Medication Assisted Treatment: Naltrexone — history, overview, pros and cons


What Is Naltrexone?

According to the pharmaceutical encyclopedia [1], naltrexone “blocks the effects of opioid medication, including pain relief or feelings of well-being that can lead to opioid abuse.” It’s often part of a Medication Assisted Treatment (M.A.T.) program for opioid (and to a lesser extent, alcohol) dependence and “is used to prevent relapse in people who became dependent on opioid medicine and then stopped using it. Naltrexone can help keep you from feeling a ‘need’ to use the opioid.”

Brand names: Vivitrol, Revia, Depade

Forms: According to the clinician informational website Medscape [2], naltrexone is prescribed in two forms: 50mg tablets, or 380mg intramuscular injections.

Naltrexone: History

naltrexoneThe philanthropic organization The Dana Foundation [3] notes that naltrexone “was first synthesized in 1963 by Endo Laboratories, which was later purchased in 1969 by DuPont Pharmaceuticals.” Naltrexone was one of three drugs acquired by DuPont — the other two being the narcotic Percodan and the anti-clotting medication Coumadin — but because of the “low market potential” of naltrexone, it wasn’t expected to be developed as a pharmaceutical [4].

That changed in 1971, when President Richard Nixon created the Special Action Office for Drug Abuse Prevention {SAODAP), whose first director, Dr. Jerome Taffe, took a special interest in naltrexone as a potential tool in his quest to “shift the emphasis of drug abuse treatment from prisons and hospitals to community based programs,” writes Lyn Hacker for the online newspaper Kentucky Forward [5].

In 1972, passage of the Drug Abuse Office and Treatment Act was designed “for the purpose of developing non-addictive (i.e., non-agonist) treatments for heroin addiction,” according to the Dana Foundation. While methadone showed promise, its formulation as a drug that activates opioid receptors in the brain meant that it had to “be dispensed at a licensed clinic and requires careful monitoring,” and that it was “liable to abuse and diversion and, if combined with other sedating drugs (e.g., barbiturates, benzodiazepines, alcohol), can lead to overdose and death.” Naltrexone, on the other hand, is an antagonist, meaning it produces none of the sedation or euphoria of full agonist opioids and held “enormous appeal as an office-based, alternative pharmacotherapeutic option for opioid-use disorder.”

By 1974, the SAODAP had been replaced by the National Institute on Drug Abuse (NIDA), which encouraged DuPont to continue naltrexone clinical trials in order to gain Food and Drug Administration (FDA) approval. Those early trials showed remarkable promise in the development of a non-toxic, non-addictive drug to treat heroin addiction, but the clinical trials also ran into human obstacles, according to a paper provided to the U.S. Department of Health and Human Services [6]: “Dr. Arnold J. Schecter, who conducted many of the early safety and efficacy studies for naltrexone in the treatment of opioid addiction at the State University of New York, reported that patient recruitment was difficult because some patients feared a new drug, lacked a desire to become drug free, were unwilling to possibly receive a placebo, and disliked the rigid protocols associated with the clinical trials. In addition, patients had to remain opiate free for a minimum of 5 to 10 days prior to treatment because naltrexone would cause severe withdrawal symptoms in patients with opioids in their system. Many addicts were unable to remain opioid-free for the required amount of time because of the physiological withdrawal effects.”

In addition, naltrexone faced suspicion from within the addiction treatment community. Its experimental nature led to a reluctance on the part of methadone advocates to refer patients for naltrexone therapy, “partially because of their need to keep their own censuses high enough to receive funding. As a result of these difficulties recruiting patients, the naltrexone clinical researchers made no efforts to screen out patients who can be difficult to manage in clinical trials, e.g., patients who were poorly compliant, and this may have compromised the results of the clinical trials.” [6]

One of the biggest challenges was in the administration of naltrexone — because it involved the daily consumption of a pill, addicted test subjects could simply choose to not take it and return to opiate use instead. That "noncompliance was followed by almost inevitable relapse, which was (and continues to be) a major issue that limits the utility of daily oral naltrexone.” [3] Nevertheless, tests in the early 1980s — which led to FDA approval in 1984 of naltrexone as a treatment for heroin addiction (as long as taken as directed) — demonstrated its efficacy: A six-year study, published in 1981 [7], revealed that “although a large number of subjects discontinued naltrexone abruptly, treatment was related to a significant decrease in opiate and nonopiate drug use.” Another study of 300 addicts, published in 1984 [8], reported that “almost half the subjects tested naltrexone by using opiates at least once; all reported satisfactory narcotic blockade. Very few subjects switched to nonopiates to get high, although several did increase their alcohol consumption during the first weeks of therapy. One-third of subjects contacted in a follow-up study were opiate-free 6 months after stopping naltrexone, indicating a successful short-term treatment modality.”

Although the oral form of naltrexone wasn’t the “magic bullet” that could provide antagonist relief from opioid addiction some had hoped for, testing continued throughout the 1980s. “Animal studies” held during that decade “established that naltrexone decreased alcohol consumption through its action at the opiate receptors. Human clinical trials followed that confirmed that naltrexone, when used in combination with psychosocial therapy, could reduce cravings for alcohol and decrease relapse rates to alcohol use,” [9] and the FDA approved naltrexone for the treatment of alcoholism in 1994. In addition, Dr. Benjamin Srivastava and Dr. Mark Gold studied the effects of naltrexone on groups of physicians and business executives, their reason being that those populations are “often coerced into following treatment and have strong professional and financial incentives to remain abstinent. Our early results were clear: more patients than in the past took naltrexone, stayed in treatment, and were drug free for a six-month period.” [10]

Noncompliance, however, led to additional work on “an injectable, long-acting naltrexone formulation,” [11] and when the drug was combined with polymers prepared from “naturally occurring sugar acids,” the next phase of naltrexone came into focus: “The U.S. Food and Drug Administration (FDA) approved Alkermes' PLG polymer formulation of extended-release injectable naltrexone for treating alcohol dependence in April 2006.” Approval for opioid addiction followed in 2010, and today, the drug — under the brand name Vivitrol — is one of the three federally approved medications used in M.A.T.

How Does Naltrexone Work?

naltrexoneTo understand how naltrexone functions as an antagonist, it’s important to understand how it affects the brain — specifically, natural opioid receptors (mu, delta and kappa) that exist in the brain and “are activated by a family of endogenous peptides which are released by neurons,” according to Science Daily [12]. “Opioid receptors can also be activated exogenously by alkaloid opiates, the prototype of which is morphine, which remains the most valuable painkiller in contemporary medicine.” Heroin, prescription narcotics and other opioids would also serve as exogenous alkaloid activators of the brain’s opioid receptors.

Once activated, the receptors tell the body to produce dopamine — a natural chemical that “essentially trains the body to remember, ‘I liked that, let’s do it again,’” according to a report by The Associated Press [13]: "That’s the brain’s reward system, and opioids can hijack it by triggering a surge of dopamine larger than nature ever could. Repeated opioid use overloads circuits in multiple brain regions, including those involved with learning and memory, emotion, judgment and self-control. At the same time, the brain gradually releases less dopamine in response to other things the person once found pleasurable. Eventually they seek more of the drug not to get high, but to avoid constantly feeling low.”

As agonists, M.A.T. drugs like methadone — and as a partial agonist, buprenorphine, at least to a lesser extent — activate those receptors as well. However, because the dosage is controlled, it’s not a sudden torrent of dopamine flooding the system, as caused by a drug like heroin, and the idea is that they’re designed to eliminate “the jolts so there’s no high and less craving,” according to that AP report. However, naltrexone is altogether different: Its role is to “bind to opiate receptors and block the action of both opioid medications and opiate neurotransmitters.” [11]

How effective is it? According to Dr. Srivastata and Dr. Gold [10], “Some patients taking naltrexone tried to overcome the blockade by injecting large amounts of heroin and complained to the physician that they weren’t getting high and were wasting their money. Compared with methadone, patients on naltrexone did not experience any euphoria, tolerance, or withdrawal; naltrexone was clearly non-addictive.”

“As with any drug, you’ve got to know about potential side effects, but there is no drug abuse liability with naltrexone — none. Zero,” says Dr. Lane Cook, chief of Psychiatric Services at Cornerstone of Recovery. “There is for the other two (M.A.T. medications, however), and on top of that, they have really bad withdrawals if you stop taking them, because of their long half-lives. So two-thirds of M.A.T. medications are addictive.

“At Cornerstone of Recovery, we strongly encourage every person who has a problem with opioids and alcohol to use Vivitrol for 6 to 12 months, and that recommendation is as strong as the recommendation for 12 Step and appropriate follow-up care. The national average is three months, and we see a lot of people who tell us they’ve tried Vivitrol, but when we ask how long they took it, most of them do it once, or maybe two or three times, and 90 percent of them say, ‘It was good. As far as opiates go, I didn’t use.’ But when you ask them what happened when they stopped, they tell us, ‘I went right back to using.’”

And, Cook adds, it’s effectiveness isn’t limited to those whose primary drugs of choice are opioids: “In our experience, we’ve seen that Vivitrol doubles your chances of complete abstinence in alcohol use disorder, which is great.”

Naltrexone: Cons

naltrexoneAs with any medication, there may be side effects for those who use naltrexone as part of M.A.T. According to the U.S. National Library of Medicine [14], some of the more common side effects from a monthly injection of naltrexone (Vivitrol) may include: nausea, vomiting, diarrhea, stomach pain, decreased appetite, dry mouth, headache, difficulty falling asleep or staying asleep, dizziness, tiredness, anxiety, joint pain or stiffness, muscle cramps, weakness and tenderness, redness, bruising, or itching at the injection site. While many of these side effects may be temporary, as with all medications, individuals are urged to contact their prescribing physician if they persist.

One of the biggest hurdles in the administration of naltrexone as part of M.A.T. is the fact that because it is an antagonist, individuals to whom it’s administered should avoid it until their physical systems are completely cleansed of opioids, or else they risk going into immediate withdrawal. According to SAMHSA [11], “treatment with injectable naltrexone should not be initiated unless the patient is opioid free for 7 to 10 days (or at least 14 days for patients who have been taking methadone for more than 3 to 4 weeks), as determined by medical history or toxicological screening,” and “before administering injectable naltrexone, physicians should advise patients of the unpleasant physical effects of opioid withdrawal that will result if patients are not completely detoxified from opioids.”

Early in its development, naltrexone’s formulation as an oral tablet made compliance with it as a form of M.A.T. incredibly difficult, as Dr. Srivastava and Dr. Gold pointed out [10]: “Specifically, since participants needed to make the decision daily to take oral naltrexone instead of heroin, many intermittently chose to use heroin instead. Noncompliance was followed by almost inevitable relapse, which was (and continues to be) a major issue that limits the utility of daily oral naltrexone.” However, the development of Vivitrol, they added, “demonstrated markedly improved compliance over the oral formulation.”

“We do a lot better with somebody getting a shot every month over taking a pill every day,” says Dr. Fred “Kip” Wenger, Medical Director for Cornerstone of Recovery. “I think Vivitrol saves people’s lives, and I’m a huge fan of the drug even though it may not be for everybody.”

The problem, he adds, is that despite its lengthy history and well-documented use as an M.A.T. drug, Vivitrol is often overshadowed by the supposed superior effectiveness of methadone and buprenorphine.

naltrexone“As a doctor who still practices emergency medicine, I’ll run into a lot of people who have been on it, but then when you talk to nurses and the medical community, 80 percent of them have never heard of naltrexone,” Wenger says. “They don’t know what it is, how it works or how it could save lives, and I think that ignorance is a part of why it may not have the same attraction as other M.A.T. drugs.”

And because there’s a need for opioid-addicted patients to make it through the detox process before beginning M.A.T. with naltrexone, it’s easy to mistake “noncompliance” with failure, but various studies have demonstrated that if addicts have assistance through medical detox — at a drug and alcohol treatment facility like Cornerstone of Recovery, for example — then naltrexone, specifically in the form of an extended release injectable like Vivitrol, has an opportunity to make a difference without the side effects of a partial or full opioid agonist: “While naltrexone is as effective as buprenorphine once treatment begins, it is also significantly more difficult to actually start naltrexone because it requires an extensive detox period — which can span more than a week — that buprenorphine does not,” according to the online publication Vox, summarizing a 2017 study published in The Lancet [15].

However, accessibility to Vivitrol has come a long way since that 2017 study, the article points out: And given an equal playing field, so to speak, the merits of naltrexone give it equal footing with buprenorphine: “For naltrexone, the opioid relapse rate was about 52 percent. For buprenorphine, it was 56 percent. These were statistically similar, with no difference between men and women. Other measures, such as opioid-negative urine samples, opioid-abstinent days, and overdoses, did not differ between naltrexone and buprenorphine.”

However, even proponents of Vivitrol acknowledge that it’s not a silver bullet that can rid individuals of the beast of their addiction. Dr. Jason Jerry of the Cleveland Clinic’s Alcohol and Drug Recovery Center cautioned in 2016 [16] that there will be individuals on Vivitrol, like those on methadone and buprenorphine, who push the limits of the drug’s blockade effect by attempting to overwhelm it with massive doses of opioids: "The problem is the amount needed to get high is very close to the amount needed to kill them," he told Cleveland 19 News. In addition, he added, when individuals stop taking Vivitrol, “their tolerance level goes below baseline. They become much more exquisitely sensitive to the effects of the opiates,” meaning a relapse on much less than they were using before could still be enough to cause a fatal overdose.

However, as with most M.A.T. drugs, the additional component of wraparound behavioral health therapy is critical to avoid not just the potential of relapse, but to fully realize the benefits of addiction recovery under an M.A.T. umbrella.

“Naltrexone maintenance combined with psychosocial therapy is effective in reducing heroin use,” according to a paper published in March 2020 [17]. “Still, relapse rates are high if the patient receives no adjunct behavior therapy.”

Naltrexone: Pros

One of the most important pros of naltrexone — specifically Vivitrol — is that it is the only M.A.T. medication that works to counteract the potential for relapse. It’s one of the highlights of the prescribing information, according to the FDA [18] — “indicated for the prevention of relapse to opioid dependence, following opioid detoxification” — and that, says Nichole Pfohl — Director of Business Development for Cornerstone of Recovery and a former territory business manager for Alkermes, Vivitrol’s manufacturer — makes it a more attractive M.A.T. alternative.

“For any medication, if it’s FDA-approved, there’s a packet that comes with it that goes over warnings and things like that as well as indications — what it’s used for, and Vivitrol is the only FDA-approved medication that is indicated for relapse prevention,” Pfohl says. “So when people ask, ‘So, it’s like Suboxone?’ — no, it’s not. Suboxone is indicated for moderate to severe opioid use disorder, while Vivitrol is indicated for the prevention of opioid relapse post-detox. With Suboxone, you’re still on an opioid, so if I’m a caller or a family member, and I find out this is going to help my loved one not relapse? Sweet!”

That’s a claim backed by data: A 2016 study published by R.L. Wynn on the website Wolters Kluwer [19] “showed that extended-release naltrexone (Vivitrol) resulted in a lower rate of opioid relapse than the rate with usual treatment in a predominantly male and minority population of outpatient, voluntary participants with criminal justice involvement and opioid abstinence at baseline.” What’s more, Pfohl adds, Vivitrol works to reduce and, in some cases, eliminate the psychological cravings that often accompany recovery from opioid use — another indication that’s supported by science, according to experts with the Providers’ Clinical Support System on the American Society of Addiction Medicine’s website [20]: “What we do know is that craving goes substantially down in people that are on naltrexone, and that this craving reduction occurs pretty much from the beginning of treatment (first 2-3 weeks) and doesn’t seem to return after that. There are certainly people who continue to have cravings, but this is a rather small proportion and usually occurs only after coming off medication. Those who maintain treatment with naltrexone have no cravings, and some believe that combining naltrexone with personal recovery work in a 12-step based program is especially effective.”

And its effectiveness isn’t limited solely to opioids: In one randomized control trial of Vivitrol [21] utilizing a subset of patients who had abstained from alcohol for at least seven days, there were significant differences between the placebo group and the Vivitrol group. Both groups had an average of 15 heavy drinking days (defined as four or more drinks for a woman and 5 or more for a man) per month. Each group was assigned to every other week counseling for the next 6 months. At the conclusion, the placebo group managed to curtail their heavy drinking days from 15 a month to an average of 2.5 days per month, but only 19 percent were continuously abstinent for the entire six-month period. By contrast, the Vivitrol group had 40 percent total abstinence — double that of the placebo group — and had an average of only 1.2 heavy drinking days for the entire six-month period.

It’s important to point out, however, that the study, conducted in 2005, includes both Vivitrol and counseling. The addition of behavioral therapy as a wraparound service to M.A.T. is critical, and that personal recovery work is something that’s strongly encouraged through Cornerstone of Recovery’s Vivitrol program. Travis Pyle, Cornerstone’s Director of Medical Services, remembers well the drug’s introduction to the facility’s M.A.T. regime several years ago, because as an advocate of abstinence-based recovery, he greeted it with a great deal of skepticism, he admits.

“But after two years of being stubborn with my arms crossed, I noticed that the people who kept coming back all the time stopped coming back,” he says. “I saw them through the Vivitrol clinic, and I saw their lives change. Those who kept coming to get their Vivitrol shots stayed clean and sober. They didn’t have cravings. And even after they came off of Vivitrol after a year or 18 months, they just maintained their sobriety, and now I understand that part of it is that we’re blocking the effects of opioids, but we’re also knocking down the cravings.

naltrexone“And you’re not going to be addicted to it: When you stop it, you can just stop it, but the longer you stay on it, the better the chances you have of maintaining your sobriety. The sobriety, the interactions of recovery meetings, the accountability — Vivitrol allows you the time to do all of that, so it’s a combination that works, and works well.”

The combination of Vivitrol through a residential addiction and alcoholism treatment program like that offered at Cornerstone of Recovery is the ideal format for use of naltrexone as part of M.A.T. As Anna Lembke, a Stanford psychiatrist quoted in the Vox article [15] points out, the drug “a useful medication when people get on it, stay on it, and are motivated to abstain. The problem is that in the real world, which seldom resembles the clinical study world, patients are much less interested in this option.” In an strictly outpatient settings, naltrexone’s outcomes weren’t as good as those of buprenorphine, but that result, according to Cook, has more to do with the lack of behavioral health treatment around both forms of M.A.T. than it does with naltrexone itself.

“There’s no question that methadone and Suboxone decrease death, overdose, incarceration, suicide, and Hepatitis C and HIV transmissions, but the way that it’s done in 99 percent of the cases, in my opinion, is just harm reduction,” Cook says. “You’re coming off of opioids, and it’s like, ‘Let’s put you on this until you die,’ for the most part. It keeps you in contact with addicts in active addiction, because either you’re selling it, or they’re trying to buy it from you, and even if you aren’t, there’s always the temptation, because most of the Suboxone clinics are giving way too much. Patients are telling doctors, ‘I need a higher dose,’ and I think it’s mainly for diversion.

“There are no consequences for positive drug screens, no attempts to manage diversion, and everybody knows that 8 hours after you take Suboxone, give or take, you can use opioids and get high. I gave a Vivitrol talk at a local restaurant recently, and there was a Suboxone doctor there who literally said to me, ‘You can’t abuse Suboxone.’ That’s what he was told, and it’s what he believed, and on top of that, a lot of these doctors will prescribe Suboxone along with Xanax. I remember talking to one Suboxone doctor who was trying to curtail that, but he said that when he told patients he was not going to prescribe Xanax, they just started dropping out of the program for some reason.”

Vivitrol, on the other hand, has no diversion potential. It blocks opiate receptors in the brain from occupation by exogenous opioids like heroin. And because it’s an antagonist, it doesn’t activate those receptors like methadone and buprenorphine do.

“When I do presentations, I tell people to imagine M.A.T. as an umbrella with the handle down so that it sort of forms the letter T,” Pfohl says. “All M.A.T. is under the umbrella, but on the left side is methadone, in the middle is buprenorphine and on the right side is Vivitrol, which works very differently on the receptors. With methadone, they’re activated fully; with Suboxone, there’s partial activiation; but with Vivitrol, there’s no dopamine release at all.

“Now, the body can still produce and feel natural dopamine, like after a good meal or whatever, but with the injection, you’re blocked for 28 days. You get it once a month, which is easy to remember, and because it’s not a controlled substance, it can be managed by a health care professional who doesn’t have to have a special license. And on top of that, there’s no diversion, so there’s zero street value, so it can’t be taken and sold on the streets. Doctors don’t have to control a prescription, family members don’t have to worry about their loved ones getting addicted to it, and patients don’t have to worry about being tempted to sell half of it. It’s just a win-win all the way around.”

And, she added, it’s a medication covered by most commercial insurance policies, as well as Medicaid programs like TennCare, which provides state-administered health insurance for individuals who often seek treatment through Cornerstone’s sister facility, Stepping Stone to Recovery. At Stepping Stone and Cornerstone, Pyle says, Vivitrol is brought up during a patient’s admission process as a potential part of their continuum of care, but there’s always this caveat:

“We tell them what it can do, what it can’t do and that they can’t get addicted to it,” Pyle says. “We tell them how it can change their lives, but they have to work a program underneath of it. Vivitrol isn’t the answer, and it’s not the solution, but it can be a tool to help the recovery process.”

And it’s a tool, Pfohl adds, that is ideal for an abstinence-based recovery program like that offered by Cornerstone of Recovery, and for individuals who want to truly get clean from all mind- and mood-altering chemicals.

“Vivitrol is not in any way, shape or form a replacement of treatment and therapy,” she says. “It controls the physiological attachment to opioids and alcohol, but the psychological attachment is in the frontal lobe of the brain, and you can only address that through treatment and therapy. There’s no M.A.T. that is going to rewire the frontal lobe, because M.A.T. works in the limbic system of the brain, where it controls the physiological and not the psychological.

“But in getting the receptors in the brain clean and clear of all controlled substances, it allows the brain to heal, and at Cornerstone of Recovery, we believe it gives our patients the best chance. It’s not a quick fix, or a cure, but it is a medication and a tool that can be used in conjunction with therapy and programming to help those patients in long-term recovery.”