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. An injectable (intramuscular), long-acting form of naltrexone Vivitrol^®  (Alkermes, Inc., Cambridge, MA.) was  approved by the FDA in 2006 for use in alcohol dependence and in 2010 for use in opioid dependence.

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.

Medically Necessary:

Injectable naltrexone (Vivitrol) is considered medically necessary for the treatment of alcohol dependence when the individual:

• Is being treated for alcohol dependence; AND
• Has had an initial response and tolerates oral naltrexone (Revia^® ) but is unable to comply with daily dosing; AND
• Is able to abstain from alcohol for at least 7 days in an outpatient setting prior to treatment initiation; AND
• Is not actively drinking at the time of initial injectable naltrexone (Vivitrol) administration; AND
• Actively participates in a comprehensive rehabilitation program that includes psychosocial support; AND
• Is not:   
  • Currently on opioid analgesics; OR
  • Physiologically dependent on opioids; OR
  • Currently in acute opioid withdrawal; AND
• Does not have:
  • A positive urine screen for opioids; OR
  • A failed naloxone challenge test; OR
  • Acute hepatitis; OR
  • Liver failure; OR
  • Previous hypersensitivity to naltrexone, 75:25 polyactide-co-glycolide (PLG), carboxymethylcellulose or any other component of the diluent.

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

• Is being treated for opioid dependence; AND
• Has had an initial response and tolerates oral naltrexone (Revia) but is unable to comply with daily dosing; AND
• Has successfully completed an opioid detoxification program; AND
• Has been opioid-free (including buprenorphine and methadone) for at least 7 days prior to initiating treatment with naltrexone (Vivitrol) injection; AND
• Actively participates in a comprehensive rehabilitation program that includes psychosocial support; AND
• Is not:   
  • Currently on opioid analgesics for pain management; OR
  • Currently in acute opioid withdrawal; AND
• Does not have:
  • A positive urine screen for opioids; OR
  • A failed naloxone challenge test; OR
  • Acute hepatitis; OR
  • Liver failure; OR
  • Previous hypersensitivity to naltrexone, 75:25 polyactide-co-glycolide (PLG), carboxymethylcellulose or any other component of the diluent.

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.

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.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Alcohol dependency:
The efficacy of injectable Vivitrol was evaluated in a 24-week, placebo-controlled, multi-center, double-blind, randomized trial. In a published dose escalation, placebo controlled study, 624 alcohol dependent subjects were randomized into three outpatient treatment groups. Two groups received monthly injections. 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:

• naltrexone (Depade^®_, Revia): acts within the brain to reduce craving for alcohol after alcohol intake has stopped;
• acamprosate (Campral^®): is thought to work by reducing symptoms that follow lengthy abstinence, such as anxiety and insomnia;
• disulfiram (Antabuse^®): discourages drinking by inducing a 'sick' feeling, much like a hangover, after alcohol intake; may have significant risks and side effects.

When an individual who is on oral medication therapy, fails to achieve and maintain alcohol abstinence, Vivitrol, the injectable form of naltrexone (Depade, Revia) may be an option. Vivitrol is injected monthly by a healthcare provider. The monthly injections are combined with ongoing rehabilitation.

Opioid dependency:
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 tolerability 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<.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.

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 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.

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. 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.     

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 (NARCAN^®₎ is administered to verify current opioid dependence. Withdrawal symptoms evoked by naloxone's antagonist interaction with opioids confirm an individual's current dependence.

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. 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.
7. 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.
8. 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. 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/mcd/index_chapter_list.asp?from2=index_chapter_list.asp&list_type=&.  Accessed on November 8, 2010.
2. Lobmaier P, Kornør H, Kunøe N, Bjørndal A. Sustained-release naltrexone for opioid dependence. Cochrane Database Syst Rev. 2008; (2):CD006140.
3. Naltrexone In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on November 8, 2010.
4. Vivitrol^® [Product information], Cambridge, MA. Alkermes, Inc.; April 2006. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed on November 8, 2010.

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 November 8, 2010.
2. Substance Abuse and Mental Health Services Administration's (SAMHSA). Available at: http://www.dpt.samhsa.gov/medications/naltrexone.aspx. Accessed on November 8, 2010.
3. US Department of Health and Human Services. Naltrexone and alcoholism treatment: Treatment improvement protocol (TIP) Series 28. Available at: http://ncadi.samhsa.gov/govpubs/bkd268/28c.aspx. Accessed on November 8, 2010.

Acamprosate
Antabuse^®
Campral^®
Depade^®
Disulfiram
Naltrexone
Revia^®
Vivitrol^®

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.