Naltrexone is one of the most studied and effective medications for alcohol use disorder, yet only a small fraction of people who could benefit from it ever receive a prescription. It works by blocking the brain’s opioid receptors, which dampens the pleasurable buzz that alcohol produces and, over time, reduces the urge to drink. Approved by the FDA since the mid-1990s for alcohol dependence, it comes in both a daily pill and a monthly injection. The evidence behind it is solid, but the story of naltrexone is as much about underuse and practical barriers as it is about pharmacology.
How Naltrexone Changes the Way Alcohol Feels
When you drink, your brain releases beta-endorphins from a region in the hypothalamus. Those endorphins act on the brain’s reward circuitry in two ways: they directly boost dopamine release at nerve terminals, and they suppress an inhibitory brake on dopamine-producing neurons, which further amplifies the dopamine signal. The net result is a rush of dopamine that makes drinking feel rewarding.1Psychopharmacology Institute. Pharmacotherapy of Alcohol Use Disorder Naltrexone sits on the opioid receptors that beta-endorphins normally activate and blocks them. With those receptors occupied, alcohol still affects you physically, but the reinforcing “high” is blunted. Over weeks and months, this weakens the learned association between drinking and pleasure, making cravings less intense and easier to resist.
This mechanism is why naltrexone does not make you feel sick if you drink (that is disulfiram’s job). Instead, it makes drinking feel less satisfying. Many people describe the experience as drinking feeling “pointless” or “flat.” That shift is subtle enough that some users wonder whether the medication is working at all, but the cumulative effect on drinking patterns tends to show up clearly in clinical data.
What the Evidence Shows About Effectiveness
Naltrexone is considered a first-line treatment alongside acamprosate for alcohol use disorder, though the two drugs suit different goals. Naltrexone is recommended for people aiming to cut down their drinking, while acamprosate is better suited for those who have already stopped and want to stay abstinent.2PubMed Central. Long-term drug treatment of patients with alcohol dependence In clinical trials, naltrexone consistently reduces heavy drinking days, the number of drinks per session, and relapse rates compared to placebo.
A recent randomized trial of hospitalized patients with alcohol use disorder found that both oral and injectable naltrexone sharply reduced heavy drinking days over three months. The oral group went from about 67% heavy drinking days at baseline down to roughly 27%, while the injectable group dropped from about 71% to around 24%.3JAMA Internal Medicine. Oral vs Extended-Release Injectable Naltrexone for Hospitalized Patients With Alcohol Use Disorder: A Randomized Clinical Trial The injectable form produced a somewhat larger reduction, but the difference between the two formulations did not reach statistical significance. In other words, both routes of delivery helped substantially; neither was proven clearly superior in that trial.
Naltrexone also works when combined with brief counseling for younger heavy drinkers. A pilot study offering eight weeks of daily or as-needed naltrexone alongside motivational counseling found significant drops in drinks per drinking day and heavy drinking days, with those gains holding up a month after treatment ended.4PubMed Central. A pilot study of naltrexone and BASICS for heavy drinking young adults
Oral Pill Versus Monthly Injection
Naltrexone comes in two forms: a 50 mg daily oral tablet and a 380 mg extended-release intramuscular injection given once a month. The pill is inexpensive and easy to prescribe, but adherence is a persistent problem. A study of veterans found that the median time to relapse was about 50 days for those on oral naltrexone, compared with roughly 150 days for those on the injectable form.5PubMed Central. Treatment outcomes of long-acting injectable naltrexone versus oral naltrexone in alcohol use disorder in veterans That threefold difference is striking and almost certainly driven by the fact that you cannot forget or skip a monthly injection the way you can skip a daily pill.
Among hospitalized patients followed for three months, those on injectable naltrexone had nearly four times the odds of staying adherent compared to those on the oral form.6PubMed Central. Correlates of post-hospitalization naltrexone adherence for alcohol use disorder The injection removes the daily decision point entirely, which matters because the moments when a person is most tempted to drink are exactly the moments they are least likely to take a pill that would make drinking unrewarding.
The downside of the injection is cost. The branded injectable form is substantially more expensive than generic oral naltrexone, and insurance coverage varies. In the Veterans Health Administration, a large national study found that only about 3% of patients with alcohol use disorder received any form of naltrexone, and of those, just 7.5% received the injectable version.7PubMed. Long-acting injectable depot naltrexone use in the Veterans’ Health Administration: a national study
Why So Few People Get Prescribed It
Naltrexone’s biggest problem is not its effectiveness but its reach. A survey of addiction medicine physicians found that, on average, they prescribed naltrexone to only about 13% of their patients with alcohol dependence. The two most common reasons were that patients refused to take it or could not stick with the regimen (23% of physicians cited this) and that patients could not afford it (21%).8PubMed. Understanding US addiction physicians’ low rate of naltrexone prescription Physicians who had read more research on naltrexone were more likely to prescribe it, suggesting that part of the gap is simply awareness and confidence in the medication among clinicians.
There is also a cultural mismatch at play. For decades, the dominant treatment model for alcohol problems has been abstinence-based counseling and mutual-aid groups. The idea of taking a medication to manage drinking, rather than quitting outright through willpower and support, still feels foreign to many patients and providers alike. Naltrexone does not require abstinence to work. Some people take it daily whether or not they plan to drink; others use a “targeted” approach, taking it a couple of hours before they expect to be in a drinking situation. Both strategies have evidence behind them, but neither fits neatly into the abstinence-first framework that many treatment programs still emphasize.
The Adherence Problem and What Helps
Even among people who start naltrexone, staying on it is hard. By three months, only about half of patients remain adherent.9PubMed Central. Correlates of post-hospitalization naltrexone adherence for alcohol use disorder Adherence tends to slip on weekends, when drinking and cravings spike, and on days following heavier-than-usual drinking. One study tracking daily pill-taking found that weekend days were associated with about 29% lower odds of adherence compared to weekdays, partly because people drank more and craved more on those days.10PubMed Central. Predictors of Daily Adherence to Naltrexone for Alcohol Use Disorder Treatment During a Mobile Health Intervention
Factors associated with better adherence include older age, having a recent follow-up visit with a provider, and being on the injectable form. Factors linked to worse adherence include unstable housing and concurrent cocaine use.11PubMed Central. Correlates of post-hospitalization naltrexone adherence for alcohol use disorder The practical takeaway is that regular check-ins with a clinician matter a lot. Simply showing up for an office visit roughly doubled the odds of staying on track. Mobile health tools also seem to help: on days when patients completed a brief daily assessment on their phone, they were more than twice as likely to take their medication as on days they did not.12PubMed Central. Predictors of Daily Adherence to Naltrexone for Alcohol Use Disorder Treatment During a Mobile Health Intervention
Combining Naltrexone with Therapy
Naltrexone works better when paired with some form of counseling or behavioral therapy, and the combination may be genuinely synergistic rather than merely additive. A placebo-controlled trial found that naltrexone increased patients’ control over alcohol urges and improved their ability to resist thoughts about drinking, effects that dovetailed with the skills taught in cognitive behavioral therapy.13PubMed. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial The medication takes the edge off the craving; the therapy gives you tools to handle what remains.
Researchers have also explored combining naltrexone with other medications, including gabapentin, acamprosate, ondansetron, and various antidepressants. A systematic review of these two-drug combinations found that the effect sizes were generally comparable to single-drug trials, with no clear winner among the combinations. The review was limited by small trial sizes and inconsistent outcome measures.14PubMed. Systematic Review of Combined Pharmacotherapy for the Treatment of Alcohol Use Disorder in Patients Without Comorbid Conditions For now, the strongest pairing remains naltrexone plus some form of behavioral support, not naltrexone plus another pill.
Is It Safe for Your Liver?
This is probably the most common concern people have about naltrexone, and it is largely outdated. Early labeling included a black box warning about liver toxicity based on studies using much higher doses than what is prescribed for alcohol use disorder. That warning has caused decades of hesitation, particularly since heavy drinkers often already have liver problems.
Recent evidence is reassuring. A large study of nearly 3,000 patients on naltrexone found that only about 2% showed significant liver enzyme elevations. When those cases were evaluated using a standardized scoring system for drug-induced liver injury, none scored as “possible,” “probable,” or “highly probable.” About half were scored as “DILI excluded” and the other half as “DILI unlikely.”15JHEP Reports. Safety of naltrexone in patients with cirrhosis In other words, the enzyme bumps that occurred were almost certainly caused by something other than the medication.
Even in patients with existing liver disease, including compensated cirrhosis, naltrexone appears safe. A separate study found that liver enzyme levels actually dropped after patients started naltrexone, likely because they were drinking less.16PubMed Central. Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease The net effect on the liver is positive: whatever tiny hepatic risk the drug itself carries is far outweighed by the liver damage prevented by reducing alcohol intake.
The Pain Management Complication
Because naltrexone blocks opioid receptors, it creates a real problem if you need opioid pain relief, particularly in an emergency or after surgery. Standard doses of opioid painkillers will be less effective or completely blocked while naltrexone is in your system. The oral form clears within a few days, but the injectable version occupies receptors for a month. Multiple studies have confirmed that naltrexone can significantly increase the amount of opioids required to achieve adequate pain control after surgery.17PubMed. Treatment of Acute Pain in Patients on Naltrexone: A Narrative Review
This does not mean pain cannot be managed. Non-opioid options like regional nerve blocks, ketamine, lidocaine, and medications such as duloxetine can all be used. The key is that you need to tell every healthcare provider, especially emergency room staff, that you are on naltrexone. Wearing a medical alert bracelet is worth considering if you are on the injectable form, since you cannot simply stop taking it the way you can with the pill.
Genetics and Who Responds Best
Not everyone responds equally to naltrexone, and researchers have spent years trying to figure out why. The most studied genetic factor is a variation in the mu-opioid receptor gene called OPRM1. Specifically, a variant known as Asp40 (the G allele of the A118G polymorphism) has been linked to stronger naltrexone response. A meta-analysis found that naltrexone-treated patients carrying this variant had about twice the odds of avoiding relapse compared to those without it.18PubMed. Association of µ-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis A study in Korean patients found a similar pattern: those with the Asp40 variant took significantly longer to relapse when on naltrexone.19PubMed. A micro opioid receptor gene polymorphism (A118G) and naltrexone treatment response in adherent Korean alcohol-dependent patients
The picture is not settled, however. A later meta-analysis that looked more carefully across multiple drinking outcomes found that the moderating effect of this gene variant was only nominally significant for one outcome (drinks per day) and did not hold up after correcting for multiple comparisons.20PubMed Central. Systematic review and meta-analysis of the moderating effect of rs1799971 in OPRM1, the mu-opioid receptor gene, on response to naltrexone treatment of alcohol use disorder So while the OPRM1 variant likely plays some role, it is not yet reliable enough to serve as a clinical decision tool. Genetic testing for this variant is available but not standard practice. The practical implication for most people is straightforward: try naltrexone and see if it works for you, regardless of your genotype.
Alcohol Use Disorder with PTSD
People with both alcohol use disorder and post-traumatic stress disorder represent a particularly challenging treatment population. Drinking often serves as self-medication for PTSD symptoms, and treating one condition without addressing the other tends to yield disappointing results. Medications targeting the opioid, noradrenergic, and serotonergic systems have shown only modest effects in people with both conditions.21PubMed Central. Pharmacotherapy for Co-Occurring Alcohol Use Disorder and Post-Traumatic Stress Disorder
That said, naltrexone does appear to help in this population. A trial of patients with both PTSD and alcohol dependence found that those on active medication (naltrexone, disulfiram, or the combination) had better alcohol outcomes than those on placebo, and overall PTSD symptoms also improved.22PubMed. Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder When naltrexone was combined with prolonged exposure therapy, a well-established PTSD treatment, drinking outcomes at follow-up were better than with naltrexone and supportive counseling alone.23PubMed. Treatment of alcohol use disorder and co-occurring PTSD The takeaway is that naltrexone can be part of a dual-diagnosis treatment plan, but the therapy component matters even more in this group.
Pregnancy and Breastfeeding
Data on naltrexone use during pregnancy is thin, which keeps it in a gray area clinically. A case series of pregnant individuals treated with naltrexone for opioid or alcohol use disorder reported no fetal anomalies and one preterm delivery. None of the infants developed neonatal withdrawal. Side effects were limited to those on the injectable form, including nausea, fatigue, and gastrointestinal symptoms.24PubMed Central. Case series of individuals treated with naltrexone during pregnancy for opioid and/or alcohol use disorder While these early results are encouraging, animal studies using chronic naltrexone exposure during pregnancy have shown developmental changes in offspring, which means the safety question is not fully resolved.25PubMed Central. The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data
For breastfeeding, the available data comes from very small studies. In one case, the total amount of naltrexone and its metabolite transferred into breast milk was estimated at about 1% of the mother’s weight-adjusted dose, and the breastfed infant showed no adverse effects and met developmental milestones normally.26PubMed. Transfer of naltrexone and its metabolite 6,beta-naltrexol into human milk Any decision about naltrexone during pregnancy or breastfeeding requires a careful weighing of individual risks, including the very real risks of untreated alcohol use disorder during these periods.
Cost-Effectiveness
Even from a purely economic standpoint, naltrexone looks like a good deal. A modeling study found that naltrexone plus counseling, compared with counseling alone, cost less than $20,000 per quality-adjusted life year gained, well below standard thresholds for cost-effective medical interventions.27PubMed Central. Economic evaluations of alcohol pharmacotherapy For patients with alcohol-related cirrhosis specifically, both naltrexone and acamprosate were found to be not just cost-effective but actually cost-saving compared to no treatment: they produced better health outcomes while costing the healthcare system less.28PubMed Central. Cost-effectiveness of alcohol use treatments in patients with alcohol-related cirrhosis
A pilot study targeting high users of public services, people cycling through emergency departments and shelters, found that extended-release naltrexone reduced both urge-to-drink scores and emergency medical costs. Though the sample was small, total costs during the treatment period were lower than in the period before enrollment.29PubMed. Low-threshold extended-release naltrexone for high utilizers of public services with severe alcohol use disorder: A pilot study Generic oral naltrexone itself costs very little, often under a dollar per day. The injectable form is where the sticker shock hits, though for people who cannot maintain daily pill-taking, the cost may be justified by the dramatically better adherence rates.
Off-Label Uses Beyond Alcohol
Naltrexone’s mechanism of dampening reward pathways has led researchers to test it against other compulsive behaviors. In gambling disorder, a UK case series found that patients on naltrexone showed significant decreases in their craving to gamble, with 60% able to abstain completely during treatment and another 20% reducing gambling to near zero.30PubMed Central. The use of naltrexone in pathological and problem gambling: A UK case series These results are preliminary, case series level rather than randomized trials, but they fit logically with what naltrexone does to the brain’s reward circuitry. If the drug can make alcohol feel less rewarding, it makes sense that it could do the same for the dopamine rush of a winning bet. Research into naltrexone for behavioral addictions remains active, though no regulatory approvals for these uses exist yet.