Naltrexone and Injectable Naltrexone (Vivitrol) for Opioid Use Disorders (OUDs)

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The United States is a resurgent national opioid use and overdose epidemic. Physicians are encouraged to treat opioid-use disorders (OUDs), learn about addiction medicine, and help treat OUD patients with the three Food and Drug Administration approved medications (methadone, buprenorphine, and Naltrexone). There is little disagreement at this point that these medications are safe and effective [1].

We have previously described and reviewed the use of methadone in OUDs, Buprenorphine, and Buprenorphine + Naloxone. Here we will consider Naltrexone [2]. One advantage that Naltrexone has compared to the other approved Medical Assisted Treatments (MATs) is that it can be prescribed by any licensed health care provider.

Oral Naltrexone and injectable long-acting Naltrexone (Vivitrol) in OUDs can be prescribed to treat opioid use disorders and alcohol use disorders. It comes in the pharmacy as Naltrexone (ReVia, Depade) can be taken as a 50 mg pill orally, once per day. The extended-release form of the drug (Vivitrol) is injected 380 mg intramuscular once a month [3].

In the 1980s, we tested oral, 50 mg naltrexone in groups where they had jobs or professional reasons to follow medical advice and take prescribed treatments as prescribed. Physicians and business people are often coerced by Boards of Medicine and Hospitals into following treatment advice and have strong professional and financial incentives to remain abstinent, took Naltrexone, and benefited from the treatment.

Patients who take Naltrexone as prescribed stayed in treatment, and were drug-free for six months. We suggested in the 80s that MATs could not be as effective as they are unless patients were incentivized to take them and also followed longitudinally (on the order of years, not just for several weeks or 90 days). We thought treatment outcomes should be coordinated and include all medical, psychiatric, and social aspects of their addiction [4].

Naltrexone Use Today in OUDs

Naltrexone’s high affinity to mu (μ)-opioid receptors displaces opioids and blocking their access to these receptors. Naltrexone blocks the euphoric effects of drugs such as heroin, oxycontin, morphine, fentanyl, and methadone [5]. Suboxone, buprenorphine, and methadone activate opioid receptors in the brain and body that suppress cravings. Naltrexone binds and blocks opioid receptors, and like opioid agonists also reduces opioid cravings. Typically, oral Naltrexone Common dose is 50 mg per day.

Naltrexone is safe and FDA approved for the treatment of opioid and alcohol dependence [6]. Naltrexone is useful in the blockade of the effects of exogenously administered opioids in adults [7]. Naltrexone (N-cyclopropylmethylnoroxymorphone) was synthesized in 1965. A typical daily Naltrexone dose (50 mg) blocks the pharmacologic effects of 25 mg intravenous (IV) heroin up to 24 hours.

Young girl using Naltrexone to overcome OUDNaltrexone has a longer duration of action, higher potency, and more oral bioavailability than naloxone, the other FDA approved opioid antagonist. Naltrexone blocks opioid receptors, and this blockade stops patients with OUDs from getting the euphoria that they were looking for and paid for.

Naltrexone is both a deterrent to using further and an anti-craving medication. Naltrexone has been used safely in research and to treat SUDs for over four decades. Naltrexone has no abuse potential, no street value, and neither tolerance nor dependence develops.

Our work with Naltrexone and other research looking at outcomes for Naltrexone in OUDs have been closely related to low adherence to the medication and poor retention in treatment. A 2011 Cochrane review showed no significant improvements in opioid abstinence or reincarceration rates for individuals using oral Naltrexone [8].

This assessment was driven mainly by poor compliance with the medication. One of the biggest challenges with Naltrexone was getting patients to take it every day. This is why scientists, NIDA, and others encouraged the development of long-acting injectable Naltrexone.

Still, whether injected or taken orally, Naltrexone is not heroin or methadone or buprenorphine. It is the anti-opioid. It has made sense to experts that Naltrexone is not a drug of abuse or self-administered.

Naltrexone is a non-opioid that lacks drug reward compromising its adherence. Lower naltrexone retention rates for patients can be explained by a lack of mu-opioid re-enforcing effects, such as buprenorphine and methadone.

Naltrexone increases the chance of sobriety and decreases the risk of overdose [9]. Naltrexone appears to work best when there is a strong patient motivation for abstinence seems to be a key component.

Naltrexone efficacy is most closely related to compliance. Naltrexone outcome studies report treatment retention and success in highly motivated upper-middle-class individuals, health care professionals [10], and inmates on work release [11].

Developing a long-acting “depo” Naltrexone formulation was a significant public-private pharma development. Once-monthly–dosed injectable extended-release Naltrexone (Vivitrol, Alkermes Corp., Dublin, Ireland) has been FDA approved for the treatment of OUDs. Initial studies were quite promising, showing superiority in patient sobriety over oral Naltrexone.

Its primary benefit is it improves adherence by being injected monthly and working for that month. Naltrexone provides a relatively constant level of bioavailable Naltrexone to the patient.

The so-called XBOT study of Extended-Release Naltrexone vs. Suboxone Trial directly compared long-acting injectable Naltrexone with buprenorphine/naloxone (Suboxone). It showed Naltrexone [12] is as successful as Suboxone for controlling for successful detoxification from opioids. The XBOT study confirms that new drop rates are much worse with Naltrexone than buprenorphine/naloxone. When both medications are taken as prescribed, days abstinent, negative urine tests, overdose, and time-to-relapse are the same for Naltrexone as Suboxone.

Man considering treatmentMany people with OUDs who intended to start extended-release Naltrexone (XR-NTX) do not, and most that do start XR-NTX discontinue treatment prematurely. XR-NTX decreases opioid use, but adherence and willingness to take Naltrexone compared to an opioid agonist [13].

Naltrexone implants under development may increase the duration of the blockade past 30 days. Such a development would not only improve compliance but may be especially useful in some patients, especially health professionals with OUDs [14]. In one report, a Naltrexone implant compared with oral Naltrexone and a placebo implant reported abstinence rates of 74% to 79% after 12 weeks [15].


Injectable Naltrexone is safe, effective, and outcomes are better for injectable compared to oral, daily Naltrexone. Extended-release injectable Vivitrol is approved for the treatment of people with OUDs.

Naltrexone can be prescribed by any healthcare provider who is licensed to prescribe medications. It can be prescribed without a physician needing to have any specialized training. It is given after detoxification and usually 7 to 10 days before extended-release injectable Naltrexone is given.

Research, especially the work of Anna Rose Childress [16] and her group at the University of Pennsylvania, has shown that Naltrexone not only decreases opioid use and overdose but also decreases paraphernalia induced reactivity and decreases craving.

Extended-release Naltrexone reduces the Nucleus Accumbens and Orbital Frontal Cortex(OFC) cue reactivity in patients with OUD. This effect is specific to opioid-related stimuli in the mOFC only.

The reduction in neural response to opioid-related stimuli is more robust in patients with a greater decline in withdrawal severity. When extended-release injectable Naltrexone is discontinued, they may have reduced tolerance to opioids and maybe an overdose risk.


1. Oesterle TS, Thusius NJ, Rummans TA, Gold MS. Medication-Assisted Treatment for Opioid-Use Disorder. Mayo Clin Proc. 2019;94(10):2072-2086. doi:10.1016/j.mayocp.2019.03.029



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6. Croop RS, Faulkner EB, Labriola DF. The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. The Naltrexone Usage Study Group. Arch Gen Psychiatry. 1997;54(12):1130-1135. doi:10.1001/archpsyc.1997.01830240090013

7. Gold MS, Dackis CA, Pottash AL, et al. Naltrexone, opiate addiction, and endorphins. Med Res Rev. 1982;2(3):211-246. doi:10.1002/med.2610020302

8. Minozzi S. Amato L. Vecchi S. Davoli M. Kirchmayer U. Verster A. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev. 2011; : Cd001333

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10. Ling W. Wesson D.R. Naltrexone treatment for addicted healthcare professionals: a collaborative private practice experience. J Clin Psychiatry. 1984; 45: 46-48

11. Brahen L.S. Henderson R.K. Capone T.Kordal N. Naltrexone treatment in a jail work-release program. J Clin Psychiatry. 1984; 45: 49-52

12. Lee J.D. Nunes Jr., E.V. Novo P. et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018; 391: 309-318

13. Jarvis B.P. Holtyn A.F. Subramaniam S. et al. Extended-release injectable naltrexone for opioid use disorder: a systematic review. Addiction. 2018; 113: 1188-1209

14. Merlo, L. J., Greene, W. M., & Pomm, R. (2011). Mandatory naltrexone treatment prevents relapse among opiate-dependent anesthesiologists returning to practice. Journal of addiction medicine, 5(4), 279–283.

15. Foster J. Brewer C. Steele T. Naltrexone implants can completely prevent early (1-month) relapse after opiate detoxification: a pilot study of two cohorts totaling 101 patients with a note on naltrexone blood levels. Addict Biol. 2003; 8: 211-217

16. Shi, Z., Wang, A.-L., Jagannathan, K., Fairchild, V. P., O’Brien, C. P., Childress, A. R., & Langleben, D. D. (2018). Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder. Journal of Psychiatry & Neuroscience, 43(4), 254–261.

About the Author:

Mark GoldMark S. Gold, M.D., Professor, Washington University School of Medicine – Department of Psychiatry, served as Professor, the Donald Dizney Eminent Scholar, Distinguished Professor and Chair of Psychiatry from 1990-2014.

Dr. Gold was the first Faculty from the College of Medicine to be selected as a University-wide Distinguished Alumni Professor and served as the 17th University of Florida’s Distinguished Alumni Professor.
Learn more about Mark S. Gold, MD

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Published on August 4, 2020
Reviewed by Jacquelyn Ekern, MS, LPC on August 4, 2020
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