Naltrexone is primarily recognized for treating alcohol and opioid dependence, but it has been repurposed for chronic weight management. Alone, naltrexone does not lead to meaningful weight reduction. When combined with a second medication, however, it becomes an effective treatment option. This combination targets specific neurochemical pathways in the brain that regulate hunger and reward. The drug is intended to be an adjunct to a reduced-calorie diet and increased physical activity.
The Specific Combination Used for Weight Loss
The medication used for weight management is a fixed-dose combination of naltrexone and bupropion, an atypical antidepressant and smoking cessation aid. This formulation is marketed under brand names such as Contrave and Mysimba. The combination is necessary because naltrexone and bupropion work together to create a synergistic effect on appetite control that neither drug achieves effectively alone.
Naltrexone is an opioid antagonist. The drugs were combined to leverage their complementary effects on the central nervous system’s appetite regulation centers. This pairing was approved for chronic weight management in adults who meet specific health criteria.
How the Medication Affects Appetite and Cravings
The anti-obesity effect is rooted in a dual mechanism targeting both the homeostatic control of appetite and the brain’s hedonic reward system. Bupropion acts as a weak inhibitor of norepinephrine and dopamine reuptake. This action stimulates pro-opiomelanocortin (POMC) neurons in the hypothalamus, leading to the release of alpha-melanocyte-stimulating hormone (alpha-MSH).
The alpha-MSH signals the body to decrease food intake and increase energy expenditure. However, POMC neurons also release beta-endorphin, an endogenous opioid that creates an inhibitory feedback loop by binding to mu-opioid receptors on the same neurons. This self-limiting action would dampen bupropion’s appetite-suppressing effect over time.
Naltrexone, an opioid receptor antagonist, blocks this inhibitory feedback from beta-endorphin. By blocking the mu-opioid receptors, naltrexone allows the bupropion-stimulated POMC neurons to remain active, sustaining the release of alpha-MSH. This combined action enhances satiety signals and reduces the rewarding sensation associated with eating, curbing cravings.
Clinical Expectations for Weight Reduction
The efficacy of the naltrexone/bupropion combination was demonstrated in clinical trials, such as the Contrave Obesity Research (COR) studies, which evaluated treatment over 56 weeks. Patients receiving the medication alongside lifestyle modifications experienced greater weight loss than those on placebo. On average, individuals lost between 5% and 8% of their initial body weight.
A clinically meaningful threshold for weight loss is defined as achieving at least a 5% reduction in total body weight. In major studies, 42% to 50% of patients achieved this 5% benchmark with the active drug, compared to 17% to 23% in the placebo groups. Results are generally maintained throughout the 56-week duration. If a patient does not achieve at least 5% weight loss after 12 weeks at the full maintenance dose, discontinuation is recommended, as further benefit is unlikely.
Patient Selection and Administration
The combination is indicated for adults with an initial Body Mass Index (BMI) of 30 kg/m\(^2\) or greater (obese). It is also indicated for those with a BMI of 27 kg/m\(^2\) or greater (overweight) who have at least one weight-related condition. Qualifying conditions include controlled hypertension, Type 2 diabetes mellitus, or dyslipidemia. The treatment must be used alongside a reduced-calorie diet and increased physical activity.
To minimize common side effects like nausea and ensure tolerance, the drug requires a gradual increase in dosage, known as titration, over four weeks. Treatment begins with one tablet (8 mg naltrexone/90 mg bupropion) once daily during the first week. The dose is progressively increased weekly until the full maintenance dose of two tablets taken twice daily is reached by week four. This ensures the patient adjusts to the therapeutic dose of 32 mg of naltrexone and 360 mg of bupropion per day.