Medical Policy



Subject: Naltrexone Implantable Pellets
Document #: DRUG.00091 Current Effective Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description/Scope

This document addresses extended-release, implantable naltrexone. Naltrexone is an opioid antagonist that binds to opioid receptors, blocking the euphoric effects of exogenous opioids in those who have an opioid or alcohol use disorder. Currently available formulations of naltrexone implantable pellets are compounded by pharmacies using a bulk powder formulation and are not approved by the United States Food and Drug Administration (FDA).

This document does not address the extended-release, injectable naltrexone (Vivitrol® , Alkermes, Inc., Cambridge, MA) or the oral formulation of naltrexone (Revia® , Duramed Pharmaceuticals Inc., Pomona, NY).

 Note: Please see the following related documents for additional information:

Position Statement

Investigational and Not Medically Necessary:

Extended-release naltrexone implants (or pellets) are considered investigational and not medically necessary for the treatment of alcohol and opioid use disorders (alcohol and opioid dependence) and for all other indications.

Rationale

Naltrexone extended-release formulations have been made available as implantable pellets and are most commonly used for the treatment of alcohol and opioid use disorders. Neither naltrexone implants, nor the bulk powder used to compound them, are approved by the FDA.

The Substance Abuse and Mental Health Services Administration (SAMHSA, 2015) and the Agency for Healthcare Research and Quality (AHRQ, 2014) published systematic reviews and recommendations on pharmacotherapy for alcohol use disorders, as did the American Society of Addiction Medicine (ASAM; Kampman, 2015) on opioid use disorders. Although oral and injectable formulations of naltrexone are discussed and recommended in these guidelines, the implantable formulation of naltrexone is not mentioned.

A systematic review by Lobmaier and colleagues (2011) addresses the use of naltrexone implants for alcoholism and opioid use disorders (dependence). Authors concluded that large longitudinal studies are needed to understand the benefits and risks of the implantable form in comparison to other, more rigorously established, drug use disorder treatment therapies including oral and injectable forms of naltrexone. In another systematic review conducted by the National Health and Medical Research Council (NHMRC, 2010) of Australia, 15 studies were chosen for inclusion of analysis (2 of which were randomized control trials [RCTs] of the published data on implantable naltrexone). Authors concluded:

Naltrexone implants are an experimental product and as such should only be used in the context of a well conducted RCT with sufficient sample size, appropriate duration of treatment and follow up, regular robust monitoring, provision of a comprehensive psychosocial treatment program, and with comparison to current best practice. Until these trials have occurred and the relevant data are available and validated, the efficacy of the treatment, alone or in comparison to conventional first line treatments, cannot be determined.

Soyka and colleagues published recommendations in the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines (2011) on the treatment of substance use disorders (dependence). The guidelines state that "Naltrexone implants cannot yet be recommended for clinical use because although there are promising efficacy data for them, safety concerns remain and require further evaluation."

In 2014, Larney and colleagues published the results of a systematic review and meta-analysis of naltrexone implants for the treatment of opioid use disorders (dependence). Only comparison studies were considered for inclusion in the analysis; in total five randomized trials (n=576) and four non-randomized trials (n=8358) were eligible. Although naltrexone implants were found to be more effective than placebo and oral naltrexone, there was no difference between implants and maintenance therapy using methadone. The study investigators concluded:

The evidence on safety and efficacy of naltrexone implants is limited in quantity and quality, and the evidence has little clinical utility in settings where effective treatments for opioid dependence are used…Better designed research is needed to establish the safety and efficacy of naltrexone implants. Until such time, their use should be limited to clinical trials.

The majority of published literature on the safety and efficacy of naltrexone implantable pellets are from studies conducted outside of the U.S., much of which are small cohorts or retrospective in nature (Gibson, 2007; Hulse, 2005; Hulse, 2009; Kelty, 2012; Kelty, 2013; Kunoe, 2010; Ngo, 2007; Tait, 2008; Tiihonen, 2012). In addition to the lack of demonstrable efficacy of implants over the FDA approved oral and injectable formulations, the ability to stop medication administration in a timely manner upon adverse event is severely hampered by the necessity of surgical intervention for removal. Clear evidence of benefits versus risks demonstrated in large, RCTs is critical to the endorsement of implants over the less invasive, FDA approved formulations of naltrexone and other substance use disorder treatments (SAMHSA, 2015a).

Background/Overview

According to the 2014 National Survey on Drug Use and Health, approximately 21.5 million Americans met the diagnostic criteria for a substance use disorder; 17 million of which had an alcohol use disorder and 7.1 million had an illicit drug use disorder (2.6 million had co-occurring alcohol and illicit drug use disorders) (SAMHSA, 2014). The Diagnostic and Statistical Manual, 5th Edition (DSM-5), introduced in 2013, simplified the diagnosis of drug and alcohol problems to substance use disorders. The updated diagnostic terminology, alcohol use disorder (moderate to severe subtype) and opioid use disorder (moderate to severe subtype), subsume the prior edition, DSM-4, terminology of alcohol dependence and opioid dependence, respectively (American Psychiatric Association [ASA], 2013; SAMHSA, 2015b; SAMHSA, 2015c )

Naltrexone implantable pellets are compounded by pharmacies using a bulk powder formulation which is not approved or regulated by the FDA. The implants are surgically inserted into subcutaneous tissue (generally the abdomen) and release the medication over a period of 1-6 months, depending on the compounding formulation and dosage. The removal of naltrexone implants also necessitates surgical intervention. Other than the Russian Federation, no country has approved the implantable formulation of naltrexone for any indication (Lobmaier, 2011; Mannelli, 2011).

Naltrexone implantable pellets are most often used for the treatment of alcohol dependence (alcohol use disorder) and preventing opioid dependence (opioid use disorder) relapse following opioid detoxification. Naltrexone is available in daily oral (Revia) and long-acting (1 month) intramuscular (Vivitrol) formulations that are FDA approved for the aforementioned indications.

Definitions

Agonist: A drug that binds to a receptor of a cell and triggers a response by the cell. An agonist often mimics the action of a naturally occurring substance.

Antagonist: A substance that tends to nullify the action of another, as a drug that binds to a cell receptor without eliciting a biological response, blocking binding of substances that could elicit such responses.

Endogenous: Originating or produced within the body.

Exogenous: Originating from outside the body; derived externally.

Opioid: Natural or synthetic substances that act at one of the three main opioid receptor systems (mu, kappa, delta). Opioids can have analgesic and central nervous system (CNS) depressant effects as well as the potential to cause euphoria.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT    
11981 Insertion, non-biodegradable drug delivery implant [when specified as insertion of naltrexone pellets]  
11983 Removal with reinsertion, non-biodegradable drug delivery implant [when specified as reinsertion of naltrexone pellets]  
17999 Unlisted procedure, skin, mucous membrane and subcutaneous tissue [when specified as insertion of biodegradable naltrexone pellets]  
22999 Unlisted procedure, abdomen, musculoskeletal system [when specified as insertion of biodegradable naltrexone pellets]  
     
HCPCS    
J3490 Unclassified drugs [when specified as implantable naltrexone pellets]  
J7999 Compounded drug, not otherwise classified [when specified as implantable naltrexone pellets]  
   
ICD-10 Diagnosis  
  All diagnoses including, but not limited to, the following:
F10.10-F10.99 Alcohol related disorders
F11.10-F11.99 Opioid related disorders
   
References

Peer Reviewed Publications:

  1. Gibson AE, Degenhardt LJ, Hall WD. Opioid overdose deaths can occur in patients with naltrexone implants. Med J Aust. 2007; 186(3):152-153.
  2. 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.
  3. Hulse GK, Ngo HT, Tait RJ. Risk factors for craving and relapse in heroin users treated with oral or implant naltrexone. Biol Psychiatry. 2010; 68(3):296-302.
  4. Hulse GK, Tait RJ, Comer SD, et al. Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants. Drug Alcohol Depend. 2005; 79(3):351-357.
  5. Kelty E, Hulse G. Examination of mortality rates in a retrospective cohort of patients treated with oral or implant naltrexone for problematic opioid use. Addiction. 2012; 107(10):1817-1824.
  6. Kelty E, Thomson K, Carlstein S, et al. A retrospective assessment of the use of naltrexone implants for the treatment of problematic amphetamine use. Am J Addict. 2013; 22(1):1-6.
  7. 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.
  8. Kunøe N, Lobmaier P, Vederhus JK, et al. Naltrexone implants after in-patient treatment for opioid dependence: randomised controlled trial. Br J Psychiatry. 2009; 194(6):541-546.
  9. Kunøe N, Lobmaier P, Vederhus JK, et al. Retention in naltrexone implant treatment for opioid dependence. Drug Alcohol Depend. 2010; 111(1-2):166-169.
  10. Larney S, Gowing L, Mattick RP, et al. A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence. Drug Alcohol Rev. 2014; 33(2):115-128.
  11. Lobmaier PP, Kunøe N, Gossop M, Waal H. Naltrexone depot formulations for opioid and alcohol dependence: a systematic review. CNS Neurosci Ther. 2011; 17(6):629-636.
  12. Ngo HT, Tait RJ, Arnold-Reed DE, Hulse GK. Mental health outcomes following naltrexone implant treatment for heroin-dependence. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31(3):605-612.
  13. Soyka M, Kranzler HR, van den Brink W, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for substance use disorders: Guidelines for the biological treatment of substance use and related disorders. Part 2: Opioid dependence. World J Biol Psychiatry. 2011; 12(3):160-187.
  14. Tait RJ, Ngo HT, Hulse GK. Mortality in heroin users 3 years after naltrexone implant or methadone maintenance treatment. J Subst Abuse Treat. 2008; 35(2):116-124.
  15. Tiihonen J, Krupitsky E, Verbitskaya E, et al. Naltrexone implant for the treatment of polydrug dependence: a randomized controlled trial. Am J Psychiatry. 2012; 169(5):531-536.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Agency for Healthcare Research and Quality (AHRQ). Pharmacotherapy for adults with alcohol-use Disorders in outpatient settings; 2014. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/477/1908/alcohol-misuse-drug-therapy-report-140513.pdf. Accessed on July 01, 2017.
  2. American Psychiatric Association (ASA). Substance-related and addictive disorders. 2013. Available at: http://www.dsm5.org/Documents/Substance%20Use%20Disorder%20Fact%20Sheet.pdf. Accessed on July 01, 2017.
  3. Centers for Medicare and Medicaid Services. National Coverage Determination: outpatient hospital services for treatment of alcoholism. NCD #130.2, 130.6. Effective date not posted. Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=27&ncdver=1&DocID=130.2&from2=index_chapter_list.asp&list_type=&bc=gAAAAAgAAAAA&. Accessed on July 01, 2017.
  4. Center for Substance Abuse Treatment. Incorporating alcohol pharmacotherapies into medical practice: a review of the literature. Substance Abuse and Mental Health Services Administration (US); 2009. (Treatment Improvement Protocol (TIP) Series, No. 49s.). Available at: http://www.ncbi.nlm.nih.gov/books/NBK65180/pdf/TOC.pdf. Accessed on July 01, 2017.
  5. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) National practice guideline for the use of medications in the treatment of addiction involving opioid Use. 2015. Available at: http://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf?sfvrsn=24#search="naltrexone". Accessed on July 01, 2017.
  6. Lobmaier P, Kornor H, Kunoe N, Bjorndal A. Sustained-release naltrexone for opioid dependence. Cochrane Database Syst Rev. 2008;(2):CD006140.
  7. National Health and Medical Research Council (NHMRC). Naltrexone implant treatment for opioid dependence. 2010 Available at: https://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/ps0005_naltrexone_implant_treatment_literature_review_2010.pdf . Accessed on July 01, 2017.
  8. Substance Abuse and Mental Health Services Administration (SAMHSA). Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health; 2014. Available at: http://www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf. Accessed on July 01, 2017.
  9. Substance Abuse and Mental Health Services Administration (SAMHSA). Clinical use of extended-release injectable naltrexone in the treatment of opioid use disorder: A brief guide. 2015a. Available at: http://store.samhsa.gov/shin/content/SMA14-4892/SMA14-4892.pdf. Accessed on July 01, 2017.
  10. Substance Abuse and Mental Health Services Administration (SAMHSA). Federal guidelines for opioid treatment programs. 2015b. Available at: http://store.samhsa.gov/shin/content//PEP15-FEDGUIDEOTP/PEP15-FEDGUIDEOTP.pdf. Accessed on July 01, 2017.
  11. Substance Abuse and Mental Health Services Administration (SAMHSA). Medication for the treatment of alcohol use disorder: A brief guide. 2015c. Available at: http://store.samhsa.gov/shin/content/SMA15-4907/SMA15-4907.pdf. Accessed on July 01, 2017.
  12. World Health Organization (WHO). Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. 2009. Available at: http://www.who.int/substance_abuse/activities/treatment_opioid_dependence/en/. Accessed on July 01, 2017.
Websites for Additional Information
  1. National Institutes of Health (NIH) National Institute on Alcohol Abuse and Alcoholism (NIAAA): Naltrexone or specialized alcohol counseling an effective treatment for alcohol dependence when delivered with medical management. May 2, 2006. Available at: http://www.nih.gov/news/pr/may2006/niaaa-02.htm. Accessed on July 02, 2017.
  2. Substance Abuse and Mental Health Services Administration (SAMHSA). Mental and substance use disorders. Available at: http://www.samhsa.gov/disorders. Accessed on July 02, 2017.
Document History
Status Date Action
Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed 07/21/2017 Behavioral Health Subcommittee review. Updated Coding and References sections.
New 08/04/2016 MPTAC review.
New 07/29/2016 Behavioral Health Subcommittee review. Initial document development.