et al. 1988; Ehrman

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et al., 1992). The purpose of the study was to examine whether responding to these stimuli would be differentially affected by amantadine and a placebo. METHODS

Subjects The subjects were 20 black male veterans between the ages of 26 and 49 (mean = 36) seeking treatment for cocaine abuse at a Veteran's Affairs Hospital. All of the subjects had already been accepted into the double-blind, placebo-controlled study ofamantadine hydrochloride. Eight of the subjects were also enrolled in a month-long day hospital program, whereas the remaining 12 subjects were on a waiting list for an inpatient drug-treatment program. On the average, subjects reported using cocaine regularly (i.e., 3 or more times per week) over the past 6 years. For the 30 days prior to the study, subjects reported a mean of 15 days of cocaine use, spending an average of $806 to procure the drug. Nineteen of the subjects had a history of smoking free-based cocaine or crack and one injected the drug. Ten subjects in the present study received amantadine and 10 received placebo. In each group, four subjects were participants in the day hospital program and six were awaiting inpatient treatment. The Addiction Severity Index (ASI, McLellan, Luborsky, O'Brien, & Woody, 1980), a 45-60 min structured interview, was used to collect information on patient problems in the following areas: medical, employment, alcohol, drug, legal, family/social, and psychiatric. In each area, subjects receive a factor-like composite score which provides a global assessment of problems on a scale from 0 (no problem) to 1 (most severe). Comparisons of the composite scores revealed no significant group differences in any of the ASI categories.

Procedure The present article will describe only those procedures relevant to the assessments of cue reactivity. Assignment to amantadine or placebo in the medication trial was conducted according to a randomized block design whereby equal numbers of subjects were assigned to groups within each set of 10 patients. Both investigators and subjects were blind to the drug group assignment of each subject. After being admitted into the medication trial, the 20 subjects reported on here were independently recruited for participation in the cue sessions. On the day following recruitment, subjects began the medication trial. Each subject was given a bottle of 21 pills: the amantadine group received tablets containing 100 mg of the medication and the placebo group was given identical appearing pills containing no active medication. Subjects were initially instructed to take two pills per day. However, subjects were told that they could increase their dose level if symptoms of craving persisted. Subjects received two identical cue-reactivity sessions. The first session occurred on the initial medication day prior to ingestion of the first pill. The second session occurred l week after the start of the trial. During each session, subjects listened to a 10-min audiotape, watched a 10°rain videotape, and performed a simulated drug preparation ritual for 4-5 min. The audiotape featured cocaine-abuse patients discussing cocaine use. The videotape depicted a scene of buying, preparing, and using cocaine. The task required patients to simulate drug preparation using a white crystalline powder resembling cocaine and paraphernalia matched to their own method of self-administration (e.g., smoking or injecting). Each session was conceptualized as representing a single

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presentation of a compound stimulus (audio-video-task). Therefore, no attempt was made to counterbalance the order of these stimuli so as to permit a comparison of their individual effects. At the beginning of each session, subjects filled out the Profile of Mood States questionnaire (McNair, Lorr, & Droppleman, 1971) as a measure of their baseline mood. The POMS questionnaire requires subjects to rate the intensity of 65 mood items on a 0-4 scale. Scores on these items are then combined into six summary scales reflecting overall vigor, depression, anger, tension, confusion, and fatigue. Next, surface recording electrodes were placed on the subject to permit continuous physiological recording of heart rate, skin temperature, and skin resistance. Subjects were seated in a soundattenuating recording chamber and the electrodes were interfaced with a polygraph located in an adjacent control room. Each subject was then administered the Within-Session Rating Scale developed in previous studies with cocaine-abuse patients (Childress et al., 1988; Ehrman et al., 1992). This instrument asks subjects to estimate the intensity of a variety of drug-related states on a 1-10 scale. Subject reports of craving/desire for cocaine were the data used for analysis in the present experiment. Physiological recording of heart rate, skin temperature, and skin resistance was begun at this point. Subjects initially sat quietly for a 15-rain baseline period during which no external events occurred. Subjects then listened to the audiotape for 10 min, took a 2rain break, watched the videotape for 10 min, took a 2-rain break, and performed the drug preparation ritual. Following the task, subjects sat quietly for 2 min and then answered the WSRS questions again. The recording electrodes were then removed. A counselor was available if the patient reported craving or discomfort following the session. RESULTS

Baseline mood Recent work in our lab has indicated that mood states can interact with external drug cues to influence physiological and subjective responding (Childress, McLellan, Natale, & O'Brien, 1987; Childress, Ehrman, McLellan, Natale, & O'Brien, submitted). To verify that the two groups did not report different mood states prior to the cue reactivity sessions, subjects were administered the POMS before each session. The t-tests failed to detect differences between the two groups on any of the questionnaire subscales in either Session 1 or Session 2. Therefore any differences in cue responding between groups cannot be attributed to differences in mood states entering a session. Furthermore, the similarity between the two groups in mood responding prior to Session 2 demonstrates that amantadine and placebo did not differentially affect the subjects' mood. Physiological measures For each of the physiological measures (heart rate, skin resistance, and skin temperature), baseline responding for the two groups was assessed by comparing mean responding during the last 5 min of the baseline period. Past work in our laboratory with the compound stimulus used in this study has consistently shown that physiological reactivity gradually increases during the stimulus presentation. Therefore, analysis of physiological responding was conducted on data from the last segment of the compound cue when responding was expected to be at a maxi-

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mum. Drug cue responding was summarized in a difference score calculated by subtracting the mean response during the last 5 min of the baseline from the mean response during the manual task. Between-group comparisons were then performed on these difference scores for each session.

Baseline physiology Baseline measurements of physiology during each session are depicted in Table 1. The t-tests revealed no significant differences between the groups. These results indicate that the two groups were well-matched for resting physiological characteristics. Furthermore, the lack of baseline differences before Session 2 demonstrates that amantadine had no systematic effects on baseline physiology compared to a placebo.

Session 1 The two groups did not show differential responses to the cues on measures of heart rate [t(15) = 0.85, p > .05], skin resistance [t(17) = 0.37, p > .05] or skin temperature [t(18) = 0.97, p > .05] during the first cue session. This result was expected because the two groups had not been differentially treated up to this point.

Session 2 O f more interest are results from the cue session following treatment of the two groups with amantadine or a placebo. As shown in Figure 1, the amantadine group showed a significantly greater heart rate increase to the drug cues than did the placebo group [t(15) -- 2.23, p < .05]. Amantadine subjects also tended to show a greater drop in skin resistance than controls It(17) = 2.10, p = .05] (see Figure 2). However, the two groups did not differ in their skin temperature response on this day [t(18) -- 0.43, p > .05], with both showing a decrease of about 3* C. In sum, subjects taking amantadine appeared more responsive to the drug-related cues than did placebo subjects on two of the three physiological measures collected.

Cocaine craving In each of the sessions, subjects rated their perceived level of craving for cocaine on a scale of 1 to 10 both before and after drug cue presentations. Nonparametric tests were used to analyze these data because the distribution of scores was not normal. Betweengroup comparisons were made both before and after each session. Within-group changes in craving during a session were also analyzed. Median craving scores for the two groups are depicted in Figure 3. The two groups differed in baseline levels of craving during session 1 prior to the start of the medication trial [Mann-Whitney U(10,10) = 79, p < .05]. Presentation of the drug cues enhanced craving relative to baseline in the amantadine group [Wilcoxon Table I. Baselinephysiologyduring both sessions(mean _+SEM)for subjects receivingeither amantadine or placebo Session Heart rate (bpm) Skin resistance(kohms) Skin temperature(*C)

I 2 1 2 1 2

Amantadine 69.9 + 2.9 70.9 + 1.6 223.4 + 56.6 189.6 + 27.1 33.3 + 0.8 33.0 _+ 1.0

Placebo 76.9 + 3.1 68.5 + 2.8 263.2 ___84.9 158.8 + 44.8 3 !.8 + I. I 32.8 + 1.1

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T(7) = 1.5, p < .05], but not in the placebo group [T(5) = 1, p > .05]. As a result, craving did not differ between the groups following exposure to the cues [ U( 10,10) = 60, p > .05]. Comparisons of baseline craving levels during Session 2 revealed no difference between the amantadine and placebo groups [ U(10,10) = 56, p > .05]. However, as Figure 3 shows, this failure to observe a craving difference may have resulted from a floor effect because subjects in both groups reported little craving at baseline. Presentation of the stimuli reliably increased craving both for the amantadine group [T(6) = 0, p < .05] and the placebo group IT(6) = 0, p < .05]. However, there continued to be no evidence that amantadine reduced craving relative to placebo [U(IO, I O) = 51.5, p > .05].

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DISCUSSION

The present results suggest that measures of cue reactivity can reveal significant medication effects with small numbers of subjects. Significant differences in physiological reactivity to drug-related cues were observed between subjects administered amantadine or a placebo despite a small n ( 10 subjects per group). Unfortunately, these differences indicated that amantadine increased rather than reduced cue reactivity. In addition to producing changes in physiological states, the drug-related stimuli generally increased craving above baseline levels. In the first session, the two randomly assigned groups entered the laboratory, reporting different levels of craving prior to receiving differential treatments. Although the cause of this difference is unclear, its existence points out the advantage of exposing the two groups to constant drug-stimulus conditions. In this case, such exposure served to effectively equate craving reports by the two groups. In the second session, few subjects reported any craving at baseline, making a medication effect impossible to detect. However, presentation of the cues reliably increased reports of craving over baseline in both groups making a between-group comparison more meaningful. These results demonstrate that the presence of drugrelated cues can produce a more robust craving baseline against which the effects of a medication can be assessed. In this particular instance, there continued to be no evidence for an effect ofamantadine after exposure to the drug cues. It is important to note that the two groups studied here failed to show reliable differences in baseline mood states. Assessments of baseline mood are crucial to medication trials employing measures of cue reactivity. As noted earlier, data from our laboratory have shown that mood states can influence physiological and subjective responding to drug cues (Childress et al., 1987; Childress, Ehrman, McLellan, Natale, & O'Brien, submitted). Therefore, differences in group responding to drug-related stimuli could result from differential mood states prior to the session. Explicit measurements of mood prior to each session are necessary, to rule out such a confound. Such measures are especially important prior to Session 2 because the medication under study could result in mood changes in the experimental group.

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One shortcoming of the design of the present study lies in the absence of a non-drugrelated stimulus with arousing content. It is possible that the changes in physiological responding reported here reflect the effects ofamantadine on arousing stimuli in general rather than on drug-related cues in particular. In other words, amantadine may generally increase physiological lability in the presence of salient events. A similar objection could be raised if amantadine (or another medication) had been shown to decrease drug-cue reactivity (i.e., the drug could reduce physiological arousal in general and not specifically to drug-related cues). In order to control for this possibility, subjects should be presented with both drugrelated cues and non-drug-related arousing cues at each test interval. The ability of a medication to specifically reduce arousal generated by drug-related cues would be established if responsivity to the two kinds of stimuli were differentially affected. Specifically, the medication should reduce responding to the drug-related cues more than responding to the nondrug stimuli. The comparison stimuli must be carefully chosen to produce a pattern of physiological responsivity closely resembling the effects of the drugrelated cues. Otherwise, differential responding to the two stimuli under the medication might result from their different physiological effects rather than from their degree of drug-relatedness. Equal reductions in physiological responding to drug-related and nondrug cues would not necessarily rule out use of the medication if a decrease in reported craving were obtained as well. However, such results would suggest that the medication has general arousal-blunting properties which might be considered problematic. In this way, the arousal control stimulus allows one to assess a wider range of potential side effects generated by putative anticraving agents. Arousal control stimuli were not utilized in the present study because we have not yet developed nondrug cues which mimic the physiological effects of the cocaine-related stimuli. Work is currently underway in our laboratory to produce arousing comparison stimuli for future medication trials. Another improvement over the current design would be the inclusion of a third cue assessment session following termination of the medication trial. Given that a medication had effectively reduced responding to drug-related cues, this final assessment would permit examination of whether such reductions are persistent in the absence of the experimental drug. In principle, multiple cue assessment could be provided at a number of time points following cessation of the medication trial. However, providing more than three or fo'-_ total cue assessments is problematic because past research has shown that responses to drug cues decline (extinguish) with repeated presentations (e.g., Childress, McLellan, & O'Brien, 1986). Hence, the experimental and control groups would begin to converge at similarly low levels of cue responding over repeated tests. In sum, the present study suggests that measurements of cue reactivity are a potentially valuable addition to the list of dependent measures currently utilized in addiction medication trials. The results suggest that measurements of responses to drug cues may allow for rapid initial screening of promising anticraving agents with small sample sizes. Furthermore, presentations of drug-related stimuli appear to increase and standardize laboratory reports of craving, thereby providing a better test of the medication's effect on craving. Finally, the cue reactivity technique represents a direct assessment of whether a prospective medication reduces physiological and subjective responsivity to drug-related events which may represent high-risk situations for drug use. For these reasons, the inclusion of cue reactivity measurements in future medication trials for drug abuse appears warranted.

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