Cue reactivity in cocaine-dependent subjects: effects of cue type and cue modality

Addictive Behaviors, Vol. 23, No. 1, pp. 7–15, 1998 Copyright © 1998 Elsevier Science Ltd Printed in the USA. All rights reserved 0306-4603/98 $19.00 1 .00

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CUE REACTIVITY IN COCAINE-DEPENDENT SUBJECTS: EFFECTS OF CUE TYPE AND CUE MODALITY BANKOLE A. JOHNSON, Y. RICHARD CHEN, JOY SCHMITZ, PATRICK BORDNICK, and ALEX SHAFER Department of Psychiatry, University of Texas, Houston, Houston, TX, U.S.A.

Abstract — Thirty cocaine-dependent subjects were enrolled into a cue-laboratory study to determine the specificity and sensitivity of this paradigm as a craving measure. Subjects experienced three cue types (i.e., cocaine, arousing, and neutral stimuli) in three cue modalities (i.e., audio, visual, and manual). Cue types were administered in different experimental sessions with a period of 2 to 3 days between sessions. Our results showed that subjective and physiological craving for cocaine was relatively specific for the cocaine cue as compared with either the arousing or the neutral cue. The relative sensitivities of the cue modalities in decreasing order was manual, audio, and visual. We suggest that a modified conditioned-cue paradigm could be a useful tool in the repeated assessment of craving during a clinical study. © 1998 Elsevier Science Ltd I N T R O D U C T I O N

Pioneering work by Wikler (1965) highlighted the importance of conditioned stimuli to direct drug-related and indirect environmental cues in maintaining the addiction process. This work has spawned several models described in a review by Rohsenow and colleagues (1991) as including (a) the conditioned withdrawal model (Wikler, 1980); (b) conditioned compensatory response model (Siegel, 1983); and (c) the conditioned appetitive motivational model (Stewart et al., 1984). Basically, drug-withdrawal effects, compensatory responses leading to tolerance, and positive drug-reinforcing effects can become paired (i.e., conditioned) with an environmental stimulus. Presentation of the conditioned stimulus in the absence of the drug can, therefore, elicit the response with which it has been paired. Of these models, empirical studies in humans have predominantly supported the conditioned appetitive motivational model (Childress, McLellan, & O’Brien, 1988; Meyer, 1988; Niaura et al., 1988), whereby anticipatory cravings for the drug can be elicited by presentation of the conditioned stimulus. This concept of conditioning may, therefore, offer an explanation for the reinstatement of drugtaking, especially after a period of abstinence (Kranzler & Bauer, 1992; Robbins et al., 1992; Hersh, Bauer, & Kranzler, 1995). Hence, the measurement of cue-mediated physiological responses in treatment-seeking cocaine addicts may predict relapse. Various cue modalities that elicit anticipatory cravings or urges for cocaine have been described. Sight and manipulation of cocaine-related cues (including handling drugadministration apparatus) can produce consistent changes in skin conductance and temperature (Childress et al., 1988; O’Brien, Childress, McLellan, & Ehrman, 1990a, 1990b; Margolin & Avants, 1992; Margolin, Avants, & Kosten, 1994; Avants, Margolin, Kesten,

We are grateful to Ms. Eleanor Williams for skilled technical assistance. Requests for reprints should be sent to Bankole A. Johnson, Dept. of Psychiatry, Health Science Center, University of Texas, 1300 Moursund St., Houston, TX 77030. E-mail: [email protected] 7

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& Cooney, 1995). However, changes in heart rate and respiration appear to be less sensitive and specific than the other physiological measures (Rohsenow et al., 1989). The conditioned-cue paradigm has been advocated as a laboratory measure for assessing drug craving (Kilgus & Pumariega, 1994; Childress, McLellan, Ehrman, & O’Brien, 1987; O’Brien et al., 1990a, 1990b; O’Brien, Childress, McLellan, & Ehrman, 1993), and repeated cue exposure has itself been evaluated as a potential treatment for extinguishing drug craving (O’Brien et al., 1990a, 1990b; O’Brien et al., 1993). However, its usefulness for the assessment of craving has been questioned owing to the lack of a clear demonstration of its specificity to drug craving and not simply arousal (Ehrman, Robbins, Childress, & O’Brien, 1992). That is, if the arousing stimulus produces smaller cue-reactivity responses than specific drug stimulus (i.e., cocaine), then a convincing argument could be made for the specificity of the conditioning paradigm in producing cue-reactivity responses to the cocaine cues (Ehrman et al., 1992). Additionally, it can reasonably be expected that all forms of arousal (i.e., specific or nonspecific) will be associated with greater physiological responses than will neutral cues. Our first objective was, therefore, to test the specificity of the conditionedcraving response in cocaine addicts by comparing the relative strengths of the subjective and physiological effects to cocaine, arousing, and neutral cues. We predicted (a) that while increases in general and global mood would be similar for both the cocaine and arousing cues, cocaine cues, in contrast, would produce more cocaine craving than either the arousing or neutral cues, and (b) that physiological responses to cocaine cues would be greater than that for either the arousing or neutral cues. Conditioned cue-laboratory studies within clinical trials may offer a novel model for reliably measuring drug craving during treatment (Robbins et al., 1992). This is because cue-reactivity studies present (a) direct access to drug-related cue-craving stimuli that can be assessed objectively by physiological measures such as pulse, temperature, and skin conductance, and (b) provide a standardized environment where procedures and measurements can be reproduced reliably. Conducting repeated cue-laboratory studies over several sessions within each evaluation point in a clinical trial could, however, place an excessive burden on subject participation (i.e., increase drop-out) or even distort the treatment effect. Practically, these difficulties could be minimized if the cue-laboratory assessment could be completed quickly at the scheduled follow-up appointment. Since in such studies the dependent variable would be the change in cue craving over time, this could be achieved efficiently by administering only the most sensitive cue modalities. Our second objective was, therefore, to determine what cue modality (i.e., sound, sight, or manual manipulation) produced the strongest response. We predicted that there would be a direct correlation between the propinquity of the conditioned cue to the unconditioned stimulus and the strength of the physiological response. Put more explicitly, manipulation of cocaine-fixing paraphernalia would be expected to elicit a stronger physiological response than simply watching or listening to others using cocaine. M E T H O D S

Subjects Subjects were recruited from respondents to a local newspaper advertisement offering treatment for substance abuse, and compensation for attendance. Thirty out of 64 cocaine-dependent individuals aged between 21 and 65 years who were subsequently offered treatment completed this cue-reactivity laboratory study. At intake, all subjects

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received a psychiatric interview—the Structured Clinical Interview for DSM-III-R (SCID; Spitzer, Williams, & Gibbon, 1987; DSM-III-R, American Psychiatric Association, 1987)—provided details of cocaine-use characteristics, and underwent a medical examination and laboratory investigations to establish they were in good physical health. Subjects were not allowed to participate in this study if there was evidence of (a) co-morbid psychiatric disorder or (b) current opiate use or with physical signs of opiate, alcohol, or benzodiazepine dependence. Moreover, subjects did not participate on an experimental day if their urine was positive for the presence of a psychoactive substance, or they registered a measurable breath alcohol reading on the morning of testing. Such subjects were re-scheduled for testing on the next available date. Participation in this study required the subjects’ written informed consent. This study was approved by the Committee for the Protection of Human Subjects, University of Texas Health Science Center—Houston. Laboratory conditions The study was conducted in a testing room approximately 12 feet by 10 feet in size. In the center of the room was placed a comfortable chair and desk. On the desk was sited a 14-inch color television containing a video cassette, and an audiotape player and headphones. Sealed, opaque, and clearly labeled envelopes containing the manual cues were placed on a side table behind the subject. The cue-reactivity apparatus was an OrionTM model 8600 biofeedback system attached to an IBM-compatible 486 DX computer and printer. Subjects were requested to remain in the chair at all times during the experiment. At scheduled intervals, the experimenter organized the presentation of the next cue. Communication between the subject and experimenter was restricted to providing instructions concerning the experiment, attaching leads and sensors to the subject, setting up the video and audio presentations, and handing over the sealed envelope containing the manual cues. Measures Craving measures. Visual analogue scales (VAS) of craving consisted of 100-mm horizontal lines anchored on the left by “not at all” and on the right by “extremely.” These VAS contained adjectival scales stating that (a) “Right now, I desire to use cocaine;” (b) “Right now, I want to buy cocaine”; (c) “Right now, I can resist cocaine if it were offered to me”; and (d) “Right now, I am thinking about how I can get cocaine.” The VAS instrument, with similar adjectival scales of craving, has been used in previous experimental studies (Johnson & Cowen, 1993; Johnson et al., 1996). General mood measures. End of Session (EOS) general mood items contained six adjectival scales—”anger, pleasant, relax, bored, tense, and disturbed.” These items were presented as a 7-point scale (0–6) anchored on the left by “not at all” and on the right by “extremely.” The middle of the scale (3 points) corresponded to the descriptor “somewhat.” Global mood measure. Global mood was assessed using the total score on the Profile of Mood States (POMS) (McNair, Lorr, & Droppleman, 1971), a standardized 72-item inventory on which adjectival variables on mood are rated on a 5-point scale. Physiological responses. Measures of autonomic activity included pulse, skin conductance, and temperature, all of which have been used in previous cue-reactivity

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studies (for a review, see Rohsenow et al., 1989; Drummond, Cooper, & Glautier, 1990; O’Brien et al., 1990a, 1990b; Ehrman et al., 1992; Hersh et al., 1995). Physiological responses were measured continuously during the experiment using the OrionTM model 8600 biofeedback system. Procedures All subjects were familiarized with the test and laboratory conditions prior to the experiment. Subjects attended as outpatients for an additional 3 test days separated by an inter-session period of 2 to 3 days. Subjects completed this study within a 2-week period. On test days, subjects arrived in the laboratory at 09:00 hours, having been requested not to consume alcohol or caffeinated beverages at least 1 hour before arrival. A breath alcohol reading and urine sample were obtained on arrival to confirm the subjects’ alcohol and drug-free state. At 09:30 hours, subjects were seated comfortably and the pulse and temperature sensors, and skin conductance electrodes, were attached. Subjects then received exposure to one of three sets of cues. These cue types contained (a) neutral, (b) arousal, or (c) cocaine-related stimuli. The presentation of each cue type was randomized. Within each cue type were three cue modalities presented in the following order: (a) audio, (b) visual, and (c) manual. Details of the cue types and cue modalities are given in Table 1. Before the presentation of each cue type there was a 15-minute baseline period. During the presentation of each cue type, the subject listened to a 10-minute audiotape, watched a 10-minute video tape, and handled stimuli for 5 minutes. Subjects completed the VAS for craving and POMS before and at the end of each cue session. EOS general mood scales were completed at session end. Cue sessions ended at 10:00 hours. Subjects were de-briefed after each session by the experimenter to ensure that craving state returned to pre-session levels. Analytic strategies. For all measures, descriptive data are given as the mean 6 SEM. Difference scores (from baseline) were computed for the VAS, POMS, and all the physiological measurements. Between-group differences were explored using a repeatedmeasures analysis of variance (ANOVA). Post hoc t test were conducted if there was a main effect on the ANOVA. Skin conductance measurements were log-transformed. R E S U L T S

Subjects Table 2 shows the demographic and cocaine-use characteristics for subjects who participated in this study. Cocaine-use characteristics included details of the length, frequency (i.e., present and past history of consumption), and type of cocaine use, and the presence or absence of abstinence-induced mood changes. Table 1. Description of cue types and cue modalities administered to 30 cocaine-dependent subjects Cue modalities Audio Cue types Neutral Arousal Cocaine

Nature sounds Startling noises (e.g., sirens and cymbals) People talking about using cocaine

Visual Nature video Accidents in wildlife Video of people using cocaine

Manual Nature pictures Pictures of accident and burn victims Manipulation of cocaine-fixing paraphernalia

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Table 2. Demographic and cocaine-use characteristics in 30 cocaine dependent subjects Items Demography Mean age Sex distribution Ethnicity Cocaine-use characteristics Length of cocaine use • .5 years • 1–5 years • <12 months Frequency of cocaine use • Daily • 4–6 times/week • 2–3 times/week • <1 time/week Type of cocaine use • Intravenous (IV) • “crack” freebasing • intranasal 6 freebasing or IV Cocaine use in the past week • >5 g/week • 2–4 g/week • <1 g/week Longest abstinence period • none • ,1 week • 1–4 weeks • .3 months Mood/craving feelings on abstinence • Deep depression/severe cravings • Moderate depression/occasional craving • Mild depression/infrequent craving • No significant problems

Responses/subject numbers (%) 34.2 6 1.20 years 29 Males, 1 Female 16 Blacks, 10 Whites, 4 Hispanics 20 (66.7%) 7 (23.3%) 3 (10.0%) 8 (26.7%) 4 (13.3%) 10 (33.3%) 8 (26.7%) 1 (3.3%) 23 (76.7%) 6 (20.0%) 9 (30.0%) 10 (33.3%) 11 (36.7%) 2 (6.7%) 7 (23.3%) 9 (30.0%) 12 (40.0%) 10 (33.3%) 4 (13.3%) 9 (30.0%) 7 (23.3%)

Comparison of cue types of subjective measures For all subjective measures, a group effect emerged on the ANVOVA ( p , .001). From Table 3, it can be seen that a significant difference existed between the cocaine and neutral cues on VAS of craving. In contrast, there were no differences on the VAS of craving between the arousal and neutral cues. Additionally, on all but the item “resist,” significant differences existed on all other VAS items between the cocaine and arousal cues. For EOS ratings, neutral cues differed significantly from both the cocaine and arousal cues. Except for the Item “Pleasant,” no differences were found between the cocaine and arousal cues. Additionally, on ratings of global mood (i.e., the POMS), cocaine and arousal cues did not differ from each other; however, both these cues differed significantly from the neutral cues. Significant differences existed between both the cocaine and arousal cues, and the neutral cue. Comparison of cue types on physiological measures For all the physiological measures, there was a group effect on the ANOVA ( p , .001). A significant difference occurred in pulse between the cocaine and arousal cues (0.433 6 1.205 vs. 20.074 6 0.921 beats/min; p 5 .05). No significant differences existed between

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Table 3. Comparison of cue types on measures of craving, general, and global mood in 30 treatment-seeking cocaine-dependent subjects Between cue-type differences

Cue types

a VAS

craving measures (mm) Desire Want Resist Think General mood measures Anger Pleasant Relax Bored Tense Disturbed Global mood measure a POMS

Neutral (N)

Cocaine (C)

Arousal (A)

C–N

C–A

A–N

23.55 6 2.40 24.02 6 2.07 6.07 6 3.01 26.18 6 3.12

11.96 6 3.47 10.32 6 2.80 27.30 6 4.32 14.25 6 3.56

24.10 6 1.55 22.30 6 1.84 20.14 6 2.21 24.78 6 2.91

** ** ** **

** ** ns **

ns ns ns ns

0.25 6 0.16 3.81 6 0.31 4.16 6 0.30 1.94 6 0.34 0.96 6 0.26 0.42 6 0.21

1.22 6 0.32 2.05 6 0.30 2.42 6 0.33 1.35 6 0.28 2.74 6 0.35 2.38 6 0.36

1.03 6 0.29 1.24 6 0.24 2.37 6 0.29 1.27 6 0.26 2.14 6 0.39 3.01 6 0.42

** ** ** * ** **

ns ** ns ns ns ns

** ** ** ** ** **

3.03 6 2.65

2.50 6 2.34

28.29 6 3.44

**

ns

**

a VAS

items and the total POMS score represent the change in these measures from baseline. Data for the VAS and POMS items were averaged across the presentation time for the three cue modalities. On all other items, the data represent the postsession assessment. ns 5 p . .05; *p , .05; **p , .001.

the neutral and cocaine cues (0.637 6 1.431 vs. 0.433 6 1.205 beats/min; p . .05), or between the arousal and neutral cues. For skin conductance, a significant difference was seen between (a) cocaine and neutral cues (20.191 1 0.028 vs. 20.060 6 0.026 log Mhos; p , .0001), and (b) the arousal and neutral cues (20.182 6 0.043 vs. 0.001 vs 20.060 6 0.026 log Mhos, p , .0001. No significant difference in skin conductance existed between the cocaine and arousal cues. For temperature, there was a significant difference between (a) cocaine and neutral cues (20.477 6 0.376 vs. 0.911 6 0.3648F; p , .01), and (b) the cocaine and arousal cues (20.477 6 0.376 vs. 0.530 6 0.409 8F; p , .05). No significant difference in temperature existed between the arousal and neutral cues. Comparison of cue modalities on physiological measures. For pulse, the mean change in response to the manual cue was significantly greater than that for the visual cue (3.395 6 0.706 vs. 20.152 6 0.495 beats/min; p , .0001). Also, the manual cue produced a significantly greater change in pulse than the audio cue (3.395 6 0.706 vs. 20.807 6 0.466 beats/min; p , .01). No significant differences existed in pulse between the visual and audio cues. For skin conductance, there was a greater reduction in resistance for (a) the manual cue compared with the visual cue (20.326 6 0.034 vs. 20.170 6 0.023 log Mhos; p , .0001); (b) manual cue compared with the audio cue (20.326 6 0.034 vs. 20.107 6 0.027 log Mhos; p , .0001); and (c) visual cue compared with the audio cue (20.170 6 0.023 vs. 20.107 6 0.027 log Mhos; p , .001). For temperature, there was a greater reduction for the manual cue compared with the visual cue (20.091 6 0.325 vs. 0.416 6 0.290 8F; p , 0.05). Also, the manual cue produced a significantly greater reduction in temperature compared with the audio cue (20.091 6 0.325 vs. 0.639 6 0.219 8F; p , .001). No significant difference in temperature existed between the audio and visual cues.

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D I S C U S S I O N

This study demonstrated that conditioned cue-reactivity responses could be produced reliably in the laboratory. Cocaine cues presented to cocaine addicts produce a greater increase in craving than either the arousing or neutral cues. This is supported by the fact that subjects experienced their greatest craving for cocaine when presented with the cocaine cues in comparison with the arousing or neutral cues. In contrast, cocaine and arousal cues produced similar general and global mood states, although both showed significant differences from the neutral cues. That is, these cocainedependent subjects experienced comparable levels of non specific mood change irrespective of whether they were presented with the cocaine or arousing cues. Subjects may have found the neutral cues more “pleasant” than either the arousing or the cocaine cues because intense cravings can be associated with negative affect (Johnson & Cowen, 1993). Both the cocaine and arousing cues produced greater physiological responses than did the neutral cue. The trend for the cocaine cues to result in selectively greater changes in physiological responses than the arousing cue achieved statistical significance for the temperature measurements. More marked differences on pulse and skin conductance between the cocaine and arousal cues were probably not seen because the expression of both cocaine and arousing cues (a) share common physiological mechanisms and/or (b) maximal responses are readily achieved. That is, these physiological responses are sensitive to change but can be overwhelmed by intense cocaine or arousing stimuli. Although not tested specifically in this paper, the cue-reactivity paradigm may, therefore, be useful in assessing physiological craving to cocaine-related cues, even after prolonged abstinence, and thereby the risk of relapse if the individual is exposed to “high-risk” situations or environments for the presentation of these conditioned drugrelated cues. Augmenting physiological assessments with psychological and/or biological markers of autonomic reactivity (e.g., neuroendocrine response) may, therefore, serve as a means of characterizing subjects according to treatment response (i.e., responders vs. nonresponders) and thus matching these individuals to the appropriate intensity of treatment. As expected, a direct relationship existed between the propinquity of the conditioned cue to the unconditioned stimulus and the strength of the physiological response. That is, manual cues always produced greater physiological responses than did the video or audio cues, respectively. Practically, use of the conditioned-cue paradigm as part of the repeated clinical assessment of addicts can, therefore, be limited to utilization of the manual cue. We considered the possibility of cumulative sensitization in the interpretation of our results as the manual cue was always administered after the other cue modalities. However, this potential effect was minimized in this experiment by the use of a return to baseline period between the presentation of each cue modality. The demonstration of relative specificity for the cue paradigm would suggest that a further simplification would be simply to utilize comparisons between cocaine and neutral stimuli in repeated assessments of craving. We were able to confirm the impression from previous studies (for a review, see Rohsenow et al., 1989) that pulse is relatively insensitive compared with skin conductance and temperature for the assessment of physiological response. Possibly, this may be because (a) marked changes in pulse are not produced reliably by this paradigm; (b) the time taken for pulse deceleration to return to baseline following cue exposure

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usually exceeds the period of experimental measurement; or (c) paradoxical responses (i.e., pulse decelerations to intense stimuli) can occur, especially if the individual is already hyper-aroused. In summary, the results of this experiment suggest that the conditioned-cue paradigm can be utilized as a relatively specific and sensitive indicator of cocaine craving. Further studies are needed to extend these findings. Incorporation of repeated cue-reactivity studies for the assessment of craving during a clinical trial awaits exploration.

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