Methadone maintenance patients show a selective deficit to reverse positive outcomes in drug-related conditions compared to medication free prolonged opiate abstinence
Introduction
Drug addiction is a chronic relapsing disease. Most drugs users will relapse back to using drugs over and over again throughout their life. These relapses may become more frequent in the presence of contextual reminders (see Chase et al., 2011 for meta-analyses of studies in substance abuse populations; Engelmann et al., 2012 for meta-analyses of studies in nicotine abusers). For instance, places where an individual used to inject or abuse drugs, equipment (syringe, needles), or people that were present during drug abuse may become classically conditioned, evoke craving and withdrawal symptoms, and lead to drugs usage (for a review of studies in substance abuse populations see O’Brien et al., 1998).
The majority of opioid-dependent individuals require long-term opioid agonist maintenance treatment like full agonist methadone (for a review see Kreek and Vocci, 2002) or the partial agonist buprenorphine (for a review see Bart, 2012) to minimize repeated relapsing. Yet, 20–30% of opioid dependent individuals are able to successfully discontinue abusing drugs and take on a drug free life style (Haastrup and Jepsen, 1984; DSM-IV-TR, 2000). It is possible that repeated relapsing is associated with impaired reversal learning. The goal of the present study is to test differences in reversal learning in individuals who discontinued drug use and methadone maintenance patients. Specifically, we aim to test whether a sample of individuals who discontinued drug use with no need of opioid maintenance have an advantage in learning and reversing stimulus–outcome associations in drug-related conditions, compared to a sample of individuals on long-term methadone treatment. To that end, we concentrate on a unique population of DSM-IV-TR previous opiate dependence, who were either successfully discontinued their drug abuse for more than 10 years (prolonged abstinence participants) with no need of agonist treatment or patients in methadone maintenance treatment for at least 10 years. These groups were tested on a novel partial reversal paradigm, which test the ability to acquire and reverse stimulus–outcome associations in neutral and drug-related context.
Studies on cocaine abusers have shown that exposure to drug-related reminders may activate the reward brain circuit, providing temporary positive feelings (Volkow et al., 2006, Volkow et al., 2008). These positive feelings are sooner or later replaced with negative feelings and outcomes (e.g., drugs dependency, which is associated with inability to maintain stable social and occupational life and its accompanying costs). However drug users usually do not alter their behavior accordingly (for a review of substance abuse populations, see Jasinska et al., 2014).
One factor that may contribute to maintaining this mechanism is impaired reversal learning in drug users. Animal and human studies have shown that cocaine usage is associated with impaired reversal learning (Camchong et al., 2011, Izquierdo et al., 2010, Jentsch et al., 2001). Hence, after learning that a specific stimulus has a certain outcome, cocaine abusers may struggle to learn that the same stimulus is later associated with a different outcome. Another factor that may facilitate such mechanisms relates to deficits in the brain reward circuit among drug users (Volkow et al., 2010 for review see Volkow et al., 2011; for animal study see Smith et al., 2011). Specifically, drug users may continue to attribute positive outcomes to specific stimuli even in situations when it is no longer adequate. These findings may suggest that drug users have a selective impairment in reversing positive outcomes in drug-related conditions.
In order to test this assumption we developed a novel partial reversal learning paradigm. In a common reversal paradigm, participants acquire a stimulus–outcome association (S → Positive) and later need to reverse the outcome of the same stimulus (S → Negative). Such a paradigm does not take into account that stimulus dimensions regularly occur in a specific context (Mayes et al., 1992, Murnane et al., 1999). Our paradigm has three innovative aspects; first, we manipulate partial reversal learning while using different contextual conditions. Hence, participants learn stimulus–outcome associations in one contextual condition (S in Context A → Positive). Later they see the same stimulus in a new context. However now it is associated with the opposite outcome (S in Context A → Positive, while S in Context B → Negative). Second, we manipulate the type of context, using neutral and drug-related contexts. While impaired ability to reverse the outcome of stimuli presented in neutral context (Fig. 1) may reflect a general cognitive impairment, selective impairment in drug-related context (Fig. 2) might suggest a more complex mechanism. Finally, we compared performance in conditions in which a previously positive stimulus becomes negative to conditions in which previously negative stimulus becomes positive. This paradigm enables us to test possible effects of valance (positive vs. negative outcomes) and contextual condition (neutral vs. drug-related context) on the ability to reverse previously learned information.
Based on the literature cited above we predict that participants from both methadone maintenance treatment and medication free abstinent groups would equally be able to learn and retain positive and negative stimulus–outcome associations that are presented in drug and neutral context. However, we anticipate that while medication free abstinent would show intact reversal learning in both neutral and drug-related contexts, methadone maintenance patients would show a selective impairment to reverse positive outcome in a drug-related context.
Section snippets
Participants
We tested two groups of former opiate dependence individuals, who volunteered to participate in this study with no compensation and were matched for age, gender and education (Table 1). Inclusion criteria were based on DSM-IV-TR definition of opiate dependence. The first group included prolonged abstinence for at least 10 years representing a non-selective subgroup that was recruited consecutively to participate in a separate genetic study. None of these participants had any history of opioid
Results
There were no differences between the groups in lifetime opioids scores indicating amount of past opioids usage (Kellogg et al., 2003). However, the prolonged abstinence group displayed a significantly younger age of opioids onset (Table 1). In addition, there were no significant differences between the groups in levels of depression and anxiety symptoms, levels of childhood trauma, cognitive function and estimated IQ (Table 3). Finally, since there were no differences between the groups in
Discussion
In the present study, we conducted a unique comparison of former opiate-dependent individuals, who were either successfully discontinued their drug abuse for more than 10 years with no need of agonist treatment or patients in methadone maintenance treatment for at least 10 years. Participants were tested on a novel paradigm which examines the ability to reverse positive and negative outcomes in neutral and drug-related context. As predicted, the results revealed a selective impairment of
Role of funding source
Nothing declared.
Contributors
ELG – design of the paradigm, design of the study, responsible for recruiting and testing participants, analyzing data, writing and finalizing the manuscript; SK – design of the paradigm, analyzing data; ARS – testing participants, preparation of the manuscript. AS – responsible for recruiting and testing participants; MA – responsible for recruiting and testing participants. EP – design of the study, responsible for recruiting and testing participants, writing and finalizing the manuscript.
Conflict of interest
No conflict declared.
Acknowledgements
We wish to thank Anna Blekhman, Noa Chubra, Rotem Gal and Keren Israeli for their help in administrating this study. In addition, we wish to thank Yuval Gigi for her wonderful ideas and technical support.
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