Bariatric Endocrinology: 2015 Update
January 2015
Volume 6, Issue 1

Efficacy of Naltrexone/Bupropion in the CONTRAVE Obesity Research-II Trial

Obesity (Silver Spring). 2013;21(5):935-943

Introduction: Combination therapy with naltrexone/bupropion has been found to have complementary actions on the central nervous system (CNS) to reduce food intake. Bupropion stimulates hypothalamic pro-opiomelanocortin (POMC) neurons, which results in reduced food intake and increased energy expenditure, and naltrexone blocks opioid-receptor mediated POMC auto-inhibitions, to act synergistically with bupropion in augmenting POMC firing. Both agents are believed to alter CNS reward pathways leading to weight loss, according to the study authors. The present study was designed to investigate the safety and efficacy of naltrexone/bupropion in patients with overweight and obesity treated for up to 56 weeks.

Methods: The double-blind, placebo-controlled, phase 3 study involved 1,496 patients with overweight (BMI 27-45 kg/m2) or obesity (BMI 30-45 kg/m2) with controlled hypertension and/or dyslipidemia. The patients were between the ages 18 to 65 years and did not have diabetes; significant vascular, hepatic, or renal disease; weight loss of >4 kg within 3 months of enrollment; history of seizures; or serious psychiatric illness. The patients were randomized in a 2:1 fashion to 32 mg/day naltrexone sustained-release (SR) plus 360 mg/day bupropion SR or placebo for up to 56 weeks. The medication was given in divided doses, twice a day with dose escalation for the first 3 to 4 weeks.

The coprimary endpoints were percent weight change and proportion of patients achieving a 5% weight loss at week 28. Patients in the treatment arm who did not achieve an at least 5% weight loss between weeks 28 and 44 were re-randomized to continue their current dose or increase to 48 mg/day naltrexone SR plus 360 mg/day bupropion SR for the rest of the 56 weeks.

Results: Approximately 54% of patients in both study groups completed the trial. In both groups, the median age was 44 years, approximately 84% were female, and 83% to 84% were white.

Naltrexone/bupropion treatment was linked to significantly greater weight loss at week 28 and week 56, as well as a significantly greater proportion of patients achieving ≥5%, ≥10%, and ≥15% weight loss in a prespecified modified intent-to-treat analysis using the last observation on the study medication (Table). Treatment also was linked to significant improvements in control of eating, weight-related quality of life, and cardiovascular risk factors (ie, waist circumference, lipid levels, fasting insulin level, and insulin sensitivity).

The most common adverse events were nausea, constipation, and headache that were generally mild to moderate in severity and rarely lead to treatment discontinuation. Serious adverse events were rare in both groups (2.1% with naltrexone/bupropion and 1.4% with placebo). Consistent with previous trials of bupropion, a seizure rate of 0.1% was found in the naltrexone/bupropion group and minimal changes in blood pressure and pulse rate were found in the naltrexone/bupropion group. Treatment was not linked to an increased risk for depression, depressed mood, or suicidality.

Conclusions: Treatment with naltrexone/bupropion was linked to significantly greater weight loss and improvement in cardiovascular risk factors compared with placebo. Efficacy over placebo was demonstrated at week 4 and was maintained over the 56-week study.


Contrave® (a combination of bupropion and naltrexone) was approved for marketing in the United States in 2014. In essence, this combination of medications, through its combined mechanism of action, takes away the compulsive feeding behavior and the pleasure of feeding, leading to weight loss.

The CONTRAVE Obesity Research (COR) registration trials included COR-I, COR-II (reviewed here), COR-BMOD (BMOD, behavior modification) and COR-Diabetes. All COR trials were multicenter, double-blinded, randomized, placebo-controlled, and included a 3-week dose escalation period (from one tablet every morning, to two tablets twice a day). COR-I and COR-II compared Contrave to diet, exercise, and behavioral instruction in patients who did not have a diagnosis of diabetes. COR-Diabetes included the same study design but focused on patients with diabetes. COR-BMOD compared intensive behavior modification to Contrave.

Across the board, weight loss was significantly better with Contrave than the comparison group. The registration data documented better reductions in hemoglobin A1c in people with type 2 diabetes with Contrave than placebo. Furthermore, in a subset of 124 patients in COR-I, Contrave led to more loss of fat mass than placebo; assessed with DXA body composition analysis.

Contrave's most significant side effect was nausea, which affected 32.5% of 2,545 patients treated with the combination medication, compared to 6.7% of 1,515 patients treated with placebo. The nausea is due to the naltrexone component. This is the reason why the medication has to be escalated by one pill a day every week. Furthermore, this is why dosing the components separately is not practical. Compared to the 8 mg of naltrexone in every Contrave tablet, naltrexone tablets start at 50 mg.

Next Article:
Current Evidence on Naltrexone/Bupropion in the Treatment of Obesity
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