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

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. .upenn
American Journal on Addictions (Impact Factor: 1.74). 03/2011; 20(2):106-12. DOI: 10.1111/j.1521-0391.2010.00107.x
Source: PubMed


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. 

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    • "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]. "
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    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.
    PLoS ONE 12/2012; 7(12):e52812. DOI:10.1371/journal.pone.0052812 · 3.23 Impact Factor
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    • "Recent studies also suggest that gamma-hydroxybutyric acid (Addolorato et al. 2009), acamprosate (Mann et al. 2008), baclofen (Soyka and Rosner 2010), and desipramine (O'Brien et al. 2011) may have potential for the treatment of alcohol dependence, most likely through varied and unidentifi ed mechanisms. This variability is not surprising given that alcohol addiction is a polygenic disease that involves many neurobiological pathways and numerous genes (for review see Goldman et al. 2005). "
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    ABSTRACT: Substance addiction is a maladaptive behavior characterized by compulsive and uncontrolled self-administration of a substance (drug). Years of research indicate that addictive behavior is the result of complex interactions between the drug, the user, and the environment in which the drug is used; therefore, addiction cannot simply be attributed to the neurobiological actions of a drug. However, despite the obvious complexity of addictive behavior, animal models have both advanced understanding of addiction and contributed importantly to the development of medications to treat this disease. We briefly review recent animal models used to study drug addiction and the contribution of data generated by these animal models for the clinical treatment of addictive disorders.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 03/2012; 53(1):4-13. DOI:10.1093/ilar.53.1.4 · 2.39 Impact Factor
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    ABSTRACT: Extended-release naltrexone (XR-NTX; Vivitrol), developed to address poor adherence in addictive disorders, is approved for use in alcohol and opioid-dependence disorders. In alcohol-dependent adults with ≥ 4-day initial abstinence, XR-NTX increased initial and 6-month abstinence. An fMRI study found that XR-NTX attenuated the salience of alcohol visual and olfactory cues in the absence of alcohol, and post hoc analyses demonstrated efficacy even during high cue-exposure holiday periods. Safety and tolerability have generally been good, without adverse hepatic impact or intractable acute pain management. XR-NTX use appears feasible in primary care and public systems, and retrospective claims analyses have found cost savings and decreased intensive service utilization relative to oral agents. In opioid dependence, following detoxification, XR-NTX shows efficacy for maintaining abstinence, improving retention, decreasing craving, and preventing relapse. Trials are also exploring its use for the treatment of stimulant dependence. XR-NTX appears compatible with counseling and self-help attendance. While more research is needed, current findings suggest that a formulation of naltrexone that was sought beginning over three decades ago is fulfilling its promise as an extended-release pharmacotherapeutic.
    Annals of the New York Academy of Sciences 01/2011; 1216(1):144-66. DOI:10.1111/j.1749-6632.2010.05900.x · 4.38 Impact Factor
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