Abstract
BACKGROUND:
Extended-release naltrexone (XR-NTX) is an effective maintenance treatment for opioid use disorder, but induction from active opioid use is a challenge as individuals must complete detoxification before induction. We aimed to determine whether use of methadone or buprenorphine, long acting agonist opioids commonly used for detoxification, were associated with decreased likelihood of induction onto XR-NTX.
METHODS:
We performed a secondary analysis of a large open-label randomized trial of buprenorphine versus XR-NTX for treatment of individuals with opioid use disorder recruited from eight short term residential (detoxification) units. This analysis only included individuals randomized to the XR-NTX arm of the trial (N= 283). The method of detoxification varied according to usual practices at each inpatient program. Logistic regression models estimating the log-odds of induction onto XR-NTX were fit, with detoxification regimen received as the predictor.
RESULTS:
In the unadjusted logistic regression model, detoxification drug received (either methadone or buprenorphine) was significantly associated with decreased likelihood of induction onto XR-NTX compared to receiving non-opioid detoxification (Overall: P<.001; buprenorphine vs non-opioid detoxification: OR (95% CI)= 0.32 (0.15–0.67); methadone vs nonopioid detoxification: OR (95% CI)= 0.23 (0.11–0.46). After controlling for site as a random effect, the association of detoxification drug with induction success lost statistical significance.
CONCLUSIONS:
Use of agonist medication during detoxification was associated with XR-NTX induction failure. Medication choice was determined by each site’s clinical practice and therefore this association could not be separated from other site level variables.
Keywords: Naltrexone, Methadone, Buprenorphine, Pain, Opioid Use Disorder
1. Introduction
Opioid use disorder (OUD) is a chronic relapsing disorder that can lead to significantly increased risk of criminality, mental and physical morbidity, and mortality (Bertschy 1995, Fischer, Rehm et al. 2005). An alarming trend in the Unites States has shown a substantial increase in opioid use and overdose death over the last twenty years (Rudd, Seth et al. 2016). Currently, there are several effective medications approved by the FDA for achieving abstinence and reducing the risks associated with OUD: the opioid receptor agonist methadone, the partial agonist buprenorphine, and the opioid receptor antagonist naltrexone (Mattick, Kimber et al. 2008, Mattick, Breen et al. 2009, Kreek, Borg et al. 2010, Krupitsky, Nunes et al. 2011). Although the oral form of naltrexone has not been shown to be effective in OUD treatment due to problems with compliance, extended release naltrexone (XR-NTX) provides sustained blockade at the opioid receptor and reduces opioid use (Krupitsky, Nunes et al. 2011) as well as the subjective effects of opioids (Comer, Collins et al. 2002).
XR-NTX differs from agonist therapies in that naltrexone is a non-controlled substance and has no abuse or diversion potential (Comer, Collins et al. 2002). Furthermore, XR-NTX may be advantageous in special patient populations, including those within a correctional environment, those whose jobs may discourage treatment with agonists, and for individuals not wanting to be on agonist therapy (Marcus, Bojko et al. 2018, Nahata, Mancino et al. 2018).
One limitation of the clinical utility of XR-NTX is the induction process which requires detoxification from opioids prior to initiating naltrexone to avoid precipitated withdrawal. If administered to opioid tolerant individuals with occupied opioid receptors, naltrexone displaces the opioid from the receptor leading to a severe and sudden onset of withdrawal (Comer, Collins et al. 2002). The current official prescribing information recommends that individuals be opioid free for 7–10 days prior to XR-NTX injection to prevent precipitated withdrawal (Alkermes 2010). The need to undergo a detoxification followed by a washout period creates a significant hurdle, particularly in outpatient settings, and places individuals at risk for relapse and overdose because many patients return to opioid use before naltrexone can be initiated. Strategies to improve XR-NTX induction are therefore needed.
Two general clinical approaches exist in opioid detoxification: 1] gradual opioid agonist taper with methadone or buprenorphine and 2] the utilization of non-opioid medications for symptomatic withdrawal relief (Sigmon, Bisaga et al. 2012). Non-opioid management of withdrawal uses a variety of medications to address the symptoms of withdrawal, such as alpha-2-agonists, anti-emetics, and sedative-hypnotics (Gold, Pottash et al. 1980, Gold, Pottash et al. 1980, Kleber, Gold et al. 1980). Detoxification utilizing a gradual taper of methadone or buprenorphine has shown more symptomatic control in studies of detoxification protocols when compared to detoxification with clonidine alone (Amass, Ling et al. 2004, Ling, Amass et al. 2005, Gowing, Farrell et al. 2009, Ziedonis, Amass et al. 2009). In a head-to-head trial, buprenorphine was more effective than clonidine for detoxication, both in the inpatient (77% vs 22%) and outpatient (29% vs. 5%) setting (Ling, Amass et al. 2005). In cases of planned induction onto XR-NTX however, non-opioid detoxification offers the advantage of a decreased opioid washout period and therefore a decreased time window of relapse risk (Sigmon, Bisaga et al. 2012). The long half-lives of methadone and buprenorphine require an extended washout period of a week or more before administering XR-NTX. This leads to a long delay between taper completion and the possibility of XR-NTX initiation and therefore may increase the possibility of failed induction due to dropout and/or resumption of illicit opioids. A trial comparing a slow buprenorphine taper to a more rapid induction approach utilizing only one day of buprenorphine showed the second approach to be significantly more likely to lead to successful induction, implying that the long delay caused by prolonged agonist tapers leads to increased incidence of non-induction (Sullivan, Bisaga et al. 2017). Despite these shortcomings, methadone and buprenorphine continue to be used in most treatment programs to manage opioid withdrawal.
In the X:BOT study (CTN-0051), conducted in the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN), patients with OUD admitted to eight community-based inpatient treatment programs across the United States were randomly assigned to sublingual buprenorphine versus XR-NTX for a 6-month comparative effectiveness trial (Lee, Nunes et al. 2016, Nunes, Lee et al. 2016, Lee, Nunes et al. 2018). For patients assigned to XR-NTX, the method of detoxification was allowed to vary according to the usual practices at each inpatient program and consisted of a mixture of non-opioid detoxification or detoxification with buprenorphine or methadone. The initiation of XR-NTX that followed detoxification was standardized and required three or more days without opioid use, a urine toxicology sample that was negative for opioids (including buprenorphine and methadone), and a negative naloxone challenge. The variation in detoxification procedures provided a quasi-experiment in naturalistic treatment settings to test the hypothesis that strategies utilizing non-opioid medications would lead to a higher likelihood of XR-NTX induction compared to strategies based on a standard methadone or buprenorphine taper.
Besides the variation in medications used in detoxification, the eight programs also differed in their flexibility to allow longer lengths of stay. Every program had a medically supervised detoxification unit which provided intensive monitoring that lasted 3–7 days due to logistical restrictions. Some programs also had the option of transferring patients to short-term residential treatment for 14 days or more after patients completed the detoxification stay, which allowed a longer period for washout of opioids in a controlled residential environment. Randomization to buprenorphine or XR-NTX could occur early in the inpatient stay, while most of the induction hurdle was yet to be surmounted, or after detoxification and washout had been completed later in the stay.
Here we report a secondary analysis of the X:BOT trial (CTN-0051) examining the association between successful XR-NTX initiation and non-opioid vs buprenorphine or methadone induction strategies, length of stay, and early vs late randomization. We hypothesized that the use of buprenorphine or methadone taper for detoxification would be associated with lower likelihood of successful XR-NTX induction compared to detoxification with non-opioid medications when controlling for covariates likely associated with induction such as longer lengths-of-stay and later randomization.
2. Materials and methods
A full description of the study design and rationale has been published previously and includes a complete description of inclusion and exclusion criteria for participants and study sites (Nunes, Lee et al. 2016). In brief, individuals seeking treatment for OUD were recruited during their inpatient stay at eight short-term inpatient/residential detoxification units. The study was approved by the Institutional Review Boards of New York University Medical Center and each of the participating sites, and all patient-participants provided written informed consent. Those meeting eligibility criteria were randomized to receive either buprenorphine or XR-NTX and followed on an outpatient basis over a 24-week period. Induction was encouraged as soon as possible following randomization. Detoxification procedures were naturalistic and varied among the eight sites. The detoxification approaches included a brief 3 to 7-day methadone taper (three sites), a 3 to 14-day buprenorphine taper (two sites) or use of clonidine and other non-opioid medications for detoxification (three sites). Although sites predominantly utilized one detoxification approach, there was some variation in method at some sites. As mentioned above, according to the study protocol utilized at all sites, individuals were not given the initial XR-NTX injection until their urine was negative for all opioids including buprenorphine or methadone to ensure that the opioid washout was complete. Once the urine was negative for opioids a naloxone challenge was conducted and XR-NTX was initiated after a negative challenge.
Participants were English speaking individuals over 18 years of age meeting DSM-5 criteria for OUD with non-prescribed opioid use in the last 30 days. The primary sample excluded those who had serious medical/psychiatric/substance use disorders, elevated transaminases (>5× upper limit of normal), required opioids for chronic pain or were on methadone maintenance treatment (>30mg/day). The exploratory analyses presented in this manuscript included only those who were randomized to the XR-NTX arm of the trial (n=283).
2.1. Analysis
The sample was described in terms of baseline demographics and study variables (using frequencies and proportions for categorical variables and means and standard deviations for continuous variables) both for the overall XR-NTX sample, and by detoxification drug received. Detoxification regimen received was defined as a 3-level categorical variable (receipt of any methadone vs. receipt of any buprenorphine vs. receipt of non-opioid detoxification). Of note, a few patients received one or two days of buprenorphine to begin the detoxification process. These were included in the analysis in the buprenorphine group. One participant who received both methadone and buprenorphine was excluded from analyses. Additional descriptive statistics were also produced for each of the eight study sites.
A logistic regression model estimating the log-odds of induction onto XR-NTX was fit, with detoxification regimen received as the predictor. The model was then re-fit, adding a random effect for site. In addition to the random effect of site, further models were also fit that included each of the following covariates: 1) the length of stay in the detoxification unit before discharge to the community, and 2) whether individuals were randomized within three days of last opioid (early randomizers) or longer than three days since last opioid (late randomizers).
All analyses were performed using SAS® version 9.4, and all statistical tests were 2-sided with a 5% level of significance.
3. Results
Two hundred eighty-three patients were randomized to the XR-NTX arm. Table 1 shows demographic and clinical characteristics of this sample, in total, and divided according to the three categories of induction regimen. A majority of these primarily used heroin in the 7 days prior to detoxification admission (81.3%, n=230). Patients primarily using buprenorphine (2.1%, n=6), methadone (1.1%, n=3), and opioid analgesics (15.2%, n=43) made up the remainder of the study population, with one patient missing this information on primary opioid used. Further demographics are listed in Table 1. Of note, likely due to site effects, the group detoxified with a methadone taper had a higher percentage of minority patients, homeless patients, and patients that preferred XR-NTX. Individuals in the group receiving no opioid medications during detoxification also had lower OUD severity than the other two groups. Nearly all the individuals who were inducted (97%) had a negative urine before induction as required by the study protocol. Of the 79 individuals who were not inducted, 68 (86%) had a positive urine before drop-out, while 11 (14%) had a negative urine but still were unable to induct.
Table 1.
Baseline Demographic Data Among Individuals Randomized to XR-NTX
| Total Sample (n=282*) | Received Methadone (n=101) | Received Buprenorphine (n=81) | Received Non-Opioid Detoxification (n=100) | |||||
|---|---|---|---|---|---|---|---|---|
| Variables | n | % | N | % | N | % | n | % |
| Age at Randomization (Mean (SD)) | 282 | 34.0 (9.5) | 101 | 36.5 (10.9) | 81 | 32.3 (8.1) | 100 | 32.8 (8.4) |
| Gender | ||||||||
| Male | 194 | 68.8% | 72 | 71.3% | 54 | 66.7% | 68 | 68.0% |
| Female | 88 | 31.2% | 29 | 28.7% | 27 | 33.3% | 32 | 32.0% |
| Race | ||||||||
| Caucasian | 206 | 73.0% | 63 | 62.4% | 59 | 72.8% | 84 | 84.0% |
| Black | 28 | 9.9% | 12 | 11.9% | 12 | 14.8% | 4 | 4.0% |
| Asian | 8 | 2.8% | 1 | 1.0% | 5 | 6.2% | 2 | 2.0% |
| Other | 40 | 14.2% | 25 | 24.8% | 5 | 6.2% | 10 | 10.0% |
| Ethnicity | ||||||||
| Not Hispanic | 237 | 84.0% | 77 | 76.2% | 79 | 97.5% | 81 | 81.0% |
| Hispanic | 45 | 16.0% | 24 | 23.8% | 2 | 2.5% | 19 | 19.0% |
| Housing Status | ||||||||
| Domiciled | 209 | 74.1% | 70 | 69.3% | 66 | 81.5% | 73 | 73.0% |
| Homeless | 73 | 25.9% | 31 | 30.7% | 15 | 18.5% | 27 | 27.0% |
| Preferred Naltrexone | ||||||||
| Disagree/Neutral | 203 | 72.2% | 66 | 65.3% | 60 | 75.0% | 77 | 77.0% |
| Agree | 78 | 27.8% | 35 | 34.7% | 20 | 25.0% | 23 | 23.0% |
| OUD Severity Strata | ||||||||
| Low | 170 | 60.3% | 58 | 57.4% | 40 | 49.4% | 72 | 72.0% |
| High | 112 | 39.7% | 43 | 42.6% | 41 | 50.6% | 28 | 28.0% |
| Induction Status | ||||||||
| Not Inducted | 79 | 28.0% | 40 | 39.6% | 26 | 32.1% | 13 | 13.0% |
| Inducted | 203 | 72.0% | 61 | 60.4% | 55 | 67.9% | 87 | 87.0% |
One participant who received both methadone and buprenorphine was excluded from analyses.
Of the total sample of patients randomized to XR-NTX, 203 (72.0%) were successfully inducted. A higher percentage of individuals receiving a non-opioid detoxification regimen were inducted (87.0%) followed by those receiving buprenorphine (67.9%) and methadone (60.4%) tapers (Figure 1). In the unadjusted logistic regression model, detoxification drug received (both methadone or buprenorphine) was significantly associated with decreased likelihood of induction onto XR-NTX compared to receiving non-opioid detoxification (Overall: F (2,279)=8.55; P<.001; buprenorphine vs non-opioid detoxification: OR (95% CI)= 0.32 (0.15–0.67); methadone vs non-opioid detoxification: OR (95% CI)= 0.23 (0.11–0.46)). After controlling for site as a random effect, the association of detoxification drug with induction success lost statistical significance (P=0.056). This reflects the fact that, although there was some variation within sites, sites mostly used one induction regimen, resulting in a strong association between site and type of regimen. Covariates of number of days on the unit and being a late randomizer were then added and both were found to be significantly associated with the greater likelihood of induction (P= 0.002 and 0.035 respectively). Table 2 summarizes four logistic regression models: Model 1 with the addition of site as a random effect, model 2 with a random effect of site and adjusted by late randomization, model 3 with random effect of site and adjusted by length of stay on the unit, and model 4 with random site and adjusted by late randomization, and length of stay. Table 3 describes detoxification medication along with other predictive variables organized by site. The three sites in which individuals received only non-opioid medications during detoxification predominantly also nearly exclusively recruited individuals who were defined as late randomizers.
Figure 1:
Percent XR-NTX Induction by Medication
Table 2.
Logistic Regression Models Tested
| Detoxification Drug | Randomization Timing | Length of Stay | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Model | N | OR (95% CI) Buprenorphine vs Non-opioids | OR (95% CI) Methadone vs Non-opioids | F | Pr > F | OR (95% CI) Early vs Late | F | Pr > F | OR (95% CI) 1 Day Longer | F | Pr > F |
| Random Site | 282 | 0.45 (0.15, 1.38) | 0.28 (0.10, 0.79) | F(2,272)=2.92 | 0.0556 | Not Applicable | Not Applicable | ||||
| Random Site and Late Randomization Adjusted | 282 | 0.59 (0.22, 1.53) | 0.46 (0.18, 1.19) | F(2,271)=1.3 | 0.2743 | 0.36 (0.18, 0.74) | F(1,271)=7.78 | 0.0057 | |||
| Random Site and Length of Stay Adjusted | 279 | 0.38 (0.12,1.31) | 0.37 (0.14, 1.00) | F(2,268)=2.16 | 0.1178 | Not Applicable | 1.06 (1.03, 1.10) | F(1,268)=11.94 | 0.0006 | ||
| Random Site, Late Randomization and Length of Stay Adjusted | 279 | 0.48 (0.17, 1.34) | 0.57 (0.22, 1.48) | F(2,267)=1.08 | 0.3400 | 0.44 (0.21, 0.94) | F(1,267)=4.51 | 0.0346 | 1.05 (1.02, 1.09) | F(1,267)=9.76 | 0.0020 |
Table 3.
Site level differences
| Site 1 (n=46) | Site 2 (n=40) | Site 3 (n=33) | Site 4 (n=40) | Site 5 (n=45) | Site 6 (n=32) | Site 7 (n=30) | Site 8 (n=16) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Variables | N | % | N | % | N | % | n | % | n | % | n | % | n | % | n | % |
| Detoxification Drug Received | ||||||||||||||||
| Non-opioids | 1 | 2.2% | 40 | 100.0% | 2 | 6.1% | 6 | 15.0% | 0 | 0.0% | 31 | 96.9% | 4 | 13.3% | 16 | 100.0% |
| Buprenorphine | 45 | 97.8% | 0 | 0.0% | 7 | 21.2% | 2 | 5.0% | 0 | 0.0% | 1 | 3.1% | 26 | 86.7% | 0 | 0.0% |
| Methadone | 0 | 0.0% | 0 | 0.0% | 24 | 72.7% | 32 | 80.0% | 45 | 100.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| Randomization Timing | ||||||||||||||||
| Early | 34 | 73.9% | 0 | 0.0% | 19 | 57.6% | 16 | 40.0% | 36 | 80.0% | 0 | 0.0% | 2 | 6.7% | 0 | 0.0% |
| Late | 12 | 26.1% | 40 | 100.0% | 14 | 42.4% | 24 | 60.0% | 9 | 20.0% | 32 | 100.0% | 28 | 93.3% | 16 | 100.0% |
| Length of Stay in Days (Mean (SD)) | 23.1 (19.0) | 46.7 (30.8) | 20.6 (29.6) | 22.4 (37.8) | 6.4 (1.8) | 8.8 (9.4) | 24.0 (6.9) | 18.1 (7.6) | ||||||||
| Induction Status | ||||||||||||||||
| Not Inducted | 20 | 43.5% | 2 | 5.0% | 15 | 45.5% | 7 | 17.5% | 22 | 48.9% | 5 | 15.6% | 4 | 13.3% | 4 | 25.0% |
| Inducted | 26 | 56.5% | 38 | 95.0% | 18 | 54.5% | 33 | 82.5% | 23 | 51.1% | 27 | 84.4% | 26 | 86.7% | 12 | 75.0% |
4. Discussion
In this secondary analysis of individuals assigned to XR-NTX in a large open-label randomized trial for treatment of OUD, we found receipt of methadone and buprenorphine during detoxification was significantly associated with decreased likelihood of XR-NTX induction, but this association was not significant when considering site as a random variable in the regression model. Other variables such as length of stay were also significantly associated with induction success, but as with medication, lost significance when considering site as a random variable.
These findings are consistent with our hypothesis that a non-opioid induction strategy will be associated with greater success in naltrexone initiation, compared to buprenorphine or methadone taper strategies. However, due to the strong association between sites and induction strategies, namely that most sites used predominantly one or another induction strategy, we cannot disentangle whether the difference in induction success reflect induction strategy per se, or other differences between sites. At five of eight sites more than 96% of patients at the site received the same induction strategy. In the remaining three sites more than 70% received the same induction strategy. The homogeneity of induction method at each site likely reflected that the induction strategy was largely determined by the preference of the local clinical providers. Sites differed in several other important ways including in the length of time individuals could stay on the units, and comfort and experience among clinical staff to offer nonopioid based detoxification. Having more time to remain on an inpatient detoxification or residential unit is intuitively helpful for induction, which requires an extended period of abstinence. Sites also differed in the number of individuals who were recruited late in their stay, effectively sampling only individuals who were immediately ready to be inducted onto XR-NTX and who may have been more motivated to remain in treatment. In addition, sites that primarily used a methadone detoxification strategy had a higher proportion of minority, homeless and more severe patients, all of which might be expected to conspire against induction success.
Our study has several limitations. First as noted, patients were not randomized to receive methadone or buprenorphine, or non-opioid detoxification. Since the detoxification regimen was decided by the clinical team at each site, the medications used were strongly associated with site as noted above. The analysis was also limited in focus due to statistical power concerns and we did not include demographics, comorbidity, or opioid use disorder severity in the analysis models. We also did not consider the effect of ancillary medications used in combination with opioid-based detoxification regimens. There are also other important clinical considerations in choosing a detoxification regimen (for example, patient preference, cost, and optimal management of withdrawal and craving symptoms) that were beyond the scope of this analysis. These must be factored into clinical decision making along with the finding that more than half of the individuals receiving a methadone taper were successfully inducted. It is also likely the requirement of the protocol for an opioid-negative urine prior to induction disproportionately delayed induction following agonist tapers. This likely lowered successful induction rates as participants declined to stay on the unit for an extended period and left the detox units. The large proportion of individuals who failed to induct and did not have an opioid-negative urine before leaving detoxification (86%) highlights this barrier. As other XR-NTX induction studies imply that induction can take place in the presence of a buprenorphine-positive urine, this requirement likely unduly handicapped individuals receiving buprenorphine and methadone. Nearly every patient who left the detoxification or residential unit before receiving the XR-NTX induction did not return for outpatient follow up or had returned to opioid use and were clinically ineligible for induction. These discharges were due to a variety of factors (insurance issues, administrative discharges due to conflicts with staff/patients, leaving against medical advice, work/family issues).
Further investigations should seek optimal strategies for induction onto XR-NTX in both inpatient and outpatient settings. Outpatient approaches are more cost effective and often more acceptable to patients and their families and have been successfully used to facilitate outpatient induction (Bisaga, Mannelli et al. 2018). Many trials used low dose naltrexone during detoxification based on evidence that this may attenuate withdrawal symptoms and decrease the length of time until XR-NTX can be administered (Mannelli, Patkar et al. 2009). An open-label pilot trial showed outpatient detoxification to be a possibility for a large portion of patients (Mannelli, Wu et al. 2014) and a follow-up outpatient trial randomized individuals to either a short induction procedure involving one day of buprenorphine followed by non-opioid medications targeting symptoms or to an extended buprenorphine taper. This trial showed that individuals were significantly more likely to be inducted when randomized to the rapid protocol using minimal agonist treatment (Sullivan, Bisaga et al. 2017). A recent large multisite trial again showed the feasibility of performing outpatient inductions but failed to show an added benefit of low dose naltrexone (Bisaga, Mannelli et al. 2018). Although these trials highlight the possibility of outpatient induction, significant implementation barriers exist. The rapid outpatient approach requires a day hospital type setting and intensive attention from staff. Most outpatient programs are not currently equipped or staffed to provide this level of care. Thus, future trials must examine clinical effectiveness along with implementation considerations to maximize the impact of novel induction approaches.
5. Conclusion
Overall, detoxification with long-acting opioids was associated with lower successful XR-NTX induction. However, the role of medication choice was confounded by site and decreased induction could relate to these or other differences between sites. More research is needed to improve methods for initiating patients with OUD onto XR-NTX.
Highlights for the Association Between Methadone or Buprenorphine Use During Medically Supervised Opioid Withdrawal and Extended-Release Injectable Naltrexone Induction Failure.
Several approaches exist in opioid detoxification to facilitate XR-NTX induction.
These include methadone or buprenorphine taper, and non-opioid medications.
In the X-BOT trial the detoxification approach was determined by site preference.
Receipt of non-opioid medications was associated with greater XR-NTX induction.
Medication receipt could not be disentangled from other site characteristics.
Acknowledgments
Grant Funding: The study in this presentation was funded by the NIDA grant U10 DA013035 (PI: Nunes). Dr Shulman and Dr. Wai were funded by the NIDA grant T32 DA007294.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Disclosures/ Conflict of Interest: Dr. Nunes has received medication for research studies from Alkermes/Cephalon, Duramed Pharmaceuticals, and Reckitt-Benckiser. Dr. Rotrosen reports medication for the present study from Indivior, and medication and/or funds for other studies (as principle investigator or investigator) from Indivior and Alkermes. The remaining authors have no conflicts of interest to report.
Clinical Trial Registration: NCT02032433
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