Anti-Obesity Drugs: Buproprion/Naltrexone

The third emerging anti-obesity drug discussed in our Nature Endocrine Reviews article on anti-obesity medications focussed on the published data related to the fixed combination of buproprion and naltrexone.

Although this combination has yet to be approved for obesity treatment by the FDA, the data have been resubmitted for consideration to this agency.

Bupropion is a noradrenaline and dopamine reuptake inhibitor that has been used in the treatment of depression for more than three decades and is also widely used for smoking cessation. The modest weight loss sometimes seen in patients receiving bupropion therapy has been attributed to its stimulatory effect on POMC-producing neurons in the arcuate nucleus of the hypothalamus.

While the decreased energy intake and increased locomotor activity and thermogenesis seen with buproprion result from secretion of α-MSH and subsequent activation of MC4‑R. However, increased synaptic concentration of POMC increases the production of β-endorphin, an endogenous opioid, which inhibits POMC via a negative-feedback loop that reduces the secretion of α-MSH. This autoregulatory mechanism is believed to limit the antiobesity effect of bupropion monotherapy.

Naltrexone is an opioid antagonist and has been used since 1963 to treat opiate addiction and, since 2006, for alcohol addiction. Although naltrexone alone has no effect on body weight, it is postulated that when co-administered with bupropion, it reduce β‑endorphin levels, thereby suppressing the negative-feedback regulation resulting from elevated POMC levels and increasing and sustaining bupropion’s effect on energy intake and expenditure. Moreover, some evidence suggests that the anti-opioid effect of naltrexone could reduce the β‑endorphin-induced pleasurable sensations associated with the ingestion of palatable food.

A total of 15 phase I and four phase II studies (reviewed elsewhere) have investigated combinations of naltrexone and bupropion. Because in these studies, the combination of naltrexone 32 mg with bupropion 360 mg was associated with smaller decreases in both systolic (–0.5 mmHg versus –1.6 mmHg) and diastolic (–0.7 mmHg versus –1.3 mmHg) blood pressure versus placebo led, the FDA declined approval of this combination in early 2011 and required the initiation of the Cardiovascular Outcomes Study of Naltrexone SR–Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The LIGHT Study), which is expected to be completed by mid‑2017.

In out review we limit our discussion to the results of the four large phase III randomized controlled trials that included about 4,500 participants. Placebo-adjusted weight loss was in the active treatment group was about 4.5% of initial weight. Although this average response appears modest, patients receiving active treatment exhibited a significant increase in the proportion of 5% weight loss achievers (39% in the low-dose group and 48% in the high-dose group versus 16% in the placebo group).

Adverse effects were higher in the active treatment group but were in line with the known side effects of these compounds: nausea (32%), constipation (18%), headache (17%), vomiting (10%), dizziness (10%), insomnia (9%) and dry mouth (8%). Pooling the results from the aforementioned studies, no effect on the incidence of depression or mood changes was associated with bupropion–naltrexone treatment compared to placebo (2.8% versus 3.5%).

If and when this combination receives approval for obesity treatment remains to be seen and much will depend on the outcome of the ongoing LIGHT trial.

@DrSharma
Boston, MA

Disclaimer: buproprion and naltrexone alone and in combination are currently not approved for obesity treatment. I am currently on the Data Safety Monitoring Board of the LIGHT trial. 

Rueda-Clausen CF, Padwal RS, & Sharma AM (2013). New pharmacological approaches for obesity management. Nature reviews. Endocrinology, 9 (8), 467-78 PMID: 23752772

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