Buprenorphine Implant (Probuphine) and Extended-Release Injectable (Sublocade)

Number: 0910

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Aetna considers Probuphine (buprenorphine) implant for subdermal administration medically necessary for maintenance treatment of opioid dependence in members who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (i.e., doses of no more than 8 mg per day of Subutex (buprenorphine) or Suboxone (buprenorphine and naloxone) sublingual tablets or generic equivalent), when Probuphine is used as part of a complete treatment program that includes drug testing, counseling and psychosocial support.

Aetna considers buprenorphine implant experimental and investigational for new entrants to treatment and for members who have not achieved and sustained prolonged clinical stability, while being maintained on buprenorphine 8 mg per day or less of Subutex or Suboxone sublingual tablets or generic equivalent.

Aetna considers Sublocade (buprenorphine), once-monthly injectable, medically necessary for the treatment of moderate-to-severe opioid use disorder (OUD) in members who have initiated treatment with a transmucosal buprenorphine-containing product and have been on a stable dose of buprenorphine treatment for a minimum of seven days, when Sublocade is used as part of a complete treatment program that includes drug testing, counseling and psychosocial support.

Aetna considers buprenorphine implant and once-monthly injectable experimental and investigational for all other indications.


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

CPT codes covered if selection criteria are met :

11981 Insertion, non-biodegradable drug delivery implant
11983 Removal with reinsertion, non-biodegradable drug delivery implant
+20700 Manual preparation and insertion of drug-delivery device(s), deep (eg, subfascial) (List separately in addition to code for primary procedure)

HCPCS codes covered if selection criteria are met:

G0516 Insertion of non-biodegradable drug delivery implants, 4 or more (services for subdermal rod implant)
G0517 Removal of non-biodegradable drug delivery implants, 4 or more (services for subdermal implants)
G0518 Removal with reinsertion, non-biodegradable drug delivery implants, 4 or more (services for subdermal implants)
J0570 Buprenorphine implant, 74.2 mg
Q9991 Injection, buprenorphine extended-release (sublocade), less than or equal to 100 mg
Q9992 Injection, buprenorphine extended-release (sublocade), greater than 100 mg

ICD-10 codes covered if selection criteria are met:

F11.10 - F11.99 Opioid related disorders


Probuphine contains buprenorphine, a partial opioid agonis, and is approved by the U.S. Food and Drug Administration (FDA) for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphinecontaining product. Probuphine implants are available as ethylene vinyl acetate implants that are 26 mm long and 2.5 mm in diameter. A probuphine implant contains 74.2 mg of buprenorphine and is indicated for maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low to moderate doses of a trasmucosal buprenorphine-containing product (i.e., doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet or generic equivalent).  Four probuphine implants are inserted into the upper arm for a six month course of treatment and are removed at the end of the sixth month period. Probuphine implants are not indicated for new entrants into a treatment program.  Probuphine is also not indicated for patients who have not achieved prolonged sustained clinical stability while being maintained on 8 mg per day or less of a Subutex or Suboxone sublingual tablet or generic equivalent (Braeburn Pharms, 2016).

The FDA approval for the probuphine implant specified the following warnings and precautions: serious complications can occur from insertion and removal, buprenorphine can be abused in a manner similar to other opioids, respiratory depression and death have occurred particularly with intravenous administration, neonatal opioid withdrawal is expected secondary to prolonged use during pregnancy, adrenal insufficiency can occur, unintentional pediatric exposure can occur if the implant protrudes or comes out, withdrawal symptoms can occur with abrupt discontinuation, and risk of hepatitis.  Clinical supervision is required for patients using probuphine implants, including examination of the site one week following insertion, and then no less than once per month, including continued counseling and psychosocial support.  It should be noted that insertion and removal of Probuphine is associated with the risk of implant migration, protrusion, expulsion, and nerve damage resulting from the procedure and that Probuphine is available only through a restricted program called the Probuphine REMS program. Providers must complete a live training program prior to prescribing Probuphine (Braeburn Pharms, 2016).

White et al (2013) conducted a 6 month open-label study in 12 heroin-addicted patients in three treatment centers in Australia. The goal of this study was to evaluate the efficacy, safety and pharmacokinetics of 2 or 4 doses of Probuphine in patients who had been switched from daily sublingual probuphrine dosing.  Dosage was dependent on basic daily maintenance buprenorphine of 8 or 16 mg.  No subjects were withdrawn, but 1 patient was lost-to-follow up after the end of the 6 month study period.  Results showed that Probuphine implants provided continuous steady-state delivery throughout the 6 month study period.  Overall, 66% of self-reports of heroin use were negative, 28% indicated use of heroin, and 6% reported use of other opioids.  Three study subjects in the 2 implant group and 4 in the 4 implant group received sublingual buprenorphine as rescue medicine for withdrawal for an average of 4.8 +/- 5.1 days out of a total of 168 +/- 4.6 implant days.  No serious adverse events or deaths occurred during the course of the study.  Although this was a small scale study, these results encouraged further research on the use of probuphine implants.

Ling et al (2011) noted that Probuphine relieves the need for daily dosing and reliably provides a a sustained and constant blood level through the six months of implantation.  They noted a previous study by Ling et al which was a placebo-controlled trial in 164 patients showing less opioid use in Probuphrine patients than controls and better retention.  They also noted that although at that time phase III trials were underway for the FDA New Drug Application, there were statistically significant findings regarding percentages of urine samples testing negative for opioid use over the 24 week study period (p<,0001). 

Rosenthal et al (2013) conducted a randomized, double-blind, placebo controlled trial of opioid dependent adult outpatients.  Inclusion criteria required participants to have achieved a target dose of 12 to 16 mg per day of buprenorphine/naloxone tablets (BNX).  Study subjects were randomized in a 2:1:2 to 4 buprenorphine implants, 4 placebo implants, or ope-label BNX.  Randomization was stratified by gender and continued for a 24 week study period.  The primary study endpoint was the percents of urine negative for opiods from week 1 to week 24. A secondary endpoint compared the two treatment groups.  Results indicated that the buprenorphine implant (BI) cumulative distribution function was significantly different between BI and placebo (p < 0.0001).  A comparison of the two treatment groups also showed significantly different findings (p < 0.0001).  The mean (95 % confidence interval [CI]) proportion of urine opioid negatives were as follows:  BI = 31.2 % (25.3, 37.1) and PI = 13.4 % (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26 %, p < 0.0001), lower clinician-rating (p < 0.0001) and patient-rated (p < 0.0001) withdrawal, lower patient-ratings of craving (p < 0.0001), and better subjects' (p = 0.031) and clinicians' (p = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (p = 0.0016).  Minor implant-site reactions were comparable in the buprenorphine [27.2 % (31 of 114)] and placebo groups [25.9 % (14 of 54)].  BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95 % CI) = 33.5 (27.3, 39.6); 95 % CI for the difference of proportions = (-10.7, 6.2)].

Rosenthal et al (2016) indicated that the effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion. The authors conducted a study to determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence which was designed as an outpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study. Participants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks). Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician. The study included 177 participants (mean age, 39 years; 40.9 % female), 90 of whom were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo.  Over the 6 month course of the study, 72 of 84 (85.7 %) receiving buprenorphine implants and 64 of 89 (71.9 %) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95 % CI: 0.018 to 0.258; p = 0.03). Non-implant-related and implant-related adverse events occurred in 48.3 % and 23 % of the buprenorphine implant group and in 52.8 % and 13.5 % of participants in the sublingual buprenorphine group, respectively. The investigators concluded that among adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine, the use of buprenorphine implants compared with continued sublingual buprenorphine did not result in an inferior likelihood of remaining a responder. However, the investigators also noted that the study population had an exceptionally high response rate in the control group, and further studies are needed in broader populations to assess the efficacy in other settings.

Sublocade is a drug-device combination product that utilizes buprenorphine and the Atrigel Delivery System in a pre-filled syringe. It is injected by a health care professional subcutaneously as a solution, and the delivery system forms a solid deposit, or depot, containing buprenorphine. After initial formation of the depot, buprenorphine is released by the biodegradation of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

The safety and efficacy of Sublocade were evaluated in two clinical studies (one phase 3 double-blind efficacy and safety study (13-0001, NCT02357901) and an opioid blockade study (13-0002, NCT02044094) in adults with a diagnosis of moderate-to-severe opioid use disorder (OUD) who began treatment with buprenorphine/naloxone sublingual film (absorbed under the tongue). Once the dose was determined stable, patients were given Sublocade by injection. A response to medication-assisted treatments was measured by urine drug screening and self-reporting of illicit opioid use during the six-month treatment period. Results indicated that Sublocade-treated patients had more weeks without positive urine tests or self-reports of opioid use, and a higher proportion of patients had no evidence of illicit opioid use throughout the treatment period, compared to the placebo group.

In Study 13-0002, NCT02044094, the opioid blockade was evaluated the blockade of subjective opioid effects, PK and safety of SC injections of SUBLOCADE in 39 subjects with OUD (not treatment-seeking). The peak (Emax) effect of “Drug Liking” Visual Analog Scale (VAS measurement after challenge with IM. injections of 6 mg and 18 mg hydromorphone (HM) was not inferior (i.e., shown to be not substantially more likeable) compared to the Emax of “Drug Liking” VAS, measured after challenge with placebo (at weeks 1 through 4 following the first injection of 300 mg SUBLOCADE).  The noninferiority (NI) margin, the largest difference allowed for the 6 or 18 mg HM VAS to exceed the placebo VAS (the maximum VAS recorded following IM injection of 0 mg HM) before being considered significant, was set at 20. Based on comparison to the historical response to opioid agonists in unblocked subjects, a difference of less than 20 points (on a unipolar scale) between the mean maximum response to hydromorphone and the mean maximum placebo response for the same challenge was considered to indicate near-complete blockade. All 12 weeks of the treatment period demonstrated blockade for both 6 mg and 18 mg following SUBLOCADE injections. However, wide variation can be seen in isolated measurements from individual subjects. For comparison, stabilization doses of SL buprenorphine in Week 0 failed to provide full blockade to 18 mg of HM. Complete blockade continued throughout the 8 weeks of observation that followed the second SUBLOCADE injection.

In Study 13-0001, NCT02357901, the efficacy of SUBLOCADE for the treatment of opioid use disorder was evaluated in a phase-III, 24-week, randomized, double-blind, placebo-controlled, multi-center trial in treatment-seeking patients who met the DSM-5 criteria for moderate or severe opioid use disorder. Patients were randomized to one of following dosing regimens: 6 once-monthly 300-mg doses, 2 once-monthly 300-mg doses followed by 4 once-monthly 100-mg doses, or 6 once-monthly SC injections of placebo. All doses were administered by a physician or suitably qualified designee and were separated by 28 ± 2 days. In addition to study medication, all subjects received manual-guided psychosocial support at least once-weekly (Individual Drug Counseling = IDC). Prior to the first dose, treatment was initiated with SUBOXONE® (buprenorphine/naloxone) sublingual film (SUBOXONE SL Film); doses were adjusted from 8/2 mg to 24/6 mg per day over a period of 7 to 14 days. Patients were randomized to SUBLOCADE injection or placebo after cravings and withdrawal symptoms were clinically controlled. After randomization, supplemental dosing with SUBOXONE SL Film was not permitted during the study. Efficacy was evaluated over Weeks 5 through 24 based on weekly urine drug screens combined with self-reported use of illicit opioid use. A “grace period” was applied for Weeks 1 through 4 to allow patients to stabilize in treatment. During this period, opioid use, if it occurred, was not considered in the analysis. Missing urine drug screen samples and/or self-reports during Weeks 5 to 24 were counted as positive for illicit opioids.

A total of 504 patients were randomized 4:4:1:1 [203 subjects in the 300 mg/100 mg group, 201 patients in the 300 mg/300 mg group and 100 patients in the placebo group (2 groups of volume-matched placebo)]. Based on the cumulative distribution function (CDF) of the percentage of urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use collected from Week 5 through Week 24, regardless of dose, SUBLOCADE was superior to the placebo group with statistical significance.  The proportion of patients achieving treatment success (defined as patients with greater than or equal to 80 % opioid-free weeks) was statistically significantly higher in both groups receiving SUBLOCADE compared to the placebo group (28.4 % [300 mg/100 mg], 29.1 % [300 mg/300 mg], 2 % [placebo]).

The most common side effects from treatment with Sublocade include constipation, nausea, vomiting, headache, drowsiness, injection site pain, pruritus at the injection site and abnormal liver function tests. The safety and efficacy of Sublocade have not been established in children or adolescents less than 17 years of age. Clinical studies of Sublocade did not include participants over the age of 65. Sublocade has a boxed warning that includes the risks of intravenous self-administration. If the product were to be administered intravenously rather than subcutaneously, the solid mass could cause occlusion, tissue damage or embolus, which can lead to death. Sublocade must be prescribed and dispensed as part of a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the product is not distributed directly to patients. Sublocade will be provided to HCPs through a restricted program, administered only by HCPs in a health care setting, and will require health care settings and pharmacies that dispense Sublocade to complete an enrollment form attesting that they have procedures in place to ensure that Sublocade is dispensed only to HCPs and not directly to patients.

The FDA is requiring post-marketing studies to assess which patients would benefit from a higher dosing regimen, to determine whether Sublocade can be safely initiated without a dose stabilization period of sublingual buprenorphine, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly and to determine a process for transitioning patients with long-term stability on a transmucosal buprenorphine dose to a monthly dose of Sublocade without the use of a higher dose for the first two months of treatment (loading dose).

Rosenthal (2019) stated that extended-release buprenorphine formulations for treatment of OUD offer significant advantages over traditional sublingual and buccal routes of administration.  Comparative advantages for individual patient treatment include more consistent pharmacokinetics and predictable range of plasma levels; prolonged exposure to steady-state treatment, with decreased relapse and opioid overdose risk; elimination of direct patient control that reduces non-adherence; and a wider interval over which to safely bridge treatment continuation.  Population-level advantages include reduction in risk of diversion and in accidental exposure and poisoning; also, because buprenorphine treatment reduces all-cause and overdose mortality, improved length of exposure to buprenorphine treatment may reduce transitions from use of prescription pain medication to use of illicit opioids.

Chappuy and colleagues (2020) noted that buprenorphine and methadone are the 2 main opioid agonist treatments approved for OUD.  Buprenorphine is a partial agonist of the mu opioid receptors, which has been merely available through sublingual form until now.  In practice, the use of buprenorphine is smoother than that of methadone, and it induces reduced risks of overdose.  However, sublingual buprenorphine also exposes to risks (e.g., withdrawal, misuse) and constraints (e.g., daily intake).  Three new galenic formulations of prolonged-release buprenorphine (PRB) are being commercialized and should allow some improvements in patients' comfort and safety.  These investigators described the main technical features, safety and efficacy data of these PRBs, as well as patients' and professionals' expectancies and concerns, using data of the scientific literature and the regulatory texts.  PRBs consist of 1 subcutaneous implant and 2 subcutaneous injection depots. Sixmo/Probuphine is a 6-month-long implant that needs to be surgically placed and removed and is approved for subjects previously treated with a maximum daily dose of 8-mg of sublingual buprenorphine, and can be used only for 2 successive periods of 6 months before the subject needs to be switched back to sublingual form.  Sublocade is a 1-month-long depot formulation that is indicated in switch from sublingual buprenorphine, and which proposes only 2-dose schemes, i.e., 100-mg and 300-mg monthly.  Buvidal/Brixadi is a 1-week- or 1-month-long depot formulation with multiple dosages, which can be used in initiation or in switched from sublingual formulations.  While opioid users reported some concerns with a risk of coercive use of long-acting forms of buprenorphine, both users and professionals deemed that these new specialties could be particularly appreciated in stabilized patients bothered with the daily intake of the treatments, or specific situations at risk of treatment drop-out (e.g., following hospital discharge or prison release).

Morgan and colleagues (2021) noted that while the U.S. is in the midst of an opioid epidemic, effective treatments are under-utilized and commonly discontinued.  Innovations in medication delivery (including an extended-release (ER) formulations) have the potential to improve treatment access and reduce discontinuation.  These investigators examined ER buprenorphine discontinuation among individuals with OUD in a real-world, nationally representative cohort.  Participants were commercially insured individuals initiating 1 of 4 FDA-approved medications for OUD (MOUD) in 2018: ER buprenorphine, ER naltrexone, mucosal buprenorphine (mono- or co-formulated with naloxone), or methadone.  The primary outcome was medication discontinuation, defined as a gap of more than 14 days between the end of 1 prescription or administration and the subsequent dose.  These researchers identified 14,358 individuals initiating MOUD in 2018, including 204 (1 %) ER buprenorphine, 1,173 (8 %) ER naltrexone, 12,171 (85 %) mucosal buprenorphine, and 810 (6 %) methadone initiations.  Three months after initiation, 50 % (95 % CI: 40 % to 60 %) of ER buprenorphine, 64 % (95 % CI: 61 % to 69 %) of ER naltrexone, 34 % (95 % CI: 33 % to 35 %) of mucosal buprenorphine, and 58 % (95 % CI: 54 % to 62 %) of methadone initiators had discontinued treatment.  The authors concluded that across all treatment groups, medication discontinuation was high, and in this sample of early adopters with limited follow-up time, these researchers found no evidence that ER buprenorphine offered a retention advantage compared to other MOUD in real-world settings.  Retention continues to represent a major obstacle to treatment effectiveness, and interventions are needed to address this challenge even as new MOUD formulations become available.

In a retrospective study, Erdogan et al (2022) compared the effectiveness of extended-release naltrexone (XR-NTX) implant and buprenorphine-naloxone (BUP-NX) in relapse prevention in OUD.  Medical records of 400 patients who were treated for OUD between 2016 and 2020 were examined concerning socio-demographic and clinical characteristics and abstinence duration with either BUP-NX (192 patients) or XR-NTX (208 patients) as maintenance treatments.  The median age of patients using BUP-NX was 25.00 years, and the median age of patients using XR-NTX was 25.50 years (p = 0.785).  The ratio of female patients in the BUP-NX group and the XR-NTX group was 7.3 % (n = 14) and 6.7 % (n = 14), respectively.  A significantly higher abstinence time was observed in the BUP-NX group (median = 4 months) than in the XR-NTX group (median = 3 months) (p = 0.015).  Liver function tests were within the normal ranges at the 3 time-points, which were just before the beginning and in the 1st and 3rd months of treatment.  The authors concluded that these findings suggested that BUP-NX might be more effective than XR-NTX in preventing relapse in OUD and both drugs are safe for the liver.  Moreover, these researchers stated that prospective randomized studies are needed to validate these findings.

Poliwoda et al (2022) stated that buprenorphine, a novel long-acting analgesic, was developed with the intention of 2 purposes: analgesia and opioid use disorder.  Regarding its pharmacodynamics, it is a partial agonist at mu receptors, an inverse agonist at kappa receptors, and an antagonist at delta receptors.  For the purpose of analgesia, 3 formulations of buprenorphine were developed: IV/IM injectable formulation (Buprenex), transdermal patch formulation (Butrans), and buccal film formulation (Belbuca).  Related to opioid dependence, the formulations developed were subcutaneous extended release (Sublocade), subdermal implant (Probuphine), and sublingual tablets (Subutex).  Lastly, in order to avoid misuse of buprenorphine for opioid dependence, 2 combination formulations paired with naloxone were developed: film formulation (Suboxone) and tablet formulation (Zubsolv).


The above policy is based on the following references:

  1. Braeburn Pharma. Probuphine (buprenorphine) implant for subdermal administration. Prescribing Information. Reference ID: 3937415. Princeton, NJ: Braeburn Pharma; revised May 2016.
  2. Carter JA, Dammerman R, Frost M. Cost-effectiveness of subdermal implantable buprenorphine versus sublingual buprenorphine to treat opioid use disorder. J Med Econ. 2017;20(8):893-901.
  3. Chappuy M, Trojak B, Nubukpo P, et al. Prolonged-release buprenorphine formulations: Perspectives for clinical practice. Therapie. 2020;75(5):397-406.
  4. Chavoustie S, Frost M, Snyder O, et al. Buprenorphine implants in medical treatment of opioid addiction. Expert Rev Clin Pharmacol. 2017;10(8):799-807.
  5. ECRI Institute. AHRQ Healthcare Horizon Scanning System Potential High-Impact Interventions: Priority Area 14: Substance abuse. Prepared by ECRI Institute for AHRQ under Contract No. HHSA290201000006C. Rockville, MD: Agency for Healthcare Research and Quality; December 2013.
  6. Erdogan A, Topcuoglu M, Coskun MN, et al. Comparison of naltrexone implant and oral buprenorphine-naloxone in the treatment of opiate use disorder. Hum Psychopharmacol. 2022;37(2):e2813.
  7. Indivior Inc. Sublocade (buprenorphine extended-release) injection, for subcutaneous use. Prescribing Information. North Chesterfield, VA: Indivior Inc.; revised November 2017.
  8. Itzoe M, Guarnieri M. New developments in managing opioid addiction: Impact of a subdermal buprenorphine implant. Drug Des Devel Ther. 2017;11:1429-1437. 
  9. Lee JD, Malone M, McDonald R, et al. Comparison of treatment retention of adults with opioid addiction managed with extended-release buprenorphine vs daily sublingual buprenorphine-naloxone at time of release from jail. JAMA Netw Open. 2021;4(9):e2123032.
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  11. Morgan JR, Walley AY, Murphy SM, et al. Characterizing initiation, use, and discontinuation of extended-release buprenorphine in a nationally representative United States commercially insured cohort. Drug Alcohol Depend. 2021;225:108764.
  12. Onuoha EN, Leff JA, Schackman BR, et al. Economic evaluations of pharmacologic treatment for opioid use disorder: A systematic literature review. Value Health. 2021;24(7):1068-1083.
  13. Peckham AM, Kehoe LG, Gray JR, Wakeman SE. Real-world outcomes with extended-release buprenorphine (XR-BUP) in a low threshold bridge clinic: A retrospective case series. J Subst Abuse Treat. 2021;126:108316.
  14. Poliwoda S, Noor N, Jenkins JS, et al. Buprenorphine and its formulations: A comprehensive review. Health Psychol Res. 2022;10(3):37517.
  15. Rosenthal RN. Novel formulations of buprenorphine for treatment of opioid use disorder. Focus (Am Psychiatr Publ). 2019;17(2):104-109.
  16. Rosenthal RN, Ling W, Casadonte P, et al. Buprenorphine implants for treatment of opioid dependence: Randomized comparison to placebo and sublingual buprenorphine/nalaxone. Addiction, 2013;108(12):2141-2149.
  17. Rosenthal RN, Lofwall MR, Kim S, et al. Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: A randomized clinical trial. JAMA. 2016;316(3):282-290.
  18. U.S. Food and Drug Administration (FDA). FDA approves first once-monthly buprenorphine injection, a medication-assisted treatment option for opioid use disorder. Silver Spring, MD: FDA; November 30, 2017. 
  19. White J, Bell J, Saunders JB et al. Open-label dose-finding trial of buprenorphine implants (Probuphine) for treatment of heroin dependence. Drug Alcohol Depend. 2009;103:37-43.