Results of a baseline urine test predict levels of cocaine use during treatment.

Sixty-one cocaine dependent outpatients submitted a single urine sample at least 1 week prior to entry into a 4-week treatment study. Participants were then expected to provide three urine samples per week during the month of treatment. The 61 patients studied here all completed treatment and provided an average of more than 11 of 12 scheduled urine samples. Participants who submitted a cocaine-positive sample prior to treatment provided more positive urine samples during the 4-week trial, were less likely to be completely abstinent during the month, and took longer to reach an initial abstinence criterion of three consecutive cocaine-free urines. Thus, a single pretreatment urine test represents a powerful predictor of subsequent cocaine use. The results suggest that future randomized trials stratify group assignment based on the results of a baseline urine test.

A randomized, double-blind, placebo-controlled study of ritanserin pharmacotherapy for cocaine dependence.

Eighty cocaine-dependent individuals enrolled in outpatient treatment took part in a randomized, double-blind, placebo-controlled trial of ritanserin, a 5-HT(2) antagonist, as an adjunct therapy. Participants attended an outpatient day hospital therapy program each day and received tablets containing placebo or 10 mg ritanserin for a 4-week period. Primary outcome measures included retention in treatment, urine drug tests, and self-reports of craving. Secondary outcome measures were depression scores on the Beck and Hamilton inventories, negative mood as measured by the Profile of Mood States, and life functioning as measured by the Addiction Severity Index. Although participants showed improvement over the 4 weeks, there were no group differences on any of the measures. These results fail to support the use of ritanserin as a complement to outpatient psychosocial therapy for cocaine dependence.

Mood state and recent cocaine use are not associated with levels of cocaine cue reactivity.

Eighty-one cocaine-dependent outpatients were assessed for their reactions to cocaine-related cues in a laboratory setting. All subjects contributed a urine sample prior to the session. Compared with non-drug control cues, the cocaine stimuli produced increases in physiological arousal, self-reports of high, craving, and withdrawal, and self-reports of negative mood. Subjects who tested cocaine-positive on the day of testing differed only in skin resistance responding from those who tested cocaine-negative. Changes in cue-induced physiological and self-report measures were also not associated with between-subject variations in mood as measured by the Profile of Mood States (POMS) questionnaire administered prior to cue assessment. Thus, variations in baseline mood and recent cocaine use history do not introduce an additional source of variability in cue reactivity measurements. However, negative mood states at the start of a session were associated with higher levels of self-reported craving, high, and withdrawal both before and after cue exposure.

Comparing levels of cocaine cue reactivity in male and female outpatients.

Thirty-eight female and 26 male cocaine-dependent outpatients were exposed to cocaine cues in a laboratory setting. Stimuli consisted of an audiotape of patients discussing cocaine use, a videotape of simulated cocaine preparation and use, and the handling of cocaine paraphernalia. Overall, the stimuli produced significant decreases in skin temperature and skin resistance, and significant increases in heart rate, self-reported drug states (high, craving, and withdrawal), and self-reported negative moods. Females were more likely to report increased craving in response to the cues than males, but there were no other gender differences in any of the responses. Levels of reactivity in females were comparable to the results of previous studies with all male samples. These results support the use of a constant set of cues in future treatment studies employing gender-balanced patient samples.

Reliability and validity of the aggregate method of determining number of cigarettes smoked per day.

The authors evaluated the reliability of two pretreatment assessments (screening and intake) of cigarettes smoked per day (CPD) by the commonly used aggregate method. The validity of the aggregate method was also determined by comparison with results of the timeline followback (TLFB) method for the identical periods. The study participants were 49 outpatients undergoing nicotine patch treatment. The reliability of the two aggregate method evaluations of CPD was quite high by Pearson product-moment correlation (r) and good when based on the intraclass correlation. Correspondence between the CPD assessments based on the aggregate and TLFB methods for the two time-points ranged from fair (screening) to good (intake). Overall, the study findings indicate that the aggregate method provides reasonably consistent data.

Laboratory exposure to cocaine cues does not increase cocaine use by outpatient subjects.

Sixty-nine cocaine-dependent outpatients were exposed to cocaine-related stimuli and to non-drug events on separate days. Cocaine cue sessions were always followed by a meeting with a trained clinician designed to eliminate any craving that remained following cue presentations. Urine samples were collected before each laboratory session and 1 to 3 days later. Neither rates of cocaine use nor average urine metabolite values differed following the two sessions. Nearly 90% of subjects had the same urine test result both before and after the cocaine cue session. Thus, laboratory presentation of cocaine cues to outpatient subjects did not increase their risk of subsequent drug-taking. These results suggest that with proper clinical protections, cue exposure can be used as a treatment outcome measure and a behavioral intervention in outpatient settings without increasing the risk of drug use.

Cocaine use is associated with increased craving in outpatient cocaine abusers.

Sixty-one cocaine abuse patients provided self-reports of craving and urine samples 3 times a week. Within-subject analyses revealed several relationships between the measures. First, peak craving levels were higher for 2-3-day intervals during which cocaine use had occurred than for preceding or following abstinent intervals. Second, average craving ratings during cocaine use intervals were double the ratings given during abstinent intervals. Third, cocaine use was 4 times more likely to occur during a period of elevated craving than during comparison intervals. Finally, participants who provided at least 1 positive urine sample reported more craving increases over 4 weeks than did abstinent individuals. These results demonstrate a strong association between craving increases and naturally occurring cocaine use but do not allow a determination of whether craving caused cocaine use or cocaine use caused craving.

Comparing self-reported cocaine use with repeated urine tests in outpatient cocaine abusers.

Sixty-one participants in outpatient therapy for cocaine dependence provided urine samples and self-reports of cocaine use 3 times a week for 4 weeks. Participants later gave a retrospective self-report of cocaine use for the month on the addiction Severity Index (ASI). Comparisons with urine test values revealed substantial underreporting of cocaine use on both measures, and results from the 2 forms of self-report were only imperfectly correlated. More participants admitted to at least 1 cocaine use episode on the ASI than on the repeated self-reports, but the repeated reports provided a more accurate index of the relative frequency of cocaine use during the month. Self-reports can enhance cocaine use detection when urines are infrequently collected and can help determine whether consecutive positive urine samples represent elevated metabolite levels from a single drug use episode. However, self-reports cannot substitute for regular urine sampling.

Relationships among physiological and self-report responses produced by cocaine-related cues.

In response to cocaine cues, 150 subjects with a history of cocaine abuse showed decreases in skin temperature and skin resistance and increases in heart rate and reported craving, high, and withdrawal responses. These responses were consistent across four years of data collection. Craving reports were not consistently associated with either high or withdrawal responses, and many subjects endorsed increases in both high and withdrawal states. Correlations revealed no pattern of association among physiological variables and responding did not differ between subjects who did and those who did not report increases in each of the drug states. Finally, physiological variables did not predict reported drug states in discriminant analyses. Cocaine cue reactivity cannot be easily related to a unitary state of high, withdrawal, or craving. It is suggested that future studies focus more on the prediction and measurement of treatment outcome than on the form of cue responses.

Failure of ritanserin to block cocaine cue reactivity in humans.

As part of a double-blind placebo-controlled study of the effects of ritanserin on cocaine use and craving, reactivity to cocaine-related events was assessed both before and during medication. Twenty-two patients receiving ritanserin and 23 receiving placebo were exposed to cocaine cues while continuous measures of heart rate, skin temperature, and skin resistance were taken. Self-reports of high, withdrawal, and craving were also collected. The cues produced significant physiological responding as well as significant increases in high and craving during both sessions. Ritanserin reduced cue-elicited decreases in skin temperature, but had no effect on heart rate and skin resistance or on cue-induced high and craving. The results demonstrate that cue reactivity is a robust phenomenon across two assessment sessions but fail to support the use of ritanserin as a means of reducing cue-elicited drug states.

Effect of smoking cues and cigarette availability on craving and smoking behavior.

This study examined whether smokers respond differently to smoking cues than to affectively neutral or unpleasant cues without smoking content, and whether reactivity is affected by expectations regarding the opportunity to smoke. Expectancy was manipulated by telling subjects in group SMOKE that they could smoke, and subjects in group NO SMOKE that they could not smoke following each cue-reactivity session. The dependent variables were subjective ratings of "desire to smoke", "high", "withdrawal", and mood, as well as latency to initiate smoking measured in group SMOKE. Statistical analyses demonstrated that only group SMOKE (a) reported greater "desire to smoke" and "withdrawal" to the smoking cues compared to the baseline, (b) reported greater "desire to smoke" to the smoking cues than to the unpleasant or to the neutral cues, and (c) smoked faster after the smoking cues than after the neutral cues. Both groups rated the unpleasant cues as affectively more negative than the neutral cues. The data suggest that the impact of drug-cues on craving and subsequent drug-use is due to their drug-related content, and not to negative affect. Furthermore, the impact of drug-related cues appears to be influenced by perceived drug-availability.

Reliability and validity of 6-month timeline reports of cocaine and heroin use in a methadone population.

Fifty-nine persons addicted to heroin and maintained by methadone reported on daily heroin and cocaine use during 2 timeline calendar interviews administered 6 weeks apart. Retrospective reports covering 6 months were compared with urine samples taken weekly during the interval. Test-retest correlations were high and timeline estimates of drug use frequency were significantly correlated with the frequency of drug-positive urine results. Thus, timeline reports of drug-use frequency appeared both reliable and valid. Individual participants either over- or under-reported by an average of about 15%, and they did not identify instances of drug use with greater than chance accuracy when particular episodes of drug use occurred. These results support the use of timeline reports to make group comparisons of long-term drug use, but suggest that timeline data should not be used to identify specific drug-use episodes. Work with other drug-use population is necessary to extend these conclusions.

Cue reactivity and cue reactivity interventions in drug dependence.

Despite a venerable history dating back to Pavlov and countless testimonials from patients such as those in the opening paragraphs of this chapter, there is much that remains to be learned about drug signals and, particularly, about ways of reducing their adverse effects on human drug users. There is a substantial amount of data showing increased craving and signs of physiological arousal to drug-related versus neutral cues in drug users for both drug classes reviewed here. Additional controlled studies will be useful in refining which responses among those studied are, in fact, conditioned in origin and therefore can be subjected reasonably to learning-based interventions. Most attempts to modify cue responsivity for clinical benefit have met with only modest success, and there is ample room for creative, but controlled, treatment-outcome studies. In recent years, several other groups have joined in the effort to understand drug-related cue reactivity, extending the research area to alcohol and nicotine (Monti et al. 1987; Niaura et al. 1988, 1989; Cooney et al. 1984; Hodgson and Rankin 1982; Drummond 1990; Laberg 1990). The interested reader is referred to several additional reviews of cue reactivity and cue exposure research related to alcohol and nicotine (Niaura 1988; Drummond 1990; Laberg 1990), opiates (Powell 1990), opiates and cocaine (Childress et al. 1988b; O'Brien et al. 1990), and all the preceding areas (Rohsenow et al. 1991).

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

The use of responding to drug-related stimuli as a dependent measure for studies of anticraving 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 of the 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 of anticraving agents.

Designing studies of drug conditioning in humans.

There has been much recent interest in the possibility that signals for drug use in humans acquire the ability to evoke classically conditioned (learned) states which motivate drug taking. Much data now suggest that cues paired with drug use come to elicit physiological responses and subjective reports of drug-related feelings like craving and withdrawal. However, the designs employed do not permit the conclusion that the observed responding results from classical conditioning. Studies which look directly at conditioning in the laboratory by pairing neutral stimuli with drug administration have not provided appropriate controls for unlearned effects such as sensitization or pseudo-conditioning. Similarly, studies which assess responding to cues thought to signal drug use in the natural environment (e.g., the sight of someone injecting heroin) have not adequately assessed whether such cues have unconditioned (unlearned) effects. Determining whether responding to drug-related cues results from classical conditioning has important implications for the development of drug treatments. Consequently, the purpose of the present review is to outline a set of criteria for determining that responses to drug-related stimuli in humans are learned. Existing studies are reviewed in light of these criteria and paradigms for further work are suggested.

Conditioned responses to cocaine-related stimuli in cocaine abuse patients.

Subjects with a history of free-basing and smoking cocaine but no history of opiate injections were exposed to three sets of stimuli. They received cocaine-related stimuli in one session, opiate-related stimuli in a second session, and non-drug stimuli on a third occasion. Compared to the opiate and non-drug cues, the cocaine-related events caused reliable decreases in skin temperature and skin resistance, and reliable increases in heart rate, self-reported cocaine craving, and self-reported cocaine withdrawal. Furthermore, control subjects lacking a history of cocaine or opiate use failed to show such differential responding. These results suggest that cocaine-related stimuli evoke Pavlovian conditioned responses in cocaine abuse patients. Such findings encourage continuing efforts to develop drug treatment strategies based on conditioning principles.

Opiate receptors, neuropeptides in CNS and CSF of two Macaca species with different responsiveness to opiates.

Of two related Macaca species, the rhesus (M. mulatta), acquires opiate tolerance and dependence more readily than the cynomolgus (M. fascicularis). In the cynomolgus, mu-opiate receptors were significantly fewer in the caudate nucleus and globus pallidus; delta-sites were fewer in the thalamus. kappa-Sites showed no species difference. The levels of [Met5]enkephalin, substance P and dynorphin B in various brain areas were comparable. On the other hand, receptor-assayed endorphin activity was higher in CSF of cynomolgus than rhesus monkeys.