What are the side effects of Naltrexone?

Naltrexone Side Effects

Naltrexone's most common side effects include nausea (10%), headache (7%), dizziness (4%), nervousness (4%), and fatigue (4%), with the most serious concern being dose-dependent hepatotoxicity at doses above 50 mg daily. 1, 2

Most Common Side Effects (Occurring in ≥2% of Patients)

When used at standard doses (50 mg daily for alcohol/opioid dependence or 16 mg twice daily in combination with bupropion for weight loss), the following side effects are most frequently reported:

Gastrointestinal Effects

• Nausea (10%) - the most common side effect and most frequent reason for discontinuation 1, 3
• Vomiting (3%) 1
• Abdominal pain/cramps (2-24%) 1, 2
• Constipation (when combined with bupropion) 1
• Diarrhea 2

Neurological/Psychiatric Effects

• Headache (7%) 1, 3
• Dizziness (4%) 1
• Nervousness/anxiety (4%) 1
• Insomnia (3%) 1
• Somnolence (2%) 1

General Effects

• Fatigue/low energy (4%) 1
• Joint and muscle pain 2

Serious Safety Concerns

Hepatotoxicity (Most Critical)

At doses of 300 mg daily (5-fold higher than standard), 19% of patients developed significant liver enzyme elevations (ALT 3-19 times baseline), though this was not observed at the standard 50 mg dose. 2

• Patients should have baseline and periodic liver function tests, particularly those with alcohol-related liver disease 4
• Patients should be warned to seek medical attention if symptoms of hepatitis develop 4
• At standard 50 mg doses, hepatotoxicity has not emerged as a clinical problem 5

Precipitated Opioid Withdrawal (Critical in Opioid Users)

Naltrexone can precipitate severe, acute withdrawal in patients not completely free of opioids, with agitation being the most prominent and difficult symptom to manage (occurring in 96% of cases). 2, 6

• Other withdrawal symptoms include altered consciousness (39%), nausea (28%), vomiting (27%), abdominal pain (24%), diarrhea (17%), bone/muscle pain (16%), tachycardia (13%), and dilated pupils (11%) 6
• Patients must be opioid-free for 7-10 days before initiating naltrexone 2
• Patients should carry identification indicating they cannot receive opioid pain medications 4

Psychiatric Effects

• Depression, suicidal ideation, and suicide attempts have been reported in 0-15% of patients (similar to placebo rates of 0-17%) 2
• When combined with bupropion, there is a black box warning for suicidal behavior/ideation in patients younger than 24 years 1, 7
• Close monitoring for mood changes is essential, particularly during treatment initiation 7

Side Effects Specific to Naltrexone/Bupropion Combination

When used as the combination product for weight loss:

Additional Common Effects

• Dry mouth (xerostomia) 1
• Elevated heart rate and blood pressure 1
• Paresthesia 1

Specific Contraindications and Warnings

• Seizure risk: Bupropion lowers seizure threshold; contraindicated in patients with seizure disorders, eating disorders (anorexia/bulimia), or abrupt discontinuation of alcohol/benzodiazepines 1, 7
• Contraindicated with uncontrolled hypertension 1
• Contraindicated with chronic opioid therapy 1
• Contraindicated with MAOIs or within 14 days of MAOI discontinuation 7

Less Common Side Effects (<10% Incidence)

Cardiovascular

• Nosebleeds, phlebitis, edema, increased blood pressure, palpitations, tachycardia 2

Respiratory

• Nasal congestion, rhinorrhea, sneezing, sore throat, cough 2

Genitourinary

• Delayed ejaculation, decreased potency 2
• Increased urinary frequency or discomfort 2

Dermatologic

• Skin rash, oily skin, pruritus, acne 2

Special Senses

• Blurred vision, burning eyes, light sensitivity, tinnitus 2

Opioid Withdrawal-Like Syndrome in Opioid-Free Patients

A small fraction of opioid-free patients may experience a withdrawal-like symptom complex including tearfulness, mild nausea, abdominal cramps, restlessness, bone/joint pain, myalgia, and nasal symptoms. 2

• This may represent unmasking of occult opioid use or symptoms attributable to naltrexone itself 2
• The principal symptoms reported in non-dependent volunteers include loss of energy, gastrointestinal disturbances, and mental depression 8

Important Clinical Considerations

Discontinuation Rates

• Naltrexone is discontinued in approximately 15% of patients due to adverse events, most frequently nausea 3

Alcohol Interaction

• Naltrexone does not cause unpleasant reactions when combined with alcohol (unlike disulfiram) and does not prevent intoxication 4

Pregnancy and Nursing

• All naltrexone formulations are contraindicated in individuals who are pregnant, actively trying to conceive, or nursing 1

Monitoring Requirements

• Baseline and periodic liver function tests 4
• Blood pressure monitoring, especially in first 8 weeks when combined with bupropion 7
• Psychiatric symptom surveillance at each visit 7