Pharmacological enhancement of naltrexone treatment for opioid dependence: a review

Abstract

Purpose Opioid dependence (OD) is a serious and growing clinical condition with increasing social costs that requires expanding treatment beyond opioid agonist substitution. The opioid antagonist naltrexone has displayed a remarkable association of theoretical effectiveness and poor clinical utility in treating OD due to noncompliant behavior and low acceptability among patients, only partly modified by psychosocial interventions. We reviewed pharmacological studies, including naltrexone depot formulations and combination treatments. Method We searched PubMed for clinical studies on the use of naltrexone implants and slow-release injections in OD, and investigations using adjunct medications to improve naltrexone maintenance therapy of OD. We discussed the results in view of their application to the clinical practice. Results Significant reduction in opioid use and improved retention in treatment have been found in several studies using depot naltrexone formulations, some of which are controlled clinical trials. Pilot investigations have gathered initial positive results on the use of naltrexone in combination with serotonin reuptake inhibitors, α-2 adrenergic, opioid, and γ-aminobutyric acid agonist medications. Conclusion Current evidence suggests that more research on effectiveness and safety is needed in support of depot naltrexone treatment for OD. Further research comparing slow-release with oral naltrexone and opioid agonist medications will help characterize the role of opioid antagonist-mediated treatment of OD. Preliminary investigations on naltrexone combination treatments suggest the opportunity to continue study of new mixed receptor activities for the treatment of OD and other drug addictions.

Cocaine reverses the naltrexone-induced reduction in operant ethanol self-administration: The effects on immediate-early gene expression in the rat prefrontal cortex

“…One reasonable explanation is that the neurobiological changes induced by cocaine overcome those induced by naltrexone. Naltrexone exhibits an affinity 10e25 times higher for the mu opioid receptors than for the kappa or delta receptors (Mannelli et al, 2011). The activation of mu opioid receptors indirectly causes excitatory effects in dopaminergic neurons by inhibiting the release of the inhibitory neurotransmitter GABA in critical brain areas regulating euphoria and reward (Corbett et al, 2006;Guy et al, 2011;Nestler, 2001).…”

Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: A very low dose naltrexone and buprenorphine open label trial

“…Naltrexone (NTX) offers a different approach but low interest and high dropout among patients that were treated with the oral formulation (Minozzi et al, 2011) led to the dismissal of NTX as a meaningful treatment in the minds of many clinicians and researchers (Adi et al, 2007; Mannelli et al, 2011). Concerns have also been expressed that NTX increases depression and anxiety and the risk for overdose death (Miotto et al, 1997; Ritter, 2002), however data from studies of oral and extended release naltrexone have shown that depression and anxiety actually decrease in patients that continue NTX (Krupitsky et al, 2012, 2004, 2006) and that there is no apparent increased risk of overdose death after treatment ends (Woody and Metzger, 2011).…”

“…The introduction of sustained release injectable NTX with the recommendation to be given every 4 weeks or once a month (XR-NTX; Vivitrol®; Vivitrol®, 2013), has attracted growing interest due to its advantages for improved adherence, however patients must be free of physiological opioid dependence before it is administered to avoid precipitating withdrawal, thus effective use is contingent on the management of opioid discontinuation (Mannelli et al, 2011). Among available interventions, outpatient detoxification has had very low success rates (Kleber, 2007) and though inpatient treatment is accessible to insured patients, the coverage often falls short of providing the 7 to 10 opioid-free days necessary to eliminate physiological dependence (Gonzalez and Brogden, 1988; Kleber, 2007) and avoid precipitated withdrawal with the first dose XR-NTX (Vivitrol®, 2013).…”

Advances in Opioid Antagonist Treatment for Opioid Addiction

“…Such combinations require careful evaluation by well-designed controlled clinical studies to understand the added therapeutic effects as well as safety issues. 14 The availability of XR-NTX represents a potentially valuable approach for replicating and improving studies done with oral naltrexone, because XR-NTX is likely to eliminate concern about medication compliance the adherence issue. Meanwhile, clinicians must balance the potential benefit against the added side effects and the potential for abuse of the added medications.…”