We found that increased mOR binding in frontal and temporal cortex, and changes in binding over 12 weeks of enforced abstinence, are associated with time to relapse (and the related variable time to lapse) after release from enforced abstinence on a closed research ward. Regional mOR binding contributed significant predictive power beyond that provided by standard clinical variables such as drug and alcohol use and employment status.
These findings suggest that brain mOR binding could serve as a predictive marker for patient response to cocaine addiction treatment. Confirmation of this finding offers the potential to use mOR binding as a tool to identify patients at greater risk of relapse and to better allocate limited drug addiction treatment resources to patients most in need. The observation of a significant correlation between time to relapse and mOR binding 11 weeks before discharge suggests that mOR binding may have predictive value prior to or early in treatment. All significant R2 values (square of correlation coefficient) were within the range of 0.57–0.79 ( and ). Our sample size was too small to provide sufficient statistical power to evaluate whether any of these were significantly higher (i.e., more predictive) than the others.
Subjects’ mood is unlikely to have confounded the observed relationship between brain mOR binding and relapse. Subjects had no current DSM-IV mood disorder and low self-rated depression or anxiety (SCL-90R subscales) throughout the study. Furthermore, there were no significant correlations between depression or anxiety scores and mOR binding (Gorelick, et al. 2005
We are aware of only two other studies, both involving subjects with alcoholism, in which a human brain imaging parameter was significantly correlated with relapse to substance use (Grusser, et al. 2004
; Guardia, et al. 2000
). In one study, detoxified alcoholic patients who relapsed during 3 months of outpatient treatment had significantly greater dopamine D2 receptor availability in the striatum (assessed by single photon emission computed tomography (SPECT) with radiolabeled iodobenzamide) during their initial inpatient detoxification than did patients who did not relapse (based on self-reported drinking status) (Guardia, et al. 2000
). In the other study, the intensity of activation in the anterior cingulate, medial prefrontal cortex, and striatum (measured by fMRI) in response to alcohol-related cues was significantly correlated with amount of alcohol intake over the subsequent 3 months in 10 alcoholic patients scanned while abstinent (Grusser, et al. 2004
The mechanism mediating the relationship between brain mOR binding and relapse cannot be directly determined from this study. Based on animal studies and our previous human studies (Zubieta, et al. 1996
; Gorelick, et al. 2005
), we suggest that increased mOR activation (due to increased binding potential) mediates increased cocaine craving, which increases the risk of relapse in many (Palij, et al. 1996
; Rohsenow, et al. 2007
; Weiss, et al. 2003
), but not all (Kosten, et al. 2006
), studies of cocaine addiction treatment. The mechanism by which mORs are upregulated is incompletely understood, but may be related to tonically reduced release of endogenous opioid receptor ligands associated with long-term cocaine exposure (Daunais, et al. 1997
; Laforge, et al. 2003
; Przewlocka and Lason 1995
). In this study, two of the brain regions showing significant correlations between increased mOR binding and time to or severity of relapse were the inferior frontal cortex and anterior cingulate cortex. Activation of these brain regions has been associated with cocaine craving, salience of reinforcers, and risk of relapse in animal models of relapse to drug self-administration (Daglish and Nutt 2003
; Goldstein and Volkow 2002
; Kalivas and McFarland 2003
). Thus, increased activation of mORs in these brain regions may have mediated the increased tendency to relapse to cocaine use among our subjects (Gianoulakis 2004
). The inferior frontal cortex is an important region in brain circuits involved with memory for reinforcement and risk-reward decision-making (Robbins and Everitt 2002
; Volkow, et al. 2002
), i.e., the ability to make decisions that appropriately balance the probability and magnitude of positive and negative consequences. The anterior cingulate cortex also has a role in risk-reward decision-making (Bush, et al. 2002
; Williams, et al. 2004
This study has some limitations. Subjects were not representative of all cocaine-dependent individuals because we excluded those with other current substance use disorders (except tobacco dependence) and with more than minimal recent opiate use. This was done to minimize possible effects on brain mOR binding from other substance use and give greater ability to detect a relationship between mOR binding and relapse. However, there is no reason to believe that the underlying relationship observed in our somewhat selected sample would not also hold for subjects with current substance use other than cocaine.
Subjects were not treatment-seeking and did not receive drug abuse treatment during their 3-month residential stay or one-year follow-up. Previous studies showing an association between sociodemographic and drug use variables and relapse to cocaine use have been conducted in treatment settings with treatment-seeking patients (Ciraulo, et al. 2003
; Kampman, et al. 2002
; McKay, et al. 1999
; McMahon 2001
; Poling, et al. 2007
; Reiber, et al. 2002
). In our sample of non-treatment-seeking subjects, few of these clinical variables showed a significant correlation with time to lapse or relapse. This lack of correlation may be due, in part, to our relatively small sample size (15 subjects), but also could reflect a difference in valid predictors of relapse between treatment and non-treatment samples. Thus, the generalizability of our findings to treatment-seeking cocaine users in a treatment setting remains to be confirmed.
Cocaine use during follow-up was measured by subject self-report, with periodic confirmation by urine drug testing. The study procedures should have maximized valid self-report (Brown, et al. 1992
; Hamid, et al. 1999
; Harrison 1995
; Nelson, et al. 1998
). There was 80% overall agreement between self-report and the urine drug tests, comparable to the agreement reported in large published studies (Brown, et al. 1992
; Harrison 1995
; Hersh, et al. 1999
; Nelson, et al. 1998
; Simpson, et al. 2002
). In any case, distortions of self-report would have decreased the ability to detect a significant correlation with mOR binding (unless one assumes a significant association between mOR binding and tendency to under-report drug use).
The PET scanning procedure used does not distinguish between increased numbers of mOR and increased receptor affinity. This limits the ability to deduce the mechanism of the observed effect. Animal studies suggest that cocaine exposure in a binge pattern increases mOR number rather than affinity (Unterwald, et al. 1992
In summary, our findings show that increased regional brain mOR binding is associated with shorter time to relapse and more severe relapse to cocaine use after monitored abstinence. These findings improve our understanding of the neuropharmacological mechanisms involved in cocaine addiction and could lead to improved treatment and prediction of treatment outcome.