What is the recommended protocol for initiating low‑dose naltrexone (LDN), including starting dose, weekly titration, contraindications (active severe liver disease, opioid use, pregnancy, breastfeeding), baseline liver function tests (alanine aminotransferase, aspartate aminotransferase, bilirubin) and renal function assessment, monitoring schedule, and patient counseling on empty‑stomach administration and alcohol avoidance?

Initiating Low-Dose Naltrexone: Evidence-Based Protocol

Starting Dose and Titration Schedule

Begin low-dose naltrexone at 1–1.5 mg taken once daily at bedtime, then increase by 0.5–1 mg every 3–7 days until reaching a target maintenance dose of 3–4.5 mg daily. 1 This gradual titration minimizes initial side effects while allowing the body to adapt to transient opioid-receptor blockade.

• Start with 1 mg at bedtime for the first 3–7 days 1
• Increase to 2 mg at bedtime for the next 3–7 days 1
• Advance to 3 mg at bedtime for the next 3–7 days 1
• Reach the target dose of 3–4.5 mg at bedtime by week 2–3 1
• The typical therapeutic range for low-dose naltrexone is 1–5 mg daily, substantially lower than the standard 50 mg dose used for opioid or alcohol dependence 1, 2

Absolute Contraindications

Do not prescribe low-dose naltrexone to patients currently using opioid medications, as naltrexone will precipitate severe opioid withdrawal regardless of dose. 3 This includes prescription opioids, methadone, buprenorphine, tramadol, and illicit opioids.

• Active opioid use of any kind (prescription or illicit) 3
• Acute hepatitis or decompensated cirrhosis 4, 5
• Pregnancy and breastfeeding due to insufficient safety data 3
• Patients must be completely opioid-free for at least 7–10 days before starting naltrexone to avoid precipitated withdrawal 3

Baseline Laboratory Assessment

Obtain baseline liver function tests (ALT, AST, total bilirubin) and serum creatinine before initiating low-dose naltrexone, even though hepatotoxicity occurs only at supratherapeutic doses well above the low-dose range. 3, 6

• Measure alanine aminotransferase (ALT) 3
• Measure aspartate aminotransferase (AST) 3
• Measure total bilirubin 3
• Assess serum creatinine or estimated glomerular filtration rate (eGFR) 3
• Document any history of liver disease, including alcoholic liver disease, viral hepatitis, or cirrhosis 5

Monitoring Schedule

Repeat liver function tests every 3–6 months during the first year of treatment, then annually if stable. 3 However, hepatotoxicity with naltrexone has been documented only at doses of 300 mg/day or higher—far exceeding the 1–5 mg range used in low-dose protocols. 6, 7

• Month 3: Repeat ALT, AST, bilirubin 3
• Month 6: Repeat ALT, AST, bilirubin 3
• Month 12 and annually thereafter: Repeat liver panel if continuing therapy 3
• Studies of naltrexone at doses up to 300 mg/day for 36 months showed no significant hepatotoxicity in most patients 6
• At the standard 50 mg dose for alcohol dependence, naltrexone does not cause liver injury 3

Special Populations: Liver Disease

Naltrexone is safe in patients with compensated cirrhosis and non-cirrhotic liver disease when used at standard doses (50 mg), and low-dose naltrexone (1–5 mg) carries even lower risk. 5 A 2022 study of 160 patients with alcohol use disorder—including 47 with cirrhosis—found that liver enzymes actually decreased after naltrexone initiation, with 2-year survival of 90.8% in the cirrhosis group. 5

• Compensated cirrhosis: Low-dose naltrexone is safe; monitor liver enzymes every 3 months 5
• Decompensated cirrhosis: Use with extreme caution; more safety data are needed, though the 2022 study showed 81.3% 2-year survival in this group 5
• Acute hepatitis: Contraindicated 4
• Hepatotoxicity warnings stem from studies using 300 mg/day, not the 1–5 mg range 6, 7

Patient Counseling: Administration and Lifestyle

Instruct patients to take low-dose naltrexone on an empty stomach at bedtime to optimize absorption and minimize daytime side effects. 1

• Take at bedtime (not with food) 1
• Avoid alcohol during treatment, as naltrexone is often used to reduce alcohol cravings and alcohol may exacerbate liver enzyme elevations 5
• Warn patients they cannot use opioid pain medications while on naltrexone, as the antagonist will block analgesic effects 3
• If surgery is planned, discontinue oral naltrexone 2–3 days before the procedure if opioid analgesia will be needed 3
• Patients who stop naltrexone have decreased opioid tolerance and face increased overdose risk if they resume opioid use 3

Common Pitfalls to Avoid

• Do not start at the full 50 mg dose used for opioid/alcohol dependence; low-dose naltrexone requires a much lower starting dose (1 mg) and gradual titration 1
• Do not skip the opioid-free verification period; patients must be off all opioids for 7–10 days to prevent precipitated withdrawal 3
• Do not withhold naltrexone solely due to mild liver enzyme elevations (e.g., AST/ALT 1.5–2× upper limit of normal), as hepatotoxicity occurs only at doses ≥300 mg/day 6, 7
• Do not confuse low-dose naltrexone (1–5 mg) with standard-dose naltrexone (50 mg); the pharmacodynamics differ substantially, with low-dose naltrexone modulating glial inflammation and upregulating endogenous opioid signaling rather than providing complete opioid-receptor blockade 1

Mechanism and Therapeutic Rationale

Low-dose naltrexone exerts effects distinct from standard-dose naltrexone by transiently blocking opioid receptors, which triggers a compensatory upregulation of endogenous opioid production and reduces glial inflammatory responses via Toll-like receptor 4 modulation. 1 This mechanism has shown promise in fibromyalgia, Crohn's disease, multiple sclerosis, complex regional pain syndrome, and other inflammatory conditions, though large-scale clinical trials are still needed. 1, 2