What is the role of the bupropion (BUP)-naltrexone (NLT) combination in weight loss management?

Bupropion-Naltrexone Combination for Weight Loss

The bupropion-naltrexone combination is an effective FDA-approved medication for weight loss that achieves approximately 6% weight reduction compared to 1% with placebo, making it a valuable option for patients with obesity who have comorbid depression or addictive eating behaviors. 1

Mechanism of Action

The combination works through dual mechanisms:

• Bupropion: A dopamine and norepinephrine reuptake inhibitor that:

  • Stimulates hypothalamic proopiomelanocortin (POMC) neurons
  • Modulates central reward pathways triggered by food
  • Has mild anorectic effects on its own 1

• Naltrexone: An opioid antagonist that:

  • Blocks opioid-mediated POMC autoinhibition
  • Enhances bupropion's anorectic properties
  • Reduces reactivity to food cues 1

Together, they reduce food cravings and improve dysregulation of eating control in mesolimbic pathways.

Efficacy

Clinical trials demonstrate consistent weight loss benefits:

• Weight reduction: 6.1% with naltrexone/bupropion vs 1.3% with placebo in COR-I trial 1
• Responder rates: 48% of treated patients lost ≥5% of body weight vs 16% with placebo 1
• Diabetic patients: 44.5% achieved ≥5% weight loss vs 18.9% with placebo 1
• HbA1c reduction: 0.6% reduction from baseline vs 0.1% with placebo 1

The most recent evidence from the 2023 JAMA review confirms these findings, showing approximately 6% weight loss compared to 1% with placebo across multiple studies 1.

Dosing and Administration

• Formulation: Tablets containing 8 mg naltrexone + 90 mg bupropion (extended-release)
• Titration schedule:
  1. Week 1: 1 tablet daily (morning)
  2. Week 2: 1 tablet twice daily
  3. Week 3: 2 tablets morning, 1 tablet afternoon
  4. Week 4 onward: 2 tablets twice daily (maintenance dose) 1
• Administration: Second dose should not be taken late in day to minimize insomnia risk 1
• Evaluation: If <5% weight loss after 12 weeks at maintenance dose, discontinue as patient is likely a poor responder 1

Patient Selection

Ideal candidates include:

• Patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related complications 1
• Those with comorbid depression (bupropion component has antidepressant effects) 1
• Patients attempting smoking cessation or alcohol reduction 1
• Those reporting food cravings or addictive eating behaviors 1

Contraindications and Precautions

• Absolute contraindications:

  • Patients requiring opioid therapy (naltrexone blocks opioid effects) 1
  • Uncontrolled hypertension 1
  • History of seizures or conditions predisposing to seizures 1
  • Anorexia or bulimia nervosa 1
  • Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 1
  • End-stage renal disease 1

• Dose adjustments:

  • Moderate to severe renal impairment: Reduce to half dose (1 tablet twice daily) 1
  • Moderate to severe hepatic impairment: Maximum 1 tablet daily 1

Adverse Effects

Common side effects include:

• Gastrointestinal: Nausea (most common), constipation, vomiting, dry mouth 1
• Neurological: Headache, dizziness, insomnia 1
• Cardiovascular: Small increases in blood pressure and heart rate 1, 2

Serious but rare adverse effects include:

• Suicidal thoughts (black box warning for bupropion in young adults) 1
• Seizures 3

Drug Interactions

Important interactions to monitor:

• Monoamine oxidase inhibitors (MAOIs) 1
• Opioids (reduced efficacy or precipitated withdrawal) 1
• Drugs that lower seizure threshold 1
• Antihypertensive medications (reduced efficacy) 3

Special Considerations

• Procedures requiring opioids: Discontinue naltrexone-bupropion before procedures requiring opioid analgesia (e.g., endoscopies using fentanyl) 1
• Cardiovascular risk: Monitor blood pressure and heart rate, especially in the first 8 weeks 1
• Psychiatric monitoring: While clinical trials showed no significant difference in anxiety or depression compared to placebo, monitor for mood changes 1

Comparison to Other Weight Loss Medications

In systematic reviews, phentermine-topiramate demonstrated greater weight loss than naltrexone-bupropion, while GLP-1 receptor agonists (semaglutide, tirzepatide) show substantially greater efficacy 1. However, naltrexone-bupropion offers the advantage of oral administration and may be particularly beneficial for specific patient populations with comorbid depression or addictive eating behaviors.