Summary

Chasing the Dragon Away:
Personality as a protective factor and extended-release naltrexone as a treatment for heroin dependence

Objectives
The main objectives of this thesis were (a) to gain better insight in the process of getting addicted to heroin in order to develop personality-based prevention strategies, by studying distinctive personality patterns in heroin users that became
heroin dependent and heroin users that never became dependent; (b) to assess the interest of heroin dependent patients and their treatment providers in treatments directed at total abstinence and specifically in the treatment with extended-release naltrexone (XRNT); and (c) to study whether treatment with XRNT in heroin dependent patients results in decreased striatal dopamine transporter (DAT) availability and in anhedonia and depression as potential side-effects.

Chapter 1 provided a brief introduction to the epidemiology, the treatment situation and the pathophysiology of heroin dependence, its neurobiological aspects and XRNT treatment. The chapter ended with an outline of this thesis.

In Chapter 2 we compared personality traits of illicit opioid users who never became dependent (n=161) with personality traits of opioid dependent patients (n=402) and healthy controls (n=135) using the Temperament and Character Inventory (TCI, Cloninger, 1994) in order to better understand the potential protective role of personality in the development of opioid dependence in subjects who start to use illicit opioids. We found that never-dependent opioid users reported a strong need for social approval (high Reward Dependence) and high self-efficacy (high Self-Directedness), which may have protected them against becoming heroin dependent despite their tendency to seek novel and/or spiritual experiences and to avoid punishment (high Novelty Seeking, Self-Transcendence and Harm Avoidance, respectively), which, at least partly, may be the reason why they had started to use opioids. These results may be used in the development of prevention programs for young people with an increased risk for opioid use and dependence. Personalized interventions may be developed, based on a personality profile, similar to the successful interventions used by Conrod et al. in the prevention of alcohol and drug use (problems) (1,2).

In Chapter 3 we explored the support for abstinence oriented treatments and the acceptability of XRNT injections for heroin dependent patients in The Netherlands. We also studied the acceptability of XRNT injections among treatment providers. A total of 261 patients and 188 treatment providers filled out questionnaires, showing that 58% of the patients wanted to become abstinent from all opioid agonists, 83% of which were interested in XRNT injections. Similarly, 81% of the treatment providers supported the prescription of XRNT to opioid dependent patients. Most of these patients were currently in an opioid agonist maintenance program and given these data it seems reasonable to regularly ask these patients about their treatment goal and not to automatically continue substitution treatment in these patients. In addition, we should investigate whether it would be possible to get XRNT available for patients in The Netherlands. There are some high quality studies (3–6) and one meta-analysis (7) indicating that XRNT is much more effective than oral naltrexone, and new initiatives should be taken to improve the access to XRNT for heroin dependent patients in The Netherlands.

However, among both patients and treatment providers, there are worries about the possibility of naltrexone-induced anhedonia and depression, because naltrexone blocks the µ-opioid receptor, which in turn may result in a decreased hedonic response to natural rewarding activities. This blockade of the µ-opioid receptor may indirectly cause a reduction of dopamine release and finally a down- regulation of striatal DATs. Therefore, we tested the hypothesis that treatment with (extended-release) naltrexone results in anhedonia and decreased striatal DAT availability. In Chapter 4 we report on a study in rats after 3 mg/kg short acting naltrexone for 10 days, and in Chapter 5 we present data on a study in humans two weeks after an intramuscular injection with 380 mg naltrexone using [123I]FP-CIT as a radiotracer for assessing DAT binding, using storage phosphor imaging in rats and Single-Photon Emission Computed Tomography (SPECT) imaging in humans. In rats, food intake, body weight gain and abdominal fatpad weight were studied as measures of anhedonia. In humans, we assessed symptoms of anhedonia and depression using self-report questionnaires. In both studies, no statistical significant effect of naltrexone treatment on striatal DAT availability was found, and there was also no effect of naltrexone on food intake in rats or on anhedonia in humans. This suggests that treatment with naltrexone has no negative effects on hedonic responses and that clinical use of naltrexone is compatible with a maintained pleasurable response to natural rewarding activities, at least in acute and subchronic treatment. Interestingly, we also showed that baseline striatal DAT binding (i.e., before the start of XRNT treatment) was significantly lower in opioid dependent patients than in matched controls, which is in agreement with previous studies (8–11), suggesting that chronic opioid use is associated with a decrease in striatal DAT availability. It is not clear whether this phenomenon represents a causal factor or a consequence of the disorder and we also do not know whether this low DAT availability is reversible.