What is the recommended low‑dose naltrexone dosing schedule for weight loss in an adult obese patient who is not taking opioids, not pregnant or breastfeeding, and has no severe hepatic impairment?

Naltrexone-Bupropion Dosing for Weight Loss

For an adult obese patient without contraindications, naltrexone-bupropion ER (Contrave) should be initiated at 8 mg naltrexone/90 mg bupropion once daily in the morning, then titrated weekly over 4 weeks to the maintenance dose of 16 mg naltrexone/180 mg bupropion twice daily (2 tablets twice daily). 1

Titration Schedule

The American Gastroenterological Association recommends the following escalation protocol 1, 2:

• Week 1: One tablet (8/90 mg) once daily in the morning
• Week 2: One tablet twice daily (morning and evening)
• Week 3: Two tablets in the morning, one tablet in the evening
• Week 4 and beyond: Two tablets twice daily (maintenance dose = 32 mg naltrexone/360 mg bupropion total daily)

The second daily dose must be taken before 3 PM to minimize insomnia risk, as bupropion has activating properties that can disrupt sleep when administered late in the day. 1, 2

Efficacy Assessment and Discontinuation Criteria

If the patient has not achieved at least 5% body weight loss from baseline after 12 weeks on the full maintenance dose, discontinue naltrexone-bupropion, as continued treatment is unlikely to produce meaningful benefit. 1, 2 This 12-week assessment is critical—approximately 44.5% of patients achieve ≥5% weight loss at 56 weeks in clinical trials, compared to 18.9% with placebo. 1

In the pivotal COR trials involving 4,536 patients, naltrexone-bupropion produced mean weight loss of 6.1% versus 1.3% with placebo at 56 weeks, with 48% of treatment patients losing ≥5% body weight compared to 16% of placebo patients. 1

Absolute Contraindications

Do not prescribe naltrexone-bupropion if the patient has any of the following 1, 2, 3:

• Current opioid use or anticipated need for opioid analgesia (naltrexone precipitates severe opioid withdrawal) 2, 3
• Uncontrolled hypertension (≥130/80 mmHg must be controlled before initiation) 1, 2, 3
• Seizure disorder or any condition predisposing to seizures (eating disorders, abrupt alcohol/benzodiazepine discontinuation, brain tumor, head trauma) 1, 3
• Pregnancy or breastfeeding 1
• Severe hepatic impairment 1
• Current or recent MAOI use (within 14 days) 1

Dose Adjustments for Organ Impairment

For moderate to severe renal impairment (eGFR <90 mL/min), reduce the total daily dose by half—maximum one tablet twice daily instead of two tablets twice daily. 2 Avoid entirely in end-stage renal disease, as bupropion metabolites accumulate and are not effectively cleared by dialysis. 2

For moderate to severe hepatic impairment, do not exceed one tablet daily (8 mg naltrexone/90 mg bupropion), as bupropion clearance is significantly reduced. 1, 2

Critical Safety Monitoring

Cardiovascular Monitoring

Measure blood pressure and heart rate at baseline, then weekly to biweekly during titration and throughout the first 8 weeks of therapy. 2 Naltrexone-bupropion causes statistically significant increases in both systolic and diastolic blood pressure, particularly during the initial treatment period. 2, 3 Continue periodic monitoring thereafter. 2

Neuropsychiatric Monitoring

Assess for depression, anxiety, suicidal ideation, and behavioral changes at every visit, especially during the first 1–2 months when suicide risk is highest. 2 Bupropion carries an FDA black-box warning for increased suicidal thoughts in patients younger than 24 years. 1, 3 However, pooled trial data show no significant difference in depression rates (0.1%–1.3% vs 0.2%–1.6% placebo) or anxiety rates (0.6%–5.4% vs 0.2%–4.3% placebo) with naltrexone-bupropion. 2

Seizure Risk

The seizure risk with bupropion at the 360 mg daily dose in Contrave is approximately 0.1% (1 in 1,000 patients). 1 This risk increases markedly if maximum doses are exceeded or if predisposing conditions exist. 1, 3

Common Side Effects and Management

The most frequent adverse effects include nausea (4.6%–9.6%), constipation, headache, dizziness, insomnia, vomiting, and dry mouth. 1, 3 These are typically mild to moderate and often improve after the first few weeks. 1 In clinical trials, 25% of patients discontinued due to adverse effects versus 10% with placebo. 3

If nausea or gastrointestinal symptoms occur during titration, pause at the current dose for an additional week before advancing, rather than abandoning therapy prematurely. 2

Perioperative Management

Discontinue naltrexone-bupropion at least 7–10 days before any procedure requiring opioid analgesia (e.g., colonoscopy with fentanyl, surgery), as naltrexone blocks opioid receptors and prevents effective pain control. 2 The naltrexone component has a duration of action that necessitates this washout period.

Clinical Advantages and Patient Selection

Ideal candidates include patients with concomitant depression (bupropion treats both conditions), those trying to quit smoking or reduce alcohol intake, and patients describing food cravings or addictive eating behaviors. 1 Unlike phentermine, naltrexone-bupropion is neither a controlled substance nor requires injection, improving accessibility. 1

The combination activates pro-opiomelanocortin neurons in the hypothalamus, promoting release of α-melanocyte-stimulating hormone, an anorectic neuropeptide involved in body weight regulation. 1 Bupropion inhibits reuptake of dopamine and norepinephrine, modulating central reward pathways triggered by food, while naltrexone antagonizes an inhibitory feedback loop that would otherwise limit bupropion's anorectic properties. 1

Common Pitfalls to Avoid

• Do not initiate without confirming blood pressure is controlled (<130/80 mmHg). 2, 3
• Do not prescribe to patients on chronic opioid therapy or those who may need opioids in the near future. 2, 3
• Do not skip the 12-week efficacy assessment—continuing therapy beyond this point without adequate weight loss wastes resources and exposes patients to unnecessary side effects. 1, 2
• Do not administer the second daily dose late in the evening, as this significantly increases insomnia risk. 1, 2
• Do not exceed the maximum dose of 32 mg naltrexone/360 mg bupropion daily, as seizure risk increases substantially. 1, 3