Curr Treat Options Psych (2017) 4:221–230 DOI 10.1007/s40501-017-0110-4

Substance Use Disorders (FG Moeller, Section Editor)

Antagonist Treatment for Opioid Dependence: Promise and Hurdles Evgeny Krupitsky, MD, PhD, DMedSci1,2,3,* Elena Blokhina, MD, PhD1 Edwin Zvartau, MD, PhD, DMedSci1 George Woody, MD3 Address 1 Laboratory of Clinical Pharmacology of Addictions, First Pavlov State Medical University of St. Petersburg, Lev Tolstoy St. 6-8, Saint Petersburg, Russian Federation 197022 *,2 Department of Addictions, Bekhterev Research Psychoneurological Institute, Bekhtereva St., 3, Saint Petersburg, Russian Federation 192019 Email: [email protected] 3 Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

Published online: 20 April 2017 * Springer International Publishing AG 2017

This article is part of the Topical Collection on Substance Use Disorders Keywords Opioid dependence I Naltrexone I Sustained release formulations I Naltrexone implant I Pharmacogenetics

Opinion statement Relapse rates among treatment-seeking opioid-addicted individuals are extremely high but can be markedly reduced by agonist-based maintenance therapies such as methadone or buprenorphine. However, these therapies are not always available due to a limited number of providers, waiting lists to access treatment, or laws that prevent their use. In addition, some persons do not want agonist-based therapy because they do not like its subjective effects, tried it with less than optimal results, and had trouble stopping it when they felt ready or because family or other external pressures oppose it. For these individuals, antagonist-based therapy can fill an important niche, particularly when administered as an extended-release formulation that blocks opioid effects for several weeks or months, thus offering protection from the adverse effects of opioid use including overdose and giving the patient a chance to begin working on lifestyle changes that are necessary to work toward sustained remission. This paper will review existing findings on naltrexone for opioid addiction treatment. Antagonist treatment, particularly when delivered as an extended-release formulation, is a meaningful addition to current treatment options for opioid-dependent patients who do not want or do not have easy access to agonist or longterm residential treatment. Genetic analysis might be useful for determining potential responders to naltrexone treatment of opioid dependence but additional studies are needed.

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Introduction Opioid use disorders (opioid dependence or “addiction”) are one of the most significant substance use disorders worldwide due to its association with mortality, morbidity, and criminal behavior. To date, the US Food and Drug Administration has approved three medications for preventing relapse to opioid addiction. One is naltrexone, a competitive μ-opioid receptor antagonist that blocks exogenous opioids and the euphoric effects of heroin and prescription opioids [1]. One 50-mg oral capsule or tablet provides opioid blockade for 24–36 h and long-term use does not cause tolerance to its blocking effect [2]. Patients need to complete detoxification and be free of physiologic dependence before naltrexone is administered; otherwise, it will precipitate withdrawal. Provided this condition has been met, it is easy to administer (one dose per day or two every other day), safe (no serious adverse events if used as

recommended), and well tolerated (few side effects) and does not have addictive potential. Because of its blocking action, self-administration of opioids at usual doses produces no euphoric effect so that the patient either stops using opioids or ceases taking naltrexone [3]. Like other medications, naltrexone is effective only so long as the patient takes it; thus. compliance is very important [4–6]. It is facilitated by involving families or other significant others in supervised dosing; where there is substantial external motivation to remain abstinent, such as with individuals under criminal justice supervision or health care professionals who are at risk for losing their license if they use; in settings where naltrexone is the only available treatment option [1, 7]; or when long-acting sustained release formulations are used rather than tablets or pills. The results of studies using these formulations are reviewed below.

Oral naltrexone Naltrexone only The earliest studies of oral naltrexone were done in the USA where agonist maintenance is available and inpatient detoxification is limited due to its high cost and has little success [8, 9]. However, a successful placebo-controlled, randomized trial was conducted in the late 1990s in St. Petersburg, Russia [4]. It aimed to evaluate the efficacy and safety of oral naltrexone for relapse prevention and reducing HIV risk in heroin addicts and involved 52 consenting patients with heroin dependence who were randomized to a 6-month course of naltrexone, 50 mg/day, or placebo after completing detoxification at local addiction treatment hospitals. All treatments were combined with relapse prevention counseling one or more close family members (e.g., mother, spouse) agreed to supervise daily dosing. Significant differences in retention and relapse rate favoring naltrexone were seen starting at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 (44%) patients in the naltrexone group remained in the study and had not relapsed compared to 4 of 25 (16%) in the placebo group (p G 0.05). Among patients who remained in the study, compliance with medication measured by a riboflavin marker in the urine was about 90%, likely the result of family supervision. The number of opiate positive urine tests was equal in both naltrexone and placebo groups early in the study, followed by substantially higher dropout and relapse among placebo patients. A limited number of side effects were reported and no patients dropped out due to them, thus providing evidence of good tolerability, similar to findings from other studies. Although this study demonstrated that oral naltrexone was significantly more effective than detoxification and counseling alone, a later Cochrane review found

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no statistically significant difference between naltrexone, placebo, or other treatment studies that did not have pharmacological treatments [10]. The two major problems of oral naltrexone treatment the review identified were high dropout rate and lack of effect on protracted withdrawal-related psychiatric symptoms.

Naltrexone with other psychoactive medications Naltrexone and selective serotonin reuptake inhibitors Since the use of oral naltrexone was associated with poor retention and low patient adherence, some thought that combining it with an antidepressant might alleviate symptoms related to protracted withdrawal and improve adherence and outcomes. The first double-blind pilot study provided little or no data to indicate that naltrexone itself reduced the depression, anxiety, and anhedonia that are typically associated with heroin dependence and withdrawal following detoxification [4]. Therefore, addition of antidepressants might eliminate these symptoms and improve the results of naltrexone therapy. To study this possibility, the clinical efficacy of naltrexone combined with selective serotonin reuptake inhibitors was evaluated in several clinical trials. In particular, Krupitsky et al. (2006) conducted a randomized placebo-controlled trial aimed to evaluate the efficacy of naltrexone with or without fluoxetine [5] among 280 consenting heroin-dependent patients that completed detoxification at addiction treatment hospitals in St. Petersburg, Russia, and were randomly assigned under double-dummy, double-blind conditions to one of four treatment groups (n = 70 in each): naltrexone (N, 50 mg once a day) plus fluoxetine (F, 20 mg once a day), naltrexone plus fluoxetine placebo (FP), naltrexone placebo (NP) plus fluoxetine, or double placebo. The study was 6 months in duration, the primary outcome was relapse to opioid (heroin) dependence, and all participants were offered biweekly drug counseling. Urine drug testing and brief psychiatric evaluations were conducted at each study visit and medication compliance was evaluated biweekly using a riboflavin marker; more extensive psychiatric evaluations were done at 3 and 6 months. A survival analysis revealed significant differences in retention between groups receiving naltrexone (N/F and N/FP) and those randomized to naltrexone placebo (p G 0.001). At the end of 6 months, 43% of patients treated with N/F remained in the study and had not relapsed as compared with 36% in the N/FP group, 21% in the NP/F group, and 10% in the double placebo group. The difference between the naltrexone/fluoxetine and naltrexone alone groups was not significant. Overall, adding fluoxetine did not improve naltrexone treatment outcomes; however, a secondary analysis focused on women participants showed that the N/F group had a non-significant trend toward an advantage when compared to women receiving naltrexone and placebo fluoxetine (N/FP; p = 0.08). The combination of naltrexone and fluoxetine was well tolerated, the number of side effects was small, and neither serious adverse events nor lethal overdose occurred [5].

Naltrexone and alpha-adrenergic agonists Previous studies have been shown that stress plays a key role in drug craving and addiction relapse [11]. Hyman et al. demonstrated that opioid-dependent

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Substance Use Disorders (FG Moeller, Section Editor) patients experience higher level of stress than healthy control subjects and have a maladaptive response to stress [12]. The first study in humans to assess alpha2 adrenergic receptor agonist lofexidine as an anti-stress and relapse prevention treatment was conducted at Yale where a study of 18 opioid-dependent patients treated with oral naltrexone and lofexidine for 4 weeks revealed a higher opioid abstinence rate and reduction of stress-related craving among naltrexonelofexidine patients compared to placebo [13]. How many were in the placebo group? This finding provided support for as study that combined an alphaadrenergic agonist to target persistent withdrawal and stress-related opiate craving with naltrexone to reduce the subjective effects of opioid administration. The study used a randomized, double-blind, double-dummy, placebocontrolled design study to evaluate the safety and tolerability of guanfacine (a presynaptic alpha-adrenergic ligand used to treat hypertension) in combination with naltrexone for treatment of heroin addiction [14]. It randomized 301 consenting, heroin-dependent patients who had completed inpatient detoxification into the one of the four groups: naltrexone (N) 50 mg/day + guanfacine (G) 1 mg/day (N/G) (n = 75), naltrexone + guanfacine placebo (N/GP) (n = 76), naltrexone placebo + guanfacine (NP/G) (n = 75), and double placebo (NP/GP) (n = 75) [14]. At the end of 6 months, there was no significant difference in retention between the N/G and N/GP groups. In particular, retention in the N/G group was 26.7%, in N/GP group 19.7% (p = 0.26 to N/G), in the NP/G group 6.7% (p G 0.05 to both N groups), and in the NP/GP group 10.7% (p = 0.013 to N/G group, Fisher exact test). The combination of naltrexone and guanfacine was safe but the alpha-adrenergic agonist guanfacine did not have a statistically significant effect on treatment retention or number of opioid-free urines. In summary, combining naltrexone with the antidepressant fluoxetine (an SSRI) or with an alpha-adrenergic agonist did not reduce the high dropout problem.

Long-acting formulations Injectable naltrexone At the moment, only one injectable formulation of naltrexone (Vivitrol®) is approved in Europe and the USA. It is injected into the gluteal muscle and produces a stable and pharmacologically effective plasma naltrexone level for approximately 28 days. The US Food and Drug Administration approved this medication based on the results of a phase 3, double-blind, placebo-controlled, randomized, multicenter trial conducted at 13 sites in Russia [15•]. This study recruited adult patients meeting DSM-IV criteria for heroin dependence that had completed inpatient opioid detoxification and been free of opioids for at least 7 days. It randomized 250 consenting patients to 24 weeks of extendedrelease injectable naltrexone 380 mg or placebo in a 1:1 ratio. The primary outcome was confirmed abstinence during weeks 5–24, assessed by urine drug tests and self-report of non-use. Medical staff administered injections within a week following detoxification and then every 4 weeks for a total of six injections over the 6-month period of study. Outcomes showed that patients treated once monthly with the study medication had a median of 90% confirmed opiate abstinent weeks vs. 35% for those in the placebo group (p = 0.0002); total abstinence occurred in 36% of patients receiving the study medication vs. 23%

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(p = 0.02) on placebo. An unexpected an anti-craving effect was also observed; at baseline, there was no difference between groups on the Visual Analog Scale (0–100; 21.8 vs. 18.2); however, during treatment, the experimental drug showed a mean reduction of 10.1 (vs. +0.7 for placebo; p G 0.0001). Retention in treatment among patients receiving the experimental medication was significantly higher than in the placebo group. Adverse events were reported by 50% of participants in the medication group vs. 32.3% on placebo, and most were rated mild or moderate. This study had a 1-year open-label extension phase aimed to assess drug use and safety among patients that wanted to continue the experimental medication. A total of 114 participants continued on the experimental medication (67 from the drug condition and 47 from placebo) [16]. Based on urine testing, 50.9% (41.5%, 60.4%) were abstinent from opioids at all assessments during the 1-year open-label phase. Were these on NTX? Overall, 21.1% of patients reported study drug-related adverse events. Do you mean naltrexone and placebo or just naltrexone? Injection site reactions were uncommon (6.1%) and none were serious. The effectiveness of injectable naltrexone for relapse prevention among persons under criminal justice supervision has been evaluated in several recent clinical trials [17•, 18, 19]. A 24-week open-label trial randomized consenting, detoxified, opioid-addicted former prisoners on probation or parole to extended-release injectable naltrexone, or brief counseling with referral to community treatment programs [18]. The primary endpoint was time to opioid relapse. Results were that participants assigned to extended-release naltrexone had a longer median time to relapse than those assigned to usual treatment (10.5 vs. 5.0 weeks, p G 0.001; hazard ratio, 0.49; 95%CI 0.36 to 0.68), a lower rate of relapse (43 vs. 64%, p G 0.001; OR 0.43; 95%CI, 0.28 to 0.65). Notably, there were no overdoses in the extended-release naltrexone group and seven in the usual-treatment group (p = 0.02). Future studies are needed to evaluate its effectiveness in the treatment of dependence on prescription opioids. Also, little or no data have been published on studies comparing injectable naltrexone with opioid maintenance therapy.

Implantable naltrexone Four different naltrexone implants have been developed and are being used, but at the moment, only Prodetoxone®, manufactured by Fidelity Capital in Moscow, is registered and registration is only in the Russian Federation. It contains 1000 mg of naltrexone that is slowly released after being inserted subcutaneously in the abdominal wall via a small incision and maintains a therapeutically effective naltrexone blood level for about 3 months. A recent double-blind, double-dummy, placebocontrolled, 6-month trial randomized 306 consenting, detoxified opioid addicts to one of three medication groups (n = 102 each): naltrexone implant (every 2 months) + oral placebo daily (NI/OP); placebo implant + oral naltrexone 50 mg/day (PI/ON); or double placebo (implant and oral; PI/OP). All patients were offered drug counseling every 2 weeks and urine drug testing and brief psychiatric evaluations were done at each visit [20••]. The primary outcome was percent of patients retained in treatment without relapse. At the end of 6 months, 54/102

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Substance Use Disorders (FG Moeller, Section Editor) (53%) of the NI/OP patients remained in treatment without relapsing compared to 16/102 (16%) in PI/ON (survival analysis, log rank test p G 0.001) and 11/102 (11%) in PI/OP (p G 0.001). The proportion of opiate negative urine tests was higher in the naltrexone implant group: 63.6% (CI 60–66%) vs. 42.7% (CI 40–45%) for PI/ON and 34.1% (CI 32–37%) for PI/OP (p G 0.0001, Fisher exact test to NI/OP group). Local adverse events such as wound infections, local rednes, and swelling were observed in 9 of 102 patients (8.8%) in the NI/OP group and in 2 of 102 patients (2.0%) in the PI/ON group (p = 0.02). Using the number of visits as the denominator, non-local site AEs were reported by 1% of participants in all treatment groups. There was no evidence of increased opioid overdose death after naltrexone treatment ended. No significant differences were detected between groups in depression, anxiety, physical, and social anhedonia. These psychiatric symptoms were elevated at baseline but reduced to normal within the first 1–2 months for patients who remained in treatment and did not relapse. These findings do not support concerns that naltrexone treatment of opioid dependence interferes with normal pleasurable stimuli and increases craving, depression, anxiety, or anhedonia [21]. Results of two randomized, 6-month trials of a naltrexone implant developed by an Australian clinician also demonstrated advantages over oral naltrexone [22] and usual-treatment aftercare [23]. In summary, these implants were more effective in preventing relapse than oral naltrexone and placebo. However, it is important to keep in mind that both implants require a minor surgical procedure that carries with the risk of wound infections and cosmetic defects. Second, it is possible for the patient to remove the implant within the first few weeks before it begins to dissolve. Third, Prodetoxone® appeared to block opioids for less than 2 months in some patients (G10%). Therefore, an injectable long-acting formulation might have some advantages over an implant formulation (it is simple to use and does not require surgery); however, disadvantage of injectable naltrexone is a shorter blockade (1 month). Also, the implants are not covered by some insurance in the USA because they are not FDA approved.

Pharmacogenetics of naltrexone The effectiveness of naltrexone pharmacotherapy might depend on genetic variations between individuals. We choose logical candidate genes for the study of naltrexone pharmacodynamics after implantation of long-acting formulation. One the one hand, it is necessary to evaluate influence of genes coding opioid receptors (naltrexone’s targets). Single nucleotide polymorphism (SNP) А118G located within exon 1 of the μ-opioid receptor is common and encodes an amino acid substitution. This SNP is functional, reportedly resulting in a threefold increase in binding affinity for the endogenous opioid peptide βendorphin [24]. Recent meta-analysis confirmed the association of this variant with the effectiveness of naltrexone treatment among patients with alcohol dependence [25]. μ- and δ-opioid receptors can mediate positive reinforcing effects of opioids, while κ-opioid receptors mediate their negative effects, warranting the study of polymorphisms in these genes encoding these

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naltrexone targets. On the other hand, dopamine neurotransmitter system that plays a key role in modulating neural activity in mesolimbic reward pathway was involved in drug use so that genes coding this system also became logical candidates of this analysis [26, 27]. In the current study, we analyzed gene polymorphisms in opioiddependent patients under randomized clinical trial and evaluated effectiveness of oral and implantable naltrexone for relapse prevention and stabilization of remission, for a genotype-phenotype correlation. Included were polymorphisms with known relations to drug addiction: μopioid receptor (OPRM1), κ-opioid receptor (OPRK1), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase (DBH), and the dopamine transporter gene (SLC6A3); the clinical study was on treatment outcomes of opioid dependence with implantable and oral naltrexone, which was randomized, double blinded, double dummy, and placebo controlled. Three hundred six patients with opioid dependence were randomized in three treatment groups (102 patients in each). The first group received implantation of 1000 mg naltrexone every 2 months during the 6 months period + oral naltrexone placebo; the second group, placebo implant every 2 months + oral naltrexone (50 mg/day); and the third. placebo implant + oral naltrexone placebo. All enrolled participants provided blood sample at baseline for genetic analysis. Regardless of the provided treatment, several polymorphisms of these genes were associated with high risk of relapse: an allele L (2R) DRD4 120 bp (p = 0.05; OR (95%CI) = 3.3(1.1–10.1)); an allele С DRD2 NcoI (р = 0.051; OR (95%CI) = 2.86 (1.09–7.52)); and the genotype 9.9 DAT VNTR 40 bp (р = 0.04; OR (95%CI) = 1.4 (1.3–1.5)); on the contrary, ((СС+СТ)-(ТТ)) variants of OPRK1-DRD2Ncol increased a chance to complete the treatment program (р = 0.004; OR (95% CI) = 7.4 (1.8–30.4)), Kaplan-Meier survival analysis (р = 0.016). The probability of completing treatment program by the carriers of these variants was higher in the oral naltrexone group (p = 0.016), lower in the double placebo group (p = 0.015) but did not influence on treatment outcomes in the naltrexone implant group. Thus, the study has shown the influence of opioid receptor genes and genes of dopaminergic system on treatment outcomes of opioid dependence [28••].

Naltrexone and antiretroviral therapy HIV-positive opiate users often have poor adherence to antiretroviral therapy (ART). The Russian implant containing 1000 mg extended-release naltrexone implant (NI) prevents relapse for up to 3 months and improves addiction treatment outcomes. A recently completed and as yet unpublished study aimed to see if a Russian NI that contains 1000 mg naltrexone and blocks opioid effects for 2–3 months improves outcomes of patients starting ART for HIV disease, as compared to oral naltrexone 50 mg/day (ON). In this study, 200 consenting, detoxified, HIV+ opiate-addicted patients starting ART in St. Petersburg, Russia, were randomized 1:1 to 12 months treatment with NI + ON placebo or ON + NI placebo. All were offered biweekly drug counseling. Viral load (VL), adherence to addiction and HIV treatment, CD4 count, opiate

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Substance Use Disorders (FG Moeller, Section Editor) use, and adverse events were recorded. The primary outcome was VL G400 copies/ml at month 12. Results of this study showed that the two groups did not differ in baseline characteristics. Addiction treatment completion was significantly better in NI than ON (32 vs. 17%, respectably, p G 0.05), and ART retention was better in NI than ON (46 vs. 32%; p G 0.05). Undetectable VL was more common in NI than ON [66 vs. 50%; OR (95% CI) = 1.94(1.10–3.43)], and the mean number of MEMS cap openings was higher in NI than ON (247.5 ± 77.1 vs. 63.9 ± 58.5, p G 0.01). The CD4 count was higher in those who continued on naltrexone, regardless of group assignment, vs. those who dropped out (453.1 cells/mm3 ± 271.0 vs. 293.6 cells/mm3 ± 170.3, p G 0.001). The groups did not differ in adverse events (32% for ON vs. 30% for NI). So this study demonstrated that NI, compared to ON, improved addiction and HIV treatment outcomes in opiate-addicted patients starting ART in Russia. Extended-release naltrexone may be a useful alternative to methadone or buprenorphine maintenance for opioid-addicted patients on ART who do not want agonist therapy or where it is difficult to access or unavailable.

Conclusion Oral naltrexone can be effective, particularly when family members or other third sources of external motivation supervise its administration. In other less closely supervised situations, extended-release formulations are more effective than oral naltrexone and are important additions to current treatment options for opioid-addicted patients who do not want or do not have ready access to agonist or long-term residential treatment. How extended-release naltrexone formulations compare with maintenance treatment using methadone or buprenorphine in settings in which all three treatment options are available is a topic for future studies. Genetic analysis might be useful for determining potential responders to naltrexone treatment of opioid dependence but additional studies are needed. Extended-release naltrexone might improve adherence and outcomes of ART.

Acknowledgments The studies of oral naltrexone with or without fluoxetine were supported by NIDA grants P60-DA05186l (Dr. O’Brien) and DA017317 and K05-DA 17009 (Dr. Woody) and the Department of Veterans Affairs. Alkermes (USA) supported the study of injectable naltrexone (Vivitrol®) in Russia. Disclosure DuPont Pharmaceutical provided naltrexone, and Gideon Richter provided fluoxetine for the studies of oral naltrexone with or without fluoxetine. Fidelity Capital (Russia) provided Prodetoxone at reduced cost. Dr. Krupitsky had been serving as a consultant for Alkermes in 2007–2010. The study of naltrexone and ART was supported by NIDA grants R01-DA026336, K05-DA17009, and U10-DA013043. No other potential conflicts of interest relevant to this article were reported.

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Compliance with Ethical Standards Conflict of Interest Dr. Krupitsky reports grants from National Institute Drug Abuse and personal fees from Alkermes during the conduct of the study. Dr. Woody reports Alkermes has provided Vivitrol and Vivitrol placebo for studies on which he is the principal investigator. Fidelity Capital provided Prodetoxone at reduced price for studies in St. Petersburg. Drs. Elena Blokhina and Edwin Zvartau declare that they have nothing to disclose. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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