Can naltrexone be used for weight loss in adults with a body mass index (BMI) of 30 or higher, or a BMI of 27 or higher with weight-related conditions such as diabetes or hypertension?

Naltrexone for Weight Loss

Yes, naltrexone combined with bupropion (naltrexone/bupropion ER) is FDA-approved and recommended for weight loss in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with weight-related comorbidities like diabetes or hypertension, and should be used as an adjunct to lifestyle interventions. 1

Mechanism and Efficacy

Naltrexone/bupropion ER works through complementary mechanisms: bupropion inhibits dopamine and norepinephrine reuptake to modulate central reward pathways, while naltrexone antagonizes an inhibitory feedback loop that would otherwise limit bupropion's appetite-suppressing effects, ultimately activating pro-opiomelanocortin neurons in the hypothalamus. 1

The combination produces clinically meaningful weight loss:

• Mean weight loss of 4.7-6.1% compared to 1.3% with placebo at 56 weeks 1, 2
• 44-48% of patients achieve ≥5% weight loss versus 16-19% with placebo 1
• In patients with type 2 diabetes, hemoglobin A1c decreases by 0.5-0.6% more than placebo 1, 2

Dosing Protocol

Follow this specific titration schedule to minimize side effects: 1

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

The gradual titration is critical because nausea occurs in the majority of patients but is typically mild-to-moderate, peaks in week 1, and resolves with median duration of 9-14 days. 3 Importantly, weight loss is independent of nausea—patients who experience nausea lose the same amount of weight as those who don't. 3

Absolute Contraindications

Do not prescribe naltrexone/bupropion ER if the patient has: 1, 4, 5

• Current opioid use (naltrexone will precipitate severe withdrawal)
• Seizure disorders or any condition predisposing to seizures
• Uncontrolled hypertension
• Eating disorders (anorexia or bulimia nervosa)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs within the past 2 weeks
• Current or recent (within 14 days) MAOI use
• Pregnancy or inadequate contraception in women of childbearing potential

Ideal Candidates

Prioritize naltrexone/bupropion ER for patients with: 1

• Comorbid depression (bupropion component treats both conditions)
• Active smoking cessation attempts (addresses nicotine dependence and prevents cessation-related weight gain)
• Food cravings or addictive eating behaviors
• Alcohol use disorder requiring treatment
• Concerns about controlled substance use (unlike phentermine, this is not a scheduled medication)

Monitoring Requirements

Implement this monitoring protocol: 1, 4, 5

• Blood pressure and heart rate at baseline, then periodically (especially first 12 weeks), as the medication can elevate both parameters
• Mental status assessment for suicidal ideation, particularly in patients under 24 years old (black box warning for increased suicidal thoughts in young adults during first few months)
• Pregnancy testing monthly in women of childbearing potential
• Serum bicarbonate levels periodically with long-term use (topiramate component has carbonic anhydrase inhibitor properties)

Dose Adjustments for Organ Dysfunction

Reduce dosing in hepatic or renal impairment: 1, 4

• Moderate to severe hepatic impairment: Maximum 150 mg bupropion daily (one tablet)
• Moderate to severe renal impairment: Reduce total daily dose by 50%
• End-stage renal disease: Avoid use

Common Side Effects and Management

The most frequent adverse effects are gastrointestinal: nausea (occurs in approximately 50% of patients), constipation, vomiting, dry mouth. 1 Neuropsychiatric effects include headache, dizziness, insomnia, and rarely seizures (risk approximately 0.1% at approved doses). 1, 6

To minimize insomnia, take the second daily dose before 3 PM. 7

Critical Safety Considerations

Blood pressure increases are a concern—placebo shows greater improvement in systolic blood pressure and pulse compared to naltrexone/bupropion. 2 This is why uncontrolled hypertension is an absolute contraindication and regular monitoring is mandatory. 1, 4

The cardiovascular outcomes trial (Light Study) was terminated early due to interim analysis issues, leaving long-term cardiovascular safety incompletely characterized. 6 However, the medication significantly improves cardiometabolic risk factors including triglycerides, HDL, fasting insulin, and insulin resistance. 2

Comparison to Other Weight Loss Medications

Unlike lorcaserin (which requires caution with cardiac valvular disease) or phentermine (a controlled stimulant), naltrexone/bupropion is neither a controlled substance nor requires injection like liraglutide 3.0 mg. 1 This makes it particularly suitable for patients with cardiovascular disease or substance use concerns who cannot receive stimulant-based medications. 1

The 2022 AGA guidelines conditionally recommend naltrexone-bupropion ER with lifestyle interventions over lifestyle interventions alone, based on moderate certainty evidence. 1