ALCOHOL USE DISORDER

• ACRONYMS AND DEFINITIONS

• APA - American Psychiatric Association
• AUD - Alcohol use disorder
• CIWA-Ar - Clinical Institute Withdrawal Assessment, Revised
• DSM - Diagnostic and Statistical Manual
• IM - intramuscular
• NIAAA - National Institute on Alcohol Abuse and Alcoholism
• NIDA - National Institute on Drug Abuse
• SADQ - Severity of Alcohol Dependence Questionnaire
• SAWS - Short alcohol withdrawal scale

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• DEFINITIONS

• Drink definition - one drink is defined as the following:
• Beer (∼ 5% alcohol): 12 oz (354 ml)
• Malt liquor (∼ 7% alcohol): 8 oz (237 ml)
• Wine (∼ 12% alcohol): 5 oz (148 ml)
• Hard liquor (80 proof = 40% alcohol): 1.5 oz (44 ml)
• A pint is 16 oz (473 ml) of hard liquor and contains 11 drinks
• A fifth is 25 oz (739 ml) of hard liquor and contains 17 drinks
• A handle bottle has 59 oz (1.75 L) of hard liquor and contains 39 drinks

• Binge drinking - consumption of ≥ 5 drinks on one occasion for males and ≥ 4 drinks for females

• Heavy alcohol use - binge drinking on 5 or more occasions in the last month [1]

• Alcohol use disorder - drinking that leads to significant impairment or distress. See alcohol use disorder criteria below.

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• EPIDEMIOLOGY

• Data from observational studies and surveys have found the following about alcohol abuse:
• 10 - 15% of adults (≥ 15 years old) in the U.S. meet criteria for alcohol use disorder (see diagnosis)
• 26.2% of adults in the U.S. report at least one episode of binge drinking (≥ 4 drinks/women | ≥ 5 drinks/men) during the preceding month
• Alcohol is a contributing factor in about 10% of deaths in the U.S.
• Globally, alcohol use disorders affect 8.6% of men and 1.7% of women [1,2]

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• RISK FACTORS

• Family history - most important risk factor; in studies, up to 50% of people with alcohol use disorder have an affected family member
• Male sex - men are affected five times more than women
• Childhood stressors (e.g. physical, emotional, and sexual abuse)
• Lower socioeconomic status
• Impulsive personality
• Parental drinking
• Social acceptance of drinking [1,2]

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• PATHOLOGY

• The effects of alcohol in the brain primarily occur through enhanced dopamine release and the stimulation of gamma-aminobutyric acid (GABA) receptors. GABA receptor stimulation dampens overall brain activity, and increased dopamine levels stimulate reward systems in the mesolimbic dopamine areas. Alcohol also affects the opioid, cannabinoid, glutamate, serotonin, and norepinephrine systems.
• Genetic differences in the components of these systems affect individual responses to alcohol [1,2]

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• SCREENING

• Overview
• The USPSTF recommends that all adults 18 years and older and pregnant women be screened for unhealthy alcohol use. Despite this guidance, only 1 in 6 U.S. adults reports ever being asked about alcohol consumption by their primary care provider.
• Three screening tools recommended by the USPSTF are described below. If a screening test is positive, patients should then be evaluated for alcohol use disorder using the DSM-5 criteria (see DSM-5 criteria below).

• Alcohol Use Disorders Identification Test (AUDIT)
• AUDIT is a 10-item alcohol use screening tool that can be administered by providers or given to the patient to fill out. AUDIT scores range from 0 to 40, and a score of 8 or more indicates possible harmful alcohol use.
• AUDIT pdf from the NIDA with patient and provider forms

• Alcohol Use Disorders Identification Test–Consumption (AUDIT-C)
• AUDIT-C is an abbreviated version of the AUDIT that contains the first 3 AUDIT questions. In trials, it has been found to be equally as accurate as the full AUDIT. AUDIT-C scores range from 0 to 12, and in men, a score of 4 or more indicates possible harmful alcohol use. In women, a score of 3 or more is considered positive.
• AUDIT-C pdf
• Online AUDIT-C tool from MDCalc

• Single question screening
• Patients can be screened by asking a single question such as "How many times in the past year have you had 5 (for men) or 4 (for women) or more drinks in a day?" One or more episodes is considered positive. [3,4]

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• DIAGNOSIS

• DSM-5 alcohol use disorder diagnostic criteria
• The DSM-5 AUD criteria are widely used to diagnose and qualify alcohol abuse. The criteria consist of 11 true or false items that pertain to alcohol use, and AUD is categorized as mild, moderate, or severe based on the number of symptoms present.
• Mild: 2 to 3 symptoms present
• Moderate: 4 to 5 symptoms present
• Severe: ≥ 6 symptoms present
• The table below lists the criteria as they are described in the DSM-5. A link to a pdf form that presents the items as questions to the patient is also provided.


• DSM-5 AUD criteria patient questionnaire (pdf)

• Reference [1]

DSM-5 Alcohol Use Disorder Criteria
Alcohol use disorder is diagnosed based on the presence (within the past 12 months) of the 11 symptoms detailed below. The severity of AUD is defined as follows: Mild: 2 to 3 symptoms present Moderate: 4 to 5 symptoms present Severe: ≥ 6 symptoms present
Alcohol is often taken in larger amounts or over a longer period than was intended
There is a persistent desire or unsuccessful efforts to cut down or control alcohol use
A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects
Craving or a strong desire or urge to use alcohol
Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home
Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol.
Important social, occupational, or recreational activities are given up or reduced because of alcohol use
Recurrent alcohol use in situations in which it is physically hazardous
Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol.
Tolerance, as defined by either of the following: A need for markedly increased amounts of alcohol to achieve intoxication or desired effects A markedly diminished effect with continued use of the same amount of alcohol
Withdrawal, as manifested by either of the following: The characteristic withdrawal syndrome for alcohol Alcohol (or closely related substance, such as benzodiazepine) taken to relieve or avoid withdrawal symptoms

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• ACUTE TREATMENT

• Outpatient vs inpatient
• When treating alcohol use disorder, it's important to evaluate a patient's risk of having severe withdrawal symptoms, which may include seizures, hallucinations, metabolic disorders, and even death. High-risk patients should receive inpatient care, while other patients may be treated as outpatients.
• The patient's previous history of withdrawal symptoms can help make this determination, as can a tool called the Severity of Alcohol Dependence Questionnaire (SADQ).
• In general, stable patients who have not had a drink in more than 5 days may be treated as outpatients [5]

• Withdrawal symptoms
• In heavy drinkers, alcohol withdrawal symptoms typically begin within 24 - 48 hours of quitting and can last for 5 - 7 days. The table below groups symptoms by their severity.

• Reference [5,6]

Alcohol withdrawal symptoms (typically begin within 24 - 48 hours)
Mild symptoms
Anxiety / Irritability / Agitation Tremor Insomnia Headache Palpitations Nausea and vomiting Decreased appetite
Moderate symptoms
Sweating Increase in blood pressure Shortness of breath Tachycardia Difficulty focusing or concentrating Mild confusion Sensitivity to light, sound, or tactile sensations
Severe symptoms (delirium tremens)
Disorientation / Confusion Hallucinations (visual or auditory) Delusions (usually paranoid or persecutory) Hyperthermia Seizures

• Indications for inpatient detox
• Patients with any of the following features are at increased risk for severe alcohol withdrawal
• History of delirium tremens (hallucinations, confusion)
• History of alcohol withdrawal seizure(s)
• History of numerous prior withdrawal episodes
• Symptoms of autonomic hyperactivity (e.g. high BP, tachycardia, sweating with blood alcohol level > 100 mg/100 ml [BAC > 0.10])
• Severe withdrawal symptoms
• Age > 65 years
• Long-term daily consumption of ≥ 20 drinks
• SADQ score > 30
• AUDIT score ≥ 20
• CIWA-Ar score ≥ 10 on presentation
• Concomitant benzodiazepine use/abuse
• Other significant psychiatric diagnosis (e.g. major depression, suicidal, psychosis)
• History of non alcohol-related seizures
• Concomitant acute illness (e.g. pneumonia)
• Concomitant poorly-controlled chronic medical problem (e.g. diabetes, COPD, heart failure) [5,7,8,15]

• SADQ assessment
• The Severity of Alcohol Dependence Questionnaire (SADQ) is a tool that can be used to predict the potential severity of alcohol withdrawal based on a patient's response to 20 questions. SADQ scores range from 0 to 60, and the following is true:


• Score ≤ 15: acute withdrawal treatment is not typically needed
• Score 16 - 30: acute treatment with medications may be needed but can typically be managed as an outpatient as long as there are no indications for inpatient treatment (see inpatient indications above)
• Score > 30: inpatient detox indicated


• Links to pdf and online versions of the tool are available below
• SADQ pdf (ZenaMed)
• SADQ pdf (SMART charity)
• SADQ online calculator from MDApp

• Indications for acute withdrawal treatment
• Medications are used to treat and prevent moderate to severe withdrawal symptoms. Benzodiazepines are most commonly prescribed, while other therapies, including anticonvulsants and medicines that suppress autonomic hyperactivity (e.g. clonidine, beta blockers), may be appropriate in some patients. Chronic alcoholics may also require thiamine (100 mg/day) and folic acid (1 mg/day) supplements. Benzodiazepines should only be used to treat acute withdrawal and are not recommended for chronic AUD treatment.
• Indications for acute withdrawal treatment are listed below. Patients who have not had a drink in ≥ 5 days and are not experiencing severe symptoms do not typically need acute treatment. [5,8]
• Indications for acute withdrawal treatment
• Patients requiring inpatient detox
• Patients with SADQ score of 16 - 30
• Patients with moderate-to-severe withdrawal symptoms

• Medication regimens
• Benzodiazepines are most commonly used to treat acute alcohol withdrawal. Dosing may be fixed or given on a symptom-triggered basis. For inpatients, symptom-triggered dosing based on periodic patient assessment is typically used, and studies have found that this method leads to lower cumulative benzodiazepine doses. For outpatients, objective symptom assessment is not always available, so fixed regimens may be more desirable. Providers should warn patients that benzodiazepines should not be taken if the patient starts to drink again. In addition, only short courses of benzodiazepines should be prescribed to help prevent abuse.
• Diazepam and chlordiazepoxide are often recommended because they have longer half-lives (up to 48 hours), and this can help to prevent breakthrough symptoms. Lorazepam, which has an intermediate half-life (12 hours), undergoes minimal hepatic metabolism and may be preferred in patients with liver disease. Lorazepam may also be preferred in patients being treated with disulfiram because disulfiram can inhibit the metabolism of diazepam and chlordiazepoxide.
• The table below provides dosing regimens for diazepam, chlordiazepoxide, and lorazepam. Information on gabapentin and carbamazepine, which have also been studied in alcohol withdrawal, is also provided. When treating alcohol withdrawal, ongoing symptom assessment should be performed, and several tools that can facilitate this are detailed below (see ongoing assessment).

• References [5,9,10,12,13,14,15]

Medications for acute alcohol withdrawal
Chlordiazepoxide (Librium®) Dosage form - capsule 5 mg 10 mg 25 mg Fixed dose regimen Day 1: 25 - 100 mg four times daily Day 2: 25 - 100 mg three times daily Day 3: 25 - 100 mg twice daily Day 4: 25 - 100 mg at bedtime Symptom-triggered regimen Day 1: 25 - 100 mg every 4 - 6 hours as needed Day 2: 25 - 100 mg every 6 - 8 hours as needed Day 3: 25 - 100 mg every 12 hours as needed Day 4: 25 - 100 mg at bedtime as needed Dose amount based on CIWA-Ar CIWA-Ar < 10: 25 - 50 mg CIWA-Ar 10 - 18: 50 - 100 mg CIWA-Ar ≥ 19: 75 - 100 mg Other Peak plasma concentration: 2 hours Half-life: 24 - 48 hours Disulfiram increases chlordiazepoxide exposure See chlordiazepoxide for more
Diazepam (Valium®) Dosage form - tablet 2 mg 5 mg 10 mg Fixed dose regimen Day 1: 10 mg three or four times a day Day 2: 10 mg three times daily Day 3: 10 mg twice daily Day 4: 10 mg at bedtime Day 5: 5 mg at bedtime Symptom-triggered regimen Day 1: 10 mg every 6 hours as needed Day 2: 10 mg every 8 hours as needed Day 3: 10 mg every 12 hours as needed Day 4: 5 - 10 mg every 12 hours as needed Day 5: 5 mg every 12 hours as needed Other Peak plasma concentration: 1 - 1.5 hours Half-life: Diazepam - up to 48 hours Active metabolite - up to 100 hours Half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age Disulfiram decreases the clearance of diazepam See diazepam for more
Lorazepam (Ativan®) Dosage form - tablet 0.5 mg 1 mg 2 mg Fixed dose regimen Day 1: 2 mg every 8 hours Day 2: 2 mg every 8 hours Day 3: 1 mg every 8 hours Day 4: 1 mg every 12 hours Day 5: 1 mg at bedtime Symptom-triggered regimen Day 1: 2 mg every 6 hours as needed Day 2: 2 mg every 6 hours as needed Day 3: 1 mg every 8 hours as needed Day 4: 1 mg every 12 hours as needed Day 5: 1 mg every 12 hours as needed Other Peak plasma concentration: 2 hours Half-life: 12 hours Lorazepam undergoes minimal hepatic metabolism and may be preferred in patients with liver disease Disulfiram does not appear to affect the metabolism of lorazepam See lorazepam for more
Gabapentin (Neurontin®) Dosage form Tablet 100 mg 300 mg 400 mg 600 mg 800 mg Capsule 100 mg 300 mg 400 mg Dosing Small studies have looked at the use of gabapentin for treating alcohol withdrawal. In general, these studies have found that gabapentin is effective in patients with mild to moderate symptoms but should probably not be used in patients with severe symptoms. For outpatient treatment of mild to moderate symptoms, gabapentin may be a good choice for those at risk for benzodiazepine abuse. A study that compared gabapentin to lorazepam (N=100) found that gabapentin was equally effective in treating withdrawal symptoms. [PMID 19485969] Dosing used in that trial was as follows: Days 1 - 3: 300 - 400 mg three times daily Days 4 and on: 300 - 400 mg twice daily Rescue packs were provided that contained two 100 mg doses and one 300 mg dose for use on Day 1. The 300 mg dose was to be reserved for evening or night use. On Days 2 - 4 the gabapentin rescue packs provided three 100 mg doses. Other Peak plasma concentration: 2 - 3 hours [11] Half-life: 5 - 7 hours See gabapentin for more
Carbamazepine (Tegretol®) Dosage form (tablet) 100 mg 200 mg 300 mg 400 mg Dosing Small studies have found carbamazepine to be effective at treating alcohol withdrawal symptoms. For outpatient treatment, carbamazepine may be a good choice for patients who are at risk for benzodiazepine abuse. A study that compared carbamazepine to lorazepam (N=136) in outpatients with moderate alcohol withdrawal found that carbamazepine was equally effective in treating withdrawal symptoms and superior at preventing rebound symptoms and post-treatment drinking. [PMID 12047731] Typical dosing in trials was as follows: Starting dose of 600 - 800 mg/day tapered to 200 mg/day over 5 - 9 days. Carbamazepine can be given in 3 - 4 divided doses. Other See carbamazepine for more

• Treatment assessment
• Once alcohol withdrawal treatment is started, patients should be assessed for ongoing symptoms on at least a daily basis. A number of tools have been developed to assist with this. The Clinical Institute Withdrawal Assessment, Revised (CIWA-Ar) tool is one of the most widely recognized and validated tools. It can be used in outpatient and inpatient settings, but it is intended to be administered by a healthcare professional. Another tool, the Short Alcohol Withdrawal Scale (SAWS), is self-administered, which makes it convenient for outpatient/telemedicine use. Both tools are described below.

• Clinical Institute Withdrawal Assessment, Revised (CIWA-Ar)
• CIWA-Ar is intended to be administered by a healthcare professional. CIWA-Ar has 10 components and a score that ranges from 0 to 67. Categories of withdrawal based on CIWA-Ar scores are as follows:
• CIWA-Ar < 10: Mild withdrawal. Medications may be tapered/reduced. Patients who are not receiving medications do not typically need them.
• CIWA-Ar 10 - 18: Moderate withdrawal. Pharmacotherapy is indicated.
• CIWA-Ar ≥ 19: Severe withdrawal. Inpatient detox is indicated.


• Online CIWA-Ar calculator
• CIWA-Ar PDF version

• Short alcohol withdrawal scale (SAWS)
• SAWS is self-administered, which makes it more amenable to outpatient treatment. SAWS assesses 10 symptoms, and each symptom is scored from 0 (none) to 3 (severe). Categories of withdrawal based on SAWS totals are as follows:
• SAWS < 12: Mild withdrawal. Medications may be tapered/reduced. Patients who are not receiving medications do not typically need them.
• SAWS ≥ 12: Moderate to severe withdrawal. Pharmacotherapy is indicated. Some patients may need inpatient detox.


• SAWS questionnaire (pdf)

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• CHRONIC TREATMENT

• Overview
• Like any drug addiction, the treatment of alcohol use disorder is difficult. That being said, studies have shown that adults who receive treatment have a better chance of achieving abstinence. Treatment primarily consists of two components - psychosocial therapy (e.g. counseling, AA) and medications. Overall, treatment is greatly underutilized, with only about 8% of patients with alcohol use disorder receiving any type of formal therapy. [1]

• Psychosocial
• A number of psychosocial resources are available for patients with AUD. The NIAAA has a website that helps people who are interested in AUD treatment find care. Links to relevant pages on the website are provided below.
• AUD treatment overview
• Finding AUD treatment providers
• AUD support groups (e.g. AA, LifeRIng, etc.)

• Medications
• Acamprosate, disulfiram, and naltrexone are FDA-approved for the chronic treatment of AUD. Gabapentin and topiramate have also been studied. Recommendations for their use from the APA are provided below.

• APA 2018 AUD treatment recommendations
• Naltrexone or acamprosate are preferred and should be offered to patients with moderate to severe alcohol use disorder who
• have a goal of reducing alcohol consumption or achieving abstinence,
• prefer pharmacotherapy or have not responded to nonpharmacological treatments alone, and
• have no contraindications to the use of these medications.
• Disulfiram may be offered to patients with moderate to severe alcohol use disorder who
• have a goal of achieving abstinence
• prefer disulfiram or are intolerant to or have not responded to naltrexone and acamprosate
• are capable of understanding the risks of alcohol consumption while taking disulfiram, and
• have no contraindications to the use of this medication
• Topiramate or gabapentin may be offered to patients with moderate to severe alcohol use disorder who
• have a goal of reducing alcohol consumption or achieving abstinence,
• prefer topiramate or gabapentin or are intolerant to or have not responded to naltrexone and acamprosate, and
• have no contraindications to the use of these medications
• Antidepressants and benzodiazepines should not be used specifically to treat AUD [17]

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• ACAMPROSATE

• Overview
• Acamprosate is FDA-approved for the treatment of AUD. Its mechanism in treating AUD is believed to occur through its interaction with glutamate and GABA neurotransmitter systems in the CNS. Chronic alcohol use alters the normal balance between these systems, and acamprosate helps restore equilibrium. [13]

• Dosage form
• 333 mg delayed-release tablet
• Generic available | 180 tablets cost $50 - $100

• Dosing
• Check serum creatinine before starting therapy
• CrCl > 50 ml/min: 666 mg (2 tablets) three times daily
• CrCl 30 - 50 ml/min: 333 mg three times daily
• CrCl ≤ 30 ml/min: DO NOT USE
• Lower doses may be effective in some patients
• Treatment should be started immediately after alcohol withdrawal and maintained if the patient relapses
• Treatment is usually for 6 months but may be longer for those who are benefiting
• Acamprosate can be used in patients with liver disease
• May take without regard to food [8,13]

• Side effects
• In trials, side effects of acamprosate were similar to placebo, with only diarrhea (16% vs 10%) occurring at a rate that was greater than 1% more than placebo. [13]

• Contraindications / Precautions
• Kidney disease - acamprosate is eliminated primarily through the kidneys
• CrCl > 50 ml/min: no dose adjustment necessary
• CrCl 30 - 50 ml/min: starting dose should be 333 mg three times daily
• CrCl ≤ 30 ml/min: DO NOT USE


• Suicidality and depression - in controlled trials lasting one year, suicidal events were reported in 2.4% of acamprosate-treated patients and 0.8% of placebo-treated patients. Many of the events occurred in the context of alcohol relapse. Patients taking acamprosate should be monitored for depressive symptoms. [13]

• Drug interactions
• Acamprosate has no known drug interactions. Acamprosate does not affect the pharmacokinetics of alcohol. The pharmacokinetics of acamprosate are not affected by alcohol, diazepam, or disulfiram, and clinically important interactions between naltrexone and acamprosate have not been observed. [13]

• Effectiveness
• A number of small studies have looked at the effects of acamprosate in AUD. A meta-analysis that combined results from 27 acamprosate studies (N=7519) found the following:
• Return to any drinking: acamprosate reduced the risk by 9% when compared to placebo, with a number needed to treat of 12
• Percent drinking days: acamprosate reduced the percent of drinking days by 8.8% when compared to placebo
• Acamprosate vs naltrexone: analysis of the 4 trials (N=1141) that directly compared acamprosate to naltrexone found no significant difference between the treatments [16]

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• NALTREXONE

• Overview
• Naltrexone is FDA-approved for the treatment of AUD. Naltrexone is an opioid antagonist, and its effects in alcohol AUD are not completely understood but may occur through the following mechanisms:
• Suppression of alcohol-mediated betaendorphin stimulation of dopamine neurons in the nucleus accumbens
• Reduction of beta-endorphin disinhibition of the tonic inhibition of dopamine cells by gamma-aminobutyric acid neurons in the ventral tegmental area [6]

• Dosage forms
• Tablet (Revia®)
• 50 mg
• Generic available | 30 tablets cost < $50
• Injection (Vivitrol®)
• 380 mg vial
• Carton comes with vial, diluent, special needle, and syringe
• No generic | 1 vial costs > $1000

• Dosing
• Tablet: 50 mg once daily
• Injection: 380 mg intramuscularly every 4 weeks
• Vivitrol should only be given as a deep intramuscular gluteal injection administered by a healthcare professional
• Therapy should be started after alcohol withdrawal is complete
• Treatment is usually for 6 months but may be longer for those who are benefiting [8,13]

• Side effects
• The table below shows the incidence of side effects from AUD trials involving naltrexone 380 mg IM every 4 weeks. Only side effects that occurred at an incidence of > 1% more than placebo are listed.

• ^✝ Includes pain, tenderness, induration, swelling, erythema, bruising, or pruritus
• Reference [13]

Side effect	Naltrexone 380 mg (N=205)	Placebo (N=214)
Injection site reactions✝	69%	50%
Nausea	33%	11%
Headache	25%	18%
Decreased appetite	14%	3%
Vomiting	14%	6%
Insomnia	14%	12%
Dizziness	13%	4%
Diarrhea	13%	10%
Anxiety	12%	8%
Arthralgia	12%	5%
Abdominal pain	11%	8%
Muscle cramps	8%	1%
Depression	8%	4%
Rash	6%	4%
Somnolence	4%	1%

• Contraindications / Precautions
• Patients receiving opioids - naltrexone is an opioid antagonist, and it will block the effects of opioid medications. It should not be given to patients who are receiving opioids or those going through acute opioid withdrawal.


• Precipitated opioid withdrawal - naltrexone may precipitate opioid withdrawal in patients receiving opioids. Naltrexone-induced withdrawal typically occurs within 5 minutes of ingestion and lasts up to 48 hours. Symptoms may be more severe than what is seen with typical opioid discontinuation, and patients may need to be hospitalized. Opioid-dependent patients taking short-acting opioids should be opioid-free for 7 - 10 days before starting naltrexone, and those taking buprenorphine or methadone may experience naltrexone-induced withdrawal for up to 2 weeks after opioid discontinuation.


• Increased sensitivity to opioids - patients who have received naltrexone for a period and then discontinue it may be more sensitive to opioid medications. These patients should be warned that they may be at increased risk of an overdose if they take opioids after stopping naltrexone. Naloxone should be offered to these patients.


• Overcoming naltrexone blockade - naltrexone blockade of opioid receptors is competitive and can be overcome by high plasma concentrations of opioids. Patients who try to overcome naltrexone by taking large doses of opioids are at increased risk of overdose. Patients should be warned that they may experience fatal overdose should they try to overcome naltrexone blockade.


• Emergency pain control - emergency pain control in patients taking naltrexone may be achieved through regional analgesia, conscious sedation with a benzodiazepine, non-opioid analgesics, or general anesthesia. In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged.


• Surgery / Procedures - oral naltrexone should be discontinued at least 72 hours before planned surgery. Intramuscular naltrexone should be stopped at least 30 days before surgery. After 30 days, oral naltrexone may be used up to 72 hours before surgery. After surgery, patients should be off opiates for 3 - 7 days before restarting naltrexone. If the procedure does not require opioid use, it may be reasonable to continue naltrexone uninterrupted.


• Hepatotoxicity - cases of hepatitis have been reported in patients receiving naltrexone. Since patients receiving naltrexone often have pre-existing liver disease, it is difficult to establish causality. Patients who experience symptoms of hepatitis during naltrexone therapy (e.g. jaundice, nausea, vomiting, dark urine, abdominal pain) should stop naltrexone and receive prompt evaluation.


• Depression and suicidality - depression and suicidality in patients receiving naltrexone have been reported in the postmarketing setting. Patients being treated for opioid and alcohol abuse often have coexisting depression, so it is difficult to establish causality. Patients who experience depressive symptoms while taking naltrexone should report them immediately.


• Drug testing - naltrexone may cause some urine drug screens to show a positive opioid result. Naltrexone hydrochloride does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used to separate and detect morphine, methadone, or quinine in the urine. Naltrexone hydrochloride may or may not interfere with enzymatic methods for detecting opioids, depending on the specificity of the test. Please consult the test manufacturer for specific details.


• Eosinophilic pneumonia (IM naltrexone) - rare cases of eosinophilic pneumonia have been reported in patients receiving IM naltrexone (Vivitrol). If a patient develops progressive dyspnea and hypoxemia, the diagnosis of eosinophilic pneumonia should be considered.


• Hypersensitivity reactions (IM naltrexone) - hypersensitivity reactions including urticaria, angioedema, and anaphylaxis have been reported in patients receiving IM naltrexone (Vivitrol)


• Injection site reactions (IM naltrexone) - injection site reactions, including tenderness, pain, and swelling, are common with IM naltrexone. Rare cases of cellulitis, abscess, and necrosis requiring surgery, have been reported. IM naltrexone should only be administered by a healthcare professional.


• Kidney disease
• CrCl ≥ 50 ml/min: no dose adjustment necessary
• CrCl < 50 ml/min: has not been studied. Because naltrexone and its primary metabolite are excreted in the urine, caution is recommended.


• Liver disease
• Child-Pugh A/B: no dose adjustment necessary
• Child-Pugh C: has not been studied. Use caution. The APA recommends that naltrexone not be used in patients with acute hepatitis or hepatic failure. [13,17]

• Drug interactions
• Opiate medications - naltrexone may block the effects of opioid medications, including dextromethorphan and antidiarrheals. See Precautions above.
• Disulfiram - naltrexone and disulfiram may both cause hepatitis, and their combined use has not been studied. Use caution when prescribing together. [13]

• Effectiveness in alcohol use disoder
• A number of small studies have looked at the effects of naltrexone in AUD. Results from a meta-analysis that combined data from 53 naltrexone studies (N=9140) are presented in the table below.

• NS - result was statistically nonsignificant
• Reference [16]

Outcome	% decrease compared to placebo
Naltrexone 50 mg/day oral
Return to any drinking	5%
Return to heavy drinking	9%
% drinking days	5.4%
% heavy drinking days	4.1%
Naltrexone injection
Return to any drinking	4% (NS)
Return to heavy drinking	1% (NS)
% drinking days	8.6%
% heavy drinking days	4.6%
Analysis of the 4 trials (N=1141) that directly compared acamprosate to naltrexone found no significant difference between the two drugs

• Binge drinking
• The small study detailed below evaluated the effects of as-needed naltrexone on binge drinking in men

• STUDY
  Naltrexone vs Placebo for Binge Drinking in Men, Am J Psychiatry (2023) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=120 | length = 12 weeks) in sexual and gender minority men
• Treatment: Naltrexone 50 mg vs Placebo. Participants were instructed to take one pill during periods of alcohol craving and/or when they perceived a high risk for heavy alcohol consumption (i.e., when binge drinking was anticipated)
• Primary outcome: Primary endpoints were binge-drinking intensity, defined as 1) number of drinks in the past 30 days; 2) any binge drinking in the past week; 3) number of binge-drinking days in the past week; and 4) number of drinking days in the past week
• Results:
• Number of drinks in past 30 days: Naltrexone 31% lower than placebo (p=0.01)
• Any binge drinking in past week: Naltrexone 17% lower than placebo (p=0.01)
• Number of drinking days in past week: Naltrexone 2% lower than placebo (p=0.80)
• Number of binge-drinking days in past week: Naltrexone 26% lower than placebo (p=0.03)
• Findings: Targeted naltrexone significantly reduced drinking outcomes among sexual and gender minority men with mild to moderate alcohol use disorder during treatment, with sustained effects at 6 months posttreatment. Naltrexone may be an important pharmacotherapy to address binge drinking in populations with mild to moderate alcohol use disorder.

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• DISULFIRAM (ANTABUSE®)

• Overview
• Disulfiram is FDA-approved to treat AUD. Disulfiram blocks an enzyme called aldehyde dehydrogenase (AD) that is involved in the metabolism of alcohol. Blockage of AD causes blood levels of acetaldehyde to rise when alcohol is consumed, and this produces unpleasant symptoms including flushing, palpitations, tachycardia, headache, nausea, and vomiting. Knowledge that these reactions may occur acts as a deterrent to drinking alcohol. After mild ingestion, reactions typically last 30 - 60 minutes. Significant ingestion can lead to reactions that last several hours or longer. Reactions may occur up to 14 days after stopping disulfiram. [6,13]

• Dosage form (tablet)
• 250 mg
• 500 mg
• Generic available | 30 tablets cost < $50

• Dosing
• Check liver function tests at baseline, after 14 days of therapy, and periodically thereafter
• Starting: 250 - 500 mg once daily
• Maintenance: 125 - 500 mg once daily
• Maximum: 500 mg once daily
• Patients should abstain from alcohol for at least 12 hours before taking disulfiram
• Reactions with alcohol may occur for up to 14 days after discontinuing disulfiram
• Tablets may be crushed and mixed with liquid

• Side effects
• In general, disulfiram is well-tolerated and side effects are uncommon. The prescribing information lists the reactions below as possible adverse events but does not provide a prevalence. The strength of association is also unknown because there is no placebo comparator.
• Drowsiness that usually resolves after several weeks
• Metallic or garlic-like aftertaste
• Rashes including dermatitis and acneiform eruptions
• Impotence
• Headache
• Psychotic reactions
• Optic neuritis
• Peripheral neuropathy
• Hepatotoxicity [1,13]

• Contraindications / Precautions
• State of alcohol intoxication - DO NOT GIVE


• Patients who wish to reduce drinking - DO NOT GIVE. Disulfiram should not be given to patients who do not plan on abstaining from alcohol.


• Hypersensitivity to rubber - patients with a history of rubber contact dermatitis should be evaluated for hypersensitivity to thiuram derivatives before receiving disulfiram


• Alcohol-containing products (e.g. cough syrup, certain foods) - patients taking disulfiram need to be aware that certain products besides alcoholic beverages contain alcohol. If these products are consumed, a reaction may occur. Examples include over-the-counter medications (e.g. Dayquil), prescription medications (e.g. solutions, elixirs), mouthwashes, flavored extracts for cooking, sauces, vinegar, tonics, aftershave, hand sanitizers, and rubbing alcohol. Reactions may occur up to 14 days after stopping disulfiram


• Hepatotoxicity - hepatotoxicity, including liver failure, has occurred in patients receiving disulfiram (1 case per 10,000 - 30,000 patient-years). Toxicity can occur at any time during treatment and in patients without a history of liver disease. Liver function tests should be checked at baseline, after 14 days of therapy, and periodically thereafter. Periodic CBC and serum electrolytes are also recommended. Patients should report symptoms of hepatitis immediately (e.g. fatigue, jaundice, dark urine, nausea, vomiting).


• Coronary artery disease - DO NOT GIVE. Disulfiram may induce tachycardia if alcohol is ingested, which can lead to ischemia.


• Heart failure - DO NOT GIVE. Disulfiram may induce tachycardia if alcohol is ingested, which can worsen heart failure.


• Psychosis - DO NOT GIVE. Disulfiram may worsen psychosis


• Epilepsy - alcohol ingestion may precipitate seizures in patients receiving disulfiram


• Conditions exacerbated by dehydration - the disulfiram-alcohol reaction may lead to dehydration. Use caution when giving to patients who have conditions that may be worsened by dehydration (e.g. diabetes, kidney disease, liver disease).


• Kidney disease - manufacturer makes no recommendation


• Liver disease - manufacturer makes no recommendation. Disulfiram may cause hepatotoxicity. Use caution. [13,17]

• Drug interactions
• Benzodiazepines - disulfiram may increase exposure to benzodiazepines. Use caution when combining and monitor for excessive sedation.
• Isoniazid - DO NOT COMBINE. May increase the risk of psychosis.
• Metronidazole - DO NOT COMBINE. May increase the risk of psychosis.
• Oral anticoagulants - disulfiram may alter the effects of anticoagulants, particularly warfarin. Monitor PT/INR closely if combining.
• Phenytoin - disulfiram may increase phenytoin exposure. Monitor phenytoin levels closely when combining.
• Theophylline - disulfiram may increase theophylline exposure by up to 50%. Monitor theophylline levels closely when combining. [6,13,18]

• Effectiveness
• The effectiveness of disulfiram depends on whether the patient takes it. Studies that have used supervised administration have found it to be very effective. Trials with unsupervised administration have had mixed results and high dropout rates. [1,6,17]

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• GABAPENTIN

• Overview
• Gabapentin is an antiepileptic that is mainly used to treat neuropathic pain. It is not FDA-approved to treat AUD but has been found to be effective in small studies. Two studies that compared gabapentin to placebo in adults with AUD are reviewed below.
• See gabapentin for a review of side effects, precautions, drug interactions, etc.

• STUDY
  Gabapentin vs Placebo for AUD with Withdrawal Symptoms, JAMA Intern Med (2020) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=96 | length = 16 weeks) in adults with AUD who were having withdrawal symptoms and had been abstinent for at least 3 days
• Treatment: Gabapentin vs Placebo. Gabapentin was given as follows: day 1: 300 mg at bedtime; day 2: 300 mg in the morning and at bedtime; days 3 and 4: 300 mg in the morning, at noon, and at bedtime; day 5 and on: 300 mg in the morning and at noon and 600 mg at bedtime
• Primary outcome: Percentage of participants with no heavy drinking days (≥ 5 drinks/day for men and ≥ 4 drinks/day for women)
• Results:
• Baseline % of heavy drinking days: 83% in both groups
• Primary outcome (% with no heavy drinking days): Gabapentin - 27%, Placebo - 9% (p=0.02)
• Total abstinence: Gabapentin - 18%, Placebo - 4% (p=0.04)
• Findings: These data, combined with others, suggest gabapentin might be most efficacious in people with AUD and a history of alcohol withdrawal symptoms. Future studies should evaluate sleep changes and mood during early recovery as mediators of gabapentin efficacy.

• STUDY
  Gabapentin vs Placebo for Alcohol Dependence, JAMA Intern Med (2014) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=150 | length = 12 weeks) in adults with alcohol dependence who had been abstinent from alcohol for at least 3 days
• Treatment: Gabapentin 300 mg TID vs Gabapentin 600 mg TID vs Placebo
• Primary outcome: coprimary outcome of complete abstinence and no heavy drinking over 12 weeks
• Results:
• Primary outcome (complete abstinence): Gab 300 mg - 11.1%, Gab 600 mg - 17%, Placebo - 4.1% (p=0.02 for linear dose effect)
• Primary outcome (no heavy drinking): Gab 300 mg - 29.6%, Gab 600 mg - 44.7%, Placebo - 22.5% (p=0.04 for linear dose effect)
• Findings: Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.

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• TOPIRAMATE

• Overview
• Topiramate is an antiepileptic that is also used to treat migraines and obesity. It is not FDA-approved to treat AUD but has been found to be effective in small studies. A trial that compared topiramate to placebo in adults with AUD is reviewed below.
• See topiramate for a review of side effects, precautions, drug interactions, etc.

• STUDY
  Topiramate vs Placebo for Alcohol Dependence, JAMA (2007) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=371 | length = 14 weeks) in adults with alcohol dependence
• Treatment: Topiramate vs Placebo. Topiramate was started at 25 mg once daily and increased at weekly intervals over a 5-week period to a maximum of 100 mg in the AM and 200 mg in the PM.
• Primary outcome: Self-reported percentage of heavy drinking days (≥ 5 drink for men and ≥ 4 drinks for women)
• Results:
• Baseline percentage of heavy drinking days: Topiramate - 82%, Placebo - 82%
• Primary outcome: Topiramate - 44%, Placebo - 52% (p=0.002)
• Topiramate was also signifcantly better than placebo for days abstinent (38% vs 29%) and drinks per drinking days (6.5 vs 7.5)
• Findings: Topiramate is a promising treatment for alcohol dependence

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• BIBLIOGRAPHY

• 1 - PMID 30167705 - Diagnosis and Pharmacotherapy of Alcohol Use Disorder: A Review, JAMA (2018)
• 2 - PMID 31478502 - Alcohol use disorders, Lancet (2019)
• 3 - PMID 23698791 - Screening and Behavioral Counseling Interventions in Primary Care to Reduce Alcohol Misuse: U.S. Preventive Services Task Force Recommendation Statement, Ann Intern Med (2013)
• 4 - USPSTF website
• 5 - PMID 24364635 - Outpatient management of alcohol withdrawal syndrome, Am Fam Physician (2013)
• 6 - Medication for the Treatment of Alcohol Use Disorder: A Brief Guide, U.S. Department of Health and Human Services (2013)
• 7 - PMID 23343065 - Alcohol Use in Adults, NEJM (2013)
• 8 - Alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence, NICE guideline (2011)
• 9 - PMID 25895020 - Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders, CNS drugs, (2015)
• 10 - PMID 19485969 - A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal, Alcohol Clin Exp Res (2009)
• 11 - PMID 25214768 - Single dose pharmacokinetic equivalence study of two gabapentin preparations in healthy subjects, Drug Des Devel Ther, (2014)
• 12 - PMID 12047731 - The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial, J Gen Intern Med (2002)
• 13 - Manufacturer's package insert
• 14 - PMID 22876380 - Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications, NICE Guidelines
• 15 - PMID 32511109 - The ASAM Clinical Practice Guideline on Alcohol Withdrawal Management, J Addict Med (2020)
• 16 - PMID 24825644 - Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis, JAMA (2014)
• 17 - PMID 29301420 - The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder, Am J Psychiatry (2018)
• 18 - Drugs.com interaction checker