Side Effects of Naltrexone
Nausea is the most common side effect of naltrexone, occurring frequently enough that it led to treatment discontinuation in approximately 5% of patients in controlled trials, and should be anticipated when initiating therapy. 1
Common Side Effects (Occurring in >2% of Patients)
The FDA-approved labeling identifies the following adverse reactions that occurred in 2% or more of patients treated with naltrexone for alcohol dependence 1:
- Nausea (10%) - the most frequently reported side effect 1
- Headache (7%) 1
- Dizziness (4%) 1
- Nervousness (4%) 1
- Fatigue (4%) 1
- Insomnia (3%) 1
- Vomiting (3%) 1
- Anxiety (2%) 1
- Somnolence (2%) 1
For patients being treated for opioid addiction, additional common symptoms (>10% incidence) include difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint and muscle pain, and headache 1.
Gastrointestinal Side Effects
Constipation is a significant side effect that warrants particular attention, especially in patients with liver disease who are at increased risk of hepatic encephalopathy. 2, 3 The American Diabetes Association guidelines note that constipation is a common side effect of the naltrexone/bupropion combination product 2. For patients with cirrhosis receiving opioids for pain, naltrexone may be useful as part of a purging program to limit opioid-induced constipation 2.
Other gastrointestinal effects occurring in less than 10% of patients include loss of appetite, diarrhea, increased thirst, and abdominal pain 1.
Hepatotoxicity - Critical Safety Concern
Naltrexone causes dose-dependent hepatocellular injury, particularly at doses above 50 mg daily, which is the most serious safety concern with this medication. 1 The FDA labeling explicitly warns that placebo-controlled studies using doses up to 300 mg per day (five-fold higher than recommended) showed that naltrexone causes hepatocellular injury in a substantial proportion of patients 1.
Liver function tests must be obtained at baseline and monitored every 3-6 months during treatment. 3, 4 The American Academy of Family Physicians recommends this monitoring schedule for all patients on naltrexone therapy 3.
Naltrexone is contraindicated in patients with acute hepatitis or decompensated cirrhosis and is not recommended for patients with alcoholic liver disease due to hepatotoxicity risk. 3, 5 For patients with alcohol-induced liver disease requiring medication to maintain abstinence, baclofen or acamprosate should be considered as safer alternatives 3, 5.
Cardiovascular Effects
When naltrexone is combined with bupropion (as in the weight loss medication), the following cardiovascular effects occur 2, 3:
- Elevated heart rate 2, 3
- Increased blood pressure 2, 3
- Contraindicated in patients with unmanaged hypertension 2, 3
The American Diabetes Association guidelines specifically note that the naltrexone/bupropion combination should be avoided in patients with uncontrolled hypertension 2.
Psychiatric and Neurological Effects
Depression and suicidal ideation have been reported in patients treated with naltrexone, though no causal relationship has been established. 1 The FDA labeling notes that depression, suicidal ideation, and suicide attempts occurred at rates of 0-15%, 0-17%, and 0-1% to 0-3% respectively when comparing naltrexone to placebo in alcoholism treatment trials 1.
For the naltrexone/bupropion combination, there is a black box warning for increased risk of suicidal behavior and ideation in people younger than 24 years old who have depression. 2, 3
Additional neuropsychiatric effects include 1:
- Irritability
- Feeling down
- Altered level of consciousness (38.6% in withdrawal scenarios) 6
- Cognitive impairment (with naltrexone/bupropion combination) 2
Withdrawal-Related Side Effects
In opioid-dependent patients who are not completely opioid-free, naltrexone precipitates severe hyperacute withdrawal syndrome that can be life-threatening. 1, 6 A study of 132 patients who used naltrexone while opioid-dependent found 6:
- Agitation (96.2%) - the most prominent and difficult symptom to manage 6
- Altered level of consciousness (38.6%) 6
- Nausea (28%) 6
- Vomiting (27.3%) 6
- Abdominal pain (24.2%) 6
- Diarrhea (16.7%) 6
- Bone and muscle pain (15.9%) 6
- Tachycardia (12.9%) 6
- Dilated pupils (11.4%) 6
Patients must be completely opioid-free for a minimum of 7-10 days before starting naltrexone, and those transitioning from buprenorphine or methadone may require up to 2 weeks to avoid precipitated withdrawal. 1
Less Common Side Effects (<10% Incidence)
The FDA labeling documents additional side effects occurring in less than 10% of patients 1:
Respiratory: Nasal congestion, itching, rhinorrhea, sneezing, sore throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness, cough, shortness of breath 1
Cardiovascular: Nose bleeds, phlebitis, edema, increased blood pressure, non-specific ECG changes, palpitations, tachycardia 1
Sexual dysfunction: Delayed ejaculation, decreased potency 1
Other: Skin rash, chills, dizziness 1
Special Considerations for Combination Products
When naltrexone is combined with bupropion for weight management, additional safety concerns include 2, 3:
- Contraindicated in patients with seizure disorders 2, 3
- Acute angle-closure glaucoma 2, 3
- Birth defects - contraindicated in pregnancy 2
- Contraindicated with chronic opioid therapy 2
- Contraindicated with monoamine oxidase inhibitors 2, 3
Drug Interactions and Pain Management Concerns
Naltrexone blocks the effects of all opioid medications, including those used for pain, cough suppression, and diarrhea control. 1 Patients on naltrexone will not benefit from opioid-containing medicines 1. In emergency situations requiring opioid analgesia, greater than usual doses may be needed, and resulting respiratory depression may be deeper and more prolonged 1.
For patients on oral naltrexone requiring elective surgery, the medication should be held for 2-3 days prior to the procedure; for extended-release injectable naltrexone, it should be held for 24-30 days after the last injection. 4
Risk of Overdose After Discontinuation
Patients who discontinue naltrexone have increased risk of opioid overdose and death due to decreased opioid tolerance. 4, 1 The FDA labeling emphasizes that patients who previously used opioids may be more sensitive to lower doses after naltrexone treatment is discontinued or temporarily interrupted 1.
Clinical Monitoring Recommendations
To minimize side effects and ensure safety 3, 4, 1:
- Obtain baseline liver function tests and monitor every 3-6 months 3, 4
- Screen for depression, anxiety, and insomnia before initiating treatment 4
- Ensure patients are completely opioid-free before starting therapy 1
- Perform naloxone challenge test if occult opioid dependence is suspected 1
- Educate patients and families about increased overdose risk after discontinuation 1
- Combine with comprehensive psychosocial treatment for optimal outcomes 3, 5, 4