[Skip to Content]
[Skip to Content Landing]

Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid DependenceA Randomized Clinical Noninferiority Trial

Educational Objective
To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals.
1 Credit CME
Key Points

Question  Are monthly intramuscular injections with extended-release naltrexone hydrochloride as effective as daily oral buprenorphine–naloxone hydrochloride in reducing the use of heroin and other illicit substances in newly detoxified, opioid-dependent individuals?

Findings  In this 12-week, open-label randomized clinical trial including 159 opioid users, treatment with intramuscular extended-release naltrexone was as effective as oral buprenorphine-naloxone in reducing the use of heroin, opioids, and other illicit substances.

Meaning  Maintaining short-term opioid abstinence with extended-release naltrexone should be considered an equal treatment alternative to buprenorphine-naloxone as medication-assisted treatment for opioid-dependent individuals.

Abstract

Importance  To date, extended-release naltrexone hydrochloride has not previously been compared directly with opioid medication treatment (OMT), currently the most commonly prescribed treatment for opioid dependence.

Objective  To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals.

Design, Setting and Participants  A 12-week, multicenter, outpatient, open-label randomized clinical trial was conducted at 5 urban addiction clinics in Norway between November 1, 2012, and December 23, 2015; the last follow-up was performed on October 23, 2015. A total of 232 adult opioid-dependent (per DSM-IV criteria) individuals were recruited from outpatient addiction clinics and detoxification units and assessed for eligibility. Intention-to-treat analyses of efficacy end points were performed with all randomized participants.

Interventions  Randomization to either daily oral flexible dose buprenorphine-naloxone, 4 to 24 mg/d, or extended-release naltrexone hydrochloride, 380 mg, administered intramuscularly every fourth week for 12 weeks.

Main Outcomes and Measures  Primary end points (protocol) were the randomized clinical trial completion rate, the proportion of opioid-negative urine drug tests, and number of days of use of heroin and other illicit opioids. Secondary end points included number of days of use of other illicit substances. Safety was assessed by adverse event reporting.

Results  Of 159 participants, mean (SD) age was 36 (8.6) years and 44 (27.7%) were women. Eighty individuals were randomized to extended-release naltrexone and 79 to buprenorphine-naloxone; 105 (66.0%) completed the trial. Retention in the extended-release naltrexone group was noninferior to the buprenorphine-naloxone group (difference, −0.1; with 95% CI, −0.2 to 0.1; P = .04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (P = .33, log-rank test). Treatment with extended-release naltrexone showed noninferiority to buprenorphine-naloxone on group proportion of total number of opioid-negative urine drug tests (mean [SD], 0.9 [0.3] and 0.8 [0.4], respectively, difference, 0.1 with 95% CI, −0.04 to 0.2; P < .001) and use of heroin (mean difference, −3.2 with 95% CI, −4.9 to −1.5; P < .001) and other illicit opioids (mean difference, −2.7 with 95% CI, −4.6 to −0.9; P < .001). Superiority analysis showed significantly lower use of heroin and other illicit opioids in the extended-release naltrexone group. No significant differences were found between the treatment groups regarding most other illicit substance use.

Conclusions and Relevance  Extended-release naltrexone was as effective as buprenorphine-naloxone in maintaining short-term abstinence from heroin and other illicit substances and should be considered as a treatment option for opioid-dependent individuals.

Trial Registration  clinicaltrials.gov Identifier: NCT01717963

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Lars Tanum, MD, DMSci, The Norwegian Centre for Addiction Research, The University of Oslo, PO Box 1039 Blindern, 0315 Oslo, Norway (lars.tanum@medisin.uio.no).

Accepted for Publication: August 25, 2017.

Published Online: October 18, 2017. doi:10.1001/jamapsychiatry.2017.3206

Author Contributions: Dr Kunøe had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Tanum, Kunøe.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Tanum, Solli, Šaltytė Benth, Kunøe.

Critical revision of the manuscript for important intellectual content: Solli, Latif, Šaltytė Benth, Opheim, Sharma-Haase, Krajci, Kunøe.

Statistical analysis: Solli, Šaltytė Benth, Kunøe.

Obtained funding: Tanum, Opheim, Kunøe.

Administrative, technical, or material support: Tanum, Solli, Latif, Opheim, Sharma-Haase, Krajci, Kunøe.

Study supervision: Tanum, Krajci, Kunøe.

Conflict of Interest Disclosures: None reported.

Funding/Support: The study was supported by unrestricted grants from the Research Council of Norway and the Western Norway Regional Health Authority. Financial support was also received from the Norwegian Centre for Addiction Research, University of Oslo, and from Akershus University Hospital.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication; however, Alkermes Inc was allowed to comment on the manuscript before submission for publication.

Additional Contributions: All data analyses were conducted by study-independent statistician Jūratė Šaltytė Benth, PhD (Akershus University Hospital and University of Oslo). Zhanna Gaulen, MSc (Department of Addiction Medicine, Haukeland University Hospital), Anne-Lill Mjoelhus Njaa, MSc (Center for Alcohol and Drug Research, Stavanger University Hospital), and Linn Wergeland Digranes, BSc (Department of Addiction Medicine, Akershus University Hospital), contributed to data collection. There was no financial compensation. Alkermes Inc supplied extended-release naltrexone for the study. We thank all study site personnel for their efforts, as well as all participating patients.

References
1.
Volkow  ND, Frieden  TR, Hyde  PS, Cha  SS.  Medication-assisted therapies—tackling the opioid-overdose epidemic.  N Engl J Med. 2014;370(22):2063-2066.PubMedGoogle ScholarCrossref
2.
McLellan  AT, Lewis  DC, O’Brien  CP, Kleber  HD.  Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation.  JAMA. 2000;284(13):1689-1695.PubMedGoogle ScholarCrossref
3.
Dole  VP, Nyswander  M.  A medical treatment for diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride.  JAMA. 1965;193:646-650.PubMedGoogle ScholarCrossref
4.
 Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. Geneva, Switzerland: World Health Organization; 2009.
5.
Duke  AN, Correia  CJ, Walsh  SL, Bigelow  GE, Strain  EC.  Acute effects of intramuscular and sublingual buprenorphine and buprenorphine/naloxone in non-dependent opioid abusers.  Psychopharmacology (Berl). 2010;211(3):303-312.PubMedGoogle ScholarCrossref
6.
Mattick  RP, Breen  C, Kimber  J, Davoli  M.  Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.  Cochrane Database Syst Rev. 2014;2(2):CD002207.PubMedGoogle Scholar
7.
Bukten  A, Røislien  J, Skurtveit  S, Waal  H, Gossop  M, Clausen  T.  A day-by-day investigation of changes in criminal convictions before and after entering and leaving opioid maintenance treatment: a national cohort study.  BMC Psychiatry. 2013;13:262.PubMedGoogle ScholarCrossref
8.
Skeie  I, Brekke  M, Gossop  M,  et al.  Changes in somatic disease incidents during opioid maintenance treatment: results from a Norwegian cohort study.  BMJ Open. 2011;1(1):e000130.PubMedGoogle ScholarCrossref
9.
Bukten  A, Stavseth  MR, Skurtveit  S, Tverdal  A, Strang  J, Clausen  T.  High risk of overdose death following release from prison: variations in mortality during a 15-year observation period.  Addiction. 2017;112(8):1432-1439.PubMedGoogle ScholarCrossref
10.
Chutuape  MA, Jasinski  DR, Fingerhood  MI, Stitzer  ML.  One-, three-, and six-month outcomes after brief inpatient opioid detoxification.  Am J Drug Alcohol Abuse. 2001;27(1):19-44.PubMedGoogle ScholarCrossref
11.
Strang  J, McCambridge  J, Best  D,  et al.  Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study.  BMJ. 2003;326(7396):959-960.PubMedGoogle ScholarCrossref
12.
Degenhardt  L, Larney  S, Kimber  J, Farrell  M, Hall  W.  Excess mortality among opioid-using patients treated with oral naltrexone in Australia.  Drug Alcohol Rev. 2015;34(1):90-96.PubMedGoogle ScholarCrossref
13.
Minozzi  S, Amato  L, Vecchi  S, Davoli  M, Kirchmayer  U, Verster  A.  Oral naltrexone maintenance treatment for opioid dependence.  Cochrane Database Syst Rev. 2011;4. PubMedGoogle Scholar
14.
Roozen  HG, de Waart  R, van den Brink  W.  Efficacy and tolerability of naltrexone in the treatment of alcohol dependence: oral versus injectable delivery.  Eur Addict Res. 2007;13(4):201-206.PubMedGoogle ScholarCrossref
15.
Sullivan  MA, Vosburg  SK, Comer  SD.  Depot naltrexone: antagonism of the reinforcing, subjective, and physiological effects of heroin.  Psychopharmacology (Berl). 2006;189(1):37-46.PubMedGoogle ScholarCrossref
16.
Krupitsky  E, Nunes  EV, Ling  W, Illeperuma  A, Gastfriend  DR, Silverman  BL.  Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial.  Lancet. 2011;377(9776):1506-1513.PubMedGoogle ScholarCrossref
17.
Krupitsky  E, Zvartau  E, Blokhina  E,  et al.  Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence.  Arch Gen Psychiatry. 2012;69(9):973-981.PubMedGoogle ScholarCrossref
18.
Lee  JD, Friedmann  PD, Kinlock  TW,  et al.  Extended-release naltrexone to prevent opioid relapse in criminal justice offenders.  N Engl J Med. 2016;374(13):1232-1242.PubMedGoogle ScholarCrossref
19.
Lee  JD, McDonald  R, Grossman  E,  et al.  Opioid treatment at release from jail using extended-release naltrexone: a pilot proof-of-concept randomized effectiveness trial.  Addiction. 2015;110(6):1008-1014.PubMedGoogle ScholarCrossref
20.
Hulse  GK, Morris  N, Arnold-Reed  D, Tait  RJ.  Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone.  Arch Gen Psychiatry. 2009;66(10):1108-1115.PubMedGoogle ScholarCrossref
21.
Kunøe  N, Opheim  A, Solli  KK,  et al.  Design of a randomized controlled trial of extended-release naltrexone versus daily buprenorphine-naloxone for opioid dependence in Norway (NTX-SBX).  BMC Pharmacol Toxicol. 2016;17(1):18.PubMedGoogle ScholarCrossref
22.
Sheehan  DV, Lecrubier  Y, Sheehan  KH,  et al.  The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10 J Clin Psychiatry. 1998;59(suppl 20):22-33.PubMedGoogle Scholar
23.
McLellan  AT, Luborsky  L, Cacciola  J,  et al.  New data from the Addiction Severity Index: reliability and validity in three centers.  J Nerv Ment Dis. 1985;173(7):412-423.PubMedGoogle ScholarCrossref
24.
Kokkevi  A, Hargers  C.  EUROPASI: European adaptation of a multidimensional assessment instrument for drug and alcohol dependence.  Eur Addict Res. 1995;1(4):208-210.Google Scholar
25.
Kokkevi  A.  Psychosocial assessment in substance abuse and dependence.  Curr Opin Psychiatry. 2001;14(3):167-172.Google ScholarCrossref
26.
Cochrane Drugs and Alcohol. CDAG resources for authors http://cda.cochrane.org/cdag-resources-authors. Accessed January 7, 2016.
27.
Pavot  W, Diener  E, Suh  E.  The Temporal Satisfaction With Life Scale.  J Pers Assess. 1998;70(2):340-354.Google ScholarCrossref
28.
Joukamaa  M, Lehtinen  V, Karlsson  H, Rouhe  E.  SCL-25 and recognition of mental disorders reported by primary health care physicians.  Acta Psychiatr Scand. 1994;89(5):320-323.PubMedGoogle ScholarCrossref
29.
Derogatis  LR, Lipman  RS, Rickels  K, Uhlenhuth  EH, Covi  L.  The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory.  Behav Sci. 1974;19(1):1-15.PubMedGoogle ScholarCrossref
30.
Sobell  LC, Sobell  MB, Litten  RZ, Allen  JP.  Timeline Follow-Back: a Technique for Assessing Self-Reported Alcohol Consumption. Totowa, NJ: Humana Press; 1992.
31.
Sullivan  M, Bisaga  A, Pavlicova  M,  et al.  Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine.  Am J Psychiatry. 2017;174(5):459-467.PubMedGoogle ScholarCrossref
32.
Sigmon  SC, Bisaga  A, Nunes  EV, O’Connor  PG, Kosten  T, Woody  G.  Opioid detoxification and naltrexone induction strategies: recommendations for clinical practice.  Am J Drug Alcohol Abuse. 2012;38(3):187-199.PubMedGoogle ScholarCrossref
33.
Mannelli  P, Wu  LT, Peindl  KS, Swartz  MS, Woody  GE.  Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.  Drug Alcohol Depend. 2014;138:83-88.PubMedGoogle ScholarCrossref
34.
EMCDDA.  European Drug Report: Trend and Developments. Lisbon, Portugal: European Monitoring Centre for Drugs and Drug Addiction; 2015.
35.
Sullivan  MA, Rothenberg  JL, Vosburg  SK,  et al.  Predictors of retention in naltrexone maintenance for opioid dependence: analysis of a stage I trial.  Am J Addict. 2006;15(2):150-159.PubMedGoogle ScholarCrossref
36.
Nunes  EV, Krupitsky  E, Ling  W,  et al.  Treating opioid dependence with injectable extended-release naltrexone (XR-NTX): who will respond?  J Addict Med. 2015;9(3):238-243.PubMedGoogle ScholarCrossref
37.
Degenhardt  L, Randall  D, Hall  W, Law  M, Butler  T, Burns  L.  Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved.  Drug Alcohol Depend. 2009;105(1-2):9-15.PubMedGoogle ScholarCrossref
38.
UNODC.  World Drug Report 2015. Vienna: United Nations Office on Drug and Crime; 2015.
39.
Waal  H, Bussesund  K, Clausen  T, Skeie  I, Håseth  A, Lillevold  P. The annual OMT status survey for 2016. Statusrapport 2016-Er kvalitetsforbedring nå viktigere enn kapasitetsutvikling? Oslo, Norway: Norwegian Centre for Addiction Research; 2017.
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements