The investigational combination therapy of naltrexone/bupropion alters hypothalamic brain regions that regulate appetite and energy expenditure, as well as reward-system mediating eating behavior. In addition, clinical trials suggest that this combination agent induces significant weight loss compared to placebo, according to a literature review by Billes et al.
Most patients who have obesity are not able to maintain weight loss with lifestyle changes alone, the authors note. Thus, weight-loss medications are necessary to facilitate and maintain weight loss over the long term. The authors attribute the limited success of currently available obesity medications to the complexity of brain pathways related to hunger, food cravings, and eating behaviors.
Naltrexone is an opioid antagonist that has a high affinity for the μ-opioid receptor, which is implicated in eating behavior. Animal studies suggest that naltrexone blocks the increase in dopamine in the nucleus accumbens that occurs when eating and also decreases food intake, food seeking, and binge-like eating. In clinical studies, monotherapy with this agent has not produced consistent findings of decreased food intake in humans. This agent is currently approved in the United States for the treatment of alcoholism and opioid addiction.
Bupropion is an atypical antidepressant that is approved for the treatment of depression, seasonal affective disorder, and as an aid in smoking cessation. This agent blocks the reuptake of dopamine and norepinephrine, and is a weak nicotinic acetylcholine receptor antagonist. In clinical studies, weight loss is a common side effect of bupropion use.
In animal studies, injection of naltrexone and bupropion results in synergistic decreases in food intake, suggesting that the agents have independent and complementary effects on the reward system, according to the authors. In the melanocortin system, bupropion stimulates activity of pro-opiomelanocortin (POMC) cells in the hypothalamus and naltrexone amplifies this effect by blocking the endogenous opioid-mediated autoinhibition of POMC cells. POMC cells produce α-melanocyte stimulating hormone (α-MSH)—an agonist of melanocortin-4 receptors that decrease appetite and increase energy expenditure when stimulated in animal and human studies.
Naltrexone/bupropion appears to be similar to lorcaserin and phentermine/ topiramate in efficacy as an appetite suppressant.
Clinical Trial Findings
In 2 clinical trials—CONTRAVE Obesity Research (COR-I) and COR-II—weight loss with naltrexone/bupropion was comparable to that of the approved weight-loss medications lorcaserin, orlistat, and phentermine/topiramate. These studies involved patients with overweight and obesity randomized to naltrexone/ bupropion or placebo for 56 weeks in addition to a reduced-calorie diet, behavioral counseling, and increased physical activity. While COR-I and COR-II also included a low- and high-dose naltrexone/bupropion arm, the majority of patients were treated with the recommended dosing of 32 mg/day naltrexone sustained release (SR) plus 360 mg/day bupropion SR.
Patients who received the recommended dosing of naltrexone/bupropion lost a significantly greater percentage of body weight (-8.1% and -8.2%, in the respective trials) compared with the placebo groups (-1.8% and -1.4%; P<0.01 for both comparisons). The proportion of patients with weight loss of ≥5% was 63% and 65% in the respective treatment arms versus 23% and 22% in the placebo arms (P<0.01).
In the COR-BMOD (BMOD, behavioral modification) trial, patients treated with naltrexone/ bupropion in addition to an intensive behavior modification program designed for weight loss showed a significantly greater percentage of weight loss (-11.5% vs -7.3%; P<0.01) and a significantly greater percentage of patients with weight loss ≥5% (80% vs 60%; P<0.01) compared with patients treated with the intensive behavior modification program alone.
Finally, in the COR-Diabetes study, patients with overweight and obesity with type 2 diabetes who were randomized to naltrexone/bupropion showed significantly greater percentage of weight loss (-5.9% vs -2.2%; P<0.01) and a significantly greater percentage of patients with weight loss ≥5% (53% vs 24%; P<0.01) compared to patients given placebo regardless of whether patients were taking concurrent diabetes medications.
The most common adverse events with naltrexone/bupropion treatment are nausea, constipation, headache, and vomiting. These adverse events are generally mild to moderate in severity and occur early in the treatment course during dose escalation. Small increases in mean blood pressure and pulse rate have been reported in clinical trials. The combination treatment was not linked to increased risk for depressive/anxiety symptoms or serious psychiatric events compared with placebo in clinical trials.
The authors noted that only 2.7 million people in the United States were taking obesity medications in 2011, suggesting a low use of these agents. This low utilization means that the long-term effects of these medications remain largely unknown.
Billes SK, Sinnayah P, Cowley MA. Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss. Pharmacol Res. 2014;84:1-11.
Commentary by J. Michael Gonzalez-Campoy MD, PhD, FACE
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.