Contrave (Bupropion / Naltrexone)

What is Contrave?

Contrave is a combination, prescription weight-loss medication with two active components – bupropion and naltrexone. Individually, these active components are both approved by the U.S Food and Drug Administration (FDA) for various treatment indications:

• Bupropion (bupropion hydrochloride also sold under the brand names Wellbutrin and Zyban): Indicated for the treatment of seasonal affective disorder (SAD - a type of depression), depression and as an aid in the cessation of a smoking habit. This medication is primarily classed as an aminoketone antidepressant (dopamine / norepinephrine-reuptake inhibitor) but is also effective for decreasing appetite. Chemically this drug resembles the structure of diethylpropion (a stimulant that is chemically similar to amphetamine, which also works as an appetite suppressant and is able to influence the central nervous system). Bupropion is highly soluble in water and white in colour.

• Naltrexone (naltrexone hydrochloride): Indicated for the treatment of alcohol and opioid substance dependency (i.e. problems with addiction). This medication (which is classed as an opioid antagonist) is effective in blocking the narcotic effect of substances but can also alleviate food cravings and decrease appetite. Naltrexone is similar to another potent opioid antagonist – naloxone, which is often used to reduce the risk of misuse when prescribed with an opioid substance, helping to block or reverse the effects of the narcotic medication, making it less addictive. Naltrexone is also soluble in water and is white to yellowish in colour.

Manufactured as an extended-release, fixed-dose combination medication, each Contrave tablet contains 8mg of naltrexone and 90mg of bupropion. A rapidly-dissolving inert layer makes up the filler or bulking agent component (excipient) of each tablet.

Contrave was initially rejected by the FDA in 2011 due to a lack of sufficient long-term clinical study evaluating the impact of the drug on the cardiovascular system. Subsequent clinical research submitted provided enough safety and efficacy data for FDA approval in 2014.

The approved combination is classed as an anorexiant (i.e. an appetite suppressant drug). FDA approval essentially allows Contrave to be used for controlled weight management in the case of diagnosed weight-related medical conditions and obesity. The medication is typically prescribed by a medical doctor alongside a strategic plan involving physical exercise (usually increased amounts of regular activity) and a more nutritious diet (most often a reduced-calorie diet) to enable a person to effectively lose weight and maintain that which is lost thereafter.

Although Contrave’s two active components may be prescribed independently for the control of substance and depressive / mental conditions, Contrave is not indicated for such prescription uses and is not likely to be recommended by any medical professional in this regard. It is only recommended for weight control and will be carefully prescribed where patients show signs of other weight-related medical problems such as hypertension (high blood pressure), high cholesterol levels (dyslipidaemia) or type 2 diabetes.

Contrave should not be used alongside other substances or supplements intended for weight loss, including over-the-counter, prescription and herbal varieties. It is also not recommended that it be taken if a patient has uncontrolled hypertension, problems with seizures or an eating disorder. Individuals who have existing issues with opioid addiction (or any addiction to alcohol or drugs or are going through the various stages of withdrawal), or who are already taking other forms of narcotic medications or bupropion varieties (like Zyban or Wellbutrin) should also not combine these with Contrave. Such combinations in the system can result in various unwanted side-effects.

It has not been well established if Contrave is safe to use in children under the age of 18. Women who are pregnant should not take Contrave either.

Inactive ingredients in Contrave include:

• Colloidal silicon dioxide
• Crospovidone
• Edetate disodium
• Hydroxypropyl cellulose
• Hypromellose
• Lactose anhydrous
• Lactose monohydrate
• L-cysteine hydrochloride
• Magnesium stearate
• Microcrystalline cellulose
• Opadry II Blue
• FD&C Blue #2 aluminum lake (also known as FD&C Blue #2 indigo carmine – a common food colouring)

How does Contrave work?¹

Contrave’s pair of active components have a neurochemical effect which assists a person in achieving the ultimate goal of weight loss.

Bupropion is considered a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine (neurotransmitters or ‘chemicals’ that carry messages between cells that play an important role in mood, behaviour and weight regulation) in the brain and naltrexone is purely an opioid antagonist (i.e. it blocks the effects of opioids). Both affect areas of the brain that are involved in food intake regulation. These areas include the appetite regulatory centre – the hypothalamus, and the reward system – the mesolimbic dopamine circuit. In affecting these systems, Contrave:

• Helps to reduce appetite (and thereby food intake)
• Promotes satiety
• Improves energy expenditure.

In this way a safe amount of weight loss can be achieved.

Within the hypothalamus, pro-opiomelanocortin cells or neurons (POMC), located in the arcuate (bow-shaped or curved) nucleus of this region of the brain, produce alpha-MSH (a melanocyte-stimulating hormone) and beta-endorphin (an opioid). The production of alpha-MSH in turn activates MC4R (melanocortin-4 receptor) which is thought to help reduce appetite and stimulate improved energy expenditure. Beta-endorphins work to decrease the activity levels of the POMC cells by actively binding to MOP-R (mu-opioid receptors).

Bupropion, on its own enhances POMC cell production and stimulates the release of alpha-MSH and beta-endorphins. This increases dopamine activity in the brain. Naltrexone blocks or inhibits MOP-R, further increasing beta-endorphin interaction activity with POMC cells. The combination of these active components thus enhances the effect of POMC cells. Individually, each component has an appetite suppressing effect, which is enhanced when the two are combined. Food cravings and overeating can be better controlled and the dopamine reward system (i.e. the system that is responsible for the pleasure experienced when eating) regulated. 

Pharmacological mechanism of action
	Absorption	Metabolism	Distribution	Elimination
Bupropion	Peak absorption or concentration (single oral administration) occurs within 3 hours. Doses should never be taken with a high-fat meal as this increases the level of drug exposure in the system.	This medication is metabolised via the liver (Cytochrome P450 2B6 enzymes). Metabolites involved in this process include hydroxybupropion, erythrohydrobupropion and threohydrobupropion. All of these metabolites have a longer half-life (i.e. the time it takes for them to reach half the dose taken) than bupropion.	84% of the medication binds to plasma proteins.	87% of the medication is eliminated from the body via urine. 10% is excreted in faeces (stools). This substance has a half-life of 21 hours (i.e. this is the time it takes for the medication to reach half of its strength when a single oral dose is taken).
Naltrexone	Peak absorption or concentration (single oral administration) occurs within 2 hours. Doses should never be taken with a high-fat meal as this increases the level of drug exposure in the system.	This medication is metabolised via the liver (6-beta-naltrexol metabolite).	21% of the medication binds to plasma proteins.	53% – 79% of the medication dose is eliminated from the body via urine (the kidneys). This substance has a half-life of 5 hours (per single oral dose) – the 6-beta-naltrexol metabolite is slowly eliminated, circulating the body in higher concentrations than naltrexone.

Contrave use considerations in specific populations

• Race and gender: No specific clinical evidence appears to show any significant issues between different genders and ethnic groups taking Contrave. Pharmacological mechanisms of action appear the same for both men and women, of any race.
• Paediatric use: Contrave has not been sufficiently analysed for use in children under the age of 18 in clinical trials. Thus, use is not recommended.
• Senior citizens: An insufficient amount of study evidence has adequately evaluated the effects of Contrave in senior populations. Of the individuals assessed during drug trials, few were over the age of 65. No one older than 75 has been assessed either. Drug concentrations and risk factors may be similar to those who are of a younger age. However, single and multiple dose schedules can potentially increase the risk for an accumulation of bupropion and its metabolites in the system. In general seniors are more prone to medication sensitivity and adverse central nervous system reactions. In those with impaired kidney function the elimination of the medication may be problematic, and more so in older individuals. The general rule of thumb for all prescribing physicians is that Contrave prescriptions issued for senior populations will be carefully considered and patients periodically monitored.
• Individuals who smoke: There is no specific clinical evidence showing differences in the pharmacological mechanisms of the drug between smoking and non-smoking populations. Elimination of the medication also appears similar in both groups (i.e. no significant differences have been noted).
• Impaired liver function: Caution is warranted in individuals with hepatic difficulties, such as alcoholic liver disease or liver cirrhosis. Concentrations of naltrexone may increase to between 5 and 10-fold in individuals with liver impairment (compared to those with a healthy functioning liver)². The half-life of bupropion may be somewhat longer in these individuals. Studies conducted in this regard have been small, so caution will be exercised if Contrave is prescribed at all and smaller dosages recommended.
• Impaired kidney function: Plasma concentrations of the medication may increase significantly, especially if a patient shows signs of severe renal impairment. Caution may be exercised in individuals with mild to moderate kidney dysfunction. The medication may not be recommended for individuals with severe kidney function impairment or those receiving dialysis – no clinical studies have been conducted to assess individuals with end stage renal dysfunction either.

References:

^{1. US National Library of Medicine - National Institutes of Health. May 2011. Naltrexone SR/Bupropion SR (Contrave) - A New Approach to Weight Loss in Obese Adults: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138366/ [Accessed 23.08.2018]}

^{2. US National Library of Medicine - PubChem Open Chemistry Database. 24 June 2005. Naltrexone: https://pubchem.ncbi.nlm.nih.gov/compound/naltrexone#section=Top [Accessed 23.08.2018]}