Naltrexone has very few and minor side effects. It is the treatment of choice in highly motivated patients, especially physicians, nurses, pharmacists and attorneys. However, clinical experience using naltrexone for treating opiate addiction has been replete with data on the poor medication compliance. There was reported a 6% retention for 60 days and 2% retention for 9 months in 276 methadone maintained patients who expressed some interest in trying naltrexone treatment.

Another study with 252 street heroin addicted patients treated with naltrexone had only 5% retention for 60 days and no retention for 9 months. The main reason given for this poor treatment retention and low patient compliance is that naltrexone's lack of agonist activity does not provide any drug reinforcement when taken and produces no negative consequences (withdrawal symptoms) when discontinued.

Some people have side effects like nausea, headache, constipation, dizziness, nervousness, insomnia, drowsiness, or anxiety. Up to 10% of people who take naltrexone have nausea, but most of the possible side effects don’t happen very often.