Contrave® is a unique formulation reduces hunger and cravings, combining 8mg naltrexone hydrochloride and 90mg bupropion hydrochloride. Bupropion is a dopamine and norepinephrine (noradrenaline) reuptake inhibitor, while naltrexone is an opioid receptor antagonist. 

The new weight-loss treatment drug acts in two regions of the brain: 

• Hypothalamic hunger centre
• Mesolimbic reward system.

HYPOTHALAMIC HUNGER CENTRE 

Bupropion directly increases pro-opiomelanocortin (POMC) neuronal activity while naltrexone indirectly sustains POMC neuronal activity by blocking a negative feedback loop. This means that hunger is reduced. Hunger being an urge to eat to satisfy a metabolic need for food. 

MESOLIMBIC REWARD SYSTEM 

Naltrexone and bupropion are believed to work together to regulate neurotransmitters that stimulate feelings of pleasure when eating. This reduces cravings, which are an intense desire to eat food in the absence of metabolic need. Examples of foods that can cause cravings include foods high in fat, sugar and salt. 

The dual-acting drug reduces hunger and cravings to deliver weight loss that is significant, sustained and behaviour-changing. Patients taking the combination drug achieved significant weight loss while on therapy compared to placebo.  

Patients experienced significant cardiovascular and metabolic risk factor improvement (HDL cholesterol, triglyceride and HbA1c) (p<0.001 vs placebo). Patients also achieved sustained weight loss while on therapy compared to placebo.  

The product helps change eating behaviour from week eight of treatment. Although the exact neurochemical appetite suppressant effects of naltrexone/bupropion are not fully understood, there have been a number of clinical trials examining their efficacy in weight loss. 

EFFICACY AND SAFETY  

Hollander et al (2013) assessed the efficacy and safety of 32mg naltrexone sustained-release (SR)/360mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetics drugs. 

Research design and methods: This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardised lifestyle intervention and were randomised 2:1 to NB or placebo. Coprimary endpoints were per cent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c,7% (53mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose and lipids.  

Results: In the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106kg, body-mass index (BMI) 37kg/m2, and HbA1c 8% [64mmol/mol]), NB resulted in significantly greater weight reduction (5 vs 1.8%; P<0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs 18.9% P<0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (0.6 vs 0.1% P<0.001), per cent of patients achieving HbA1C <7% (53mmol/mol)
(44.1 vs. 26.3%; P<0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42 vs 7%), constipation (17 vs 7%), and vomiting (18 vs 3%). No difference was observed between groups in the incidence of depression, suicidal ideation or hypoglycaemia. 

Conclusions: NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycaemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes. 

EFFECT ON WEIGHT LOSS 

Greenway et al (2010) looked at the effect of naltrexone plus bupropion on weight loss in overweight and obese adults in a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. 

Methods: Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m² and uncomplicated obesity or BMI 27-45 kg/m² with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the US. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32mg per day plus sustained-release bupropion 360mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16mg per day plus sustained release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward).  

Findings: 1 742 participants were enrolled and randomised to double-blind treatment (naltrexone 32mg plus bupropion, n=583; naltrexone 16mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1 453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was –1·3% (SE 0·3) in the placebo group, -6·1% (0·3) in the naltrexone 32mg plus bupropion group (p<0·0001 vs placebo) and-5·0% (0·3) in the naltrexone 16mg plus bupropion group (p<0·0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32mg plus bupropion (p<0·0001 vs placebo) and 186 (39%) assigned to naltrexone 16mg plus bupropion (p<0·0001 vs placebo).

The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32mg plus bupropion, 171 participants [29.8%]; naltrexone 16mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5mmHg in mean systolic and diastolic blood pressure was followed by a reduction of around 1mmHg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo. 

Billes et al reviewed the individual actions of naltrexone and bupropion in the brain and described how NB influenced food intake and produced weight loss. NB was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behaviour that affect body weight.  

Preclinical studies show that the naltrexone/bupropion combination acts in hypothalamic brain regions that regulate appetite and energy expenditure, while also influencing eating behaviour that is mediated by the reward system. The weight loss produced by NB is likely attributed to these dual actions. In clinical studies, a consistently substantial proportion of overweight and obese subjects responded to NB32 treatment with at least 5% or 10% weight loss. “These treatment responders are likely those who would benefit most from NB treatment in clinical practice,” the study authors stated.  

References available on request.  

LP 3853 10/2021