Opioid use disorder (OUD) is a chronic, life-threatening, relapsing condition, often associated with legal, interpersonal, and employment problems. FDA approved safe and effective medications for OUD are methadone (a full opioid agonist), Buprenorphine (a partial agonist), Naltrexone, and Naltrexone-long-acting injectable or Vivitrol (opioid antagonists).
Methadone and Buprenorphine suppress opioid withdrawal symptoms by being other opioid agonists. But they also reduce the use of opioids and are treatments for OUDs by reducing or attenuating the effects of other opioids. Naltrexone – Vivitrol is simply blockers of opioid receptors that block opioid agonists like heroin, fentanyl, or oxycontin.
We have reviewed Buprenorphine, Buprenorphine + Naltrexone, and Methadone previously for Addiction Hope. Of the MATs, methadone has the most persuasive evidence for long-term effectiveness. Treatments for OUD are usually defined by there adherence to treatment.
However, low adherence and drop-outs are the rule and all too common. MAT fails when patients stop coming to therapy and medications leading to high rates of relapse and overdose after leaving treatment [1]. Longer duration of therapy allows the restoration of social connections and is associated with better outcomes.
The 1970s to today: Naltrexone to Vivitrol [2]
Naloxone is, in essence, a short-acting version of Naltrexone. Naloxone saves lives by working right away and has a half-life of three hours. Naltrexone is taken orally and acts slowly. Naltrexone has a half-life of 13 hours. Both Naloxone and Naltrexone block mu-opioid receptors. They compete against opioids to bind to the “Mu” opioid receptor for a while.
These mu receptors are on neurons, ultimately preventing the patient with opioid use disorder (OUD) or others from being able to feel opioid effects. Heroin, fentanyl, and other opioids reduce respiration, heart rate, and blood pressure, which can be reversed by naloxone and blocked by Naltrexone.
As a “Mu opioid receptor (MOR) antagonist,” naloxone reverses the potentially deadly effects of an opioid overdose. Intravenous Narcan was approved by the Food and Drug Administration (FDA) for opioid overdose reversal in 1971.
Like Naloxone, the long-acting Naltrexone is an antagonist synthesized in 1963 by Endo Laboratories. At that time, methadone, a long-acting MOR agonist, like morphine or heroin in many ways, was the only medication available for opioid addiction.
Oral Naltrexone was the only non-addicting and non-opioid available as a treatment for OUD patients. It had many advantages. It was taken by mouth; it did not cause many side effects; it was not sedating, euphoric, and had no diversion or street value. The problem with oral Naltrexone being a cure for OUD was that patients did not want to take it.
Compared to Methadone or Buprenorphine, few OUD patients would choose to take Naltrexone. It was not an opioid; it did not reinforce and stimulate its taking. Naltrexone also, as a long-acting antagonist, is safe, but not only does the patient have to take it, they can quit at any time and not have withdrawal or a reason other than preventing relapse from taking another dose.
After Vivitrol is given by intramuscular injection, naltrexone plasma concentrations have an initial peak approximately 2 hours after injection. Naltrexone blood levels peak again 2-3 days later. 14 days after dosing, concentrations start to slowly decline. They slowly decline over the month.
So, once a month injections of 380mg have become the standard and approved dosing. Also, OUD patients need to be opioid-free, and the manufacturer suggests at least 7 days to be given safely. It has enormous appeal as an office-based, alternative pharmacotherapeutic option for opioid-use disorder. Noncompliance was followed by almost inevitable relapse.
The FDA approved Naltrexone in 1984 for OUDs in treating heroin addiction. They noted at the time that Naltrexone is not an opioid and does not reinforce medication compliance. So, taking Naltrexone is voluntary and up to the patient with OUD and the therapeutic relationship with the treatment program or health provider.
Naltrexone is an opioid receptor blocker, preventing heroin or fentanyl or other opioids from producing euphoria. It is reported that some OUD patients test the naltrexone blockade by injecting massive amounts of heroin. Most ultimately say that they weren’t getting high and were wasting their money trying to use opioids while taking Naltrexone.
Naltrexone was non-addictive. Naltrexone does not produce any euphoria, tolerance, or withdrawal. The naltrexone pill that we gave to patients in the ’70s at Yale was great as long as you took it. But, few patients complied with this daily or every other day oral short-acting naltrexone treatment. Sadly, most relapsed.
The game-changer was the development of an extended-release form, administered in monthly injections (Vivitrol.). Injected Naltrexone or Vivitrol guarantees compliance over the pill form, short-acting Naltrexone. Alkermes [3] received FDA approval in 2010 for OUDs.
Vivitrol-Naltrexone is an Effective MAT
MATs are an important, essential element in OUD treatment. But, to be effective, patients need to be incentivized to take a MAT and followed for months and years, so we know the outcome of the therapy. Naltrexone-taking is virtually equivalent to naltrexone efficacy.
When patients are coerced or have naltrexone-taking linked to their license or job, outcomes are improved. Naltrexone has excellent efficacy in the treatment of impaired physicians. Naltrexone has also been used successfully in patients in the criminal justice system.
Naltrexone makes a person with OUDs, virtually immune to opioid abuse. But you have to take it. Now, it is monthly with Vivitrol. In the 1980s, we tested Naltrexone in groups that had professional reasons to adhere to prescribed treatments: physicians and businessmen, who are coerced and have strong professional and financial incentives to remain abstinent, have excellent outcomes to match.
Our early results were noticeable. More patients than in the past took Naltrexone. They stayed in addiction treatment and were drug-free for six months.
Naltrexone is safe and effective and widely used in the treatment of OUDs among criminal justice-involved individuals [4]. Extended-release Naltrexone (XR-NTX) is the most widely-accepted, evidence-based OUD pharmacotherapy in criminal justice settings, and ensures approximately 30 days of protection from an opioid overdose.
The high cost of XR-NTX serves as a barrier to uptake by many prison/jail systems. Initiating XR-NTX for OUD before release from incarceration may improve patient health and well-being, while also producing downstream cost-offsets [5].
Our experiences suggest that patients need help taking treatment as prescribed and for as long as necessary. All of the MATs plus therapies have better outcomes than just detoxification and abstinence, and some experts classify this approach as lacking scientific evidence [6]. OUD patients who are older and also those who go to therapy and/or AA meetings have positive naltrexone outcomes [7].
You Must Be Detoxed First To Take Naltrexone or Vivitrol
The treatment of opioid withdrawal is an essential area first step before Naltrexone. Medically supervised detox or withdrawal treatments include replacement with μ-opioid receptor agonists (e.g., Methadone), partial agonists (e.g., Buprenorphine), and non-addicting antihypertensive α2-adrenergic receptor agonists (e.g., Clonidine) [8].
You can provoke withdrawal when you give naloxone or Naltrexone to a patient with an OUD who is using opioids. We have recommended that patients have at least five days of washout after their last use of opioids to reduce the risk of precipitated opioid withdrawal.
The patient then receives an injection of Vivitrol 380 mg XR-NTX. Typically, the OUD patient would be opioid-free on urine testing, not showing physiological dependence or symptoms on the naloxone challenge.
Researchers and clinicians have tried to accelerate detox to start Naltrexone sooner. Two procedures [9] may shorten the period following abrupt opioid agonist discontinuation.
First, Buprenorphine can be given for one day, then followed by 1–2 days of washout and a gradual ascending titration of oral Naltrexone over the subsequent 3–5 days, beginning with a low dose of 1–3 mg. In this procedure, patients receive standing doses of adjunctive medications, usually clonidine and clonazepam.
The second procedure employs buprenorphine taper in combination with very low doses of oral Naltrexone (1 mg/day) over the first 2–3 days, followed by a gradual up-titration of Naltrexone to full blocking doses (25 mg/day), usually accomplished within seven days. These procedures have allowed 50–70% of outpatients to successfully initiate treatment with XR-NTX with favorable tolerability and no serious adverse events due to precipitated withdrawal.
What Do Patients Think
Currently, three medications that modulate the function of the opioidergic receptors, methadone, buprenorphine, and Naltrexone, have been approved by the US Food and Drug Administration (FDA) to treat OUD. We provide a brief review of the three primary medications used in the treatment of OUD [10].
Many patients will describe that they feel better when back in their home environment or at work. They may be advised to stay away from triggers—people, places, and things to prevent relapses. This reduction in real-life provoked cravings may reduce relapse and be due to Naltrexone’s binding to the opioid receptors reducing drug cue-induced cravings.
So, Vivitrol has been shown to reduce drug cue reactivity in patients with OUDs. This effect may explain some real benefits that injectable Naltrexone has compared to other treatment options [11].
OUD patients primarily learned about methadone and buprenorphine from other individuals with OUD. They became interested in starting buprenorphine and methadone after seeing the medications work effectively in peers. Patients with OUDs often think of methadone as a last resort.
In contrast, OUD patients, when they know about Vivitrol, only learn about it after receiving information from health practitioners. OUD patients feel stigma and external pressure to stop buprenorphine and methadone, but not Vivitrol or Naltrexone [12]. But, treatment with buprenorphine or methadone is associated with reductions in overdose, and Emergency visits and medical problems compared with other medications [13].
In summary, there are only 3 Food and Drug Administration-approved medications to treat OUD (methadone, buprenorphine, Vivitrol, and Naltrexone). But, there is no real debate over whether they are useful, and if anything, they are not used as often as they should.
There are differences between agonists (Methadone, Buprenorphine, and Buprenorphine+Naltrexone). We have covered all of these agonists previously here at Addiction Hope. While some have argued that these agonist MATs are just replacing one opioid with another, it is this opioid feature that supports patient adherence and makes these MATs effective.
Vivitrol makes sense as MATs for physicians and others with patient treatment coordinators, regular urine testing, and follow up and those in cognitively demanding and drug-free occupations. Vivitrol is approved by the FDA for the prevention of relapse to opioid dependence, following opioid detoxification.
Many patients do not want to be addicted to therapy and chose Naltrexone. Still, it is more difficult to initiate patients to XR-NTX than on the agonists or Buprenorphine + Naloxone. One problem is getting to the first dose and initial retention and relapse. However, once started, Vivitrol is comparable in outcomes and equally safe and effective [14].
Treatment of OUDs’ work! Treatment with all FDA approved MATs, is evidence-based and works. Compared with patients receiving MAT, untreated patients with OUDs have a higher risk of all-cause mortality and overdose mortality. Those patients who leave treatment have a higher risk of all-cause and overdose death.
Retention in MAT of over 1-year is associated with a lower mortality rate than that with retention ≤1 year. Vivitrol can cause premature death among persons with OUD [15] and prevents relapse to opioid dependence, following opioid detoxification [16]. Naltrexone – Vivitrol is a wonder drug which makes the OUD patient immune to opioid’s high and overdose.
We need better detoxification success to give more patients with OUDs a chance to get their first injection. Currently, that dose lasts for one month. We need longer-acting Naltrexone and other long-acting injectable MATs. It would be helpful if we had treatments available that are so new that I did not use them in the 70s, 80s, or 90s [17].
References:
1. Bell J, Strang J. Medication Treatment of Opioid Use Disorder. Biol Psychiatry. 2020;87(1):82-88. doi:10.1016/j.biopsych.2019.06.020
2. Srivastava, A. B., & Gold, M. S. (2018). Naltrexone: A History and Future Directions. Cerebrum: the Dana forum on brain science, 2018, cer-13-18.
3. https://www.vivitrolhcp.com/what-is-vivitrol
4. Bahji A, Carlone D, Altomare J. Acceptability and efficacy of naltrexone for criminal justice-involved individuals with opioid use disorder: a systematic review and meta-analysis. Addiction. 2020;115(8):1413-1425. doi:10.1111/add.14946
5. Murphy SM, Jeng PJ, Poole SA, et al. Health and economic outcomes of treatment with extended-release naltrexone among pre-release prisoners with opioid use disorder (HOPPER): protocol for an evaluation of two randomized effectiveness trials. Addict Sci Clin Pract. 2020;15(1):15. Published 2020 Apr 22. doi:10.1186/s13722-020-00188-5
6. Strang J, Volkow ND, Degenhardt L, et al. Opioid use disorder. Nat Rev Dis Primers. 2020;6(1):3. Published 2020 Jan 9. doi:10.1038/s41572-019-0137-5
7. Bergman BG, Ashford RD, Kelly JF. Attitudes toward opioid use disorder medications: Results from a U.S. national study of individuals who resolved a substance use problem. Exp Clin Psychopharmacol. 2020;28(4):449-461. doi:10.1037/pha0000325
8. Srivastava AB, Mariani JJ, Levin FR. New directions in the treatment of opioid withdrawal. Lancet. 2020;395(10241):1938-1948. doi:10.1016/S0140-6736(20)30852-7
9. https://doi.org/10.1111/ajad.12711
10. 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
11. Shi Z, Wang AL, Jagannathan K, et al. Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder. J Psychiatry Neurosci. 2018;43(4):254-261. doi:10.1503/jpn.170036
12. Randall-Kosich O, Andraka-Christou B, Totaram R, Alamo J, Nadig M. Comparing Reasons for Starting and Stopping Methadone, Buprenorphine, and Naltrexone Treatment Among a Sample of White Individuals With Opioid Use Disorder. J Addict Med. 2020;14(4):e44-e52. doi:10.1097/ADM.0000000000000584
13. Wakeman SE, Larochelle MR, Ameli O, et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open. 2020;3(2):e1920622. Published 2020 Feb 5. doi:10.1001/jamanetworkopen.2019.20622
14. Lee JD, Nunes EV Jr, 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(10118):309-318. doi:10.1016/S0140-6736(17)32812-X
15. Ma J, Bao YP, Wang RJ, et al. Effects of medication-assisted treatment on mortality among opioids users: a systematic review and meta-analysis. Mol Psychiatry. 2019;24(12):1868-1883. doi:10.1038/s41380-018-0094-5
16. Syed YY, Keating GM. Extended-release intramuscular naltrexone (VIVITROL®): a review of its use in the prevention of relapse to opioid dependence in detoxified patients. CNS Drugs. 2013;27(10):851-861. doi:10.1007/s40263-013-0110-x
17. Chalhoub RM, Kalivas PW. Non-Opioid Treatments for Opioid Use Disorder: Rationales and Data to Date [published online ahead of print, 2020 Aug 10]. Drugs. 2020;10.1007/s40265-020-01373-1. doi:10.1007/s40265-020-01373-1
About the Author:
Mark 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
The opinions and views of our guest contributors are shared to provide a broad perspective of addictions. These are not necessarily the views of Addiction Hope, but an effort to offer a discussion of various issues by different concerned individuals.
We at Addiction Hope understand that addictions result from multiple physical, emotional, environmental and genetic factors. If you or a loved one are suffering from an addiction, please know that there is hope for you, and seek immediate professional help.
Published on August 21, 2020
Reviewed by Jacquelyn Ekern, MS, LPC on August 21, 2020
Published on AddictionHope.com