Is Naltrexone (opioid receptor antagonist) effective for weight loss?

Naltrexone for Weight Loss

Naltrexone alone is not effective for weight loss, but the combination of naltrexone-bupropion ER with lifestyle interventions is suggested for adults with obesity or overweight with weight-related complications. 1

Efficacy of Naltrexone-Bupropion ER

• The American Gastroenterological Association (AGA) suggests using naltrexone-bupropion ER with lifestyle interventions compared to lifestyle interventions alone for weight management (conditional recommendation, moderate certainty evidence) 1
• Naltrexone-bupropion ER produces modest weight loss of approximately 3.01% total body weight loss (TBWL) more than placebo (95% CI: 2.47-3.54% lower) 1
• In clinical trials, 5-10% of participants achieved clinically significant weight loss with naltrexone-bupropion ER compared to placebo 2
• The combination works by modulating central reward pathways triggered by food - bupropion inhibits reuptake of dopamine and norepinephrine while naltrexone antagonizes an inhibitory feedback loop that would otherwise limit bupropion's anorectic properties 1

Clinical Considerations for Use

• Naltrexone-bupropion ER may be particularly beneficial for patients who are attempting smoking cessation or have depression 1, 3
• In clinical practice, patients who describe food cravings or addictive behaviors related to food may respond well to this medication 1
• The medication should be discontinued if a patient has not lost at least 5% of total body weight after 12 weeks on the maintenance dose 4
• Compared to other anti-obesity medications approved since 2012, naltrexone-bupropion ER is neither a controlled substance nor an injectable agent 1

Dosing Protocol

• Start with one tablet (8 mg naltrexone/90 mg bupropion) once daily in the morning, then increase weekly following the titration schedule 4
• The maintenance dose is two tablets twice daily (32 mg naltrexone/360 mg bupropion daily total) 4
• The second dose should not be taken late in the day to minimize insomnia risk 4

Safety Considerations and Monitoring

• Treatment discontinuation due to adverse effects is significantly higher with naltrexone-bupropion ER compared to placebo (25% vs 10%; RR 2.39; 95% CI 1.69-3.37) 1
• Most common adverse effects include nausea (4.6%-9.6%), vomiting (0.7%-2%), headache (0.9%-1.8%), dizziness (0.7%-1.4%), and depression (0.2%-0.6%) 1
• Blood pressure and heart rate should be monitored periodically, especially in the first 12 weeks of treatment 1, 4
• Naltrexone-bupropion ER should be avoided in patients with:
  • Seizure disorders or risk factors for seizures 1, 4
  • Uncontrolled hypertension 4
  • Concomitant opioid medication use 1, 3

Comparative Efficacy

• Naltrexone-bupropion ER produces less weight loss compared to other FDA-approved weight loss medications:
  • Semaglutide 2.4 mg: 10.76% more TBWL than placebo 1
  • Liraglutide 3.0 mg: 4.81% more TBWL than placebo 1
  • Phentermine-topiramate ER: 8.45% more TBWL than placebo 1
  • Naltrexone-bupropion ER: 3.01% more TBWL than placebo 1

Limitations and Concerns

• High discontinuation rates (up to 50%) in clinical trials due to side effects 5
• Limited long-term data on sustained weight loss after treatment discontinuation 6
• Concerns about cardiovascular safety as cardiovascular outcome trials were terminated early 3, 6
• The modest weight loss benefit (a few kilograms) must be weighed against potentially severe adverse effects 6

Practical Approach

• Consider naltrexone-bupropion ER for patients with obesity or overweight with weight-related complications who also have depression or are attempting smoking cessation 1, 3
• Ensure patients are also following lifestyle interventions including hypocaloric diet (500 kcal/day deficit) and increased physical activity 1
• Monitor for adverse effects, particularly in the first few weeks of treatment 1
• Evaluate efficacy at 12 weeks and discontinue if <5% weight loss is achieved 4