Psychopharmacology DOI 10.1007/s00213-011-2512-0
ORIGINAL INVESTIGATION
Effect of craving induction on inhibitory control in opiate dependence Antonio Verdejo-García & Dan I. Lubman & Anne Schwerk & Kim Roffel & Raquel Vilar-López & Trudi MacKenzie & Murat Yücel
Received: 29 June 2011 / Accepted: 12 September 2011 # Springer-Verlag 2011
Abstract Rationale Current neurobiological models of addiction posit that drug seeking is much more likely to occur during emotionally charged states (such as craving), as deficits in inhibitory control become more pronounced during heightened motivational states. Objective The purpose of this study was to examine the effect of cue-induced craving states on attention and inhibitory control within addicted individuals. Methods We tested the performance of 39 opiate-dependent individuals on cognitive measures of attention (Digit Span, Digit Symbol, and Telephone Search) and inhibitory control (Counting Stroop and Go-No-Go) both before and after Electronic supplementary material The online version of this article (doi:10.1007/s00213-011-2512-0) contains supplementary material, which is available to authorized users. A. Verdejo-García : A. Schwerk : R. Vilar-López : M. Yücel Melbourne Neuropsychiatry Center, University of Melbourne, Melbourne, VIC, Australia A. Verdejo-García : R. Vilar-López Department of Clinical Psychology, Universidad de Granada, Granada, Spain A. Verdejo-García : R. Vilar-López Institute of Neuroscience F. Olóriz, Universidad de Granada, Granada, Spain A. Verdejo-García : D. I. Lubman (*) : R. Vilar-López Turning Point Alcohol and Drug Centre, Eastern Health and Monash University, 54-62 Gertrude Street, Fitzroy, VIC 3065, Australia e-mail:
[email protected] K. Roffel : T. MacKenzie : M. Yücel Orygen Youth Health Research Centre, University of Melbourne, Melbourne, VIC, Australia
exposure to an autobiographical craving script. A non-drug using healthy control group (n=19) performed the same tasks before and after listening to a relaxation tape. Results Following craving induction, opiate-dependent individuals demonstrated improved performance on tests of processing speed and attentional span (consistent with the practice effect observed in controls) and increased their response errors on the Stroop task (in contrast to controls), while selective attention was unaffected. Individual differences in compulsivity mediated the association between craving and Stroop performance, such that low-compulsive (but not high-compulsive) individuals committed more response errors after craving induction. Conclusions These findings challenge the notion of cueinduced craving as a primary trigger of disrupted cognition and drug-seeking behavior in addicted individuals, and raise the need to explore individual differences in compulsivity when addressing the links between craving and loss of control within research and clinical settings. Keywords Opiate dependence . Craving . Attention . Inhibitory control . Compulsivity . Drug-seeking behavior
Introduction Current neurobiological models conceive addiction as a brain-related dysfunction associated with inflated valuations of drug-related reinforcers and a disrupted inhibitory control system (Lubman et al. 2004; Verdejo-García and Bechara 2009). According to these models, drug seeking is much more likely to occur during emotionally charged (i.e., “hot”) states (such as craving), as deficits in inhibitory control become more pronounced during heightened motivational states (Hester and Garavan 2009). This phenom-
Psychopharmacology
enon is also consistent with classic conceptualizations of cue-induced craving as a key driver of compulsive drug taking (Robinson and Berridge 1993). Indeed, drug-related cues robustly trigger conditioned responses in animal models that lead to drug reinstatement and sustain drug seeking despite potential adverse consequences (Weiss 2005). Such drug cue reinstatement is resistant to extinction and persists despite protracted abstinence (Ciccocioppo et al. 2004). In human drug users, drug cues direct attentional processes (Lubman et al. 2009) and reliably induce craving states (Drummond et al. 2000). The brain substrates of cueinduced craving overlap with regions involved in inhibitory control, which include the anterior cingulate cortex and the lateral orbitofrontal cortex (Daglish et al. 2003). Moreover, altered functioning of these regions during performance on inhibitory control tasks is associated with drug relapse (Brewer et al. 2008). Thus, findings from both animal and human studies suggest that craving is a critical trigger for drug relapse, most likely through its impact on attentional and cognitive functioning (Franken 2003). Although the role of craving in relapse has been a central discussion point for several decades, virtually no studies have examined the effect of cue-induced craving states on inhibitory control within addicted populations. The notion that craving states should disrupt cognitive functioning is central in Tiffany’s theory (Tiffany 1990), which defines craving as a non-automatic cognitive process that interferes with performance on other cognitive skills engaged in parallel. However, there is some indirect evidence suggesting the opposite phenomenon (i.e., craving states may actually improve cognitive performance). For example, a recent study demonstrated that opiate users significantly reduced their false alarm rates when they performed the Go/No-Go task under a stress-induced craving state (Constantinou et al. 2010). In addition, studies that have revamped cognitive measures to include drug-related stimuli (e.g., learning or eliciting drug-related words) have shown that addicted individuals actually outperform controls in memory and controlled oral word production tests (Beatty and Borrell 2000; Goldstein et al. 2007). These seemingly counterintuitive findings raise the possibility that, in addicted individuals, craving states may produce cognitive enhancement and increased inhibitory control, possibly by increasing arousal levels and noradrenergic output (Sinha et al. 2003), which would result in fine tuning of attentional and response inhibition skills (Sofuoglu 2010). When examining the effects of craving on inhibitory control, it is important to note that impulsive behavior has been proposed to become compulsive during the development of addiction (Everitt and Robbins 2005; Lubman et al. 2004), thereby promoting stimulus–response (S–R) automatic behavior regardless of outcome values (Belin et al.
2008). As such, drug taking may become dissociated from the valuation of outcome expectancies (i.e., craving) in highly compulsive addicted individuals (Hogarth 2011); hence, high compulsivity may decrease the link between craving and inhibitory control. In this study, we sought to address these unresolved questions by examining the performance of opiatedependent individuals on a series of well-validated measures of attention and inhibitory control both before and after exposure to an autobiographical craving script. We also examined if levels of compulsivity (measured by an adaptation of the Yale–Brown scale designed to capture obsessions and compulsions related to opiate use) were associated with changes in inhibitory control performance after craving induction. We chose to study opiate dependence as it is thought to be one of the most pervasive forms of addiction, in which the phenomenon of cue-induced craving is extremely robust (Carter and Tiffany 1999). A well-functioning sample of opiatedependent individuals was sought, with cognitive performance levels equivalent to those of the control group, to ensure that the findings were not confounded by differences in cognitive ability.
Methods Participants Participants were recruited through public advertisements and included 19 controls (mean age, 29.2 years; SD, 7.6) and 39 opiate-dependent individuals (mean age, 31.5 years; SD, 7.0) that were stabilized on opioid substitution pharmacotherapy (23 on buprenorphine and 16 on methadone). Patients receiving buprenorphine and methadone did not differ on clinical characteristics (severity of dependence, depression and anxiety levels) or baseline cognitive performance and were therefore collapsed for the analyses. The clinical characteristics of the opiate-dependent group are displayed in Table 1. Opiate-dependent individuals and Table 1 Descriptive scores for clinical measures and IQ in opiatedependent individuals and non-drug-using participants Opiate-dependent individuals (n=39) SDS OCDUS BDI BAI Full IQ
8.3 8.9 14.2 10.6 111.6
(3.8) (19.6) (9.6) (7.5) (11.2)
SDS Severity of Dependence Scale
Controls (n=19)
T, p
– – 8.8 (4.2) 6.7 (6.8) 120.4 (10.9)
– – 5.11, p4 weeks) on methadone or buprenorphine. Participants were excluded if they had any other current comorbid psychiatric disorder, a history of significant seizures, neurological disease, electro-convulsive therapy, psychotropic or benzodiazepine treatment, impaired thyroid function or steroid use, and were dependent on more than one substance (excluding nicotine and caffeine). Control subjects were excluded if they had a current or past history of drug abuse/dependence; however, neither moderate use of caffeine ( 0.05), with the exception of GNG number of commission errors, which was significantly higher in controls, t=−2.81, p=0.007. The descriptive scores of performance indices are displayed in Table 3.
Results Effects of craving induction on desire for drugs Univariate repeated-measures ANOVAs demonstrated that the craving manipulation successfully increased craving levels in the opiate-dependent group; craving VAS ratings were significantly increased after craving induction (see Table 2). These changes were statistically significant for the average scores of desire and intention and negative reinforcement. No significant changes were observed for the control dimension.
Table 2 Descriptive scores and statistics for VAS-indexed craving ratings before and after exposure to the autobiographical craving script Craving dimensions
Desire and intention Negative reinforcement Control
Pre-craving induction
Post-craving induction
Mean SD
Mean
18.2 30.6 52.7
18.2 30.0 35.0
24.7 38.2 50.9
F(1,38) p
SD 22.7 32.2 35.1
8.68 11.82 0.20
0.005 0.001 0.66
Effects of craving induction on cognitive performance Results are presented in Table 3. Opiate-dependent individuals demonstrated significantly improved performance on Digit Span, Digit Symbol, and Telephone Search time per target scores following craving induction. The control group also demonstrated significant improvements on Digit Symbol and Telephone Search following repeated administration of these tests. Improvement on Digit Span was not found to be significant in controls, but the size of the effect was similar to that observed in the opiate group (see Table 3). Conversely, opiate-dependent individuals significantly increased their response errors on the Stroop test following craving induction—indicating poorer performance after craving, an effect that was not observed in controls following the relaxation tape. Telephone Search dual task decrements, Stroop, and GNG reaction times did not significantly change in either group following craving induction or the relaxation tape. We observed a paradoxical effect on GNG commission errors, where controls—but not the opiate group—demonstrated a significant increase in the number of errors following repeated administration. Effects of craving induction on cognitive performance in high- vs. low-compulsive opiate users Opiate-dependent individuals were classified as high (n= 20) vs. low compulsive (n=17) according to a median split on the OCDUS scale. These two subgroups did not significantly differ on any of the demographic or clinical measures, including age, IQ, depression, anxiety, and severity of dependence (see Electronic supplementary material). When we examined the differential effect of the craving manipulation on cognitive performance between subgroups, we found that low-compulsive opiate-dependent individuals, but not high-compulsive users, committed more Stroop response errors after the craving induction. As seen in Fig. 2, individuals classified as low compulsive demonstrated a doubling in their number of response errors, whereas high-compulsive subjects maintained a stable number of errors following repeated test administration.
Psychopharmacology Table 3 Descriptive scores and statistics for cognitive performance of opiate-dependent individuals before and after induction of craving, and controls before and after the relaxation tape Opiate-dependent individuals Pre-craving induction
Post-craving induction
Controls F(1,38)
Partial eta square
Pre-relaxation tape
Post-relaxation tape
F(1,18)
Partial eta square
Digit Span
17.67 (3.64)
18.62 (3.96)
5.21, p=0.03
0.12
19.58 (5.39)
20.47 (5.56)
2.54, p=0.13
Digit Symbol
75.03 (13.41)
87.26 (15.01)
46.35, p
