Long-Term Opioid Blockade and Hedonic Response: Preliminary Data from Two Open-Label Extension Studies with Extended-Release Naltrexone

ArticleinAmerican Journal on Addictions 20(2):106-12 · March 2011with6 Reads
DOI: 10.1111/j.1521-0391.2010.00107.x · Source: PubMed
Abstract
The emergence of extended-release naltrexone (XR-NTX) raises the opportunity to explore the role of endorphin blockade on hedonic response during long-term alcohol dependence treatment. A hedonic survey was administered to 74 alcohol dependent patients treated for an average of 3.5 years with nearly continuous month-long intramuscular XR-NTX. The paper-and-pencil, one-time survey asked patients about the degree of pleasure they experienced in the past 90 days with drinking alcohol, sex, exercise and other daily activities. The data revealed lower pleasure ratings for alcohol than for sex, exercise and 10 other common activities. Mean responses to drinking alcohol and gambling were significantly lower than to listening to music, sex, reading, being with friends, eating good food, eating spicy food, and playing video/card games. This effect was independent of XR-NTX dose or duration. Although this exploratory study lacked baseline data, a comparison group or control for the impact of patient discontinuation, the data indicate the feasibility of examining long-term hedonic response in recovery. The differential hedonic ratings suggest that, in patients who persist with long-term continuous therapy, XR-NTX may selectively inhibit the pleasure associated with drinking alcohol, compared to a variety of other activities. 
    • "However, we cannot rule out influences of XRNT on other parts of the dopaminergic system, e.g., on dopamine receptor availability. Importantly, although studies demonstrated that naltrexone induced anhedonia and depressive symptoms in healthy volunteers (Hollister et al. 1981; Murphy et al. 1990; Daniel et al. 1992; Yeomans and Gray 2002), our study and other studies investigating the influence of XRNT treatment on anhedonia in heroin-dependent people did not find a significant increase in anhedonia during XRNT treatment (O'Brien et al. 2010; Tiurina et al. 2011). In our study, depressive symptoms improved significantly after XRNT treatment. "
    [Show abstract] [Hide abstract] ABSTRACT: Extended-release naltrexone (XRNT), an opioid receptor antagonist, is successfully used in the treatment of opioid dependence. However, naltrexone treatment of opioid-dependent patients may reduce striatal dopamine transporter (DAT) availability and cause depression and anhedonia. The aim of this study is to investigate changes in striatal DAT availability and symptoms of depression (Beck Depression Inventory (BDI)) and anhedonia (Snaith Hamilton Pleasure Scale (SHAPS)) before and during XRNT treatment. At baseline, ten detoxified heroin-dependent patients and 11 matched healthy controls underwent [(123)I]FP-CIT single photon emission computed tomography (SPECT) imaging to assess striatal DAT binding. Patients underwent a second SPECT scan 2 weeks after an intramuscular injection with XRNT. At baseline, the mean binding potential (BPND) in the putamen was at a trend level lower and the mean BDI score was significantly higher in heroin patients (n = 10) than in controls (n = 11) (3.45 ± 0.88 vs. 3.80 ± 0.61, p = 0.067, d = -0.48 and 12.75 ± 7.40 vs. 5.20 ± 4.83, p = 0.019, d = 1.24, respectively). Post hoc analyses in subgroups with negative urine analyses for opioids and cocaine showed significantly lower baseline putamen BPND in heroin patients (n = 8) than controls (n = 10) (3.19 ± 0.43 vs. 3.80 ± 0.64, p = 0.049, d = -1.03). XRNT treatment in heroin patients was not significantly associated with changes in striatal DAT availability (p = 0.348, d = 0.48), but the mean BDI score after XRNT treatment was significantly lower than before treatment (7.75 ± 7.21 vs. 12.75 ± 7.40, p = 0.004, d = -0.68). The results of this study suggest that XRNT treatment does not reduce striatal DAT availability and has no significant effect on anhedonia, but is associated with a significant reduction of depressive symptoms.
    Full-text · Article · Mar 2015
    • "Consistent with that concern, studies on the acute effect of opioid antagonists like naltrexone and naloxone have found reduced hedonic effects of physical exercise [35][36][37], gambling [38], eating [39], sex [40] and shop- ping [41]. However, a recent study on the effect of continuous long-term opioid blockade with an extended-release formulation of naltrexone in alcohol-dependent patients showed that naltrexone primarily inhibited the hedonic response associated with drinking alcohol, while sparing the experience of pleasure associated with other activities such as listening to music, being with friends, sex, eating good food and read- ing [42]. The authors mention differences in acute versus the long-term effects and possible differences in plasma concentrations between the different formulations (oral, immediate release vs intramuscular, extended release) as a potential "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To investigate safety and tolerability of nalmefene for reduction of alcohol consumption in alcohol-dependent patients. Methods: Pooled data from three randomized, placebo-controlled studies (two 6-month; one 12-month) of 18 mg nalmefene (as-needed use) in alcohol-dependent patients looking at the total population (placebo n = 824, nalmefene n = 1123) and patients with high/very high drinking risk levels at screening and randomization (target population: placebo n = 374, nalmefene n = 450). Results: In the study, 62.7% of patients on placebo and 74.7% on nalmefene in the total population had treatment-emergent adverse events (TEAEs). Fourty-seven (5.9%) on placebo and 149 (13.0%) on nalmefene dropped out due to TEAEs. Thirty-five (4.4%) on placebo and 57 (5.0%) on nalmefene had serious adverse events. Tolerability and safety were similar in the target population and total population. Most frequent TEAEs were transient, mainly occurring at treatment initiation. There was no difference in tolerability and safety if nalmefene was taken daily or intermittently; no signal of increased risk of suicide-related behavior with nalmefene. The higher incidence of psychiatric events in the nalmefene group was mainly due to the TEAE of confusional state. Conclusions: Although there was a higher incidence of TEAEs and TEAEs leading to dropout, nalmefene was well-tolerated and no major safety issues were identified.
    Article · Feb 2015
    • "Future animal studies investigating the developmental effects of sustained-release naltrexone, particularly on addiction-related behaviours, would provide greater insight in the clinical context if maternal rats were opioid-dependent prior to treatment with naltrexone. Nonetheless, the current study still has much to offer as a clinically-relevant model in that there are a number of potential therapeutic uses for naltrexone in the non-opioid dependent patient, including in the management of alcoholism [3], [4], [99], compulsive gambling [100], [101], [102], [103], multiple sclerosis [104], [105], [106] and obesity [107], [108], [109]. "
    [Show abstract] [Hide abstract] ABSTRACT: Naltrexone is not recommended during pregnancy. However, sustained-release naltrexone implant use in humans has resulted in cases of inadvertent foetal exposure. Here, we used clinically relevant dosing to examine the effects of maternally administered sustained-release naltrexone on the rat brain by examining offspring at birth and in adulthood. Maternal treatment (naltrexone or placebo implant) started before conception and ceased during gestation, birth or weaning. Morphometry was assessed in offspring at birth and adulthood. Adult offspring were evaluated for differences in locomotor behaviour (basal and morphine-induced, 10 mg/kg, s.c.) and opioid neurochemistry, propensity to self-administer morphine and cue-induced drug-seeking after abstinence. Blood analysis confirmed offspring exposure to naltrexone during gestation, birth and weaning. Naltrexone exposure increased litter size and reduced offspring birth-weight but did not alter brain morphometry. Compared to placebo, basal motor activity of naltrexone-exposed adult offspring was lower, yet they showed enhanced development of psychomotor sensitization to morphine. Developmental naltrexone exposure was associated with resistance to morphine-induced down-regulation of striatal preproenkephalin mRNA expression in adulthood. Adult offspring also exhibited greater operant responding for morphine and, in addition, cue-induced drug-seeking was enhanced. Collectively, these data show pronounced effects of developmental naltrexone exposure, some of which persist into adulthood, highlighting the need for follow up of humans that were exposed to naltrexone in utero.
    Full-text · Article · Dec 2012
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