Stress-Induced Cocaine Craving and Hypothalamic-Pituitary-Adrenal Responses Are Predictive of Cocaine Relapse Outcomes FREE

Cocaine addiction is a chronic relapsing disorder of which the underlying mechanisms are not well understood.^1- 2 Although significant strides have been made in the development of efficacious behavioral and pharmacologic treatments for cocaine addiction,^3- 5 relapse rates in cocaine dependence remain high.^2,6- 7 A better understanding of the mechanisms that increase relapse susceptibility could contribute to the development of more effective relapse prevention treatments in cocaine dependence.

Theoretical perspectives and clinical survey reports indicate that stress is a key factor that increases risk of relapse in cocaine dependence.^6- 7 Drug use to escape from emotional distress or withdrawal-related distress (negative reinforcement models) and distress-related increases in incentive value or reinforcement threshold for the drug (incentive sensitization models) are commonly invoked to explain stress-related drug use.^8- 11 Cocaine activates central and peripheral stress pathways, and both the extrahypothalamic and the hypothalamic corticotropin-releasing factor (CRF) systems are thought to be involved in cocaine reinforcement and relapse.^9- 10 Increased levels of circulating glucocorticoids are associated with higher rates of psychostimulant self-administration.¹¹ Brain CRF and noradrenergic pathways are involved in stress-induced reinstatement of drug-seeking behavior in cocaine-experienced laboratory animals.¹² Furthermore, CRF antagonists, glucocorticoid antagonists, and α₂-adrenergic agonists are known to attenuate stress-induced drug self-administration and stress-induced reinstatement of cocaine-seeking behavior in dependent laboratory animals.^13- 14 On the other hand, while several clinical studies document that stress and negative affect increase the risk of relapse,¹⁵ no previous research, to our knowledge, has examined whether stress-related drug seeking or “craving” and its associated psychobiological responses increase relapse susceptibility.

On the basis of the aforementioned literature, we hypothesize that drug craving induced by stress imagery or by drug cue imagery and accompanying hypothalamic-pituitary-adrenal (HPA) axis activation (corticotropin and cortisol) in the laboratory will predict relapse outcomes in cocaine-dependent individuals. In previous laboratory research, our group has shown that imagery exposure to emotional stress and to drug cues increases drug craving and associated stress arousal in outpatient, treatment-engaged, cocaine-dependent individuals.¹⁶ These findings were extended in the current inpatient treatment study design to examine whether stress-induced and drug cue–induced drug craving and HPA responses are predictive of cocaine relapse outcomes. Treatment-engaged, cocaine-dependent individuals, who participated in an inpatient laboratory study of imagery exposure to stress and to drug cues,¹⁷ were followed up for 90 days after discharge from inpatient treatment of cocaine dependence to assess relapse outcomes. Findings from the laboratory study indicated that imagery exposures to stress and to drug cues each similarly increased drug craving and were accompanied by greater autonomic and HPA axis responses when compared with neutral imagery exposure in cocaine-addicted individuals.¹⁷ On the basis of the proposed hypothesis, stress-induced and drug cue–induced cocaine craving and corticotropin and cortisol responses were the primary predictor variables examined for association with relapse outcomes. Because subjective anxiety and heart rate responses also showed differences between stress, drug cue, and neutral imagery exposure in the laboratory, these were included as secondary predictor variables in the relapse analyses.

Men and women between the ages of 21 and 50 years (mean [SD] age, 37 [6.5] years) seeking inpatient treatment for cocaine dependence were examined for study participation. Fifty-four individuals (36 men and 18 women) who met DSM-IV criteria for current cocaine dependence were admitted to the Clinical Neuroscience Research Unit of the Connecticut Mental Health Center, New Haven, for 2 to 4 weeks of inpatient treatment and participation in 3 laboratory sessions. All subjects were invited for a face-to-face follow-up interview and urine toxicology screen to prospectively assess relapse and subsequent drug use 90 days after inpatient treatment and discharge. Forty-nine (91%) of the 54 subjects who completed the laboratory study¹⁷ were successfully followed up for 90 days. Thus, the data analysis for the current study is based on the follow-up sample of 49 cocaine-dependent individuals.

All subjects reported regular weekly cocaine abuse that was documented by positive urine toxicology screens on study enrollment. Individuals who met current DSM-IV criteria for dependence on another psychoactive substance other than alcohol and nicotine were excluded. In addition, individuals taking medications for medical or psychiatric problems and those in need of alcohol detoxification were excluded from the study. All subjects underwent a complete medical evaluation, including electrocardiography and laboratory tests of renal, hepatic, pancreatic, hematopoietic, and thyroid functions, to ensure good physical health. The study procedures were approved by the Human Investigation Committee of the Yale University School of Medicine, New Haven, Conn, and all subjects signed a written informed consent.

The Clinical Neuroscience Research Unit is a locked inpatient treatment research facility with no access to alcohol or drugs and limited access to visitors. Drug testing is conducted regularly to ensure continued abstinence. All subjects admitted into the study also participated in specialized substance abuse treatment that included weekly individual therapy provided by the psychiatry residents on the Clinical Neuroscience Research Unit and twice-weekly group drug counseling¹⁸ provided by an addictions specialist. The group drug treatment was part of the inpatient treatment program that was initiated on admission and included additional group programming from 9 AM to 3:30 PM that covered daily life skills and other structured activities.

During the first week of the inpatient stay, subjects underwent an initial medical evaluation and were interviewed by means of the Structured Clinical Interview for DSM-IV¹⁹ to assess psychiatric and substance abuse diagnoses. Baseline demographic characteristics and drug use history were also assessed. In the second week of the inpatient stay, subjects participated in an imagery script development session during which they were asked to identify a highly stressful event from their own lives (rated by the subject as ≥8 on a 10-point Likert scale for stressfulness); a personal drug cue–related event that involved people, place, and objects related to cocaine use; and a personal neutral relaxing event. Examples of commonly reported stressful situations included breakup with a significant other, a verbal argument with a significant other or family member, or unemployment-related stress, such as being fired or laid off from work. Commonly reported drug cue situations were being paid and using crack; buying cocaine; meeting up with a drug-using buddy and buying crack; and being at a bar and watching others drink and use drugs. Examples of neutral relaxing situations included a summer afternoon at the beach, a fall day at the park, and taking a bubble bath. (Sample scripts and script development procedures may be obtained by contacting one of us [R.S.].) Stimulus and response details for each event were elicited by means of scene construction questionnaires^20- 21 (see full description in Sinha et al¹⁷). A “script” or description of each of the 3 situations was developed for use in the laboratory sessions. The scripts were then audiotaped in random order for guided imagery presentation in the laboratory sessions.

In the third week, subjects participated in a habituation and imagery training session (see Sinha et al¹⁷ for details) followed by 3 laboratory sessions on consecutive days. Subjects were exposed to a stress, drug cue, or neutral script for guided imagery during the laboratory session; only 1 imagery condition was presented per day of laboratory testing, and the order of imagery conditions was randomized across subjects. On each day of the laboratory session, subjects abstained from breakfast and were brought into the testing room at 8:15 AM by the research nurse. After the subject settled into a sitting position in a hospital bed, a heparin-treated catheter was inserted by the research nurse in the antecubital region of the subject's nonpreferred arm, to periodically obtain blood samples. A blood pressure cuff was placed on the subject's preferred arm to monitor blood pressure, and a pulse sensor was placed on the subject's forefinger to obtain a measure of pulse. This was followed by a 1-hour adaptation period during which the subjects were instructed to practice relaxation. At 9:30 AM, subjects were provided headphones and the audiotape was played. The tape provided instructions for the imagery procedure and was followed by a description of the script for the session. The subject's task was to imagine the situation being described, as if it were happening at that time. The length of each taped script was approximately 4.5 minutes, with a total imagery period of 5 minutes. A complete description of laboratory procedures is provided by Sinha et al.¹⁷

Cocaine craving was assessed by means of a 10-point visual analog scale that measured responses to the item “desire for using cocaine at this moment.” Subjective anxiety was measured on a 10-point visual analog scale in response to the item “how jittery, tense, and anxious do you feel at this moment?” Heart rate was measured with an electronic blood pressure monitor (model SD-700; IBS Corp, Waltham, Mass), and plasma samples for corticotropin and cortisol assessments were processed at the Kreek Laboratories at Rockefeller University, New York, NY, by standard radioimmunoassay procedures. All laboratory responses were assessed at baseline (5 minutes before imagery; −5 time point), during (for heart rate) or immediately after imagery (0 time point), and at repeated recovery time points every 15 minutes (+15, +30, +45, +60, and +75 time points) after imagery. To assess the association between these evoked responses and relapse outcomes, a single averaged measure across all time points for each response variable was computed. An averaged score rather than peak scores was selected for use in the relapse analysis to include the individual variation during the recovery time points after exposure to stress and drug cue imagery in the current analyses. In particular, we previously reported slow return to baseline during the laboratory sessions for craving and anxiety measures and little recovery in the corticotropin response during the 75 minutes after imagery exposure in this sample of subjects.¹⁷ Such slow return to baseline could contribute to relapse susceptibility, and hence averaged response measures were used in the current analyses. Because cocaine craving and anxiety were measured by means of the 0 to 10 ordinal scale, the average response for these measures included baseline levels and the 6 postimagery time points. However, as physiologic (heart rate) and HPA axis (corticotropin and cortisol) measures vary considerably across subjects and within subjects across days of testing, an average of the change from baseline response for each of the 6 postimagery time points was computed to obtain a single measure of stress response for each of the stress and the drug cue imagery conditions. A summary of the baseline and average responses (craving and anxiety) and change from baseline responses (heart rate, corticotropin, and cortisol measures) for the stress and the drug cue conditions is presented in Table 1. Peak change from baseline is also provided in Table 1 as a validation check of the laboratory-based manipulation of stress and drug cue imagery exposure.

All participants were given an appointment for a follow-up interview at 90 days after discharge from the inpatient unit. Reminders were sent in the month of the appointment. Cocaine use during baseline (90 days before inpatient treatment) and during follow-up (90 days after discharge from inpatient treatment) was assessed by means of the Substance Use Calendar,²² an instrument that has been validated in drug-abusing samples²³ and widely used in assessing cocaine use outcomes in previous treatment studies.^4- 5,24 Urine and breath alcohol samples were also obtained at the 90-day follow-up appointment.

To capture both initial lapse (any use) and relapse or return to regular patterns of drug use,²⁵ relapse was examined both as a dichotomous variable (no use [success] vs any use [failure]) and as continuous measures of drug use (eg, number of days of use and amounts of use per occasion) in the 90-day follow-up period. The following cocaine use measures were computed from the follow-up substance use calendar and the urine screen and used for the relapse analysis: (1) time to relapse, the interval to the first day of any cocaine use after discharge from inpatient treatment (success vs failure); (2) frequency, the total number of days of cocaine use; and (3) quantity, the average amount of cocaine use in grams per occasion of cocaine use.

Baseline demographic data, drug use measures, and baseline laboratory responses of cocaine craving, corticotropin level, and cortisol level were first examined for association with measures of cocaine relapse. If any demographic, baseline cocaine use, or baseline response measure was significantly associated with any of the relapse outcome measures, they were included as covariates in examining the association between stress-induced and drug cue–induced craving and HPA axis response and the specific cocaine relapse measure.

Time to cocaine relapse was examined by means of Cox proportional hazards regression,²⁶ a statistical method to examine the effects of continuous variables on event-based outcomes such as when an event occurred during a specified time period (eg, first day of cocaine use after discharge during follow-up). Multiple regression or logistic regression (for demographic categorical variables) analyses were conducted to examine associations with frequency and amount of cocaine used in the follow-up period.

Two thirds of the sample (32/49 [65%]) reported using cocaine during the follow-up phase. Urine and self-report data were concordant for 48 of 49 subjects. The subject with discordant data was considered to have relapsed at day 1, and his frequency and amount of cocaine use was considered invalid and not included in the regression analyses. (Exclusion of this subject from the analyses did not affect the result.)

The demographic data, cocaine use history, and lifetime rates of other psychiatric diagnoses of the original sample who participated in the laboratory study (N = 54) and the follow-up sample (n = 49) were highly similar (Table 2).

Demographic measures of age, education level, employment status, race, marital status, history of alcohol dependence, and lifetime history of major depression, posttraumatic stress disorder, or other anxiety disorders were not associated with cocaine relapse outcomes. Baseline levels of cocaine craving, corticotropin, and cortisol levels were not associated with time to cocaine relapse or amount and frequency of follow-up cocaine use. However, baseline amount of cocaine use during the 90 days before inpatient admission was significantly associated with the time to cocaine relapse (baseline quantity: χ² = 5.81, P = .01; hazard ratio, 0.49; 95% confidence interval, 0.28-0.87). Also, baseline frequency of cocaine use was significantly associated with follow-up frequency of cocaine use (R² = 0.08, t = 2.13, P = .04).

Cox proportional hazards regression analyses showed that greater stress-induced cocaine craving response was associated with a shorter time to relapse after accounting for baseline cocaine use during the 90-day period before inpatient admission (χ² = 5.58, P = .02; hazard ratio, 1.31; 95% confidence interval, 1.03-1.60). For each additional unit increase in stress-induced cocaine craving, there was a 31% increase in the likelihood of cocaine relapse in the 90-day follow-up period (Figure 1).

Stress-induced corticotropin and cortisol responses were not associated with time to cocaine relapse and frequency of cocaine relapse. However, stress-induced corticotropin response (R² = 0.19, t = 3.25, P = .002) was significantly associated with average amount of cocaine used per occasion in the follow-up period and accounted for 19% of the variance in amount of cocaine used per occasion (Figure 2A). As a follow-up, a median split in the stress-induced corticotropin response was conducted to divide the sample into high and low responder groups. The cumulative amounts of cocaine used each week of the 90-day follow-up were then computed and a linear mixed-effects model analysis with group and time (each of the 12 weeks) as independent variables was conducted (using PROC MIXED SAS version 8.0; SAS Institute Inc, Cary, NC). Findings indicated that high corticotropin responders used significantly more cocaine over time than the low responder groups (group main effect: F_1,47 = 25.60, P<.001) (Figure 2B). Similarly, stress-induced cortisol response was significantly associated with average amount of cocaine used per occasion (R² = 0.09, t = 2.12, P = .04) and accounted for 9% of the variance in amounts of cocaine used per occasion (Figure 3A). High and low stress-induced cortisol responder groups were also computed by means of a median split, and the cumulative amounts of cocaine used during the follow-up period were examined in the manner described for corticotropin. Findings indicated that the high cortisol responder group used significantly more cocaine over time than the low cortisol responder group (group main effect: F_1,47 = 17.34, P<.001) (Figure 3B).

There were no significant associations between drug cue–induced cocaine craving and time to cocaine relapse or frequency and amount of cocaine used at follow-up. Drug cue–induced corticotropin and cortisol responses were also not found to be significantly associated with cocaine relapse measures.

However, there were significant associations between stress-induced and drug cue–induced cocaine craving response (r = 0.69, P<.001), and between stress-induced and drug cue–induced corticotropin (r = 0.43, P = .003) and cortisol (r = 0.32, P = .03) averaged change responses in the laboratory sessions, suggesting similar increases in cocaine craving and HPA axis responses during stress and drug cue imagery exposure conditions.

Secondary predictor variables of heart rate and subjective anxiety responses did not show any significant associations with cocaine relapse outcomes.

The findings from this study are the first, to our knowledge, to document that stress-related drug craving and associated psychobiological responses in the laboratory are predictive of subsequent cocaine relapse in abstinent cocaine-dependent individuals. Greater stress-induced, but not drug cue–induced, cocaine craving predicted a shorter time to initial cocaine lapse. On the other hand, stress-related HPA axis responses were not associated with time to cocaine lapse, but rather with amounts of cocaine used per occasion during follow-up. Consistent with the clinical literature that recognizes relapse and recovery as a multidetermined process,^15,27 the current findings suggest that specific components of the stress response are associated with different aspects of the relapse process. While cocaine craving, a subjective measure of intent to use cocaine, was associated with the subsequent behavioral component of relapse (ie, initial lapse and reinitiation), the stress-related HPA responses were not associated with this behavioral aspect but rather with a measure of consumption, which may represent the ability to control intake after initiation, ie, occurrence of a full-blown relapse or binge.

Exposure to footshock stress reinstates cocaine-seeking behavior in abstinent, cocaine-experienced animals that have undergone extinction,¹³ a behavior associated with the extrahypothalamic CRF and noradrenergic activity and not dependent on glucocorticoids.¹⁴ Pharmacologic attenuation of HPA function in cocaine-addicted individuals does not block the subjective effects of cocaine, including cocaine craving,^28- 29 suggesting a dissociation between the hypothalamic stress response and subjective or behavioral effects of cocaine. Our finding that the HPA measures are not associated with the behavioral lapse to drug use is consistent with these previous data and, together with the preclinical literature, suggests that the subjective and behavioral aspects of drug seeking and initial lapse are not dependent on HPA function but possibly associated with extrahypothalamic CRF and noradrenergic system activity.

Nonetheless, there is evidence that cocaine, like stress, stimulates the HPA axis via a hypothalamic CRF mechanism and that increased levels of corticosterone are important in the acquisition of cocaine self-administration.³⁰ In humans, cocaine stimulates the HPA axis and increases the peak amplitude of the secretory pulses of corticotropin and cortisol without altering the peak frequency.^31- 32 These preclinical and clinical data support the notion that HPA axis stimulation plays a role in cocaine reinforcement.^15,30- 31 This notion is supported by the current data in that increased stress-related corticotropin and cortisol responses were associated with greater amounts of cocaine consumption per occasion. It may be that increasing levels of corticotropin and cortisol during a stress-related lapse serve to “prime” higher bouts of cocaine consumption by virtue of reaching critical reward thresholds more quickly. Alternatively, it is also possible that stress-related increases in corticotropin and cortisol diminish the rewarding effects of the initial cocaine bout such that more cocaine is needed to reach satiety. Both explanations are speculative and need to be further assessed in the future.

Drug use as a way to escape from distress or as a means of coping with stress and negative affect is a commonly used explanation for addictive drug use.^33- 34 Consistent with these models, stress-related increases in drug craving could represent a proximal marker of relapse susceptibility, perhaps as a signal for drug use to ameliorate distress. Previous research suggests that individuals are able to control impulses and show effective self-regulation skills under low or manageable levels of distress, but with increasing distress, the motivation to feel better overrides the need for self-control.³⁵ In the context of the current study, stress-induced increases in cocaine craving could signal the need for regulation of distress over self-control, thereby increasing the susceptibility of relapse. Recent evidence from brain imaging studies provides further insight into the potential neural substrates that could underlie emotional distress overriding cognitive control-related processing to influence behavioral outcomes. Sanfey et al³⁶ manipulated emotional engagement during an economic decision-making task and reported that emotion-activated limbic brain regions (anterior insula) supersede activity in cognitive-control–related brain regions (dorsolateral prefrontal cortex) to influence behavioral outcomes. Cocaine-dependent patients show lower activity in the anterior cingulate during stress compared with controls but increased activity in the dorsal striatum, and activity in both the dorsal striatum and insula correlate with stress-induced cocaine craving.³⁷ Thus, hypofunction in a region (anterior cingulate) involved in conflict monitoring and emotion regulation,^38- 39 but greater stress-induced craving-related activity in limbic regions associated with obsessive-compulsive behaviors and negative emotion processing,^40- 41 could provide the neural substrates for overriding self-control and commitment to abstinence during stress, increasing relapse susceptibility.

No significant associations between cue imagery–induced cocaine craving or HPA responses and cocaine relapse outcomes were found. These data are consistent with other studies showing that drug cue–related craving is not predictive of relapse outcomes.^2,42- 43 On the other hand, the current results indicated that cocaine craving and HPA responses in the stress and the drug cue imagery conditions were significantly correlated, suggesting that cue imagery exposure produced responses similar to the stress condition, and with a larger sample size we might have seen a positive association between drug cue imagery responses and relapse. It is also important to note that this study used imagery of drug cues rather than actual exposure to drug cues themselves to produce cue reactivity. Imagery exposure to drug cues may produce a different pattern of response than those seen in actual drug cue reactivity paradigms and could have resulted in a lack of association between drug cue exposure and relapse susceptibility.

The current findings have significant clinical implications. First, stress-induced drug craving and associated HPA responses may be used as diagnostic markers to assess relapse propensity. Such assessments could inform clinicians of the need to tailor their interventions toward stress regulation and reduction of stress-induced craving. Second, while assessing stress-induced craving and hormonal responses can be informative in identifying individuals who are highly susceptible to relapse, the findings also underscore the importance of developing treatments that target attenuation of stress-induced cocaine craving and regulation of stress-related HPA axis responses in cocaine relapse prevention. There are currently no empirically validated treatments that address stress-induced drug craving and related arousal. Both CRF antagonists and α₂-adrenergic agonists attenuate stress-induced cocaine reinstatement in dependent laboratory animals.^13- 14,44 Nonpeptide CRF antagonists are currently being investigated in the treatment of affective and anxiety disorders.^45- 46 Our findings are consistent with previously cited preclinical data and support examining the efficacy of CRF antagonists in attenuating stress-induced cocaine craving and HPA responses to improve cocaine relapse outcomes. Furthermore, α₂-adrenergic agonists that inhibit norepinephrine centrally have shown promise in the treatment of attention-deficit/hyperactivity disorder,⁴⁷ in reducing opiate withdrawal symptoms,⁴⁸ and in reducing nicotine craving.⁴⁹ Their efficacy in reducing stress-induced cocaine craving and relapse susceptibility needs further testing in human studies. Behavioral treatments that target stress regulation and attenuation of stress-related cocaine craving could also have potential relevance in addressing cocaine relapse susceptibility. Finally, laboratory models of stress-induced drug craving could be effective in screening pharmacologic agents or testing behavioral strategies to attenuate stress-induced drug craving and HPA responses to reduce relapse susceptibility.

Specific limitations of the present study need to be acknowledged. While there are reports of sex differences in cocaine relapse precipitants,⁵⁰ we were not able to assess sex-specific associations because of the small number of women in the sample. It is also important to note recent evidence from the alcohol literature indicating that attenuated HPA responses are associated with alcohol relapse.⁵¹ As such, the current findings may appear to be in contrast to these data. However, the effects of withdrawal from cocaine on HPA function are different from alcohol-related withdrawal effects on HPA function. For example, cortisol responses are altered during early cocaine abstinence but, unlike protracted withdrawal from alcohol,⁵² cortisol responses are known to normalize within 2 weeks of cocaine abstinence.⁵³ Clearly, a more comprehensive study of the withdrawal-related changes in HPA function and their effects on relapse and the effects of stress-related activation of HPA responses on relapse in cocaine- and alcohol-abusing samples need further study.

Despite these caveats, the current study provides previously undocumented evidence that stress-related increases in cocaine craving and HPA responses are associated with cocaine relapse outcomes in cocaine-dependent individuals during early recovery. The findings suggest that stress-induced drug craving and hormonal responses could be used diagnostically to evaluate relapse propensity. They also support the need to address the effects of stress-induced craving and HPA responses on cocaine relapse susceptibility via pharmacologic and behavioral treatment development efforts.

Correspondence: Rajita Sinha, PhD, Department of Psychiatry, Yale University School of Medicine, 34 Park St, Room S110, New Haven, CT 06519 (Rajita.sinha@yale.edu).

Submitted for Publication: June 2, 2005; final revision received August 31, 2005; accepted September 8, 2005.

Funding/Support: This research was supported by grants R01-DA11077 (Dr Sinha), P50-DA16556 (Dr Sinha), M01-RR00125 (Yale University), P60-DA0510 (Dr Kreek), and K02-DA17232 (Dr Sinha) from the National Institutes of Health, Bethesda, Md.

Previous Presentation: This study was presented as a poster at the Annual Meeting of the American College of Neuropsychopharmacology; December 14, 2004; San Juan, PR.

Acknowledgments: We thank the staff at the Clinical Neuroscience Research Unit and the Substance Abuse Treatment Unit of the Connecticut Mental Health Center, New Haven; the General Clinical Research Center at Yale University School of Medicine, New Haven; and Kreek Laboratories at Rockefeller University, New York, NY, for their support of this research.