What are the guidelines for using Naltrexone (opioid receptor antagonist)-Bupropion (dopamine-norepinephrine reuptake inhibitor) for weight management in obese or overweight adults with a body mass index (BMI) of 30 or higher, or 27 or higher with weight-related conditions such as hypertension, type 2 diabetes, or dyslipidemia?

Naltrexone-Bupropion for Weight Management

Naltrexone-bupropion ER should be used in adults with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidities (hypertension, type 2 diabetes, dyslipidemia) as an adjunct to lifestyle interventions, with the expectation of approximately 4.8-6.4% total body weight loss at 56 weeks. 1, 2

Patient Selection Criteria

Appropriate candidates include: 1

• Adults with BMI ≥30 kg/m² regardless of comorbidities 1
• Adults with BMI ≥27 kg/m² who have at least one weight-related comorbidity such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea 1
• Patients attempting smoking cessation who need weight management 1
• Patients with comorbid depression requiring weight loss 1

Absolute contraindications: 1, 3

• Uncontrolled hypertension 1
• History of seizure disorders or conditions increasing seizure risk 1
• Bulimia or anorexia nervosa 1
• Current opioid use or anticipated need for opioid analgesia 1
• Pregnancy or inadequate contraception 1
• Use of MAOIs within 14 days 1
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs 3

Dosing Protocol

The standard titration schedule is: 1, 4

• Week 1: 8 mg naltrexone/90 mg bupropion once daily in the morning 1, 4
• Week 2: 8/90 mg twice daily 1, 4
• Week 3: 16/180 mg in the morning, 8/90 mg in the evening 1, 4
• Week 4 onward: 16/180 mg twice daily (maintenance dose = 2 tablets twice daily) 1, 4

Critical timing consideration: The second dose must be taken before 3 PM to minimize insomnia risk 3, 4

Dose adjustments for special populations: 1, 3, 4

• Moderate to severe renal impairment: Reduce total daily dose by half (maximum 1 tablet twice daily) 1, 4
• Moderate to severe hepatic impairment: Do not exceed 1 tablet daily 1, 4
• End-stage renal disease: Avoid use 4

Expected Efficacy and Assessment Timeline

Weight loss outcomes from clinical trials: 1, 5, 2

• Mean weight loss of 4.8% at 56 weeks compared to placebo (placebo-subtracted) 1
• Absolute weight loss of 6.4-6.5% at 56 weeks in treatment groups 1, 2
• 50.5-55.6% of patients achieve ≥5% weight loss 1, 2
• 26-33% achieve ≥10% weight loss (placebo-subtracted) 5

Efficacy assessment protocol: 1, 4

• Assess at 12 weeks: If patient has not lost at least 5% of baseline body weight on the maintenance dose, discontinue the medication as they are unlikely to respond 1, 4
• Monthly assessment for the first 3 months, then at least every 3 months thereafter 1

Monitoring Requirements

Baseline assessment: 1, 4

• Blood pressure and heart rate 1, 4
• Mental status examination focusing on suicidal ideation, especially in patients <24 years old 4
• Confirm patient is not taking opioid medications 4
• Document baseline weight 1

Ongoing monitoring schedule: 1, 4

• First 12 weeks: Blood pressure and heart rate checks weekly to biweekly during titration, then periodically 1, 4
• All visits: Screen for neuropsychiatric adverse effects including depression, anxiety, suicidal ideation, and mood changes 1, 4
• Week 12: Weight assessment to determine continuation (must achieve ≥5% weight loss) 1, 4
• Ongoing: Continue periodic blood pressure, heart rate, and psychiatric symptom surveillance 1, 4

Common Adverse Effects and Management

Most frequent side effects: 1, 6

• Nausea (most common, generally mild to moderate and transient) 1, 6, 2
• Constipation 1
• Vomiting 1
• Dizziness 1
• Dry mouth 1
• Headache 1
• Insomnia 1

Discontinuation rates: 1

• 25% of patients discontinue due to adverse effects versus 10% with placebo 1
• Most common reasons for discontinuation: nausea (4.6-9.6%), vomiting (0.7-2%), headache (0.9-1.8%), dizziness (0.7-1.4%) 1

Cardiovascular effects: 1, 5

• Modest but statistically significant increases in systolic and diastolic blood pressure observed 4, 5
• Blood pressure and pulse improvements were greater with placebo compared to naltrexone-bupropion 5

Cardiometabolic Benefits Beyond Weight Loss

Additional improvements observed in clinical trials: 1, 5, 2

• Waist circumference reduction 5, 2
• Triglyceride improvement 5, 2
• HDL cholesterol increase 5, 2
• Fasting insulin and insulin resistance reduction 5, 2
• In patients with type 2 diabetes: HbA1c reduction of approximately 0.5% more than placebo 1, 5
• Improved obesity-specific quality of life 5, 2
• Enhanced control of eating and reduced food cravings 7, 2

Critical Clinical Pitfalls to Avoid

Opioid interaction: 1, 4

• Naltrexone-bupropion must be discontinued before procedures requiring opioid analgesia (e.g., endoscopies with fentanyl) 4
• Cannot be used concomitantly with opioid medications 1

Seizure risk: 1, 3

• Bupropion lowers seizure threshold; avoid in any seizure disorder 1
• Maximum dose of 32/360 mg daily must not be exceeded to maintain seizure risk at approximately 0.1% 3
• Avoid in eating disorders due to increased seizure risk 1, 3

Cardiovascular considerations: 1

• Do not use sympathomimetic agents like phentermine in patients with cardiovascular disease 1
• Naltrexone-bupropion requires blood pressure monitoring but is not absolutely contraindicated in controlled cardiovascular disease 1

Premature discontinuation: 1

• Do not discontinue before 12 weeks unless significant adverse effects occur, as weight loss continues to accrue over time 1
• If <5% weight loss at 12 weeks on maintenance dose, discontinue as continued use is unlikely to be beneficial 1

Mechanism of Action

Synergistic weight loss mechanism: 1, 8

• Bupropion activates anorexigenic (appetite-suppressing) neurons in the hypothalamus 8
• Bupropion increases norepinephrine and dopamine release in the central nervous system 8
• Naltrexone blocks β-endorphin's auto-inhibitory effects on hypothalamic neurons, enhancing bupropion's anorectic properties 8
• The combination uniquely affects food craving and eating behavior control 7, 2