What are the side effects of naltrexone?

Naltrexone Side Effects

Naltrexone is generally well-tolerated with predominantly gastrointestinal and neuropsychiatric side effects, though the risk of dose-dependent hepatotoxicity at higher doses requires monitoring.

Common Side Effects

Gastrointestinal Effects

• Nausea is the most frequent side effect, occurring in approximately 10% of patients with alcoholism and representing the most common reason for discontinuation 1
• Vomiting occurs in 3% of patients 1
• Abdominal pain/cramps are reported in >10% of patients with opioid addiction 1
• Other GI effects include diarrhea, constipation, and excessive gas 1

Neuropsychiatric Effects

• Headache occurs in 7% of patients 1
• Insomnia affects 3% of patients, which can be minimized by avoiding late-day dosing when used in combination formulations 2
• Dizziness (4%), nervousness (4%), and anxiety (2%) are commonly reported 1
• Difficulty sleeping, anxiety, and nervousness occur in >10% of patients with opioid addiction 1
• Depression and suicidal ideation have been reported, though rates are similar between naltrexone (0-15% for depression, 0-1% for suicide attempts) and placebo (0-17% for depression, 0-3% for suicide attempts), suggesting no causal relationship 2, 1

Other Common Effects

• Fatigue and low energy occur in 4% and >10% of patients, respectively 1
• Joint and muscle pain are reported in >10% of patients with opioid addiction 1
• Somnolence affects 2% of patients 1

Serious Safety Concerns

Hepatotoxicity

• At doses up to 300 mg/day (5-fold higher than standard dosing), naltrexone causes hepatocellular injury in a substantial proportion of patients 1
• At the standard 50 mg dose for alcohol/opioid dependence, hepatotoxicity has not emerged as a clinical problem 1
• In one study, 19% of patients receiving 300 mg/day developed transaminase elevations (3-19 times baseline), though patients were generally asymptomatic and values returned to baseline after discontinuation 1

Opioid Withdrawal Precipitation

• Naltrexone can precipitate or exacerbate severe withdrawal symptoms in individuals not completely free of exogenous opioids 1
• This represents a critical safety concern requiring complete opioid detoxification before initiation 1
• The medication should be discontinued before procedures requiring opioid analgesia (e.g., endoscopies using fentanyl) 2

Cardiovascular Effects

• Blood pressure monitoring is required, particularly in the first 12 weeks of treatment 2
• Modest increases in systolic and diastolic blood pressure have been observed, most prominently in the first 8 weeks 2
• The medication should be avoided in patients with uncontrolled hypertension 2
• Less common effects include palpitations, tachycardia, edema, and non-specific ECG changes 1

Contraindications and Special Populations

Absolute Contraindications

• Patients requiring short-term or long-term opioid therapy should not use naltrexone, as it reduces analgesic efficacy and can precipitate withdrawal 2
• Patients with epilepsy or seizure disorders should avoid naltrexone-bupropion combinations due to lowered seizure threshold 2
• Use within 14 days of monoamine oxidase inhibitors is contraindicated 2

Dose Adjustments Required

• In moderate to severe renal impairment, reduce the total daily dose by one-half 2
• Avoid in end-stage renal disease 2
• In moderate to severe hepatic impairment, do not exceed 1 tablet daily (when using combination formulations) 2

Less Common Side Effects (<10%)

Respiratory

• Nasal congestion, rhinorrhea, sneezing, sore throat, cough, and shortness of breath 1

Dermatologic

• Skin rash, oily skin, pruritus, acne 1

Genitourinary

• Delayed ejaculation, decreased potency, altered urination frequency 1

Other

• Weight changes, chills, tremors, twitching, vision abnormalities 1

Postmarketing Experience

Additional adverse events reported after market approval include anorexia, asthenia, chest pain, hot flushes, malaise, agitation, hyperkinesia, confusion, euphoria, hallucinations, abnormal thinking, dyspnea, increased sweating, and idiopathic thrombocytopenic purpura 1

Discontinuation Rates

• In large safety studies, 15% of patients discontinued naltrexone due to adverse events, most frequently nausea 3
• In combination formulations (naltrexone-bupropion), discontinuation rates due to adverse events ranged from 4.6-9.6% for nausea, 0.7-2% for vomiting, and 0.9-1.8% for headache 2

Clinical Pearls

• Most adverse events occur early in therapy and are transient 1
• Gradual dose titration can help minimize side effects, particularly with combination formulations 2
• The overall safety profile is favorable at standard doses, with serious adverse events being uncommon 3
• No new safety concerns were identified in the largest safety study of 865 patients with heterogeneous presentations including comorbid medical and psychiatric illness 3