Injected Naltrexone for Opioid Addiction

From 2000 to 2015, more than half a million people died of drug overdoses in the U.S.[1] Many of these were fatal opioid overdoses, which have more than quadrupled in the U.S. since 1999.[2]

In addition to counseling, there are several effective drug treatments for opioid addiction. Currently, the most widely used drug treatments are weak opioids (buprenorphine/naloxone [BUNAVAIL, SUBOXONE, ZUBSOLV] and methadone [DOLOPHINE, METHADOSE]) that suppress the cravings for more potent opioid pills and heroin.

Another, far more expensive drug treatment that is now rapidly becoming more common is naltrexone, which blocks the pleasurable effects of opioids altogether. A once-daily pill version of naltrexone has been marketed for decades, but non-compliance was widespread among those taking it.

Drugmakers saw an opportunity for an injectable version that would avoid some of these compliance issues, with one company, Alkermes, gaining approval for a once-monthly injected version of naltrexone (VIVITROL).[3] The company has recently embarked on a concerted and rather novel marketing campaign to exploit the opioid epidemic. Disconcertingly, however, this marketing campaign has proceeded despite a lack of evidence that Vivitrol is effective in the long-term treatment of opioid addiction and dependence.

Approval based on a single trial

Oral naltrexone was approved by the Food and Drug Administration (FDA) in 1984 and has been used for opioid dependence and addiction. However, the effectiveness of oral naltrexone has always been limited by how easy it is for former opioid users to simply stop taking the drug and resume using opioids. The FDA-approved label of the nowdiscontinued brand-name version of oral naltrexone (generic versions are still available) noted that “there are no data” showing that oral naltrexone is effective for treatment of opioid dependence, apparently because of “poor medication compliance.”[4]

The extended-release, injectable form of naltrexone, Vivitrol, was first approved by the FDA in 2006 for the treatment of alcohol dependence.[5] The fact that Vivitrol was an injected drug and only had to be given once a month convinced Alkermes to seek additional approval of the drug for treatment of opioid dependence.

In 2010, the FDA approved Vivitrol for the prevention of relapse to opioid dependence,[6] based on a single randomized controlled trial,[7] instead of the two usually required for approval of a new drug or a new use for an existing drug. In a September 2010 advisory committee meeting that was convened to discuss whether to approve Vivitrol for the new use, two of the 13 committee members concluded that a single clinical trial was not sufficient to determine whether the drug was effective.[8]

The single clinical trial, conducted entirely in Russia, studied 250 subjects who were dependent on opioids (mostly heroin), had just completed opioid detoxification and were opioidfree for at least seven days.[9] Half of the subjects received monthly Vivitrol injections and the other half received monthly placebo injections, with all subjects receiving counseling. A large number of subjects (54 percent) withdrew from the trial before the 24-week end date. Significantly more subjects receiving Vivitrol (36 percent) than subjects receiving placebo (23 percent) were abstinent from opioids between the fifth and twentyfourth weeks of treatment, the predefined period during which opioid use was measured. Subjects receiving Vivitrol also reported significantly less craving of opioids during the trial. In a one-year follow-up study of the 114 subjects who completed the initial trial, 51 percent remained abstinent from opioids for an entire year after the completion of the initial trial. That Vivitrol was not compared with the standard, effective treatments of buprenorphine/naloxone or methadone in this trial also raises ethical questions as to why subjects in the placebo group were denied effective treatments for a life-threatening disease during the trial.[10]

A more recent, post-approval, clinical trial showed that Vivitrol also was effective in the short term in reducing the rate of relapse to opioid use after release from prison. In the study, inmates with a history of opioid dependence who were given a 24-week course of Vivitrol after release had a longer average time to relapse (10.5 weeks) and a lower rate of relapse (43 percent) than did inmates given only counseling and referrals to community treatment programs (5 weeks and 64 percent, respectively).[11] However, these benefits were apparent only as long as subjects were treated with Vivitrol. Approximately one year after stopping Vivitrol treatment, the two groups of subjects, including those who had not been on the drug during the initial 24 weeks, had equal rates of opioid-positive urine tests. Furthermore, the authors noted that the trial did not compare Vivitrol with either buprenorphine/naloxone or methadone treatments, the standard care for opioid dependence treatment, making it impossible to know whether Vivitrol is as effective as these standard treatments (such a study is currently underway).

Safety

The FDA-approved label for Vivitrol warns of the risk of sudden and severe opioid withdrawal symptoms that can require hospitalization if Vivitrol is given too soon after stopping opioids.[12] The label also warns that former opioid users may become more sensitive to the effects of opioids after treatment with naltrexone and may be more likely to overdose with opioids, particularly at the end of a one-month dosing interval or if a dose is missed.

Depression and suicidal thoughts; skin and, rarely, deep-tissue reactions at the site of Vivitrol injection that may require surgery; and allergic reactions, including those leading to pneumonia and anaphylaxis, also are listed as potential risks of Vivitrol.

Both oral and injectable forms of naltrexone are known to be associated with liver damage.[13] In the single clinical trial conducted to support approval of Vivitrol for opioid dependence, more abnormal liver blood test results were seen in subjects receiving Vivitrol than in subjects receiving placebo.[14] For this reason, the FDA-approved label for Vivitrol notes the risk of liver damage. However, the label does not recommend routine monitoring for liver abnormalities or avoidance of Vivitrol use in patients with liver disease.[15]

Novel marketing strategy

In response to the opioid epidemic and consequent mass incarceration of opioid-dependent persons, Alkermes embarked on an unusual marketing strategy, detailed in a wide-ranging June 2017 article by the independent news organization ProPublica.[16] Instead of promoting its drug to physicians who would prescribe it, the company set out to convince hundreds of judges overseeing so-called “drug courts” across the U.S. to require opioid users to take Vivitrol or be sent to prison.[17] Partly as a result of these marketing efforts, there are now 30,000 people taking Vivitrol in the U.S.[18]

This startling development, in which judges with no medical training are not only recommending, but effectively mandating, specific drug treatments, has been met with shock from some in the medical community.

“In what other medical situation do judges prescribe specific treatments from the bench?” Mark Willenbring, an addiction psychiatrist in St. Paul, Minnesota, asked ProPublica.[19]

The marketing effort was accompanied by a vast state and federal lobbying campaign to obtain favorable legislation that would steer doctors toward Vivitrol.[20] And while increasing its own market share, Alkermes also has been trying to shove aside the competition. In a June 2017 story, NPR revealed that it had obtained a document, purportedly circulated by Alkermes to federal legislators, that described buprenorphine’s side effects and potential for street diversion while ignoring its benefits in treating opioid addiction when combined with naloxone, and calling for stricter regulation of the drug.[21]

That Alkermes is pulling out all the stops in marketing Vivitrol is no surprise given the potential revenues at stake, with a list price for Vivitrol of more than $15,700 per year (compared with annual costs of $5,600 for buprenorphine/naloxone and just $147 for the older methadone treatment).[22]

What You Can Do

If you are addicted to or dependent on opioids, you should first be seen by a health care provider (such as a psychiatrist) who specializes in the management of addiction. The specialist should offer you counseling and initiate a detoxification regimen for you, which involves weaning you off of the opioids.

After this initial weaning period, we recommend that you try a supervised treatment program of buprenorphine/ naloxone because this medicine has greater evidence of long-term effectiveness than naltrexone does and is safer than methadone. For more information on buprenorphine/naloxone, see our February 2017 Worst Pills, Best Pills News article “Buprenorphine for Opioid Addiction”.

If treatment with buprenorphine/ naloxone is unsuccessful, you should consider trying either methadone or Vivitrol. If you are starting Vivitrol, you must not have taken any opioids (including buprenorphine or methadone) for a minimum of seven to 10 days before treatment begins to avoid precipitating severe opioid withdrawal symptoms.[23] Tell your health care provider immediately if you experience signs of an allergic reaction (such as trouble breathing) or of liver damage (such as yellow skin or eyes, pain in your upper right abdomen, abdominal swelling, or nausea or vomiting).

It is critical that Vivitrol treatment be combined with intensive psychological and behavioral counseling to treat your opioid addiction.

References

[1] Centers for Disease Control and Prevention. Opioid basics: Understanding the epidemic. https://www.cdc.gov/drugoverdose/epidemic/. Accessed August 15, 2017.

[2] Ibid.

[3] Alkermes. Label: naltrexone (VIVITROL). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf. Accessed August 15, 2017.

[4] Duramed Pharmaceuticals. Label: naltrexone (REVIA). October 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018932s017lbl.pdf. Accessed August 15, 2017.

[5] Food and Drug Administration. Approval letter for Vivitrol (naltrexone extended-release injectable suspension) for the treatment of alcohol dependence. April 13, 2006. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021897s000LTR.pdf. Accessed August 15, 2017.

[6] Food and Drug Administration. Approval letter for Vivitrol (naltrexone extended-release injectable suspension) for the prevention of relapse to opioid dependence. October 12, 2010. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/021897s015ltr.pdf. Accessed August 15, 2017.

[7] Alkermes. Label: naltrexone (VIVITROL). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf. Accessed August 15, 2017.

[8] Food and Drug Administration. Summary minutes of the September 16, 2010 Psychopharmacologic Drugs Advisory Committee meeting. https://wayback.archive-it.org/7993/20170404155430/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM232755.pdf. Accessed August 15, 2017.

[9] 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.

[10] Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effectiveness. Addiction. 2013;108(9):1628-1637.

[11] 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.

[12] Alkermes. Label: naltrexone (VIVITROL). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf. Accessed August 15, 2017.

[13] Food and Drug Administration. Background materials for the September 16, 2010 Psychopharmacologic Drugs Advisory Committee. https://wayback.archive-it.org/7993/20170405231020/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM225655.pdf. Accessed August 15, 2017.

[14] Ibid.

[15] Alkermes. Label: naltrexone (VIVITROL). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf. Accessed August 15, 2017.

[16] MacGillis A. The last shot. ProPublica. June 27, 2017. https://www.propublica.org/article/vivitrol-opiate-crisis-and-criminal-justice. Accessed August 15, 2017.

[17] Ibid.

[18] Ibid.

[19] Ibid.

[20] Harper, J. A drugmaker tries to cash in on the opioid epidemic, one state law at a time. NPR. June 12, 2017. http://www.npr.org/sections/health-shots/2017/06/12/523774660/a-drugmaker-tries-to-cash-in-on-the-opioid-epidemic-one-state-law-at-a-time. Accessed August 15, 2017.

[21] Ibid.

[22] Drugs for opioid use disorder. Med Lett Drugs Ther. 2017;59(1522):89-96.

[23] Alkermes. Label: naltrexone (VIVITROL). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021897s029lbl.pdf. Accessed August 15, 2017.