Treating Opioid-Use Disorder - X:BOT Offers a Pragmatic Approach

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Reviewed By


Lee JD, Nunes EV, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet 2018; 391: 309-318

Obligatory comment on the current opioid epidemic: it’s bad…and getting worse.1,2 This problem is not a new one but even with increasing national awareness of this issue, the troubling truth is that opioid overdose deaths continue to increase from year to year. Currently, we are seeing a continued shift from prescription opioids as the number one culprit of drug overdose deaths to illicit heroin and ultra-potent fentanyl/fentanyl analogues.3 While this topic has gained significant notoriety due to the increasing number of fatalities, opioid-use disorder (OUD), a risk factor and major contributor to opioid-related deaths, is often underdiagnosed and undertreated.4 The 2015 National Survey on Drug Use and Health estimates there are 1.9 million noninstitutionalized adults with OUD.5 The prevalence of OUD in the U.S. doubled from 2002 to 2012.  These facts emphasize the need to take action to diminish the damaging impact of this well-documented epidemic.4


Currently there are three FDA-approved pharmacologic treatments for OUD maintenance therapy: methadone, buprenorphine (with or without naloxone), and naltrexone.  OUD management has been dominated by the use of methadone and buprenorphine products, particularly buprenorphine/naloxone (BUP-NX, Suboxone®), both of which employ a long-acting opioid agonist to maintain a patient’s sobriety and function.  Buprenorphine has a lower risk of misuse or overdose compared to methadone because it is a partial opioid agonist with a “ceiling effect” for both analgesia and euphoria.6 This risk is further decreased by the addition of naloxone, an opioid antagonist, which is meant to prevent misuse via nasal inhalation or intravenous injection.7


Despite definitive evidence that methadone and buprenorphine products are effective in the treatment of OUD, there are still considerable accessibility and availability barriers that patients face when seeking Medication Assisted Treatment (MAT). Methadone can only be prescribed by a physician as part of a certified opioid treatment program.  Similarly, buprenorphine can only be prescribed by physicians, nurse practitioners and physician assistants who have obtained a buprenorphine prescribing waiver. These barriers are just one of several reasons that more than half of patients with OUD are not receiving evidence-based treatment.8


Naltrexone, a diametrically distinct treatment option, is an opioid antagonist that decreases cravings for opioids and blocks any euphoric or analgesic effects of exogenous opioids. Thus, it reduces or eliminates the dopaminergic reward of opioid abuse that contributes to the cyclic nature of addiction.9,10 Naltrexone was first approved as an oral tablet for the treatment of OUD in 1984, but never enjoyed widespread use for OUD because patients could not be relied on to persist with treatment.11,12  To improve treatment success, naltrexone XR (XR-NTX, Vivitrol®) was developed as a long-acting gluteal intramuscular injection for the treatment of OUD and is arguably the most novel approach to MAT.10 XR-NTX does not contain an opioid agonist and therefore it is the only FDA-approved agent for OUD that enables patients to avoid opioid intake.  Because it is not a scheduled substance, there are no prescribing restrictions for XR-NTX. A significant limitation of XR-NTX is that it cannot be initiated until a patient has undergone opioid detoxification to avoid precipitating sudden withdrawal symptoms. BUP-NX on the other hand can be initiated almost immediately. Although XR-NTX is superior to placebo, there were no studies comparing XR-NTX to mainstay treatments such as methadone or BUP-NX for the indication of OUD.9,13,14


The EXtended-release naltrexone vs Buprenorphine/naloxone for Opioid Treatment (X:BOT) trial compared the efficacy and safety of XR-NTX and BUP-NX to induce and maintain a patient with OUD on MAT as well as reducing opioid overdoses, relapses, and cravings.9 In this open-label, randomized, controlled, comparative effectiveness trial, XR-NTX was administered monthly in-office via intramuscular injection and BUP-NX was self-administered daily as a sublingual film. The primary outcome was opioid relapse-free survival over 24 weeks of outpatient treatment after the participants had received detoxification and induction therapy in an inpatient program. Relapse was defined as four consecutive weeks of any non-study opioid use by urine drug screen or self-report OR seven consecutive days of self-reported use. Inclusion criteria for this trial were broad —any adult participant diagnosed with OUD who had used non-prescribed opioids in the past 30 days was permitted to enroll in the study. Key exclusion criteria included maintenance on 30 mg or more of methadone, or a need for pain management with opioids. All participants were recruited from inpatient community treatment centers during acute opioid detoxification and were followed-up on an outpatient basis.


There were 570 participants assigned to receive either XR-NTX (n=283) or BUP-NX (n=287). The per-protocol (PP) and intention-to-treat (ITT) results from this study paint two different pictures of the comparative effectiveness of XR-NTX to BUP-NX (Table 1). ITT results show clear superiority of BUP-NX over XR-NTX in nearly every clinical outcome including induction success, opioid relapse, and relapse-free survival.  However, when comparing PP results relapse events, opioid-negative urine samples, opioid-abstinent days, and self-reported opioid craving were statistically similar between groups at week 24. Though not statistically significant, those on XR-NTX in the PP analysis self-reported 36 more opioid-abstinent days when compared to those on BUP-NX. As the authors note, the differences between the ITT and PP results were due to a significant number of induction failures with XR-NTX. Additionally, treatment dropouts (many of which were attributed to induction failure) were tallied as a relapse event. This explains the notable difference in opioid relapse and relapse-free survival between the ITT and PP results for XR-NTX.


Table 1: X:BOT Study Outcomes


XR-NTX (n=283)

BUP-NX (n=287)

Statistical Significance


204 (72%)

270 (94%)

OR 0.16;
95% CI, 0.09-0.28, p<0.001

Opioid Relapse

ITT: 185 (65%)

PP: 106 (52%)

ITT: 163 (57%)

PP: 150 (56%)

ITT: OR 1.44;
95% CI, 1.02-2.01, p=0.036

PP: OR 0.87;
95% CI, 0.6-1.25, p=0.44

Relapse-Free Survival

ITT: 8.4 weeks

PP: 20.4 weeks

ITT: 14.4 weeks

PP: 15.2 weeks

ITT: HR 1.36;
95% CI, 1.10-1.68, p=0.0040

PP: HR 0.92;
95% CI, 0.71-1.18, p=0.49

Weekly Opioid-Negative Urine Samples
(0-24 weeks)

ITT: 4 weeks

PP: 13 weeks

ITT: 10 weeks

PP: 11 weeks

ITT: p<0.0001

PP: p=0.81

Self-Reported Opioid-Abstinent Days
(0-144 days)

ITT: 39 days

PP: 123 days

ITT: 81 days

PP: 87 days

ITT: p<0.0001

PP: p=0.67


The X:BOT trial is the first randomized, controlled trial comparing the effectiveness of XR-NTX and BUP-NX for OUD in the United States. One of the greatest strengths of the X:BOT study is the commitment to comparing these agents in a pragmatic, “real-world” setting; an important feature for comparative effectiveness trials. Considering that most MAT is initiated after inpatient detoxification or residential treatment, the study was designed to allow induction of both treatments before participants were maintained on an outpatient basis. Some weaknesses of this trial include the open-label design and a lack of a third arm comparing effectiveness to methadone. A smaller, but very similar trial comparing these two medications in Norway was published one month before the X:BOT trial and produced similar results indicating that XR-NTX was as effective as, and potentially superior to BUP-NX in the treatment of OUD, even in the ITT population.13 Both of these studies prove that XR-NTX is an effective treatment option for OUD that can produce results similar to the current standard of care, BUP-NX. The bottom line: XR-NTX may not, and arguably should not, replace buprenorphine but it does offer an accessible option for a disease in which treatment accessibility is challenging and complicated by numerous treatment barriers.


Why is this study commentary showing up in your iForumRx feed? Another recently published trial that supports substance-use disorder treatment in the primary care setting is the SUMMIT trial.15 The results indicate collaborative care, including physician, nurse practitioner, physician assistant, pharmacist, and care coordinators for opioid and alcohol use disorders in the primary care setting significantly improved access to treatment and abstinence from alcohol and other drugs of abuse when compared to “usual” care.15 As pharmacist practitioners we can and should be involved in the treatment of OUD.


Ambulatory care pharmacists are keenly aware of the lack of access to healthcare providers for patients who reside in rural areas.  The push for provider status through the Pharmacy and Medically Underserved Areas Enhancement Act is intended to address this need. Access to substance abuse treatment is woefully scarce and often clustered in urban city centers. According to the 2017 National Rural Health Association report, 90% of physicians who can legally prescribe MAT for OUD were located in urban counties.16 Where can patients with OUD who are seeking MAT go if they live 5 hours away from the closest opioid treatment program or buprenorphine-waivered clinician? XR-NTX is a pragmatic option for primary care providers because there are no prescribing restrictions. Pharmacists embedded in primary care offices or in community pharmacies under collaborative practice agreements can take the lead by screening for opioid-use disorder, prescribing XR-NTX, and administering the medication every 4 weeks.


XR-NTX administration is one way in which pharmacists can take on a new role, while supporting providers who are certified to prescribe buprenorphine. How comfortable are you with addressing OUD in your clinic or community pharmacy?