Clinical UM Guideline
|Subject:||Naltrexone (Vivitrol®) Injections for the Treatment of Alcohol and Opioid Dependence|
|Guideline #:||CG-DRUG-21||Current Effective Date:||04/05/2016|
|Status:||Reviewed||Last Review Date:||02/04/2016|
This document addresses extended-release, injectable naltrexone (Vivitrol, Alkermes, Inc., Cambridge, MA). Naltrexone is an opioid antagonist that binds to opioid receptors, blocking the euphoric effects of exogenous opioids in those who are opioid or alcohol dependent.
This document does not address the oral formulation of naltrexone (Revia®, Duramed Pharmaceuticals Inc., Pomona, NY).
A. Alcohol Dependence:
Injectable naltrexone (Vivitrol) is considered medically necessary for the treatment of alcohol dependence when the individual:
B. 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 and for all other indications.
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.
|J2315||Injection, naltrexone, depot form, 1 mg [Vivitrol®]|
|Z71.41||Alcohol abuse counseling and surveillance of alcoholic|
The United States (U.S.) Food & Drug Administration (FDA) approved extended-release, injectable naltrexone (Vivitrol) for 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 later FDA approved for preventing opioid dependence relapse, following opioid detoxification (2010). Vivitrol is administered via intramuscular injection (IM) and generally produces a sufficiently sustained effect for approximately 30 days.
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.
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 treatment 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 five or more standard drinks consumed on a given day for males and four or more standard drinks consumed on a given day for females. The monthly injection method of administration addresses non-compliance which hampers efficacy of the oral medication regimen. Furthermore, the injection method reduces the first-pass delay imposed by hepatic metabolism necessitated by oral ingestion of the drug.
Alcoholism is divided into two 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.
The Vivitrol FDA 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 (2015) 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 (RCT; n=250). Enrollment criteria included no opioid use for at least 7 consecutive days prior to participation in the trial. 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%; respectively) and positive naloxone challenge testing (1%, 14%; respectively). 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=0.022). 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). In an updated publication of this trial, authors report follow-up data 1 year after an open-label phase was initiated (18 months after trial inception). A total of 47 participants remained enrolled from the placebo arm and were switched to treatment at initiation of the open-label phase; 67 remaining in the treatment group continued. In total, 114 were enrolled in this phase; 71 were available for analysis at study end (37 from the original treatment arm and 32 from the original placebo arm). Authors reported of the 62.3% who completed the phase, 50.9% remained abstinent from opioids. No new safety concerns were observed (Krupitsky, 2013).
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 3 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 three groups at the study's onset. Those who received either dose of naltrexone reported needing heroin less than the placebo group (p<0.001). 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 acquisition of Human Immunodeficiency Virus (HIV) and thus the potential for compromised immunity is also elevated in this population. They also acknowledged that larger studies with more diverse populations are needed.
In a recent randomized, placebo-controlled trial (Sullivan, 2015) four treatment groups were studied to evaluate treatment retention following inpatient detoxification and oral naltrexone induction (n=125). The four treatment groups included (1) behavioral naltrexone therapy (BNT)+Vivitrol (n=23); (2) BNT+placebo injection (n=21); (3) compliance enhancement (CE)+Vivitrol (n=24); and (4) CE+placebo injection (n=21). BNT consisted of a manual-guided therapy incorporating motivational and cognitive-behavioral techniques that have been empirically validated for the treatment of substance abuse disorders. CE is also a manual-guided intervention but was delivered by a trained research psychiatrist and incorporates basic medication management, psychoeducation, problem-solving and 12-step principles. The study found that for low-severity heroin users, a single dose of Vivitrol improved the long-term retention of oral naltrexone treatment when coupled with BNT. Larger trials are warranted to evaluate the use of Vivitrol in this treatment approach to enhance compliance with oral naltrexone in heroin users.
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 overdose can occur.
Adverse Events and Warnings
Warnings and precautions from the FDA Product Information Label (2015) include the following:
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.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
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.
|Reviewed||02/04/2016||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Reviewed||01/29/2016||Behavioral Health Sub-Committee Review. Discussion/General Information and References sections updated. Removed ICD-9 codes from Coding section.|
|Revised||01/30/2015||Behavioral Health Sub-Committee Review. Clarified Criteria, Description, Discussion/General Information and References sections updated.|
|Reviewed||02/07/2014||Behavioral Health Sub-Committee Review. Discussion/General Information and References sections updated.|
|Reviewed||02/08/2013||Behavioral Health Sub-Committee Review. Discussion/General Information and References updated.|
|Reviewed||02/10/2012||Behavioral Health Sub-Committee Review. Discussion/General Information and References updated.|
|Revised||02/11/2011||Behavioral Health Sub-Committee Review. Medically necessary criteria revised to reflect FDA approval for opioid dependence. Description, Coding, Discussion and References updated.|
|Reviewed||05/13/2010||MPTAC review. References updated.|
|Reviewed||05/21/2009||MPTAC review. Place of service deleted, references updated.|
|Reviewed||05/15/2008||MPTAC review. References updated.|
|New||05/17/2007||MPTAC review. Initial guideline development.|