Clinical UM Guideline


Subject:Naltrexone (Vivitrol®) Injections for the Treatment of Alcohol and Opioid Dependence
Guideline #:  CG-DRUG-21Current Effective Date:  04/15/2014
Status:ReviewedLast Review Date:  02/13/2014

Description

Naltrexone is an opioid antagonist that binds to the opioid receptors, blocking the euphoric effects of exogenous opioids in those who are opioid dependent.  This document addresses the extended-release injectable (intramuscular), long-acting form of naltrexone (Vivitrol, Alkermes, Inc., Cambridge, MA).

Clinical Indications

Medically Necessary:

Alcohol Dependence:

Opioid Dependence:

Injectable naltrexone (Vivitrol) is considered medically necessary for the prevention of relapse to opioid dependence following detoxification when the individual:

Not Medically Necessary:

Injectable naltrexone (Vivitrol) is considered not medically necessary for the treatment of alcohol dependence or opioid dependence when the criteria above are not met.

Injectable naltrexone (Vivitrol) is considered not medically necessary for the treatment of diagnoses other than alcohol dependence and opioid dependence.

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.

HCPCS 
J2315Injection, naltrexone, depot form, 1 mg [Vivitrol®]
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2014]
291.0-291.9Alcohol induced mental disorders
292.0-292.9Drug-induced mental disorders
303.00-303.03Acute alcoholic intoxication
303.90-303.93Other and unspecified alcohol dependence
304.00-304.03Drug dependence; opioid type dependence
304.70-304.73Drug dependence, combinations of opioid type drug with any other
V11.3Personal history of mental disorder; alcoholism
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2014]
F10.20-F10.29Alcohol dependence
F11.20-F11.29Opioid dependence
Z71.41Alcohol abuse counseling and surveillance of alcoholic
  
Discussion/General Information

The U.S. Food & Drug Administration (FDA) approved extended-release injectable naltrexone (Vivitrol) for use in treatment of alcohol dependence (2006) for individuals who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with Vivitrol. Naltrexone was FDA approved for prevention of relapse to opioid dependence, following opioid detoxification (2010).  Naltrexone is an opioid antagonist that binds to the opioid receptors, blocking the euphoric effects of exogenous opioids in those who are opioid dependent.  The neurobiological mechanism by which it reduces alcohol consumption in alcohol dependent individuals is not entirely understood, but clinical data suggests that there is involvement of the endogenous opioid system.

Alcohol and opioid dependence can be treated by rehabilitation and medication.  In some cases, oral medication does not achieve optimum therapeutic effect and for some individuals, this may be related to poor compliance in taking an oral drug.

Alcohol Dependency:
The efficacy of injectable Vivitrol was evaluated in a 24-week, placebo-controlled, multi-center, double-blind, randomized trial.  The dose escalation study included 624 alcohol dependent subjects who were randomized into three outpatient treatment groups.  Two groups received monthly injections, with one group received Vivitrol 190 mg (n=210) and the other group received Vivitrol 380 mg (n=205).  The third group (n= 209) received a matching volume placebo.  Both treatment and placebo groups received psychosocial intervention.  Compared with placebo, the group receiving Vivitrol 380 mg demonstrated a statistically significant 25% reduction in the event rate of heavy drinking days while the group receiving 190 mg of Vivitrol resulted in a 17% decrease.  Gender and pretreatment abstinence each showed significant impact with the medication group on treatment outcome.  Males and those who were alcohol abstinent for 7 consecutive days prior to treatment exhibited greater treatment effects. In contrast, the treatment effect was not evident in those who were actively drinking at the start of treatment (Garbutt, 2005).

Vivitrol is marketed as providing increased compliance as compared to the oral formulation of naltrexone.  However, there are no trials to substantiate the claim that increased compliance leads to better outcomes through either increased rates of abstinence or increased time to a first heavy drinking day.  A heavy drinking day is defined as 5 or more standard drinks consumed on a given day for males and 4 or more standard drinks consumed on a given day for females.  The monthly injection method of administration addresses non-compliance with the oral medication regimen and reduces first-pass hepatic metabolism as compared to oral naltrexone.

Alcoholism is divided into 2 categories: dependence and abuse.  Alcohol dependence, the most severe alcohol disorder, is an interrelated cluster of psychological symptoms, such as craving; physiological signs, such as tolerance and withdrawal; and behavioral indicators, such as the use of alcohol to relieve withdrawal discomfort.  Alcohol abuse implies intermittent alcohol use that causes either physical or mental impairment without dependence.

Nearly 14 million Americans meet diagnostic criteria for alcohol use disorders.  For many of these individuals, oral medication and rehabilitation successfully treat their dependence.  The oral medications work in different ways:

When an individual who is on oral medication therapy, fails to achieve and maintain alcohol abstinence, Vivitrol, the injectable form of naltrexone given monthly by a healthcare provider may be an option.  The Center for Substance Abuse Treatment (2009) notes Vivitrol is appropriate for individuals who "experience relatively low therapeutic effects from oral naltrexone, suggesting that a trial with an injectable preparation be done to rule out fluctuating blood levels of naltrexone as a possible cause."  The monthly injections are combined with ongoing rehabilitation.

Opioid Dependency:
The Vivitrol labeled indication was expanded to include prevention of relapse to opioid dependence following opioid detoxification by FDA approval on October 12, 2010.  The product information label (2013) indicates prior to initiation of Vivitrol, the individual should be opioid-free for a "Minimum of 7 – 10 days, to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization."The manufacturer proposed that there is a need for a product to treat opioid dependency that is not a controlled substance like methadone or buprenorphine both of which are agonist treatments.  The approval was based on results from a double-blind randomized controlled trial (n=250) where participants had to be opioid free for at least 7 days.  A naloxone challenge test was performed prior to randomization.  The group was either treated with Vivitrol (n=126) or placebo (n=124).  In the study populations, 51% of the Vivitrol-treated individuals and 65% of the placebo-treated individuals did not complete the full 24 weeks of treatment.  The common reason for discontinuation was lack of efficacy. Other reasons for discontinuation differed between the Vivitrol and placebo group, including withdrawal of consent (14%, 10%) and positive naloxone challenge testing (1%, 14%).  The results showed that the percentages of individuals opioid free for 20 weeks were 23% for the placebo group and 36% for the Vivitrol group (p=.0224).  Although the Vivitrol group had more participants with shorter duration of opioid dependence at baseline than those in the placebo group, a subgroup analysis showed a consistent treatment effect across both groups (Krupitsky, 2011).

Injectable naltrexone (opioid antagonist) was addressed in a feasibility study by Comer and colleagues (2006).  The study (n=60) was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week clinical trial.  Participants received an initial inpatient detoxification then oral naltrexone for three consecutive days to ensure participants were willing and able to tolerate the effects of injectable naltrexone.  Participants were then randomized into groups receiving placebo, 192 mg or 384 mg naltrexone twice at 4 week intervals.  The groups had physical evaluations twice weekly for treatment response and adverse events.  Psychosocial evaluations were conducted twice during the study period.  The highest percentage of negative urine samples occurred in the 384 mg group followed by the 192 mg group.  Heroin craving was high in all 3 groups at the study's onset.  Those who received either dose of naltrexone reported needing heroin less than the placebo group (p less than .001).  The authors noted that opioid dependents pose a greater risk for Vivitrol adverse events than alcoholic individuals in that opioid abuse can involve injectable routes of administration increasing the chance of HIV and compromised immunity.  They also acknowledged that larger studies with more diverse populations are needed.

Use of Vivitrol is not without complications.  Unlike oral medication, when an adverse event occurs, the oral medication is discontinued.  However, when an adverse event occurs with an extended-release injectable drug, stopping the drug action is much more difficult.  In a review by Johnson (2006), it was noted the "depot formulation cannot be removed from the body once injected and any allergic-type reactions that developed would be prolonged due to its long duration of action.  An approach to consider is a trial of oral naltrexone to ensure adverse events and undesired side effects are detected early.  This is more evident with opioid dependency than alcohol dependency.  There is a receptor blockade drop off prior to subsequent Vivitrol injections making opioid receptors vulnerable if the individual ingests opioids. Pain management poses a problem when narcotics are necessary during Vivitrol treatment. Inadvertent drug withdrawal or overdosage can occur.

Adverse Events and Warnings
Warnings and precautions from the FDA Product Information Label (2013) include the following:

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.

First-pass hepatic metabolism: When an oral medication undergoes passage through the gut and liver before reaching the systemic circulation; the concept provides information about the therapeutic effect of an orally administered drug versus administration via intramuscular or intravenous injection. 

Naloxone Challenge Test: A test in which naloxone is administered to verify current opioid dependence.  Withdrawal symptoms evoked by naloxone's antagonist interaction with opioids confirm an individual's current dependence.

References

Peer Reviewed Publications:

  1. Anton RF, O'Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006; 295(17):2003-2017.
  2. Ciraulo DA, Dong Q, Silverman BL, et al. Early treatment response in alcohol dependence with extended-release naltrexone. J Clin Psychiatry. 2008; 69(2):190-195.
  3. Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2006; 63(2):210-218.
  4. Dunbar JL, Turncliff RZ, Dong Q, et al. Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone. Alcohol Clin Exp Res. 2006; 30(3):480-490.
  5. Garbutt JC, Kranzler HR, O'Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005; 293(13):1617-1625.
  6. 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.
  7. Johnson, BA. A synopsis of the pharmacological rationale, properties and therapeutic effects of depot preparations of naltrexone for treating alcohol dependence. Expert Opin Pharmacother. 2006; 7(8):1065-1073.
  8. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011; 377(9776):1506-1513.
  9. Lobmaier PP, Kunoe N, Gossop M, Waal H. Naltrexone depot formulations for opioid and alcohol dependence: a systematic review. CNS Neurosci Ther. 2011; 17(6):629-636.
  10. Lucey MR, Silverman BL, Illeperuma A, O'Brien CP. Hepatic safety of once-monthly injectable extended-release naltrexone administered to actively drinking alcoholics. Alcohol Clin Exp Res. 2008; 32(3):498-504.
  11. O'Malley SS, Garbutt JC, Gastfriend DR, et al. Efficacy of extended-release naltrexone in alcohol-dependent patients who are abstinent before treatment. J Clin Psychopharmacol. 2007; 27(5):507-512.
  12. Swainston Harrison T, Plosker GL, Keam SJ. Extended-release intramuscular naltrexone. Drugs. 2006; 66(13):1741-1751.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2013®. Bethesda, MD: American Society of Health-System Pharmacists®; 2013.
  2. 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 December 18, 2013.
  3. 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 December 18, 2013.
  4. Lobmaier P, Kornor H, Kunoe N, Bjorndal A. Sustained-release naltrexone for opioid dependence. Cochrane Database Syst Rev. 2008; (2):CD006140.
  5. Minozzi S, Amato L, Vecchi S, et al. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev. 2011; (4):CD001333.
  6. Naltrexone. In: DrugPoints® System (electronic version). Truven Health Analystics, Greenwood Village, CO. Updated August 7, 2013. Available at: http://www.micromedexsolutions.com. Accessed on December 12, 2013.
  7. Vivitrol [Product information], Cambridge, MA. Alkermes, Inc.; July 29, 2013. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=74696d65-6973-6275-7461-77696e646f77. Accessed on December 18, 2013.
Web Sites 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. Available at: http://www.nih.gov/news/pr/may2006/niaaa-02.htm. Accessed on December 18, 2013.
  2. Substance Abuse and Mental Health Services Administration's (SAMHSA).  Available at: http://www.dpt.samhsa.gov/medications/naltrexone.aspx. Accessed on December 18, 2013.
Index

Acamprosate
Naltrexone 
Vivitrol®
XR-NTX (extended-release naltrexone)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
StatusDateAction
Reviewed02/13/2014Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed02/07/2014Behavioral Health Sub-Committee Review.  Discussion/General Information and References sections updated.
Reviewed02/14/2013MPTAC review.
Reviewed02/08/2013Behavioral Health Sub-Committee Review.  Discussion/General Information and References updated.
Reviewed02/16/2012MPTAC review.
Reviewed02/10/2012Behavioral Health Sub-Committee Review. Discussion/General Information and References updated.
Revised02/17/2011MPTAC review.
Revised02/11/2011Behavioral Health Sub-Committee Review. Medically necessary criteria revised to reflect FDA approval for opioid dependence. Description, Coding, Discussion and References updated.
Reviewed05/13/2010MPTAC review. References updated.
Reviewed05/21/2009MPTAC review. Place of service deleted, references updated.
Reviewed05/15/2008MPTAC review. References updated.
New05/17/2007MPTAC review. Initial guideline development.