Alcohol use disorder (AUD) is very common in the United States, with a 12-month prevalence of about 4.6% among 12- to 17-year-olds and 8.5% among adults age 18 years and older.1 AUD is an important contributor to suicide risk during severe intoxication and in the context of other psychiatric disorders.

A person’s environment and genetic profile may predispose them to AUD. Specifically, the disorder is seen in close relatives of individuals with AUD 3 to 4 times more than relatives of individuals without AUD.1 The highest rates are seen in individuals with a greater number of affected relatives, a closer genetic relationship to the affected person, and a higher severity of the alcohol-related problems in those relatives.

With this condition, major areas of life function – including driving, performance at school and work, interpersonal relationships – may be impaired,  not to mention the physical and mental health impact. While some individuals are able to stop using alcohol on their own, many need more assistance. Traditional treatment approaches include individual and/or group-based psychosocial interventions, Alcoholics Anonymous (AA) programs, and medication-assisted treatment. In this article, we will discuss the pharmacological interventions that help aid in AUD recovery – namely, those recommended by Substance Abuse and Mental Health Services Administration (SAMHSA): naltrexone, acamprosate, and disulfiram.

In this article, we hope to address questions that other residents may have including: What are the common side effects and known contraindications of the medications typically prescribed for AUD? What are some clinical pearls residents can take forward? How to I decide which medication may be most appropriate for my patient?

Naltrexone

Naltrexone’s mechanism of action in the treatment of alcoholism is through opioid antagonism, which reduces the reward pathway associated with drinking alcohol. It is one of the most commonly used drugs to treat AUD and is available orally and intramuscularly.

Orally, naltrexone should be initiated and maintained at 50 mg daily. Intramuscularly, Naltrexone is given as 380 mg every 4 weeks. The intramuscular formulation may be preferred in patients who have issues with compliance. Prior to taking naltrexone, patients must be opioid-free for 7 to 10 days as naltrexone use can precipitate acute withdrawal in opiate patients. This can be confirmed with a negative urine drug screen and/or naloxone challenge test. The naloxone challenge test involves giving 0.2 to 0.4 mg of naloxone subcutaneously or intravenously and observing for withdrawal which usually beings within minutes if a patient is physiologically dependent on opioids. These withdrawal symptoms typically peak within 30 minutes and subside in 3 to 4 hours.

Naltrexone is metabolized by the liver through dihydrodiol dehydrogenase, not by the CYP450 enzyme system. As such, this medication may be used safely with medications that induce or inhibit CYP450 enzymes.

In terms of interaction with other medications, small doses of opioids such as analgesic, antidiarrheal, or antitussive drugs may be blocked by naltrexone and fail to produce a therapeutic effect. For naltrexone-treated patients requiring emergency pain management, alternatives to opiates such as regional analgesia, non-opioid analgesics, and general anesthesia should be considered.

Common side effects of naltrexone include headache, nausea, somnolence, and vomiting. Naltrexone is contraindicated in acute hepatitis or liver failure. As there is a serious but rare boxed warning of dose-related hepatocellular injury, clinicians should monitor the liver by obtaining baseline liver transaminase levels. This test should be repeated at 6 and 12 months and again every 12 months thereafter. If signs and symptoms of acute hepatitis develop, the medication should be discontinued.

Naltrexone may be discontinued if there is no significant reduction in alcohol use within 3 months. In addition, efficacy and safety beyond 8 months are unclear, thus, after 8 months clinicians should reassess patients regularly for adverse effects and the need for continuation of therapy.

Acamprosate

The mechanism of acamprosate is thought to work indirectly as an NMDA receptor antagonist and positive allosteric modulator of GABAA receptors. For alcohol abstinence, dosing should be initiated at 666 mg 3 times a day. Patients with moderate renal impairment (30 to 50 ml/min), patients weighing less than 60 kg, and patients who had an adverse event on higher doses should be given 333 mg 3 times a day. Due to this being taken three times due to the low half-life of the drug, this may not be an appropriate option for patients who have compliance issues.

Since acamprosate is contraindicated in severe renal impairment (CrCl <30 ml/min), baseline creatinine clearance should be checked before starting it. Although absorption is not affected by food, taking this medication with meals may improve compliance.

Common side effects include diarrhea (which is dose-related and transient), weakness, peripheral edema, insomnia, and anxiety. Serious but rare side effects include acute renal failure, and suicidal thoughts. Acamprosate has no significant drug interactions; it is not metabolized by the liver and, thus, is not impacted by alcohol use. Therefore, it may be given to patients with hepatitis or liver disease and to patients who continue drinking alcohol. Acamprosate has been found to be more effective than placebo in reducing risk of returning to drinking and increasing the cumulative duration of abstinence. The medication may be stopped if patients see no clinically important reduction in alcohol use within 3 months and the safety/efficacy beyond 1 year is uncertain.

Disulfiram

Disulfiram is metabolized primarily through CYP450 and works through irreversibly inhibiting aldehyde dehydrogenase, leading to an accumulation of aldehyde which causes many of the symptoms seen in hangovers such as flushing, nausea, vomiting, hypotension, and palpitations. These reactions last anywhere from 30 to 60 minutes to several hours or as long as alcohol remains in the bloodstream. Due to this, it should only be used when abstinence is the treatment goal.  It should be initiated at 250 mg nightly and continued at a maintenance dose of 250 mg to 500 mg nightly.

Duration of therapy typically lasts until the patient is fully recovered (no longer dependent on alcohol or having any cravings), and maintenance therapy may be required for months or even years. Abstinence from alcohol for at least 12 hours is required before starting disulfiram to avoid a potentially serious disulfiram alcohol reaction. In addition, abstinence for 3 to 5 days without developing withdrawal symptoms verifies that the patient does not need medically assisted withdrawal therapy/detoxification.

Common side effects include metallic taste, skin eruptions (acne, allergic dermatitis), drowsiness, fatigue, impotence, and headache. Serious but rare side effects include severe hepatitis or hepatic failure, psychotic episodes, peripheral neuropathy, and optic neuritis. When taking this medication and for 1 to 2 weeks after stopping, patients should avoid medications containing alcohol (including topicals), metronidazole, disguised forms of ethanol (cough syrup), oral solutions or liquid concentrates containing alcohol such as sertraline.

Contraindications include cardiovascular, respiratory, or renal disease, severe hepatic dysfunction (transaminase levels >5 times upper limit of normal or abnormal bilirubin), severe psychiatric disorders including psychotic and cognitive disorders, metronidazole, and ketoconazole. Given these indications, baseline evaluations prior to starting disulfiram should include liver transaminases, a screen for psychiatric conditions, an electrocardiogram for older patients with a history of cardiac disease, and verification of abstinence from alcohol. Clinicians should repeat liver transaminases in 10 to 14 days, then monthly for 3 months, and every 12 months thereafter to monitor for hepatotoxicity.

Disulfiram may be stopped if the patient is unable to avoid alcohol within 3 months. One potential drawback is that patients can stop taking this medication if they want to drink alcohol so as to avoid feeling an unpleasant reaction. As such, compliance may be increased with another family member dispensing out the medication.

Additional Prescribing Considerations

Generally, naltrexone and acamprosate are tried before disulfiram because they have better safety profiles. Naltrexone and acamprosate may be used together, however combination may not increase efficacy based on available studies. With any of these medications, patients have a better chance to remain abstinent from alcohol, continuing their recovery journeys on a path toward a better life.

Tips From the Authoring Residents

A major challenge to prescribing these medications is that they are sometimes not taught in general psychiatry programs. I personally find it difficult to decide which medication to prescribe for alcohol abstinence. I have learned, however, that engaging the patient’s overall motivation and level of compliance can help when trying to narrow down medications. Along with this, it is important to remember certain instances where a medication should not be prescribed, such as avoiding naltrexone in patients who have taken opioids in the previous 10 to 14 days. If I am unsure of what to do, I look up the medication in question on Epocrates or UptoDate.
–Danielle Weitzer, DO (read her Resident’s Corner column on burnout)

I sometimes find it hard to determine if a medication is working in a particular patient. Specifically, asking patients and family members about the cravings for alcohol can be a clue. I think there is also a common struggle with adherence. For example, some individuals may choose to avoid taking their disulfiram to either start drinking again or to avoid side effects from taking the drug with alcohol. I have found that instructing patients to have family members manage, dispense, and observe them taking their dose increases medication adherence. If I have access to a family member, then I will share this request with them directly. When all options have been explored, and adherence remains an issue, I may switch the patient to IM naltrexone as it is only given once per month in an office setting.
–Christopher Lee, DO

References
Last Updated: Nov 18, 2020