Abstract

• Weight loss and its long-term maintenance are mainly based on dietary measures and regular physical activity. There are currently no weight-loss medications with a favourable harm-benefit balance.
   
• Bupropion is chemically related to certain amphetamines, while naltrexone is an opioid receptor antagonist. A fixed-dose combination of these two drugs has received marketing authorisation in the European Union for obese patients and for overweight patients with other cardiovascular risk factors.
   
• In five placebo-controlled, randomised, double-blind trials, the patients, weighing on average between 100 kg and 105 kg (average body mass index 36 kg/m2), the naltrexone + bupropion combination was associated with an average weight loss of a few additional kilograms compared with placebo, after 6 months or one year of treatment. There are no post-trial follow-up data to show whether or not the patients regained their lost weight after treatment discontinuation.
   
• One trial including more than 8900 patients examined the effect of the naltrexone + bupropion combination on the frequency of major cardiovascular events, but poor handling of an interim analysis undermined the validity of the final results.
   
• The known adverse effects of bupropion consist of potentially severe neuropsychiatric disorders such as aggressiveness, depression and suicidal ideation, and also allergic reactions, including Stevens-Johnson syndrome. Misuse and excessive consumption have been reported.
   
• In trials in obese or overweight patients, the naltrexone + bupropion combination caused sometimes severe neuropsychiatric disorders, including seizures, cognitive impairment, dizziness, anxiety, sleep disorders and psychotic symptoms.
   
• In clinical trials, the combination led to an increase in blood pressure compared with placebo, and also an excess of cardiac arrhythmias. 
   
• About half of patients who took naltrexone + bupropion experienced gastrointestinal disorders such as nausea, vomiting and constipation.
   
• The naltrexone + bupropion combination is subject to many pharmacokinetic interactions, as well as pharmacodynamic interactions leading to additive convulsive or hypertensive effects, or undermining the action of antihypertensive drugs.
   
• A teratogenic effect of bupropion cannot be ruled out.
   
• In practice, given the limited effect of the naltrexone + bupropion combination on weight loss (a few kilograms), along with the lack of evidence supporting a persistent benefit or a decrease in the clinical complications of obesity, there is no reason to expose patients to its many potentially severe adverse effects. 

©Prescrire 1 October 2015

"Naltrexone + bupropion (Mysimba°). Too risky for only modest weight loss" Prescrire Int 2015; 24 (164): 229-233. (Pdf, subscribers only)