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. Author manuscript; available in PMC: 2025 Aug 1.
Published in final edited form as: J Subst Use Addict Treat. 2023 Sep 19;163:209162. doi: 10.1016/j.josat.2023.209162

Comparing Outcomes of Extended-Release Naltrexone in Adolescents and Young Adults with Opioid Use Disorder

Shannon Gwin Mitchell a,*, Jesse B Fletcher a, Laura B Monico a, Jan Gryczynski a, Marc J Fishman b, Kevin E O’Grady c, Robert P Schwartz a
PMCID: PMC10948374  NIHMSID: NIHMS1937834  PMID: 37730015

1. Introduction

1.1. Opioid use among US youth

According to current CDC records, more than 3,300 adolescents and young adults (e.g., persons aged 15–24 years) die annually in the United States from opioid overdose (CDC 2020), making it one of US youth’s leading causes of death (CSUP 2016). Furthermore, adolescent and young adult opioid use disorder (OUD) rates, risky opioid use among youth, and unintentional youth opioid poisonings have increased dramatically in the United States over the past two decades (Banta-Green & Cooley 2018; Carney et al., 2018; Chang et al., 2018), with OUD diagnosis rates among youth increasing nearly six-fold from only 0.26 per 100,000 person years at the turn of the century to 1.51 per 100,000 person years by 2014 (Hadland et al., 2017). In 2016, the American Academy of Pediatrics released a policy statement recommending the prescription of medication to US youth to combat severe OUD (Committee on Substance Use and Prevention, 2016). Despite this, adolescents and young adults remain significantly less likely than their adult counterparts to be prescribed medication for OUD (e.g., methadone, buprenorphine, naltrexone; Alinsky et al., 2020a); only about one-in-four youth with OUDs are prescribed medications for OUD (Hadland et al., 2017; Hadland et al., 2018; Banta-Green & Cooley 2018), and the younger the patient is, the less likely they are to be prescribed any medication (Hadland et al., 2017; Hadland et al., 2018). Currently, the Food and Drug Administration (FDA) medication labels for buprenorphine give formal approval to buprenorphine for individuals 16 years and older, and extended release naltrexone for those 18 years and older. For both, the labels indicate that safety and efficacy have not been established in the pediatric population (which refers to patients that are younger than 17 years old). Federal Opioid Treatment Program regulations for methadone indicate people younger than 18 years old must have had two documented failed attempts at short-term detoxification or drug-free treatment within a 12-month period (eCFR 2021).

1.2. Naltrexone for the treatment for OUD

Evidence clearly demonstrates the efficacy of both opioid agonist (methadone, buprenorphine) and opioid antagonist (naltrexone) treatment medications in improving health outcomes of OUD (Blanco & Volkow 2019). However, unlike methadone and buprenorphine, naltrexone has no opioid agonist effects and is unaccompanied by the feelings of euphoria associated with opioid use. Naltrexone operates by occupying opioid receptors, thereby blocking the effects normally produced by opioid use (Comer et al., 2007). A monthly intramuscular extended-release formulation of naltrexone (hereafter, “XR-NTX”) was developed to improve poor treatment adherence associated with oral naltrexone (Syed & Keating 2013; Ahamad et al., 2015) and to reduce the risk of opioid overdose associated with nonadherence (Connery & Smith 2015). Agonist-type treatments for OUD have been shown to be associated with more negative attitudes and feelings of stigma when applied among youth or young adults (Adams et al., 2021), resulting in increased interest in the use of XR-NTX among adolescents and young adults.

1.3. Application of XR-NTX to improve opioid outcomes among US youth

A dearth of head-to-head comparisons exist of opioid-treatment medications among US youth (Carney et al., 2018), with most evidence confined to small trials and case series analyses (Banta-Green & Cooley 2018). As such, issues of efficacy, retention, and adherence to medication-based treatments for OUD among youth remain incompletely understood (Viera et al., 2020). What evidence does exist implies XR-NTX is well-tolerated, safe, and feasible to apply among youth (Fishman et al., 2010; Banta-Green & Cooley 2018; Camenga et al., 2019), producing superior retention in treatment to both behavioral interventions and buprenorphine regimens (Hadland et al., 2018). Most recently, a trial of XR-NTX in young adults (18–26 years of age) demonstrated that XR-NTX or extended-release buprenorphine combined with an assertive outreach intervention improved opioid relapse outcomes through 24 weeks postinitiation compared to patients not receiving assertive outreach interventions (Wenzel et al., 2021), while our trial of US youth (15–21 years of age) demonstrated that youth receiving XR-NTX reported significantly greater reductions in opioid use over time when compared to youth receiving either sublingual buprenorphine or non-medication-based treatment-as-usual (Mitchell et al., 2021). Our findings were limited to analyses based on the treatment that participants actually received at discharge from a residential addiction treatment program, rather than intent-to-treat groupings, as participants had significant nonadherence to randomization. The current study, a secondary analysis from that parent trial of XR-NTX for youth with OUD (Mitchell et al., 2021), hopes to extend this line of inquiry by comparing the effectiveness of XR-NTX among adolescents (i.e., aged 15–17) and young adults (i.e., aged 18–21) with moderate to severe OUD.

2. Material and methods

For a full discussion of parent study methods and outcomes, please see Mitchell et al., 2021. The Friends Research Institute IRB and the Western Institutional Review Board (WIRB) approved this study. The research was covered under a federal Certificate of Confidentiality and study progress was monitored by a Data Safety and Monitoring Board. Because XR-NTX is not approved for pediatric use, we obtained an Investigational New Drug (IND) permit from the US FDA to provide this medication to patients who were 15 to 17 years of age. We registered the study at ClinicalTrials.gov (NCT 02599818).

2.1. Participants

All participants in the current secondary analyses participated in the parent trial. A total of 288 persons (n = 25 adolescents; n = 263 young adults) were enrolled from a residential addiction treatment program in Maryland between October 2013 and January 2018. Study inclusion criteria were: (1) between 15 and 21 years of age, inclusive; (2) current moderate or severe OUD (diagnosed at admission); (3) receiving treatment for opioid withdrawal; (4) able and willing to provide informed consent; and, for participants under 18 years of age, (5) parental or guardian consent and participant assent. Exclusion criteria included: (1) liver function test levels 4x greater than normal; (2) unstable medical or psychiatric illness which could impede participation; (3) suicide attempt in the past 6 months; (4) allergic to naloxone and/or naltrexone; (5) current chronic pain condition for which opioids were deemed necessary for ongoing care; (6) blood coagulation disorder; (7) Body Mass Index > 40; (8) if female: pregnant, lactating, unwilling or unable (due to parental objection) to use FDA-approved contraceptive methods; and (9) needing detoxification from benzodiazepines during inpatient treatment.

2.2. Treatment conditions

The parent study design was a randomized trial in which participants were assigned on a 1:1 basis to XR-NTX or treatment-as-usual (TAU). However, as described in Mitchell et al. (2021), the study had considerable nonadherence to the random assignment due to a number of factors spanning patient preference/choice and external constraints. Thus, the current analysis focuses on the more clinically meaningful groupings of treatment as actually received (“as-treated”).

2.2.1. XR-NTX Condition (n = 13 adolescents; n = 69 young adults).

Participants receiving XR-NTX were required to have undergone a medically assisted withdrawal (with buprenorphine over approximately five-seven days) prior to initiation of XR-NTX. Prior to inpatient discharge, and after approximately seven days without buprenorphine or other opioids, participants received an oral naltrexone lead-in over two to three days. Participants who did not have opioid withdrawal signs or symptoms within two hours of the largest (25 mg) oral naltrexone dose were then given an intramuscular injection of XR-NTX of 4 cc (380 mg naltrexone). Individuals receiving XR-NTX were able to receive another XR-NTX injection once every four weeks for up to an additional six months.

2.2.2. Treatment-as-usual (TAU; n = 12 adolescents; n = 194 young adults).

Participants not receiving XR-NTX had the option to receive treatment without buprenorphine (n = 112), following a medically assisted opiate withdrawal identical to those in the XR-NTX condition, or could begin buprenorphine maintenance treatment during their residential treatment stay (n = 94). Decisions regarding precisely which treatment option was most appropriate were collaborative, a decision made among physicians, participants, and (especially in the case of adolescents) family members. Participants receiving OUD medications were provided on average 12–20 mg buprenorphine per day, with the physicians adjusting the frequency of visits and the amount of medication provided in response to each participant’s needs.

2.3. Assessments

The study assessed participant demographics at baseline only, substance use variables were also assessed 3 and 6 months postenrollment. The study used a timeline followback procedure (Sobell & Sobell, 1992) to assess self-reported opioid use in the past 90 days.

2.4. Statistical analysis

Study arms were assembled as-treated, meaning a participant was included in the study arm that matched the treatment they actually received at the time of discharge, regardless of their initial randomization result. Additionally, participants were included in all analyses regardless of their retention or adherence to the treatments they initiated. The study analyzed variables and described them using methods most appropriate for their observed distributional properties. We described categorical variables with counts and percentages, while numeric variables were described via means and standard deviations; the primary outcome of interest, days of opioid use, was analyzed using longitudinal mixed-effect models to account for repeated measures of the same individual over time. Given the “counted” nature of the outcome (i.e., number of days in the past 90), analytical models employed the negative binomial family and log link function.

3. Results

Sample sizes for each time point were as follows: young adults Ns were 263 at baseline, 201 at 3-month follow-up, and 200 at 6-month follow-up; adolescents Ns were 25 at baseline, 23 at 3-month follow-up, and 20 at 6-month follow-up. Samples were sensitivity tested to determine potential effects of attrition. When comparing young adults with no missing data to young adults with missing data, we find that 186 young adult participants had no missing data, while 80 young adult participants did; they do not differ in terms of their gender (χ2(1) = 0.989), racial/ethnic identity (Fisher’s Exact(5) p = 0.446), age (F(1,261) = 0.07), age of first opioid use (F(1,261) = 2.50), or prior treatment experience (OR = 1.01 [SE = 0.04]; all ns). When comparing adolescents with no missing data to adolescents with missing data, we find that 19 adolescents had no missing data while six had missing data; they also do not differ in terms of gender (Fisher’s Exact(1) p = 0.125), racial/ethnic identity (Fisher’s Exact(2) p = 1.0), age (F(1,23) = 0.24), age of first opioid use (F(1,23) = 0.07), or prior treatment experience (OR = 1.61 [SE = 0.65]; all ns).

As Table 1 shows, adolescent participants (n=25) were more likely to be female (76% vs. 43%) and reported a younger age of opioid onset (14.6 vs. 15.7) relative to young adult participants (n=263). Most participants (83%) were white, and more than three-quarters (77%) reported having had prior drug treatment experience. Unpaired t tests assuming equal variances revealed that the 13 adolescent participants in the XR-NTX study arm received a significantly greater number of doses during the intervention phase (mean = 2.4 injections; SD = 2.0) relative to the 69 young adults receiving XR-NTX (mean = 1.1 injections; SD = 1.6; t = 2.452; p = 0.016). Two adolescents initiated a buprenorphine regimen during the intervention, and both reported three months of adherence; the average number of months spent on buprenorphine observed among the 92 young adults was 2.5 (SD = 2.1). Months spent on either XR-NTX or buprenorphine were not necessarily sequential, and eight participants who initially received XR-NTX prior to discharge from residential treatment reported accessing at least one buprenorphine treatment at one of their follow-up assessments, while 13 participants who initially left treatment without receiving XR-NTX eventually received at least one injection. Though the study found no differences between those who “crossed over” from one medication to another in terms of gender, age, racial/ethnic identity, or age of first opioid use, those who had received prior treatment were estimated via logistic regression to be 12.5% more likely to switch medications at some point during the trial (95% CI = 3.5% thru 22.4%; p = 0.006).

Table 1.

Participant Demographics, Age of Opioid Onset, and Prior Drug Abuse Treatment Experience

Adolescents (n = 25) N (%) or Mean [SD] Young Adults (n = 263) N (%) or Mean [SD] Total (N = 288) N (%) or Mean [SD] Test Statistic χ2, z, or t
Gender
Female 19 (76.0%) 114 (43.4%) 133 (46.2%) χ2 (1) = 9.79; p = 0.002
Racial/Ethnic Identity
White 22 (88.0%) 217 (82.5%) 239 (83.0%) z = −0.70; p = 0.485
Age
years 16.8 [0.52] 19.6 [1.0] 19.4 [1.25] --
Age at First Opioid Use
years 14.6 [1.47] 15.7 [2.10] 15.6 [2.07] t(286) = 2.56; p = 0.011
Prior Drug Abuse Treatment
Yes 203 (77.2%) 18 (72.0%) 221 (76.7%) z = 0.59; p = 0.556
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Notes. SD= Standard Deviation. df = degrees of freedom. χ2 = Chi-square test of independence. t = two independent groups t test. z = z test for differences between two proportions. Age difference wasn’t tested between age groups because age group assignment was determined by age.

Table 2 provides self-reported days of opioid use in the past 90 days, arrayed by age group, study arm, and time. Within-group paired t-tests revealed that both adolescents and young adults evidenced significant reductions in opioid use from baseline to 3-month follow-up regardless of study arm (XR-NTX adolescents: t= 4.75, p = 0.0008; TAU adolescents: t = 3.88, p = 0.0026; XR-NTX young adults: t = 14.98, p < 0.0001; TAU young adults: t = 16.78, p < 0.0001). While adolescents evidenced slight additional reductions in opioid use from the 3- to 6-month follow-up, and young adults demonstrated somewhat higher opioid use from 3- to 6-month follow-up, these findings were not significant. Participants receiving TAU reported more days of opioid use at all follow-up points relative to participants receiving XR-NTX, regardless of age group. Application of mixed-effects negative binomial regression models to these data indicate that adolescents receiving XR-NTX evidenced an estimated 48% reduction in their 90-day rate of opioid use (i.e., the counted number of days they are likely to report having used opioids in the past 90 days) from baseline through 6-month follow-up relative to adolescents receiving TAU [Incidence Rate Ratio (IRR) = 0.52; 95% CI = 0.30, 0.90; N = 25 (68 observations); Wald χ2(1) = 5.43, p = 0.0198], while young adults receiving XR-NTX evidenced an estimated 26% reduction in their 90-day rate of opioid use through 6-month follow-up relative to their TAU counterparts (IRR = 0.74; 95% CI = 0.58, 0.93; n = 263 (664 observations); Wald χ2(1) = 6.77, p = 0.0093).

Table 2.

Days of Self-Reported Opioid Use in the Past 90 Days by Age Group, Study Arm, and Time

XR-NTX
Baseline 3-Month FU 6-Month FU Sig. Sig.
(NAdol = 13; Nya = 69) (NAdol = 11; Nya = 55) (NAdol = 11; Nya = 53) Baseline to 3m FU 3m FU to 6m FU
Mean [SD] Mean [SD] Mean [SD]
Adolescents 56.3 [28.58] 7.3 [13.64] 6.1 [11.37] t= 4.75, p = 0.0008 ns
Young Adults 63.1 [25.45] 9.7 [15.15] 14.8 [22.06] t = 14.98, p < 0.0001 ns
TAU
Baseline 3-Month FU 6-Month FU Sig. Sig.
(NAdol = 12; Nya = 194) (NAdol = 12; Nya = 146) (NAdol = 9; Nya = 147) Baseline to 3m FU 3m FU to 6m FU
Mean [SD] Mean [SD] Mean [SD]
Adolescents 54.3 [17.82] 16.3 [25.34] 35.2 [40.33] t = 3.88, p = 0.0026 ns
Young Adults 66.1 [22.38] 18.0 [22.73] 20.6 [29.14] t = 16.78, p < 0.0001 ns
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NAdol: Adolescent group sample size; NYA: Young adult group sample size; FU: Follow-Up; ns: Not Significant at p < 0.05

4. Discussion

The current study compared outcomes for adolescents and young adults with OUD who received XR-NTX or other services (which included buprenorphine and no medication) following a residential treatment episode. This sample of US youth with moderate to severe OUD demonstrated high levels of opioid use at baseline. Although they demonstrated broad reductions in opioid use during treatment, strikingly the average age of opioid initiation was only 15 years of age and participants under the age of 18 demonstrated just as many prior opioid treatment episodes as their young adult counterparts. However, encouragingly, adolescents receiving XR-NTX appear to have responded favorably to the treatment and adolescents in this sample maintained their XR-NTX regimen, on average, significantly longer than their young adult counterparts (i.e., 2.4 months of injections vs. 1.1 month). In fact, adolescent XR-NTX was the only study condition in which the sample mean number of days of opioid use was lower at 6 months than at 3 months, whereas in all other conditions the 6-month mean was markedly higher than the mean at 3 months. Although these differences were not statistically different in any condition, in a larger sample with adequate levels of statistical power, statistical tests of differences within and between conditions would likely indicate maintenance of treatment gains on average for adolescents in the XR-NTX condition and deterioration in all other conditions. These preliminary results regarding the stability of treatment effects between the 3-month and 6-month follow-up measurements require further testing in a clinical trial with a larger adolescent sample. Regardless, study findings suggests that XR-NTX can be expected to confer positive benefits when applied to adolescents who are willing and able to take XR-NTX, that adherence among such adolescents appears to be at least comparable to what is observed in young adults, and that, as supplemental analyses demonstrated, opioid use reductions were not accompanied by corresponding increases in the use of alcohol or other drugs among this sample.

Of note, the TAU comparator includes both participants treated with buprenorphine and no medications. The adolescent group had only two (8%) participants treated with buprenorphine, so the comparison within adolescents is predominantly of XR-NTX to no medication. In the young adult group, 106 (40%) were treated with buprenorphine, so the comparison is to a mixed group; the comparative advantage of XR-NTX observed in the adolescent sample may thus be partially driven by its comparison to no medication. Nevertheless, in our main findings (Mitchell et al., 2021), we demonstrated that participants who received XR-NTX reported significantly lower opioid use than both the group that received no medications and the group that received buprenorphine. Overall, the MOUD effects we observed in the young adult sample were comparable to the effects generally seen in mature adult samples.

When interpreted alongside (a) over a decade of other exploratory studies of US youth with OUD being successfully treated with XR-NTX (e.g., Fishman et al., 2010; Camenga et al., 2019; Mitchell et al., 2021; Wenzel et al., 2021), (b) evidence that non-agonist treatments for OUD among youth tend to be met with fewer negative connotations and less stigma (Adams et al., 2021), and (c) the rising rate of opioid use and unintentional poisonings among youth in the US (Banta-Green & Cooley 2018; Carney et al., 2018; Chang et al., 2018), XR-NTX warrants further exploration as a viable treatment for pediatric opioid use disorder.

4.1. Limitations

Results from this study must be tempered against several limitations. First, treatment arms in these analyses were not determined randomly. Rather, participants were analyzed on an as-treated basis. Although the initial plan was to equally randomize participants to XR-NTX or TAU, as noted elsewhere (Mitchell et al., 2021), substantial nonadherence to random assignment arose from several factors (including clinicians’ recommendations and participants’ and parents’ preferences) that materialized after randomization and affected the course and configuration of participants’ treatment leading up to discharge from the residential facility. As such, findings must be viewed in the light of the fact that random assignment did not determine treatment group membership. Though this reduces internal validity, we believe the use of as-treated groups maximizes clinical interest and relevance to real-world care. Additionally, the study is limited by its inability to directly compare participants who received XR-NTX with those who received buprenorphine; only two adolescents received buprenorphine (perhaps once again demonstrating provider, patient, and/or caregiver preference for non-agonist treatments among younger patients with OUD), preventing viable statistical comparisons involving age. Relatedly, analyses presented here are limited by the relatively small number of adolescents enrolled (n = 25) relative to young adults (n = 263) in the study as a whole. Finally, several participants ended up re-engaging with care after ceasing their original medication regimen, thereby eventually receiving both medications (i.e., XR-NTX & buprenorphine), leading to a small amount of study arm cross-over.

5. Conclusion

Data presented here suggest XR-NTX is feasible and appears to be effective for treatment of moderate to severe OUD for adolescents and young adults who are motivated to receive the medication. Not only did adolescents receiving XR-NTX demonstrate comparable opioid use outcomes relative to their young adult counterparts, they demonstrated superior adherence to the six-month regimen and were thus the only group to sustain reductions in opioid use through their final follow-up assessment. Additionally, youth who received XR-NTX had reduced opioid use at all time points compared to TAU regardless of their age group. Additional trials should seek to confirm XR-NTX’s safety and document its tolerability among youth populations to improve uptake among service providers treating adolescents and young adults with OUD. In addition, our findings indicate that more research should address the role of family involvement in treatment selection, adherence, and outcomes among adolescent and young adult patients with OUD receiving medication.

Highlights.

  • Opioid use outcomes for adolescents with OUD were compared with those of young adults.

  • Results analyzed on an “as received” bases.

  • Receipt of XR-NTX associated with lower opioid use at follow-up than TAU for both groups.

  • Adolescents responded favorably to XR-NTX with similar outcomes to young adults.

Support:

This work was supported by the National Institute on Drug Abuse, Grant #5R01DA033391-05 [PI: Mitchell]. ClinicalTrials.gov identifier: NCT01843023.

Abbreviations:

OUD

opioid use disorder

MOUD

medication for opioid use disorder

XR-NTX

extended-release naltrexone

TAU

treatment-as-usual

WIRB

Western Institutional Review Board

MMTC

Mountain Manor Treatment Center

DSM-5

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

CIDI

Composite International Diagnostic Interview

SAE

serious adverse events

Footnotes

Declarations of interest: Unrelated to the present study, Dr. Mitchell in MPI on a grant receiving free Brixadi (extended-release buprenorphine) from Braeburn Pharmaceuticals. Dr. Schwartz has consulted for Verily Life Sciences. Dr. Monico has received research funding from Indivior. Dr. Gryczynski is part owner of COG Analytics and has received research funding (paid to his institution and including project-related salary support) from Indivior. He has received medication in kind for a NIDA-funded study from Indivior and Alkermes. Dr. Fishman has been a consultant for Alkermes, Verily Life Sciences, Drug Delivery LLC and US World Meds, and has received research funding from Alkermes and US World Meds. Drs. Fletcher and O’Grady report no conflicts.

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