Alcohol use disorder (AUD) is the umbrella term for a medical condition characterised by an impaired ability to stop or control alcohol consumption despite the negative social, occupational or health consequences.
The treatments for AUD can range from talking therapies to detox to medication. While drugs may be the lesser-known of the treatment options available to those living with AUD, they tap into a significant unmet need; of the estimated 586,780 dependent drinkers in England, only 18% are receiving treatment, while fewer than 10% of adults with AUD in the US receive treatment.
Alcohol is the third-leading preventable cause of death in the US; an estimated 95,000 people die from alcohol-related causes annually. Used in combination with psychological support, AUD medications hold great promise for recovery and preventing relapse – but limited awareness of drugs as a treatment option and a culture of stigma around alcoholism, means these medicines are severely underutilised.
Approved treatments for AUD
There are three drugs currently approved in both the UK and US for the treatment of AUD: naltrexone, acamprosate and disulfiram.
Disulfiram, marketed as Antabuse, was approved as an AUD treatment in 1949 in the US, and 1994 in the UK. The drug works as a deterrent; it increases the concentration of acetaldehyde, a toxic compound produced when alcohol is broken down in the body, causing unpleasant symptoms such as nausea and vomiting when alcohol is consumed.
The US FDA approved naltrexone as an oral medication for alcohol dependence in 1994 and as an extended-release injectable in 2006 before the drug became authorised in the UK in 2011. Initially developed in the 1960s to treat opioid addiction, naltrexone is used to manage AUD by reducing the cravings and pleasant sensations associated with drinking alcohol. The drug is sold under several brand names, including Vivitrol and ReVia.
Acamprosate received UK approval in 1995 and was approved for use in the US in 2011. The medicine, sold as Campral, is used to help patients maintain alcohol abstinence by reducing the urge to drink in those who have undergone an alcohol detox.
A fourth medication, the opioid antagonist nalmefene, was approved in the UK and Europe in 2013. Marketed as Selincro, the drug prevents the alcohol-induced release of dopamine to reduce the desire to continue drinking. Nalmefene is used to reduce the amount of alcohol consumed, rather than aid total abstinence.
AUD drugs in development
While naltrexone, acamprosate and disulfiram have been available for AUD patients for many years, the area is still one of significant unmet need – and pharmaceutical companies continue to seek out new alternatives.
Adial Pharmaceuticals, a US biopharmaceutical company focused on treatments for addiction, is developing an investigational, genetically targeted therapy for AUD. AD04 is a twice-daily oral drug that aims to decrease drinking levels through the reduction of cravings. Currently in Phase III trials across seven countries, AD04 was found to significantly reduce frequency of drinking, quantity of drinking and heavy drinking in a Phase II study.
Adial has developed a companion diagnostic genetic test to identify those who are most likely to benefit from treatment with AD04, and therefore enhance the likelihood of successful outcomes for patients.
The company hopes its investigational product will reduce the barriers currently faced by AUD patients seeking treatment. AD04 is designed for patients who wish to reduce or manage their alcohol consumption, rather than abstain completely – meaning adherence to treatment with AD04 could be better than that of currently approved drugs, which aim to see patients stop drinking alcohol entirely. The company also plans to eventually reduce the dosing requirement of the drug to just once daily.
GET73 is a naturally occurring neurotransmitter currently being investigated in Phase II trials as a potential treatment for AUD. Developed by Italy-based Laboratorio Farmaceutico, the molecule has been found to reduce voluntary alcohol intake, alcohol deprivation effect and anxiety-like behaviours in a study using rats.
French biotech Mapreg’s lead compound, MAP4343, is set to enter Phase II clinical trials in December 2021. The study, to be conducted in collaboration with the Scripps Research Institute and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), will evaluate the effect of six weeks of MAP4343 in conjunction with six weeks of behavioural counselling, as well as two follow-up visits, on participants with AUD.
An ‘off-switch’ for alcoholism?
Earlier this year, researchers in Australia made a breakthrough discovery in the search for new drugs to treat alcohol addiction. A study led by the Monash Institute of Pharmaceutical Sciences and the Florey Institute of Neuroscience and Mental Health found that habitual drinking and the likelihood of relapsing could be improved by targeting a specific receptor in the brain.
After performing genome-wide RNA sequencing and protein expression studies in human tissue samples from both people with AUD and non-drinkers to identify potential therapeutic targets, the team discovered that the M4 muscarinic acetylcholine receptor (mAChR) could reduce alcohol consumption in those who drink habitually.
Co-author of the study Professor Arthur Christopoulos said: “We have had a long-standing interest in the M4 receptor as a novel therapeutic target in the brain. Now that we know this protein can ameliorate habitual drinking patterns and the risk of relapse, we can move towards the next step, which is translating our findings into drug development.”
Barriers to medical treatment
Of the numerous factors preventing AUD patients from accessing medical treatment for their condition, one major obstacle is the under-prescription of these drugs. As many as 6% of US adults are living with AUD, yet only around 1.6% reported using medication for their condition. In the UK, less than 8% of service users receiving treatment for their alcohol use were prescribed an alcohol relapse prevention drug.
Dr Kim Donoghue, Department of Clinical, Educational and Health Psychology at University College London, says we need a better understanding of why AUD drugs are not routinely prescribed in the UK.
“There’s actually quite a bit in the US looking at the different reasons – there are a multitude of reasons – and for each service user there might be a different reason why they’re not being prescribed,” she says.
“But there has been very little in the UK to get to the bottom of why they’re not being prescribed. I definitely think that’s the first step, so that then we can look at solutions.”
Even when drugs are offered as a treatment option, the stigma associated with alcoholism and the burden of taking a medication that requires regular doses – the dosing regimen for acamprosate, for example, is two tablets three times a day – pose a significant barrier to recovery for those living with alcohol addiction.
Donoghue says convenience is “definitely an important factor” when it comes to improving patients’ adherence to AUD medication. As part of research looking at how adherence to acamprosate could be increased, Donoghue and her team spoke to people who had completed treatment for alcohol dependence about the reasons patients might not stick to their prescriptions.
“Some people mentioned that taking the afternoon dose is particularly difficult if they are at work, and not wanting to invite questions about why they were taking the medication,” she explains. “I think stigma is definitely a factor.”
Across the pond, AUD patients in the US face similar difficulties accessing medication. NIAAA director Dr George Koob tells Pharma Technology Focus there are a number of obstacles for both physicians and patients.
“Common reasons stated by physicians for not prescribing medications for AUD include a lack of training in the use of the FDA-approved options, a preference for referring patients to 12-step programmes or speciality care, uncertainty about the effectiveness of the medications, and in some cases stigma toward people with AUD in general,” Koob explains.
“Less is known about potential barriers on the part of patients … common reasons why people with AUD do not seek or accept help include not thinking treatment is needed, not being ready to stop, lack of insurance coverage, uncertainty about where to find help, and concerns about stigma.”
Despite evidence that these medications can be useful for patients with AUD, Koob says, “they remain underutilised”.
Donoghue echoes this point: “These medications have been found to be effective and help reduce relapse back to drinking, so I think it’s a real missed opportunity.”
AUD medications, provided alongside psychological support, can drastically reduce a patient’s alcohol consumption and dependence – but until the barriers to access are removed, these therapies will go largely unused, and many patients will go without the interventions that could help them recover from what is often a devastating addiction.