Aversion processing following chronic opioid use with and without addiction

Abstract

For millennia, humans have used opioids to relieve physical pain, anxiety, and insomnia. Today, opioids often provide a last resort for patients with chronic pain for whom other treatments fail. Repeated use, however, carries a risk of misuse and around 10 to 20 percent of users develop opioid addiction, a chronic disorder characterised by continued opioid use despite severe adverse consequences. Who develops addiction and who does not is a poorly understood, yet critically important question, especially in light of the current opioid overdose epidemic in North America, costing over 100,000 lives per year. Functionally, opioids exert their effects by stimulating the μ-receptor system which manipulates the perceived aversiveness of states. Chronic use results in neuroadaptations to this system, potentially disturbing aversion processing, an umbrella term for mechanisms related to the experience of disliking a stimulus or state. In this thesis, my aim was to systematically characterise aversion processing following chronic opioid use with and without addiction in order to 1) identify potential alterations related to chronic opioid use and 2) clarify which aspects of aversion processing are specifically altered in addicted patients and might thus contribute to the development or maintenance of opioid addiction. For this, I analysed behavioural, psycho-physiological, and functional neuroimaging data of 86 participants, 23 of whom were addicted to opioids and 25 were not addicted, but were using opioids chronically for the treatment of chronic pain. While subjective and physiological responses towards aversive stimuli were by and large similar to healthy participants, both patient groups displayed attenuated fear conditioning as well as aversive instrumental learning. Opioidergic neurotransmission underlies aversive prediction error signalling, which suggests that chronic opioid use might lead to the observed learning deficits. However, the cross-sectional nature of this study does not allow for causal inferences on the relationship between chronic opioid use and altered aversive learning. As hypothesised, opioid-addicted patients showed a higher motivational response to drug-related pictures compared to neutral pictures that had previously paired with rewards. Crucially, presentation of drug-related stimuli induced a behavioural bias, promoting approach over avoidance in disadvantageous situations and potentially contributing to relapse in opioid addiction. Contrary to theoretical considerations, there was no conclusive evidence for an overreliance on habits in opioid-addicted patients, indicating intact regulatory control over avoidance behaviour. In summary, this thesis provides valuable evidence on aversion processing following chronic opioid use and offers novel targets for understanding and treating opioid addiction.