Most naltrexone side effects are mild and last a few days to a few weeks as your body adjusts to the medication. Nausea, the most common complaint, typically hits early in treatment and fades as you continue taking it. How long side effects stick around depends on whether you’re taking the daily oral tablet or the monthly injection, and how your prescriber managed your starting dose.
The Most Common Side Effects
Nausea and vomiting top the list. After that, the most frequently reported problems include headaches, stomach pain or discomfort, fatigue, low energy, decreased appetite, trouble sleeping, and anxiety or low mood. Some people also notice small increases in blood pressure, irritability, or skin rashes. These tend to cluster in the first days of treatment, especially the stomach-related ones.
The intensity varies quite a bit from person to person. Women and younger patients appear more susceptible to nausea in particular, and people who haven’t been abstinent from alcohol for long before starting may also have a rougher initial experience.
Timeline for Oral Naltrexone
With the daily 50 mg tablet, side effects are generally temporary and resolve within a few days to a few weeks. Your body processes naltrexone relatively quickly. The drug itself has a half-life of about 4 hours, though its main breakdown product sticks around longer, with a half-life of roughly 12 hours. That means within a day or two of your last dose, the drug is essentially cleared from your system.
In practice, the pattern looks like this: the first few days are the worst for nausea and stomach discomfort. By the end of the first week, most people notice a significant improvement. Headaches and fatigue may linger a bit longer but usually settle within two to three weeks. Sleep disturbances can be among the last to resolve, sometimes stretching into the third or fourth week before normalizing.
If side effects become genuinely intolerable, stopping the oral tablet means they’ll clear within a couple of days because of that short half-life. This is one advantage of the oral form: you and your prescriber have daily control over whether to continue.
Timeline for the Monthly Injection
The injectable form (sold as Vivitrol) has a fundamentally different timeline. After the shot, naltrexone levels peak within a few hours, then peak again two to three days later. From about day seven onward, levels slowly decline over the remaining weeks. The drug maintains a therapeutic blood level for a full month.
This means that if side effects occur, they can potentially last up to 30 days, because there’s no way to remove the medication once it’s been injected. Nausea, fatigue, and headaches follow a similar pattern to oral naltrexone for most people, peaking in the first week and gradually improving. But you don’t have the option of simply stopping the medication if problems arise.
Injection site reactions are unique to this form. Pain, hardness, or tenderness at the injection site are common and can last days to weeks. In rare cases, a severe reaction at the site may develop, requiring medical attention. The overall side effect profile is otherwise similar to the oral tablet.
Why Starting Dose Matters
One of the most effective ways to shorten and reduce side effects is to start at a lower dose. Rather than jumping straight to the standard 50 mg daily tablet, many prescribers begin patients at 12.5 mg (a quarter tablet) or 25 mg (a half tablet) for the first one to two weeks, then gradually increase. Taking the medication with food also helps reduce nausea.
This gradual approach gives your body time to adjust, and clinical guidelines specifically recommend it for patients at higher risk of adverse effects. If you’re experiencing rough side effects and you started at the full dose, it’s worth asking your prescriber about temporarily stepping down.
Liver-Related Concerns
Naltrexone once carried an FDA black box warning about potential liver damage, but that warning was removed in 2013 due to lack of supporting evidence. The concern originally came from studies using very high doses, between 100 and 300 mg per day, well above the standard 50 mg. At standard doses, clinically meaningful liver problems are rare.
In a large review of patients taking naltrexone, only 2% showed elevated liver enzymes, and none of those cases were classified as probable or even possible drug-induced liver injury. The injectable form exposes the liver to substantially less naltrexone overall (380 mg per month versus roughly 1,500 mg per month with daily oral dosing), since it bypasses the digestive system entirely.
Signs of liver trouble include unusual fatigue, yellowing of the skin or eyes, dark urine, or persistent upper abdominal pain. These are distinct from the ordinary stomach discomfort that comes and goes in the first week or two. If they appear, they warrant prompt attention.
What to Expect Week by Week
Here’s a rough timeline for the oral tablet at standard dosing:
- Days 1 to 3: Nausea and stomach discomfort are at their peak. Headache, fatigue, and reduced appetite are common. These are the days most people find hardest.
- Days 4 to 7: Gastrointestinal symptoms begin to ease noticeably. Energy levels may still feel low.
- Weeks 2 to 3: Most side effects have resolved or become very mild. Sleep quality improves. Some residual fatigue or mood changes may linger.
- Week 4 and beyond: The medication is generally well tolerated at this point, with mild stomach upset and occasional sleep disturbance being the main lingering complaints for a small number of people.
For the injection, stretch each phase by roughly a week, and expect the overall adjustment period to align with the 30-day cycle. Most people find that the second monthly injection is noticeably easier than the first.