This study prospectively examined the relationship between reactivity to three human laboratory paradigms (psychosocial, pharmacologic, and drug cue exposure) and relapse to cocaine use in cocaine-dependent individuals. Controlling for pre-study cocaine use, the findings from the current study demonstrate that reactivity to laboratory paradigms is related to subsequent cocaine use.
A strength of the study is the measurement of multiple indices of response to three different paradigms. All three challenges evoked subjective stress and craving in the majority of cocaine-dependent participants. As would be expected, the psychosocial stressor, which involves uncontrollability and social evaluative threat, evoking a limbic system response (Dickerson and Kemeny, 2004
), elicited the highest levels of subjective stress and HR; the pharmacologic stressor, which directly stimulated the HPA axis, evoked the highest levels of ACTH and cortisol response; and the cocaine cue exposure paradigm elicited the highest levels of subjective craving (see ). Notably, this study is among the first to examine the association between response to a pharmacologic provocation (i.e., administration of CRH) and propensity to relapse in cocaine-dependent individuals.
Consistent with previous research in cocaine-dependent individuals (Paliwal, Hyman and Sinha, 2008
; Sinha et al., 2006
), the majority (72.3%) of participants reported at least one relapse to cocaine during the follow-up period. In spite of the fact that this was a laboratory study and subjects did not receive a treatment intervention, the amount and frequency of cocaine use decreased significantly from pre to post study. As has been found with other studies, exposure to cocaine or drug cues in a laboratory setting did not appear to increase subsequent relapse rates or severity of use (Ehrman et al., 1998
; DeSantis, Bandyopadhyay, Back, & Brady, in press
). While a robust literature documents that exposure to conditioned drug cues in the environment is relapse-promoting for many individuals with drug use disorders (Childress, 1988; O’Brien, 1998
; Volkow, 2006
), research studies employing cue exposure paradigms in laboratory settings have not been found to promote increased rates of drug use or relapse. This is likely due to numerous factors that substantially differentiate exposure to drug cues in a laboratory as opposed to in the natural environment, such as, subject selection bias (e.g., individuals who are willing to enroll in a research study may be more motivated to reduce/abstain from using drugs), the fact that inpatient and outpatient laboratory settings ensure that patients are in a safe environment, increased contact with health care providers, and the fact that subjects are not allowed to leave laboratory testing in a state of heightened craving.
Predictors of cocaine use in the month following the laboratory testing varied according to the provocation paradigm employed. In response to the psychosocial stressor (i.e., the Trier), neuroendocrine responses (ACTH in particular) best predicted cocaine use. While the relationship between craving in response to the Trier and cocaine use during the follow-up period was in the expected direction (i.e., increases in craving were positively associated with increases in cocaine use during follow-up), statistical significance was not reached. However, attenuated levels of ACTH and cortisol were associated with a significantly increased likelihood of use and a shorter time to relapse. Thus, individuals who demonstrated a more robust HPA axis response to the challenge demonstrated decreased susceptibility to cocaine use. This has been shown in several previous studies with alcohol-dependent individuals. Junghanns and colleagues (2003)
examined responses to the Trier among 36 alcohol-dependent individuals and 15 controls. Blunted ACTH and cortisol responses were observed among the alcohol-dependent subjects who relapsed to alcohol during a six-week follow-up period. Our group reported similar findings in a study of 63 alcohol-dependent individuals in which attenuated ACTH response to a laboratory stress challenge (i.e., cold pressor task) was associated with increased alcohol use during a one-month follow-up period (Brady et al., 2006
). The decrease in HPA axis response to provocation in alcohol dependence has been hypothesized to have important implications for treatment. While some studies have demonstrated that the decreased neuroendocrine response to stress may be a function of alcohol intake (Gianoulakis et al., 2003
), abnormalities in stress response may also serve as a risk factor for the development of alcohol dependence and/or relapse. Dai and colleagues (2002)
found that individuals at high risk for alcohol dependence based on family history had lower baseline and stress-induced ACTH as compared to individuals at low risk for alcohol dependence. As such, it may be that abnormalities in the response of the HPA axis are associated with both vulnerability to the development of alcohol dependence and relapse.
Sinha and colleagues (2006)
studied subjective and HPA axis responses in cocaine-dependent individuals (N
=49) following exposure to stressful and drug-cue imagery tasks after 2-4 weeks of abstinence. As in the current study, the subjective and HPA axis responses to the stress task were predictive of time to relapse and amount of cocaine use during a 90-day follow-up period. However, the Sinha et al. investigative team found that the cortisol response to stress imagery was positively associated with the amount of cocaine use during follow-up, whereas the present study found a robust relationship between blunted ACTH and cortisol response to the Trier and multiple indices of cocaine use. The discrepancies in findings may be related to differences in sample characteristics as participants in the current study had only 3-5 days of abstinence prior to testing and participants in the Sinha study had been abstinent for 2-4 weeks at the time of testing. Such a blunting of ACTH and cortisol response to the stressor of cocaine itself has been well-documented in rodent models (Mantsch et al., 2000
; Zhou et al., 1996
). There were also differences in the stress task used that might explain the differences between study findings. Of importance, both studies find meaningful relationships between neuroendocrine and subjective response to stressful stimuli in a laboratory setting and subsequent cocaine use, indicating that these paradigms may be useful in understanding the mechanisms involved in stress-induced relapse. The present study suggests that the findings in alcohol dependence linking blunting of the HPA axis stress response to relapse may be extended to individuals with cocaine dependence.
In response to the pharmacologic stress provocation (i.e., CRH), subjective stress and craving, in particular, were significant predictors of relapse. CRH is thought to play a critical role in the emotional dysregulation associated with cocaine dependence and relapse through actions on both the HPA axis and brain stress systems in the extended amygdala (Koob and Kreek, 2007
). Animal models demonstrate that escalation in cocaine intake produces activation of CRH within the processive limbic circuitry which is essential to determining the salience of environmental stressors, suggesting that CRH may play a role in stress-induced relapse (Herman and Cullinan, 1997
). A number of the brain sites hypothesized to be important for the behavioral effects of CRH are closely linked to norepinephrine systems including the locus coeruleus, bed nucleus of the stria terminalis and the central nucleus of the amygdala (Valentino, Foote and Page, 1993
; Van Bockstaele, Colago and Valentino, 1998
). Of interest, there is data suggesting that norepinephrine in these areas stimulates the release of CRH which would imply a powerful “feed-forward” system (Kreek and Koob, 1998
) that might be a mechanism for sensitization of the stress response. A publication comparing the acute response to CRH in a control group versus a cocaine-dependent group assessed in this study found a more robust subjective stress response to CRH in cocaine-dependent individuals as compared to the control group, suggesting sensitization of stress response (Brady et al., 2009
). This is of particular interest considering the finding in this study that the level of reported stress and craving following CRH administration was positively associated with the risk of any cocaine use, the severity of use (i.e., amount use per using day) and a shorter latency to first use. These findings suggest that the subjective response to CRH in cocaine-dependent individuals may have a clinically meaningful relationship to relapse.
Higher baseline HR was associated with more severe cocaine use during follow-up, In the study comparing this cocaine-dependent group to a matched control group (Brady et al, 2009
), higher heart rate was found in cocaine-dependent women as compared to a control group. Increased baseline heart rate may be indicative of noradrenergic dysfunction and associated with the CRH sensitization, discussed above, in cocaine-dependent individuals. Other investigators have reported dysregulation in noradrenergic function associated with vulnerability to panic attacks during early discontinuation of cocaine use in cocaine-dependent individuals (McDougle et al., 1994
). Findings from this study suggest that noradrenergic dysfunction in cocaine-dependent individuals may also be associated with increased cocaine use. The association between higher heart rate response to CRH and less cocaine use during follow-up is likely explained by a ceiling effect, as it is more difficult to detect a HR response in individuals with a high baseline HR. The ACTH and cortisol response to CRH was extremely robust in all study groups, was much higher that the response to either the Trier or cocaine cue, and is likely to represent maximal HPA axis stimulation in the study subjects. As such, the lack of relationship between either the ACTH or cortisol response to CRH and relapse may also be a ceiling effect.
Finally, a drug cue paradigm was explored. Cue-induced stress and craving, in particular, were significantly associated with time to relapse. In contrast, Sinha and colleagues (2006)
found no relationship between cocaine cue-induced subjective and HPA axis changes and relapse. These differences may be due to the different laboratory provocations employed (i.e., the current study used paraphernalia and a video drug cue, Sinha et al. used personalized imagery tasks), which have been shown to produce different responses in other studies of addicted individuals (Yu et al., 2007
). Previous studies have found that craving is predictive of use during treatment (Flannery et al., 2003
; Weiss et al., 2003
) and that craving at entry to inpatient treatment is predictive of use following discharge (Paliwal, Hyman and Sinha, 2008
). Brain imaging studies demonstrate that cocaine cue-induced craving is associated with increases in dopamine in the dorsal striatum (Volkow et al., 2006
) and cue-induced activation is associated with relapse (Kosten et al., 2006
). Thus, drug cue craving paradigms might be used to explore interventions designed to decrease relapse to cocaine use.
The current study has several limitations. Although the sample size is comparable to prior investigations, replication with a larger sample will be important to ascertain generalizability. The follow-up period was relatively short and future research may benefit from a longer follow-up assessment phase. It was not feasible to standardize menstrual cycle phase for women, which can impact the HPA axis (Kajantie and Phillips, 2006
). Only one dose of CRH was tested in the current study. It may be useful to test higher and lower doses in future research (Schluger et al., 2003
). Finally, a no-stress control condition was not employed. Despite these limitations, the current study builds on earlier investigations assessing the relationship between stress- and cue-reactivity and relapse. The study is strengthened by the assessment of a triad of indices of stress reactivity (subjective, physiologic, and neuroendocrine), a well-controlled research environment (the GCRC), and the use of three different stress paradigms.
In summary, the findings provide further evidence of the ability of laboratory paradigms to predict relapse and, therefore, lend support to the ecological validity of laboratory paradigms designed to induce craving or stress. The clinical importance of stress and cue reactivity is highlighted in this study by the observed associations between response to provocations in the lab setting and cocaine use outside of the lab setting. Predictors of relapse varied based on the provocation employed. As such, these varying tasks might be used in conjunction to explore the relationship between different relapse precipitants. Further investigations are needed to replicate the current findings and to identify behavioral, pharmacologic, neurofeedback or other interventions that may serve to alter reactivity and decrease relapse.