Alcohol Use Disorder – Evidence Based Recommendations for Diagnosis and Pharmacotherapy

DEFINITION OF ALCOHOL USE DISORDER

The DSM-5 defines Alcohol Use Disorder (AUD) as a problematic pattern of substance use, leading to clinically significant impairment or distress, with two or more of the following presenting in the same 12-month period:

1. Alcohol is taken in larger amounts or over a longer period than was intended.
2. Persistent desire or unsuccessful efforts to cut down or control alcohol use.
3. Significant time spent on activities relating to obtain or use alcohol or recover from its effects.
4. Craving alcohol.
5. Failure to fulfil role obligations because of recurring alcohol use.
6. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol.
7. Giving up important social, occupational, or recreational activities because of alcohol use.
8. Recurrent alcohol use in situations in which it is physically hazardous.
9. Continued alcohol use despite knowledge of recurring physical or psychological problems, likely caused by or exacerbated by alcohol.
10. Tolerance which is linked to a need for markedly increased amounts of alcohol to achieve the desired effect or a markedly reduced effect with the same continued use.
11. Withdrawal which is defined as either a characteristic withdrawal syndrome for alcohol or where withdrawal is avoided through the use of alcohol or a closely related substance (e.g., a benzodiazepine).

[American Psychiatric Association 2013] , [NIAAA 2021]

1. Mild alcohol use disorder: 2-3 criteria
2. Moderate alcohol use disorder: 4-6 criteria
3. Severe alcohol use disorder: 7-11 criteria met

Binge Drinking:

Binge drinking is defined as the consumption of >5 standard drinks on the same occasion for males and >4 for women.

In the US, one standard drink contains 0.6 fl oz or 14 gms of alcohol, while one standard drink contains 10 gms of alcohol in Australia. [NIAAA].  [NHMRC]

NHMRC Standard Drink Australia:

NIAAA Standard Drink US: 

Heavy alcohol use is defined as binge drinking on 5 or more days in the last month. [American Psychiatric Association 2013]

CHANGES TO THE DSM-5 CRITERIA

In May 2013, DSM-5 made the following changes : [NIAAA 2021]

• DSM-5 merged DSM-4 categories of ‘alcohol abuse’ and ‘alcohol dependence’ to form ‘alcohol use disorder’ with mild, moderate, and severe sub-categories.
• Legal problems were eliminated as a criterion
• Craving was added as a criterion

Assessment and diagnosis rates for alcohol use disorder have improved because of these changes, but treatment uptake remains inconsistent:

Although routine screening for heavy alcohol use can identify patients with alcohol use disorder (AUD) and has been recommended, only 1 in 6 US adults report ever having been asked by a health professional about their drinking behaviour.

Patients with AUD most commonly receive counseling. Medications are prescribed to less than 9% of patients who are likely to benefit from them, given evidence that they exert clinically meaningful effects and their inclusion in clinical practice guidelines as first-line treatments for moderate to severe AUD. [Kranzler and Soyka, 2018]

ETIOPATHOGENESIS OF ALCOHOL USE DISORDER

• 50% of alcohol use disorder risk is heritable, and around 50% is environment-related. [Verhulst et al. 2015]
• Alcohol dependence leads to neurochemical dysregulation in the basal forebrain (binge/intoxication phase), the extended amygdala (withdrawal phase), and the prefrontal cortex (preoccupation/anticipation phase).
• Dopamine reward transmission is decreased, and more alcohol is required to achieve the desired impact, leading to further compulsivity. [Noronha et al., 2014]
• Read more about  The Neurobiological Basis of Addiction – From Choice to Habit to Compulsion.

• Social and environmental stressors, including verbal, physical and sexual abuse, parental psychiatric illness, violence and substance use, were identified as strong risk factors for AUD [Dube et al., 2002], and patients often present in primary care, psychiatric outpatients, emergency departments or in medical/surgical inpatient settings. [Moyer 2013]

SCREENING AND DIAGNOSIS

To improve diagnosis rates, clinicians should routinely screen all adults over 18 for alcohol use, even if clinical or demographic risk factors are not present.

The three screening tools currently recommended for heavy alcohol use by the U.S. Preventative Services Taskforce include: [Moyer 2013]

• The Alcohol Use Disorders Identification Test (AUDIT)
• The AUDIT-C brief screening tool for heavy drinking, or;
• A single question: “How many times in the past year have you had 5 (for men)/4 (for women) alcoholic drinks in a day?”

Sensitivity and specificity were similar across all three (70-87% and 61-94% respectively) [Moyer 2013], demonstrating confidence in their clinical application.

Patients who screen positive for heavy alcohol use should be further assessed for AUD, and the severity of symptoms should then determine the most appropriate treatment approach. [Moyer 2013]

In patients experiencing alcohol withdrawal, clinicians should assess the severity and history of symptoms.

The CIWA-Ar can be used to measure its severity as treatment options differ based on severity. Download the CIWA-Ar.

The recent APA practice guideline for pharmacotherapy in alcohol use disorder is limited to moderate to severe populations. [Reus et al., 2018]

More studies are needed on the application of pharmacotherapy for mild AUD to help close this gap.

PHARMACOLOGICAL TREATMENTS FOR ALCOHOL USE DISORDER

It is estimated that only 8-9% of people who require treatment receive specialist help despite the considerable health and economic costs of AUD. [Kranzler and Soyka, 2018]

Medication is under prescribed [Mark et al., 2008], and most people needing support attend 12-step programmes, e.g., alcoholics anonymous, or counselling through primary care or other third sector organisations. [SAMHSA 2015]

In an RCT involving 170 patients with concurrent depression and AUD, combination pharmacotherapy yielded positive results. [Pettinati et al., 2010]  

Treatments given over 14 weeks included sertraline (200 mg/daily), naltrexone (100 mg/daily ), sertraline plus naltrexone or double placebo (n=39).

Abstinence rates were higher in the combination group (53.7%), with a median average of 98 days between relapses. Those in the naltrexone only, sertraline only and placebo groups showed similar respective rates of 21.3% and 26 days; 27.5% and 23 days; 23.1% and 26 days, indicating the possible benefits of combining medications to treat concurrent AUD and psychiatric disorders. [Pettinati et al., 2010]

In one of the most extensive alcohol pharmacotherapy trials to date, the COMBINE study, alcohol-related problems directly correlated with participants binge-drinking days and when binges reduced, so did many of the corresponding social complications. [Anton et al., 2006]

The study showed that while abstinence was linked to better health and social outcomes, individuals were more likely to benefit from treatments if clinicians took a ‘harm-reduction’ approach instead of forced abstinence.[Anton et al., 2006]

Disulfiram

• Disulfiram was approved in 1949 for the treatment of AUD. It works by inhibiting aldehyde dehydrogenase (ALDH), which metabolises the toxic alcohol byproduct acetaldehyde to acetate.
• This inhibition leads to elevated acetaldehyde levels, leading to a disulfiram-ethanol reaction (DER) of sweating, vomiting, nausea, hypotension and palpitations, and, rarely, cardiovascular complications. [Kranzler and Soyka, 2018]
• In a meta-analysis of 22 RCTs [n=2,414], the efficacy of disulfiram was superior to controls only in open-label studies and not statistically significant in blinded trials.
• Although the evidence does not currently support the use of disulfiram for the treatment of AUD, it may be useful for supervised use as better outcomes were reported in trials where medication was supervised. [Skinner et al., 2014]
• In an older study, adverse events such as drowsiness were reported in around 8% of cases where participants received 250mg of disulfiram per day. [Fuller et al., 2017]
• More serious (but rarer) adverse events included hepatitis, optic neuritis, peripheral neuropathy, confusion, and psychosis. Because of these risks, regular physician contact is advised, and disulfiram should be used with extreme caution. [Chick 1999]

Naltrexone

• Naltrexone reduces alcohol consumption by reducing mesolimbic opioidergic activity and modulating the dopamine-mediated reward response. [Read a detailed article on the psychopharmacology of naltrexone]

• The FDA approved its use for alcohol dependence following two 12-week RCTs where either naltrexone 50mg/day or placebo were prescribed over 12 weeks. [O’Malley et al., 1992,] [Volpicelli et al., 1992]
• Common adverse reactions of oral naltrexone include somnolence, nausea, vomiting, abdominal pain, insomnia and dizziness. [Rosner et al., 2010]
• In a meta-analysis of 16 studies (N=2,347), naltrexone was deemed efficacious in reducing both the risk of drinking relapse and in 19 studies (N=2,875) a return to binge drinking. Though the results were statistically significant, they were relatively modest in size. [Jonas et al., 2014]
• In a multicentre RCT of 624 participants, a long-acting injectable formulation of naltrexone was tested: Two doses were available (190mg/monthly and 380mg/monthly). Results showed that binge-drinking days reduced from 19.3 days per month (pre-treatment) to 3.1 days per month in the 380 mg group, 4.5 days in the 190 mg group, and 6 days in the placebo group. [Garbutt et al., 2005]
• Long-acting injectable naltrexone (once a month) was also shown to prolong abstinence. It reduced the number of heavy drinking days and drinking days in abstinent patients for as few as 4 days before treatment initiation. [O’Malley et al., 2007]
• The FDA subsequently approved the use of long-acting naltrexone injectable AUD. Because it is an opioid receptor antagonist that blocks the reinforcing effects of opioids, it is also approved for Opioid Use Disorder. [SAMHSA]

Acamprosate

• Acamprosate is an FDA approved treatment that sustains alcohol abstinence by modulating glutamatergic neurotransmission via an indirect allosteric effect on GABA transmission that may be mediated by the inhibition of GABA type B receptors in the nucleus accumbens.
• Acamprosate treatment is generally well-tolerated as it does not interact with other psychotropic drugs, and only diarrhoea was a more common reported symptom when compared to placebo. [Rosner et al., 2010]
• In 16 meta-analyses, acamprosate was associated with a reduced drinking risk among abstinent patients (N=4,847), but no reductions in binge drinking. [Jonas et al., 2014]

Nalmefene: 

• Nalmefene is a kappa-opioid receptor partial agonist and a mu- and delta-opioid receptor antagonist.
• FDA approval was granted following three multicentre European trials. Nalmefene was prescribed for women drinking >40 g ethanol or 3 standard drinks per day and in men >60 g or 4 standard drinks per day.
• In a meta-analysis, nalmefene treatment was associated with a reduction of 1.65 more binge drinking days/month than placebo at 6 months and 1.60 more binge drinking days/month at 1 year.
• Total alcohol consumption at 6-months also reduced modestly. [Palpaceuer et al., 2015]
• However, the conclusion did not support the use of nalmefene for alcohol dependence. [Palpaceuer et al., 2015]
• Common side effects include nausea, dizziness, insomnia, headache, vomiting, fatigue and somnolence. [van den Brink et al., 2015]
• The National Institute for Clinical Excellence (NICE) was criticised for approving nalmefene due to retrospective identification and analysis of patient data and a paucity of studies using an active comparator such as naltrexone. [Naudet et al., 2016]

Baclofen:

• Baclofen is a GABA-B receptor agonist approved by the FDA to reduce spasticity linked to neurodegeneration.

Meta-analysis data from 13 RCTs (N=1492) indicated that baclofen was effective in:

• Increasing the time between first drinking lapses
• Increased likelihood of abstinence during treatment
• Greater chance of abstinence than placebo. (non-significant)
• Doses <60 mg/day yielded the best effects in patients who drank more heavily at treatment onset. [Pierce et al., 2018]
• Sedation remains a significant concern in high doses of baclofen [Reynaud et al., 2017]. Common side effects include drowsiness, dizziness, headache, confusion, muscle stiffness, excessive sweating, pruritis, abnormal muscle movements, numbness and slurred speech. [Hauser et al., 2017]

Gabapentin: 

• Gabapentin is approved to treat neuropathic pain and epilepsy, but data for AUD are limited to three placebo-controlled RCTs involving just 231 patients. [Leung et al., 2015]
• In the largest trial (n=150), gabapentin (doses of 900 or 1800 mg/day) was compared to placebo over 12 weeks. Abstinence rates were highest in the high-dose group, 17.1%, compared with 11.1% in the low-dose group and 4.1% for placebo. [Mason et al., 2013]
• Common side effects include dizziness, somnolence, ataxia, and peripheral oedema [Wiffen et al., 2017].
• Approximately 1% of the general population are thought to use gabapentin recreationally or as a means of self-medication or self-harm. [Smith et al., 2016]

Topiramate

• Topiramate is known to modulate the brain’s dopamine reward pathways by acting as an antagonist of excitatory glutamate receptors at a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors and inhibiting dopamine release within the mesocorticolimbic system while enhancing inhibitory GABA (by binding to a site of the GABA-A receptor). [Paparrigopoulos T et al., 2011]
• Topiramate is FDA approved to treat seizures, prevent migraine, and weight loss (when given with phentermine). [Read about management strategies for weight gain in psychiatry]
• In a meta-analysis of 7 RCTs (n=1,125), topiramate was associated with greater abstinence and lower binge drinking rates than placebo. [Blodgett et al., 2014]
• When topiramate was compared to naltrexone, it was associated with a significantly higher reduction in aggregated binge drinking rates. [Blodgett et al., 2014]
• Low-dose topiramate (up to 75 mg /day) as an adjunct to psychotherapeutic treatment is well tolerated and effective in reducing alcohol craving and symptoms of depression and anxiety. Furthermore, topiramate helps to abstain from drinking during the first 16-week post-detoxification period. [Paparrigopoulos T et al., 2011]
• Common side effects of topiramate include paraesthesia, dysgeusia, anorexia, concentration and memory difficulties (dose-related), including mental and verbal slowness, nervousness, dizziness and pruritis. [Johnson et al., 2007]

With regards to controlled drinking, a meta-analysis examining nalmefene, naltrexone, acamprosate, baclofen or topiramate in patients with alcohol dependence or alcohol use disorder concluded that there is currently no high-grade evidence for pharmacological treatment for controlled drinking. However, nalmefene, baclofen and topiramate showed efficacy over placebo.

Naltrexone and Acamprosate were not efficacious. Indirect comparisons found topiramate to be more efficacious than nalmefene, naltrexone and acamprosate on consumption outcomes  [Palpacuer et al., 2018]

In general, except for acamprosate and naltrexone, the number of RCTs testing the efficacy of AUD treatments is imperfect. For example, they have not tested optimal treatment duration, stepped approaches, or combination therapy for poor or non-responders. Methodologies also differ between studies, making accurate comparisons and clinical projections very difficult.

PHARMACOGENETICS & ALCOHOL USE DISORDER

In the last 10 years, genetic advances have allowed clinicians to recognise alcohol-related polymorphisms [Jones et al., 2015] and indirect alcohol biomarkers that detect alcohol’s toxic effects. Those discovered so far include: [SAMHSA, 2015]

• Aspartate aminotransferase (AST)
• Alanine aminotransferase (ALT)
• Gamma-glutamyltransferase (GGT)
• Mean corpuscular volume (MCV)
• Carbohydrate-deficient transferrin (CDT)

However, despite the emergence of valuable data, findings are conflicting and inconsistent limiting the use of pharmacogenetics for the personalisation of AUD treatments. [Jones et al., 2015]

Learn more on pharmacogenomics in psychiatry. 

PSYCHOSOCIAL AND MEDICAL TREATMENTS COMBINED

Brief psychosocial interventions, including cognitive behavioural therapy (CBT), motivational therapy, behavioural and family therapies lasting around 20 minutes, are the most feasible treatments for AUD in clinical settings.

More intense treatment may be more effective when delivered by a trained therapist in conjunction with alcohol treatment issued by a medical prescriber. However, as only a few studies compare degrees of therapy intensity, optimal recommendations are not possible. [Petry et al., 2014]

During the four-month treatment period in the COMBINE study (n=1,383), 68.2% of naltrexone-treated patients had ≥1 binge drinking day compared to 71.4% of placebo patients (P=0.02). [Anton et al., 2006]

Naltrexone-treated patients who had brief therapy were abstinent on 80.6% of days compared to 75.1% in the placebo group, though medication efficacy was not enhanced. As a result, brief psychosocial intervention and a first-line alcohol treatment medication or referral for specialised psychotherapy can help patients reduce their drinking frequency and binge-drinking risk.

RECOMMENDED TREATMENT APPROACHES

Current guidelines for moderate drinking advise consuming no more than 2 drinks/day for men and 1/day for women with no bingeing. However, the threshold for the lowest risk of all-cause mortality was about 100 g per week (10 standard drinks in Australia). The highest risk for all-cause mortality was for drinkers of beer or spirits, as well as binge drinkers. This data supports the adoption of lower limits of alcohol consumption than are recommended in most current guidelines. [Wood et al., 2018]

Therefore, patients diagnosed with alcohol use disorder should be advised to cut down or stop drinking significantly. [USDHHS 2015]

The US FDA has approved three oral medications for the treatment of AUD: disulfiram, acamprosate and naltrexone, as well as an injectable version of naltrexone. Topiramate, in addition, also has clinical utility and should be considered in AUD.

FDA approved drugs, disulfiram, naltrexone, and acamprosate, should only be offered to patients with moderate to severe alcohol use disorder under guidance issued by the American Psychiatric Association (APA). [Reus et al., 2018]

Naltrexone is well-tolerated alongside brief therapies [Anton et al., 2006], and longer abstinence periods may be achieved through long-acting naltrexone or topiramate treatment. [O’Malley et al., 2007]., [Blodgett et al., 2014]

Topiramate, disulfiram, acamprosate, and naltrexone were also approved as first-line treatments for veterans with a substance misuse disorder following a significant increase in topiramate use. [Department of Veterans Affairs 2015]

Evidence herein supports the use of naltrexone to reduce binge drinking risk and acamprosate to maintain abstinence, but disulfiram should be limited to cases requiring supervised administration only.

Gabapentin and topiramate are only recommended for patients who do not tolerate first-line treatments. [Reus et al., 2018]

More intensive counselling is recommended when patients show limited or poor treatment responses.

PROGNOSIS

CONCLUSIONS

Alcohol use is linked to high morbidity and mortality rates, and high alcohol consumption is the major risk factor for AUD. Simple screening can identify heavy alcohol users, who can then be assessed for AUD. [Kranzler and Soyka, 2018]

Patients diagnosed should be offered brief counselling, first-line medication (e.g. naltrexone), or more intensive psychosocial intervention. [Kranzler and Soyka, 2018]

Harm reduction approaches are much more effective than abstinence models, especially for those with concurrent psychiatric disorders or multiple social stressors. [Anton et al., 2006]

Lack of sufficient evidence to support the use of pharmacogenetics to personalize AUD treatments, and more research is needed around pharmacogenetics to substantiate the recent breakthroughs in genetic marker identification.