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Article received on November 28, 2018 and accepted for publishing on February 14, 2019. ORIGINAL ARTICLES

Maintenance pharmacologic therapies for use disorders: beyond opioid agonists

Octavian Vasiliu1

Abstract: is a worldwide challenge for an increasing number of patients, and still the therapeutic options presented in clinical guidelines for this condition are very few. The first line pharmacological therapies for opioid use disorder continue to be opioid agonists as substitution treatment, but the need to find new treatments without the effect of prolonging opioid dependence become more and more obvious. This systematic review presents the most supported by evidence pharmacological agents that can be used as monotherapy for opioid use disorder patients (i.e., , extended release/implant and oral formulation), or as adjuvants to substitution therapy (e.g. olanzapine for aggressive behaviours, memantine or for reducing inflammatory processes related to opioid use). More good quality data derived from larger, well designed trials are needed in order to find solid recommendations for non-opioid agonists in the treatment of opioid use disorder. Keywords: opioid use disorder, naltrexone, memantine, dextromethorphan, olanzapine, maintenance treatment

INTRODUCTION Opioid dependence is a significant contributor to the global disease burden, as between 24 and 35 million The importance of opioid people globally used an illicite from this category dependence could not be in 2010 [1,2]. North America, Eastern Europe and overemphasized, and Southern sub-Saharan Africa are the most strongly during the last decade a affected by the premature mortality related to opioid continuously increasing use disorder [1]. United Nations Office on and number of alerts have Crime 2017 Report shows an overall increase of the appeared both in public and synthetic use (, media and scientific , , and ) since 2009 and environment regarding the the trend to more diversification of the opioid market negative functional impact, [3]. Disability-adjusted life years (DALY) attributable to increasing societal costs opioid dependence in 2015 reached the value of 12 and mortality risk 1 million, or 70% of the global burden of disease Department, associated with this „Dr. Carol Davila” University attributable to drug use disorder [4]. Relapse rate after Emergency Central Military pathology. Hospital, Bucharest detoxification is very high, ranging from 72% to 88% after 12-36 months [5].

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Given consideration to the importance of opioid use heroin or ). Therefore, the need to find non- disorder both at individual and societal level, addictive agents which can be used during the worldwide efforts have been constantly made in order maintenance phase is considered urgent. to find treatments able to prevent opioid use relapse and to maintain patients in remission as long as OBJECTIVE AND METHODS possible. The most validated treatments for the This systematic literature review has as primary maintenance phase are and objective finding non-opioid agonist treatments for , both with agonist actions at μ-opioid the maintenance phase in opioid use disorder receptors (the first being a , while the patients, based on good quality data. The secondary second is a full agonist). Unfortunately, due to their objective is to formulate evidence-based , both these drugs have abuse recommendations for this indication, starting from potential (less in case of buprenorphine) and associate existing data in the literature. withdrawal symptoms (although milder than in case of

Table 1. Inclusion/exclusion criteria. Operational criteria Inclusion criteria Exclusion criteria Population Minimum age for inclusion was 18 years, no Patients under age of 18. superior age limit was established. Presence of severe somatic or psychiatric co- The main diagnosis was opioid use disorder. morbidities that may have impact over Secondary diagnoses were allowed, if the study patients’ outcomes, or due to their treatment design permitted statistical analysis for at least may lead to confusion about the outcome by one outcome regarding opioid use disorder. pharmacokinetic or pharmacodynamic Diagnosis was established according to DSM-IV, interactions. IV TR, 5 or ICD-10 criteria. Intervention Any pharmacological agent without agonism Psychotherapy or psychological counselling as (either partial or complete) over opioid only type of intervention. receptors, either as add-on or as monotherapy. Non-pharmacological and non- Combined pharmacological and psychological psychotherapeutical interventions, OTC, treatment. investigational products used in phase I, II or III Treatment duration over 4 weeks. clinical trials. Environment Inpatients, outpatients. Unspecified environment. Hospitals, day care, special care, intermediate care units. Carceral environment. Primary and Changes in opioid use- related parameters, e.g. All trials with outcomes not related to the secondary days of , number of toxicology tests severity of opioid use disorder. outcomes negative, rate of rehospitalisation for opioid consumption. At least one outcome is related to the opioid use. Study design Prospective or retrospective clinical trials. Trials with unspecified or insufficiently specified Randomized, open label, single blind, or double design. blind. Case control studies. Epidemiological Variables referring to opioid use disorder were studies. Observational trials. not included in statistical analysis, or not presented in the published paper. Systematic review, narrative reviews, meta- analyses, case reports, case series. Language English, French, German, Russian Any other language, except for those already specified.

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Methods were based on the qualitative review of data secondary analysis. GRADE recommendations found in the main electronic databases- PubMed, included 5 levels: A= high quality= future research are Complete MEDLINE, EMBASE, Cumulative Index to very unlikely to change the validity of these Nursing and Allied Health Literature (CINAHL), recommendations; B= moderate quality= future National Library of Medicine and the National Institute research is likely to have an important impact on the of Health (NCBI), PsychInfo and Thomson appreciation of the recommendations; C=low quality= Reuters/Web of Science. All clinical trials and it is very likely that future research will have an epidemiological studies published between 1998 and important impact over the confidence in the estimate 2018 in English, French, German, and Russian were of effect and is likely to change the recommendations; included in the primary review. The search paradigm D= very low quality= any estimate of the effect is very used was „opioid dependence”, „ dependence”, uncertain. Intermediate steps (+ or -) represent „opioid/opiate use disorder”, combined with „non- nuances of the recommendations based on the quality opioid agonists” or „non-opioid pharmacological of trials and tolerability of intervention, as resulted treatment”. This literature review is based on from these trials [7]. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) principles of research [6]. RESULTS

Inclusion and exclusion criteria were applied to all After the primary search 2560 papers surfaced, but papers found during primary search (table 1). only 65 remained when the inclusion and exclusion criteria were applied (figure 1). A number of papers Therapeutic intervention was focused on drugs with were excluded because full text was not found, so that non-opioid agonistic properties. If any psycho- 29 studies remained to be reviewed in the final step. therapeutic intervention was administered, than it All trials included in the secondary review are was only as an add-on to the pharmacologic presented in table 2. management, and not the main method of treatment. Because this review was focused on maintenance These 29 trials included in the secondary analysis had therapy, brief interventions were not included. The a total number number of participants of 3,159, and a outcomes of therapeutic intervention had to be mean LOS of 3.58. A number of 13 trials were found to periodically evaluated, and statistically analysed. Only be high quality designed trials (LOS=5), meaning trial which produced inferential, statistically-based double-blind, either placebo-controlled or with an data were included in the final step of the review. active comparator, randomized clinical trials.

During the secondary analysis, papers were reviewed Analysis of interventions corresponding to the and their results were analyzed. Only papers to which inclusion/exclusion criteria previously mentioned full text was found were included in the final analysis. showed that non-opioid agonist drugs used in the maintenance phase in patients with opioid use All studies were ranked according to their level of disorder who have been previously detoxified were: significance (LOS). This level was determined based on (1) naltrexone implant; (2) oral naltrexone; (3) the quality of the study design: (5) double-blind ; (4) memantine; (5) dextromethorphan; randomized controlled trial, with/without an active (6) dronabinol; (7) olanzapine; (8) ; (9) comparator/placebo; (4) single-blind trials, with/ ibudilast; (10) buspirone; (11) sodium valproate; (12) without an active comparator/placebo; (3) open-label fluoxetine; (13) paroxetine; (14) clonazepam; (15) trials with/without an active comparator; (2) . The last five drugs were used only in retrospective studies, observational trials; (1) any combination with another active or as other study design. active comparators, so they were not evaluated GRADE recommendations for the level of evidence [7] separately in this review. were formulated based on the evidence found in the

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Figure 1: Stepwise filtration of titles found during electronic databases search

Naltrexone was the most investigated non-opioid for all groups for the monitoring of remission rate agonist medication for the maintenance therapy in during 6 months [15]. The mean LOS of these studies opioid use disorder, and 15 relevant trials focus on this was 3.85, and an overall number of 657 patients were drug’s efficacy have been found during the secondary included. search. Naltrexone is an , and both These trials supported a moderate efficacy and the parent drug and its (6β- tolerability of oral naltrexone: buprenorphine/ naltrexol) are competitive antagonists of the μ-, and to was superior to naloxone in the reduction of a lesser extend to κ- and δ-opioid (10-25 opioid-positive test and preserving patients times lower affinity for κ- and δ-receptors compared participation in the treatment [6], naltrexone induced to the μ-receptors) [8]. Because oral naltrexone is similar weight gain during 6 months of treatment extensively metabolized during first-pass , when compared to methadone [16], naltrexone may and because therapeutic of opioid users is improve in patients with opioid use known to be very low, various implant formulations of disorder at 6 months [12], and naltrexone was inferior this pharmacological agent have been developed. to buprenorphine (not statistically significant) in Oral formulation of naltrexone has been investigated several outcomes regarding the rate of relapse in in comparison with buprenorphine/naloxone in the detoxified heroin dependent patients [11]. post-detox phase [9], methadone in stabilized patients Naltrexone plus fluoxetine and individual psycho- [10], buprenorphine and placebo in detoxified patients therapy has been proven a useful combination [11], methadone in opioid dependent patients who especially in women with heroin dependence, because were stablized on treatment it increased the remission rate and maintenance of for controlling depressive and symptoms [12]. remission in this population [15]. Naltrexone plus Oral naltrexone as monotherapy was compared with gabapentin improved muscle pain and psychological naltrexone plus gabapentin (1200 mg/day) for the dependence severity in patients dependent on management of muscle pain and [13], and [13]. Naltrexone plus sertraline was a naltrexone plus placebo was compared with well-tolerated combination and increased on short- naltrexone plus sertraline for controlling depression term treatment retention of recently non-depressed severity and opioid craving [14]. Another trial opioid abstinent patients, but the difference between compared naltrexone (50 mg/day) + fluoxetine (20 this combo and naltrexone alone disappeared in time mg/day) with naltrexone + placebo, fluoxetine + [14]. placebo, or placebo for 6 months plus psychotherapy

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Naltrexone extended-release has been investigated in difference to placebo could be found after 12 weeks comparison with buprenorphine/naloxone [16], [25]. treatment as usual [5], oral naltrexone plus Ibudilast is an anti-inflammatory drug with psychosocial therapy [17], and methadone [18]. phosphodiesterase inhibition properties (especially Naltrexone implant was investigated also in several PDE4) which has been associated in animal studies trials as single pharmacological agent, without an with the capacity of alterating several opioid-mediated active comparator [19-22]. The mean LOS of these effects [26, 27]. When compared with placebo in a 6- trials was 2.8, and the global number of participants week RCT in patients detoxified from morphine, was 1982. ibudilast treated patients presented lower rates of The overall efficacy of naltrexone extended-release drug liking (oxycodone), lower craving to heroin/ was good, although data are derived from poor and / and lower subjective ratings of pain medium-quality designed trials. Its efficacy and vs. placebo [26]. tolerability were similar to buprenorphine/naltrexone Memantine is a noncompetitive NMDA-receptor in patients who wanted to switch from this antagonist that blocks the effects of excessive combination of drugs to naltrexone implant [16], and concentrations of glutamate, currently used for it induced a lower rate of relapse when compared to Alzheimer Disease- related neurocognitive disorder treatment as usual, at least on short-term [23]. Heroin and researched intensively for other dementias, dependent patients who received extended release ADHD, and as an agent able to reverse tolerance to formulation of naltrexone had better outcomes than opioids [28]. Memantine was administered in patients those treated with oral formulation of the same drug who were on buprenorphine/naloxone maintenance [17], and naltrexone implants but not methadone treatment, and compared to placebo [29], or in were associated with long-term benefits in decreasing patients who were on methadone-maintenance- opioid-related hospital morbidity [18]. therapy, compared to placebo plus methadone- In trials without an active comparator, naltrexone maintenance therapy [30, 31]. Memantine was also extended-release was efficient in preventing opioid investigated as maintenance treatment in detoxified overdose [22], improved depression severity at 4 non-treatment seeker heroin dependent patients weeks post-baseline, but it may also be responsible of during 8 weeks of in-patient regimen [32]. worsening late [21], improved quality of life, These trials investigating the efficacy of mematine had rate of retention, opioid-negative , opioid a mean LOS of 4.25, and an overall number of 350 craving, and rate of re-employment [20]. Also, participants. It can be observed that the quality of naltrexone plus psychological counselling improved trials focused on memantine efficacy was higher than the acceptance of opioid dependence previously mentioned research for other pharmacotherapy and prolonged the duration of investigational products. abstinence to opioids, when compared to placebo plus counselling [19]. Memantine has been proven as a useful adjunctive medication for patients treated with Topiramate is an anticonvulsant with GABA-enhancing buprenorphine/naloxone and it may provide an easier properties and AMPA and kainate-inhibitory actions, transition to buprenorphine-free therapeutic regimen involved in the modulation of extracellular [29]. Low dose memantine attenuated chronic opioid- release in the mesocortical and limbic system dependence-induced cognitive impairment, dopaminergic system, properties which decreased the daily dose of methadone, and had recommended it as a potential treatment for cocaine positive effect over probably NMDA-mediated dependence [24]. Patients with opioid use disorder inflammatory processes [30, 31]. Memantine who presented also did not decreased the subjective, but not the reinforcing benefit from the addition of topiramate to their methadone maintenance therapy, because no

56 Vol. CXXII • No. 1/2019 • April • Romanian Journal of Military Medicine effects of heroin in non-treatment seeker heroin- Olanzapine is an atypical antipsychotic investigated in dependent patients [32]. patients with opioid dependence who were on substitution therapy, as a drug targeting the aggresive Dronabinol is a synthetic form of 9-tetrahydro- behavior [40, 41]. The mean LOS of these trials was cannabinol, with similar affinity for cannabinoid 1 and 3.5, and the total number of participants was 268. 2 receptors, currently approved for use in anorexia associated with weight loss in AIDS and for the In the first trial, olanzapine (2.5-15 mg) was compared treatment of associated with chemotherapy with sodium valproate (600-1000 mg) in patients resistant to other anti-nausea treatments [33]. A stabilized on methadone, and olanzapine was slightly double-blind, placebo-controlled RCT investigated the superior in controlling aggressivity but did not differed effects of dronabinol in patients with naltrexone from valproate in reducing the number of positive extended release and a significant effect of this drug in urine samples [40]. In the second, smaller-sample size, decreasing the severity of opiate withdrawal has been olanzapine was compared to fluoxetine/paroxetine proven [34]. and clonazepam and reduced aggressive/hostile behavior in heroin addicted patients undergoing Dextromethorphan is an antitussive drug with N- substitution therapy [41]. In this second trial, methyl-D-aspartate (NMDA) olanzapine was superior to its comparators in the properties, involved also in protecting monoaminergic direct aggressiveness, overall hostility, verbal neurons against inflammation-mediated degeneration aggressiveness, and aggressive incidents; also, 70% of [35, 36]. Chronic opioid administration produces the completers achieved full remission, without systemic inflammation, and for this reason the use of significant differences between groups [41]. a drug with anti-inflammatory properties seems to be granted [37]. Based on its neuroprotective and anti- Buspirone is a non- anxiolytic which inflammatory properties, dextromethorphan was possesses 5HT1A agonistic properties, acting as full investigated as adjunctive agent in patients with agonist at 5HT1A presynaptic receptors and partial opioid use disorder. Dextromethorphan 60 mg/day agonist at postsynaptic 5HT1A receptors [42]. A single and 120 mg/day were compared with placebo as trial that compared buspirone with placebo in patients adjunctive to methadone treatment in opioid- with anxiety undergoing methadone therapy has been dependent patients [37, 38], and in another trial identified during the literature review [43]. Buspirone dextromethorphan 240 mg/day was compared with had no significant efficacy over anxiety symptoms in placebo in methadone-stabilized patients [39]. these patients, but it decreased depression severity and slowed down the return to [43]. These trials with dextromethorphan had a mean LOS of 5, and a total of 268 patients. Baclofen is a GABA-B receptor agonist that may be helpful in promoting abstinence from a variety of Dextromethorphan was useful in low doses as drugs [44]. A double-blind, placebo-controlled, 12- adjuvant treatment in methadone-treated patients week RCT with a LOS of 3, which included 40 patients both at inflammatory level and clinical level [37, 38], with opioid dependence, recently detoxified, found a but in another trial the difference versus placebo was significantly better treatment retention in the not significant in the otcome defined as mean baclofen-treated patients (60 mg/day) [45]. This trial methadone consumption [39]. The quality of life was had a small sample size and a high attrition rate, which superior in patients who reeived dextromethorphan as make difficult to generalize its results. adjuvant to methadone versus placebo plus methadone [39].

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Table 2. Trials focused on non-opioid agonist therapies during the post-detoxification phase in patients with opioid use disorder Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Pirnia B, Placebo-controlled RCT; n=50 patients Weekly urine drug Topiramate was no The efficacy of 5 Soleimani AA, topiramate (25-300 with dual screens. better than placebo in topiramate in Malekanmehr mg/day), 12 weeks, cocaine and reducing cocaine use, cocaine use P, et al. [25] escalating doses; but was superior to reduction in patients were treated dependence placebo in reducing patients with also with methadone cocaine craving. dual cocaine 20-140 mg/day and brief and opiates behavioral compliance dependence enhancement treatment was not for cocaine dependence. supported. Solli KK, Latif Prospective cohort n=54 opioid- Use of heroin and Follow-up after 9 Opioid- 4 ZE, Opheim A, study, naltrexone- dependent other illicit months showed dependent et al. [16] extended release vs. adults substances, opioid completion rates of individuals who buprenorphine- continuing craving, treatment 51.9% among elect to switch naloxone 3 month + naltrexone- satisfaction, participants continuing from participants’ choice of extended treatment naltrexone-extended buprenorphine- study medication for an release and retention, adverse release in the follow-up naltrexone after additional 9 months; the n=63 opioid events, - and 47.6% among those 3 months to active drug was dependents related problems inducted on the active extended administered every 4 inducted on treatment, with opioid release weeks (380 mg). the same abstinence rates of 53.7 naltrexone 9 treatment and 44.4%, respectively. months were experiencing similar results (treatment completion and abstinence rates) and similar rate of adverse events to those who had been on extended- release naltrexone from the start. Metz VE, Jones 6-week RCT focused on n=11 patients VAS for Patients receiving active Ibudilast may 3 JD, Manubay J, ibudilast (a nonselective detoxified measurement of ibudilast presented be useful in et al. [26] phosphodiesterase from morphine subjective effects decreased rates of drug treating opioid inhibitor) effects over addiction of oxycodone. liking after 15 mg of use disorder craving, reinforcing, oxycodone; heroin/ and may analgesic effects of tobacco/cocaine craving enhance the oxycodone in human was reduced under analgesic volunteers diagnosed active ibudilast vs. effects of with opioid placebo; mean oxycodone. dependence; patients subjective ratings of received maintenance pain were lower in the treatment with ibudilast active ibudilast (50 mg bid) or placebo condition.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Earley PH, Single-arm, multisite, n=38 enrolled Opioid drug tests At 24 months, mean Long-term 3 Zummo J, open-label study; opioid- monthly, opioid craving fell by extended Memisoglu A, extended release dependent measurements for 45.2% and quality of life release et al. [20] naltrexone injections for healthcare quality of life, (SF-36) -mental naltrexone was up to 24 months, professionals opioid craving, component score associated with combined with who had been and treatment improved by 31.1% from better quality of counselling via intensive detoxified for satisfaction baseline; of the 22 life, rates of outpatient substance at least 2 unemployed subjects at retention, abuse treatment weeks baseline, 45.5% opioid-negative programs. improved employment urines, opioid- status at 24 months. craving reduction, re- employment Lee JD, Open-label RCT, 24- n=308 criminal Time to an opioid- Participants assigned to Extended- 3 Friedmann PD, week extended-release justice relapse event extended-release release Kinlock TW, et naltrexone vs. usual offenders with (defined as 10 or naltrexone had a longer naltrexone was al. [23] treatment (brief history of more days of time to relapse than did associated with counseling and referrals opioid opioid use in a 28- those who received a rate of opioid for community dependence, day period). usual treatment, lower relapse lower treatment programs); abstinent from rate of relapse, and than that with opioids at the higher rate of opioid- usual time of negative urine samples. treatment, but randomization After one year, the rates after one year of opioid-negative urine the protective samples were equal. effects waned. During one year, there were no overdose events in the extended- release naltrexone treated participants, while in the usual- treatment group there were 7 cases. Mokri A, Single-site, two-parallel n=102 Initial duration of Mean number of days of Sublingual 5 Chwarski MC, groups, double-blind participants opioid abstinence initial duration of buprenorphine/ Taherinakhost RCT, 12-week; oral with opioid use (urine toxicology verified abstinence was naloxone was H, Schottenfeld naltrexone vs. disorder in the tests). higher with buprenor- associated with RS [9] buprenorphine/ post-detox phine/naloxone a greater naloxone. phase (p=0.205); mean num- number of ber of opioid-negative opioid-negative urine tests was higher in urine tests and the buprenorphine/ treatment naloxone-treated retention, but subjects (p=0.049); the not significantly mean number in treat- greater initial ment was also greater in abstinence buprenorphine/naloxon duration or e group (p=0.013); the proportions rate of sustained, 12- with sustained week opioid abstinence abstinence. was double in the buprenorphine/ naloxone group.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Gonzalez G, Double-blind placebo- n=80 young Change in the Memantine 30 mg/day Memantine 5 DiGirolamo G, controlled RCT, 13 adults with weekly mean significantly improved could be an Romero- weeks; patients already opioid proportion of short-term treatment useful Gonzalez M, received treatment with dependence opioid use, and with buprenorphine/ adjunctive et al. [29] buprenorphine/naloxon cumulative naloxone by reducing treatment at 30 e 16/4 mg/day and they abstinence rates relapse and opioid use mg daily for were randomized to after rapid after buprenorphine patients treated memantine 15 mg or 30 buprenorphine discontinuation, during with mg vs. placebo. discontinuation at the last 2 weeks of study buprenorphine/ week 9 participation. naloxone and helpful in the transition to buprenorphine- free therapeutic regimen. Bisaga A, Double-blind RCT, n=60 patients Severity of opioid The severity of opioid Dronabinol 5 Sullivan MA, dronabinol 30 mg/day recently de- withdrawal and withdrawal during reduced the Glass A, et al. (n=40) vs. placebo toxified from retention in inpatient phase was severity of [34] (n=20); patient opioids treatment. lower in the dronabinol opiate underwent inpatient group vs. placebo; rates witdrawal but detoxification for opioid of successful induction had no effect on dependence and onto extended release rates of extended-release naltrexone and extended- naltrexone induction; completion of treatment release dronabinol was were not significantly naltrexone administered while superior for dronabinol treatment inpatient and 5 weeks vs. placebo. induction and afterwards. retention. Chang YH, Chen RCT, memantine plus n=134 patients Cognitive Both treatment groups Low-dose 5 SL, Lee SY, et al. methadone- stabilized on performances showed improvements memantine (5 [30] maintenance-therapy methadone in their cognitive mg/day) may (n1=57) vs. placebo plus performances. attenuate methadone- Memantine add-on was chronic opioid- maintenance therapy superior to placebo in dependence- (n2=77); healthy controls the post-treatment induced were matched with cognitive improvement. cognitive methadone-treated decline. group; 12 weeks duration of monitoring. Lee SY, Chen SL, 12-week RCT, n=196 opioid Methadone dose Patients who received Low dose 5 Chang YH, et al. dextrometorphan 60 dependents required, plasma 60 mg/day dextromethorp [37,38] mg/day (n1=65), 120 morphine level, dextromethorphan had han is useful as mg/day (n2=65) vs. retention in significantly longer concomitant placebo (n3=66) as treatment. treatment retention and therapy in adjunctive to lower plasma morphine methadone- methadone treatment in levels than did the treated patients opioid-dependent placebo group. Plasma both at the patients. TNF-alpha was pathogenic- significantly decreased inflammatory in the 60 mg level, and at the dextromethorphan clinical level. group compared to placebo.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Lee SY, Chen SL, Double-blind RCT, n=128 patients Inflammatory bio- Memantine-treated Low-dose me- 5 Chang YH, et al. placebo-controlled, 12- stabilized on markers, overall patients required a mantine may [31] week duration; methadone dose of somewhat lower help patients memantine (5 mg/day) methadone methadone dose than during metha- (n1=53) vs. placebo did placebo-group done substitu- (n2=75); patients with (p=0.039), and they also tion treatment opioid dependence had significantly lower because of the undergoing methadone plasma TNF-α and overall maintenance therapy. higher TGF-β1 levels. methadone dose decrease and positive impact over inflammatory process possible related to the NMDA- receptors. Krupitsky E, Double-blind, placebo- n=250 patients Confirmed Extended-release Extended- 5 Nunes EV, Ling controlled multicentric with opioid abstinence (urine naltrexone-treated release W, et al. [19] RCT, 24 weeks; 380 mg dependence, drug tests and patients had naltrexone in extended-release who self-report). significantly longer conjunction naltrexone vs. placebo; underwent periods of confirmed with counselling sessions detoxification abstinence (p=0.0002), psychosocial were provided for both more opioid-free days treatment groups. (p=0.0004), less craving improve the (p<0.0001), more acceptance of treatment-retention opioid (p=0.0042). dependence pharmacothera py and prolongs the duration of abstinence to opioids. Krupitskii EM, RCT, patients were n=280 patients Remission rate, Naltrexone + fluoxetine Naltrexone and 5 Zvartau EE, randomized on with heroin maintenance of was more effective than fluoxetine could Tsoi-Podosenin naltrexone (50 mg/day) addiction remission fluoxetine + placebo be useful in MV, et al. [15] + fluoxetine (20 (p<0.01) and placebo patients with mg/day), naltrexone + (p<0.001) in the remi- heroin placebo, fluoxetine + ssion percentage. dependence, placebo, or placebo for Naltrexone was superior especially in 6 months; individual to placebo and fluoxe- women. psychotherapy for the tine in the efficacy of maintenance of maintenance of remi- remission was applied ssion and preventing for all gropus (one relapse in patients with session). heroin addiction. The combination of naltrexone and fluoxetine was more effective compared to naltrexone monotherapy only in women.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Zarghami M, 12-week RCT, n=201 patients Aggressive Olanzapine and sodium Olanzapine and 4 Sheikhmoonesi olanzapine (2.5-15 mg) on methadone behavior, urine valproate reduced the sodium F, Ala S, et al. vs. sodium valproate maintenance toxicology. overt aggression and valproate may [40] (600-1000 mg). treatment subscales of irritability, be useful as aggression, and adjunctive suicidality. Olanzapine- agent in treated patients decreasing presented more aggressive improvement in behavior in aggressivity. The heroin percentage of positive dependent urine samples individuals (morphine, , during ) methadone were not significantly substitution different between the treatment, with study groups. a slightly superior effect of olanzapine. Salehi M, Zargar Double-blind RCT, n=72 opiate Methadone The mean methadone Dextromethorp 5 A, Ramezani dextromethorphan vs. abusers with consumption consumption in the han might be MA [39] placebo; 6-month methadone dosage, quality of dextromethorphan- useful for opioid follow-up. maintenance life, withdrawal treated patients vs. dependence therapy symptoms. control group were 62.7 treatment, but mg/day vs. 70.4 mg/day. the differences Total mean score of the vs. placebo quality of life was were not superior in the significant. intervention group (p>0.05). Brooks AC, Quasy-experimental n=101 patients Days retained in Long-acting injectable Superior 2 Comer SD, comparison, long-acting on naltrexone treatment, naltrexone had been outcomes for Sullivan MA, et injectable naltrexone severity of drug associated with better heroin- al. [17] (n1=42) vs. oral use outcome than oral dependents naltrexone (n2=69). naltrexone on days who received Psychosocial therapy retained in treatment long-acting was also initiated for and other injectable these patients. measurements for naltrexone opiate use, while still compared to other measurements for oral naltrexone. opiate use were not significantly different; heroin users with more severe baseline use showed better retention with oral naltrexone maintenance therapy, while less severe heroin users evidenced better outcomes when treated with long-acting injectable naltrexone.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Mysels DJ, Prospective evaluation n=34 patients Depression Significant improvement Naltrexone 2 Cheng WY, using Hamilton on naltrexone severity of depression scores induction and Nunes EV, Depression Rating Scale after 4 weeks post- maintenance Sullivan MA in patients treated with baseline (p<0.0004), does not [21] naltrexone depot somatic and cognitive- worsen maintenance and affective subscales depression, but scores significantly it may cause therapy; 2 and 4 -week decline; late insomnia sleep post-baseline increased significantly at impairments evaluations. 2 weeks post-baseline. Myesels DJ, Retrospective chart n=36 opiate Change in body No difference in weight No statistically 2 Vosburg SK, review; patients were dependent weight from was detected at difference over Benga I, et al. maintained on patients baseline to 3 baseline, 3 or 6 months the weight [10] methadone (n=16) or stabilized on months and 6 between the two between naltrexone (n=20); pharmacologic months into treatment groups. methadone and al treatment treatment. naltrexone maintenance treatment. Schottenfeld Double-blind RCT, 24 n=126 Days to first Days to first heroin use, Buprenorphine 5 RS, Chawarski weeks; oral naltrexone detoxified heroin use (urine days to heroin relapse (3 was superior to MC, Mazlan M vs. buprenorphine vs. heroin- drug tests), days consecutive positive naltrexone, [11] placebo dependent to heroin relapse, tests), and maximum although for the patients maximum consecutive days most variables consecutive days abstinent had all monitored the of heroin supported the differences abstinence, superiority of were not reductions in HIV buprenorphine statistically risk behaviours (significant to placebo). significant. over 6 months. Differences between buprenorphine and naltrexone were not significant for days to heroin relapse and maximum consecutive days abstinent. Differences between naltrexone and placebo were not significant for any outcomes. HIV risk behaviours were significantly reduced by all three treatments. Ngo HT, Tait RJ, Retrospective n=836 patients Hospital Naltrexone implant Naltrexone 2 Hulse GK [18] longitudinal follow-up; treated for admissions rates, decreased risk for implants, but methadone (n1=522) or opioid adjusted changes overdose and non- not methadone, naltrexone implant dependence in risks and rates overdose-related events has been (n2=314) as of overdose- at 3.5 years, but not associated with maintenance treatment related and non- methadone; 5 drug- long-term for opioid- dependent overdose-related related after benefits in patients. Evaluations at hospital morbidity methadone and 1 after decreasing 6 months and 3.5 years associated with naltrexone opioid-related post-treatment. opioid vs. implantation. hospital nonopioid drugs. morbidity.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Gerra G, Di 12-week prospective, n=67 patients Hostility scores, Direct aggressiveness, Olanzapine may 3 Petta G, observational trial; with heroin incidence rates of overall hostility scores, be useful as D’Amore A, et open-label study; dependence aggressive verbal aggressiveness adjunctive al. [41] olanzapine vs. undergoing incidents and scores, aggressive inci- treatment in fluoxetine/ paroxetine+ substitution attacks. dents rates were signi- reducing clonazepam for therapy ficantly lower compared aggressive/hosti controlling to baseline in patients le behavior in aggressiveness. treated with olanzapine heroin addicted who comple-ted the patients who treatment. Among undergo completers, almost 70% maintenance achieved full substance substitution abuse remission, 30% therapy. partial substance abuse remi-ssion, without signifycant differences between groups. Dean AJ, Open-label RCT, n=80 patients Depressive Patients who received Naltrexone has 3 Saunders JB, naltrexone 50 mg/day stabilized on symptoms naltrexone did not a positive Jones RT, et al. (n1=42) vs. methadone methadone severity, anxiety exhibit worsening of impact over [12] (n2=38) in opioid symptoms depressive symptoms; in depressive dependent patients who severity. patients attending symptoms were stablized on follow-up assessments, during methadone those who received maintenance maintenance treatment; naltrexone presented an treatment in 6-month duration. improvement in opioid depression over time, dependent compared to the control patients. group; adherence to naltrexone correlated with lower depression severity scores. Hulse GK, Tait Cohort study, pre-post n=361 heroin Primary outcome 21 overdoses involving Sustained- 2 RJ, Comer SD, design, data were dependent was overdose 20 persons in the 6 release et al. [22] prospectively collected; persons events. months pre-treatment; naltrexone patients were evaluated none was observed in implant is before and after the 6 months post- efficient in treatment with a treatment; blood naltre- preventing sustained release xone levels at or above opioid naltrexone implant; a 3 ng/ml for approxima- overdose. subgroup (n=146) had tely 6 months after in- previously received jecttion; reduced num- treatment with oral ber of opioid overdoses naltrexone. were also observed 7-12 months after implant; for those previously treated with oral naltrexone, more opioid overdoses occured in both 6-month prior to and after oral compared to the 6-month post- implant treatment.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Comer SD, Detoxified, non- n=8 patients Subjective ratings Memantine produced Memantine 2 Sullivan MA treatment-seeker- with heroin of drug quality, modest reductions in could be a [32] heroin dependent dependence liking, willingness subjective ratings of useful agent for patients; 8 weeks; 0, 30, to pay for drugs, drug quality, liking, wi- decreasing the 60 mg/day memantine craving. llingness to pay for the subjective but as maintenance drug, and craving for he- not the treatment; intranasal roin. It had little influ- reinforcing heroin (0, 12.5, 50 mg); ence over the reinfor- effects of inpatient regimen. cing heroin effects. heroin. McRae AL, RCT, 12-week, placebo- n=36 patients Anxiety symptoms Buspirone did not Buspirone had 5 Sonne SC, Brady controlled study; receiving significantly decrease no significant KT, et al. [43] patients on methadone methadone anxiety symptoms in efficacy over who presented also maintenance opioid-dependent anxiety anxiety symptoms; treatment patients. symptoms in buspirone vs. placebo. subjects undergoing methadone maintenance treatment, but it was associated with reduction in depression scale scores and slower return to substance use. Assadi SM, Double-blind, placebo- n=40 patients The primary Treatment retention Baclofen could 5 Radgoodarzi R, controlled, 12-week with opioid outcome was was significantly higher be useful in the Ahmadi-Abhari RCT; patients received dependence, retention in in the baclofen group maintenance SA [45] fixed-schedule baclofen recently treatment. (p=0.01); 30% of treatment of 60 mg/day or placebo. detoxified patients treated with opioid baclofen completed the dependence, trial vs. 10% patients on but the sample placebo. The rates of size was small, opioid-positive urine and the attrition samples did not differ rates were high. significantly between the two groups. Baclofen was superior to placebo in terms of opiate withdrawal syndrome and depressive symptoms. Intensity of opioid craving and self- reported opioid and use were more favourably influnced by baclofen, although not statistically significant. The drug side effects of the two groups were not significantly different.

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Study design, description of Primary Authors Patients Results Conclusion LOS therapeutic outcomes intervention Kumar P, Jain Open label trial; patients n=20 opioid Muscle pain and Patients receiving Gabapentin is 3 MK [13] received (for dependent craving (rated on naltrexone + gabapentin efficient in detox) and later patients visual-analogue scored significantly controlling naltrexone p.o. (50 mg (pentazocine) scale), lower on both muscle aching, BD) as maintenance psychological parameters- pain score and no therapy vs. naltrexone dependence and craving score tolerance effect plus gabapentin (1200 severity. (p<0.001), and was observed mg/day) for 3 weeks. psychological after 3 weeks. dependence was Gabapentin significantly lower in this may reduce group (p<0.01). pain in opioid dependent patients when added to naltrexone, signaling a possible synergistic effect. Gabapentin may help in controlling the opiate craving and potentiated the effect of naltrexone in this regard. Farren CK, Double-blind, placebo- n=13 recently Depression Similar side effect Naltrexone plus 4 O’Malley S [14] controlled trial, non-depressed severity, opiate profile in both groups, sertraline was naltrexone 50 mg qd abstinent craving, adverse and similar retention well tolerated plus placebo vs. opiate addicts events rates. Significant and initially naltrexone 50 mg plus negative correlation successful in sertraline 50 mg qd; 12- between Beck increasing week monitoring Depression Inventory treatment duration. scores and duration in retention, but treatment in the the difference combined therapy to the group. Opiate craving naltrexone decreased over time in alone both groups. diminished in time.

Based on these results a number of recommendations research, only 13 articles included double-blind, can be made in patients who need maintenance controlled, randomized trials. Another limitation is treatment for opioid use disorder, if a drug without related to the low number of drugs investigated, and opioid agonistic properties is preferred (table 3). These except for naltrexone (oral and extended-release), recommendations have been hierarchized according data regarding the efficacy or tolerability of other to the GRADE system [35]. pharmacological agents were derived from few good quality trials. Only one reviewer was involved in the Regarding the limitations of current review it can be processing of data collected, so a bias related to this mentioned the overall low quality design of the clinical

66 Vol. CXXII • No. 1/2019 • April • Romanian Journal of Military Medicine aspect can not be excluded. More research is needed, launched in order to provide more accurate and larger, well designed trials focused on a more recommendation in a continuously extending diverse range of drugs are also expected to be pathology, like the opioid use disorder.

Table 3. Recommendation based on the literature review for patients with opioid use disorder with non-opioid agonist pharmacological agents Clinical GRADE Treatment Advantages/disadvantages trials recommendations Naltrexone- oral [9-15] (+) naltrexone improve depressive symptoms in patients with opioid B administration use disorder at 6 months (+) naltrexone plus fluoxetine and individual psychotherapy has been proven useful in women with heroin dependence (+) naltrexone plus gabapentin improved muscle pain and severity in patients dependent on pentazocine (+) naltrexone plus sertraline increased short-term treatment retention of recently non-depressed opioid abstinent patients (-) buprenorphine/naloxone was superior to naloxone in the reduction of opioid-positive urine test and preserving patients participation in the treatment (-) similar weight gain during 6 months of treatment when compared to methadone (-) naltrexone was inferior to buprenorphine (not statistically significant) in several outcomes regarding the rate of relapse in detoxified heroin dependent patients Naltrexone- [16-23] (+) efficacy and tolerability were similar to B+ extended release buprenorphine/naltrexone (+) lower rate of relapse when compared to treatment as usual, at least on short-term (+) better outcomes than those treated with oral formulation of the same drug (+) naltrexone implants but not methadone were associated with long-term benefits in decreasing opioid-related hospital morbidity (+) efficient in preventing (+) improved depression severity at 4 weeks post-baseline (+) improved quality of life, rate of retention, opioid-negative urines, opioid craving, rate of re-employment (+) prolonged the duration of abstinence to opioids, in combination with counselling (-) worsened late insomnia (-) requires implant of the active drug (usually subcutaneous) Topiramate [25] (-) negative results in patients with opioid and cocaine use disorder D- Ibudilast [26] (+) induced lower rates of drug liking (oxycodone), lower craving to C heroin/tobacco/cocaine and lower subjective ratings of pain vs. placebo Memantine [29-32] (+) may provide an easier transition to buprenorphine-free C+ therapeutic regimen (+) induced attenuation of chronic opioid-dependence-related cognitive impairment (+) decreased the daily dose of methadone (+) it had positive effect over probably NMDA-mediated inflammatory processes in opioid users (+) it decreased the subjective effects of heroin in chronic users (-) it did not decreased the reinforcing effects of heroin in non- treatment seeker heroin-dependent patients

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Clinical GRADE Treatment Advantages/disadvantages trials recommendations Dronabinol [34] (+) it decreased the severity of D (-) no effect over rates of naltrexone-treatment induction or retention Dextro- [37-39] (+) it was useful in low doses as adjuvant treatment in methadone- C treated patients both at inflammatory level and clinical level (+) the quality of life was superior in patients who received dextromethorphan as adjuvant to methadone versus placebo plus methadone (-) the difference versus placebo was not significant in the otcome defined as mean methadone consumption Olanzapine [40,41] (+) it reduced direct aggressiveness, overall hostility, verbal C aggressiveness, and aggressive incidents (+) improved the rate of treatment retention Buspirone [43] (+) positive effect over depressive symptoms associated to C- methadone maintenance treatment (-) no effect over anxiety Baclofen [45] (+) significantly better treatment retention C-

From the data collected in this review only extended However, information have been gathered about its release naltrexone seems to achieve a B+ level of positive effect over cognition, inflammatory recommendation, based on 8 trials, and the benefits processes, and decrease of methadone daily dose [29- of using extended-release naltrexone tend to 32]. overcome its potential disadvantages in patients with Olanzapine may be recommended for controlling opioid use disorder who underwent successful aggressivity in patients with opioid use disorder, as disintoxication. This naltrexone formulation had adjuvant treatment (level C) [40, 41]. positive impact over a large number of outcomes related to opioid use disorder, including rate of Dextromethorphan was associated with some positive relapse, quality of life, opioid-related hospital results, although it did not decrease the necessary morbidity, and depressive severity [16-23]. As an daily dose of methadone when used as adjuvant agent alternative, oral naltrexone may be tried, although [37-39]. This drug was however useful in improving negative trials exist – level B recommendation, based both clinical and inflammatory outcomes, and on 7 trials [9-15]. Naltrexone plus fluoxetine and improved patients’ quality of life [37-39]. individual psychotherapy has been proven a useful Dronabinol did not prove itself efficient in the combination especially in women with heroin maintenance phase of treatment, although it may be dependence [15]. Naltrexone plus gabapentin of some help in alleviating withdrawal symptoms in improved muscle pain and psychological dependence opioid users [34]. severity in patients dependent on pentazocine [13]. Naltrexone plus sertraline were well-tolerated and Data for ibudilast, baclofen, and buspirone are increased on short-term treatment retention of insufficient to allow for stronger recommendations in recently non-depressed opioid abstinent patients [14]. the targeted population, but further research may change this perspective. Memantine has a level C+ recommendation for its use as adjuvant treatment in opioid use disorder because CONCLUSIONS there more data to support its efficacy are needed. Low dose memantine attenuated chronic opioid- Data showing a continued increase of illegal opioids dependence-induced cognitive impairment and use are overwhelming, and it became obvious that decreased the daily dose of methadone [30, 31]. clinicians must find new solutions for treating a continuously growing population affected by opioid

68 Vol. CXXII • No. 1/2019 • April • Romanian Journal of Military Medicine use disorder. Opioid agonists like buprenorphine and As adjuvant agents, olanzapine may be efficient for methadone are considered now the first line for aggressive behaviours in opioid dependent patients, treatment of opioid dependent patients, but non- memantine could improve cognitive function and opioid agonist drugs should be investigated more, decrease the inflammatory processes associated with either as adjuvant agents or as monotherapy. These substance use disorders, and dextromethorphan may non-opioid agonist agents can lead to the also help decreasing the inflammatory processes. administration of lower doses of opioid agonists (in Further research is needed in order to verify the case of adjuvant treatment), or even to their complete efficacy and tolerability of olanzapine, memantine and replacement, in both cases diminishing the risk for a dextromethorphan as adjuvant agents. new dependence. Disclaimer From the data reviewed, extended-release naltrexone is the most supported by evidence recommendation, No funding was received for this research. followed by oral naltrexone, in patients who were The author was speaker for Servier, Eli Lilly and Bristol- successfully detoxified from opioids. Naltrexone had Myers, and participated in clinical trials funded by Janssen positive results not only on the opioid use-related Cilag, Astra Zeneca, Otsuka Pharmaceuticals, Sanofi-Aventis, outcomes, but also over associated symptoms, like Sunovion Pharmaceuticals. depression.

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