What role do opioid agonists play in weight loss?

Role of Opioid Antagonists in Weight Loss

Naltrexone, an opioid antagonist, promotes weight loss by blocking inhibitory feedback loops that limit appetite suppression and by activating pro-opiomelanocortin neurons in the hypothalamus to reduce food cravings and intake. 1

Mechanism of Action

• Naltrexone works primarily as an opioid antagonist that blocks endogenous opioid receptors, which helps reduce food cravings and hedonic eating behaviors 1
• When combined with bupropion (as in FDA-approved Contrave), naltrexone antagonizes an inhibitory feedback loop that would otherwise limit bupropion's appetite-suppressing properties 1
• This combination activates pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, promoting the release of α-melanocyte-stimulating hormone, an anorectic neuropeptide involved in body weight regulation 1

Clinical Efficacy

• In clinical trials (Contrave Obesity Research - COR trials), naltrexone/bupropion combination therapy resulted in 6.1% weight loss compared to 1.3% with placebo after 56 weeks 1
• 48% of patients on naltrexone/bupropion lost ≥5% of their body weight compared to only 16% of placebo patients 1
• In patients with type 2 diabetes, 44.5% of those receiving naltrexone/bupropion lost ≥5% of their body weight after 56 weeks compared to 18.9% on placebo 1

Side Effects and Contraindications

• Common side effects include nausea, constipation, headache, dizziness, insomnia, and dry mouth 1
• Naltrexone/bupropion is contraindicated in:
  • Patients with uncontrolled hypertension 1
  • Those with a history of seizures 1
  • Patients using opioid medications (due to antagonistic effects) 1
  • Individuals with anorexia or bulimia nervosa 1
• Bupropion carries a black box warning for potential increase in suicidal thoughts in young adults during initial treatment 1

Appropriate Patient Selection

• Ideal candidates for naltrexone/bupropion include:
  • Patients who describe food cravings or addictive behaviors related to food 1
  • Those with concomitant depression that could benefit from bupropion's antidepressant effects 1
  • Individuals trying to quit smoking or reduce alcohol intake 1

Comparison to Other Weight Loss Medications

• Unlike other anti-obesity medications approved since 2012, naltrexone/bupropion is neither a controlled substance nor an injectable agent 1
• GLP-1 receptor agonists (semaglutide, liraglutide) show greater weight loss efficacy and are preferred for patients with diabetes and obesity 1
• For patients with diabetes, naltrexone/bupropion demonstrated a 0.6% reduction in hemoglobin A1c from baseline, compared to a 0.1% reduction with placebo 1

Dosing and Administration

• Naltrexone/bupropion requires gradual dose titration to minimize side effects:
  • Week 1: 1 tablet (8/90 mg) in the morning
  • Week 2: 1 tablet twice daily
  • Week 3: 2 tablets in morning, 1 tablet in evening
  • Week 4 and beyond: 2 tablets twice daily (total 32/360 mg daily) 1
• If a patient has not lost at least 5% of baseline body weight after 12 weeks on the maintenance dose, the medication should be discontinued 1

Important Considerations and Pitfalls

• Naltrexone/bupropion should not be used with MAO inhibitors or within 14 days of discontinuing them 1
• The medication should not be discontinued abruptly but tapered over at least one week 1
• Unlike methadone (which is associated with weight gain), naltrexone does not appear to promote weight gain when used for opioid use disorder treatment 2
• Opioid antagonists should never be started in patients currently taking opioid medications, as this can precipitate withdrawal 1

By targeting the reward pathways in the brain that regulate food intake and cravings, opioid antagonists like naltrexone represent an important pharmacological option for weight management in appropriate patients.