Pharmacological Management of Alcohol Withdrawal Disorder

Educational Objectives

The goal of this program is to improve the management of alcohol withdrawal syndrome (AWS). After hearing and assimilating this program, the clinicians will be better able to:

1. Elaborate on the pathophysiology of AWS.
2. Identify common and severe symptoms of AWS.
3. Select appropriate medications for treating AWS.

Summary

Alcohol withdrawal syndrome (AWS): benzodiazepines (BZDs) are the treatment of choice for moderate to severe AWS; compared with using a high, fixed-dose taper of chlordiazepoxide (CD), giving it as needed based on the severity of AWS symptoms allows symptoms to be controlled with 25% of the total dose and with substantially shorter treatment duration; this approach has become the standard of care; only CD and diazepam are approved to treat AWS; in the United States, tobacco and alcohol are more deadly than opioids; besides caffeine, alcohol is the most commonly used psychotropic substance; ≈62% of people have used it within the last year; ≈10% of the US population meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), criteria for alcohol use disorder (AUD), and ≈50% of these meet criteria for moderate or severe AUD; DSM-5 criteria for AUD include a problematic pattern of alcohol use characterized by symptoms, eg, issues with controlling or moderating alcohol use, continued use despite real or potential adverse consequences, and psychological or physical dependence on alcohol

Pathophysiology of AWS: the excitatory effects of glutamate and inhibitory effects of γ-aminobutyric acid (GABA) in the central nervous system (CNS) usually result in a homeostatic balance; cells have a net negative charge compared with the outside environment; in electrically active cells, the process of carrying information or doing work is achieved by depolarization, where the cell becomes less negatively charged or has an action potential that causes it to become slightly positively charged; glutamate and GABA play a role in this via ligand-gated ion channels; glutamate opens channels that let in positively charged sodium ions with or without calcium ions, making the cell more positively charged and likely to have an action potential; GABA opens channels that let in negatively charged chloride ions, making the cell less likely to do work; alcohol accentuates the GABA-related inhibition and inhibits the glutamate-related excitation; the brain is less able to convey information, leading to difficulty remembering things, processing information, poor motor control, and sleepiness; occasional alcohol use does not change the balance of this system when alcohol is not being used; daily, heavy alcohol use over long periods results in less of a GABA effect and more of a glutamate effect to compensate for the presence of alcohol over time; if the person stops using alcohol, an excitatory excess now exists, causing AWS

Symptoms of AWS: when the alcohol level of a person with AWS reaches zero, the CNS is hyperexcitable for the next ≈48 hr; patients cannot sleep, are anxious, may hallucinate, and experience adrenergic effects, including elevated pulse and blood pressure; ≈10% have seizures, which should be prevented; most patients improve as the homeostatic mechanisms restore balance, but ≈10% continue to worsen over the following days; they may develop major withdrawal, ie, delirium tremens (DT) or alcohol withdrawal delirium, which is a medical emergency; these patients often need intensive care unit (ICU) management due to high blood pressure, high fever, and gross confusion; seizures and delirium tremens are serious, negative medical outcomes; symptoms should be alleviated as patients are in distress; symptoms also perpetuate the drinking cycle as alcohol relieves them, so treating them is important to achieve sobriety; AWS can also exacerbate medical conditions; fluid and electrolyte imbalances and Wernicke-Korsakoff syndrome should be treated

Managing AUD and AWS: some people can quit drinking at home without medical intervention, but others need support; the medical severity of AWS symptoms determines whether medication and monitoring are needed; others may not need much medical monitoring but may need to be removed from their usual environment to break the cycle; hospitalization can offer both; residential treatment programs, sober houses, and correctional settings provide environmental support, as patients do not have access to alcohol, and have varying levels of clinical support; partial hospital programs and ambulatory detoxification clinics offer intermediate support; some centers have sobering units where people can safely stop drinking or using drugs; they do not have clinical supervision, but paramedics on staff can assist with providing medical care if needed

Medications for AWS: BZDs increase the flow of chloride into cells when GABA is present, hyperpolarizing the cell and decreasing likelihood of action potentials; barbiturates perform a similar function without needing GABA to open the channels; both are effective for treating AWS and preventing seizures; anticonvulsant medications (eg, gabapentin, carbamazepine, valproate) inhibit the ability of glutamate to allow cations in; studies have found that, compared with other agents, only BZDs were superior to placebo at preventing seizures; they were superior to antipsychotics and noninferior to anticonvulsants; α-2 adrenergic receptor agonists and γ-hydroxybutyrate were not superior to BZDs; BZDs also reduce the incidence of delirium treatments and provide symptomatic relief

Choice of BZD: while BZDs can cause sedation, motor impairment, and amnestic effects, and can potentially lead to misuse and addiction, they carry a low risk when used in short-term monitored settings to treat AWS; patients with DT tend to be agitated and activated, while patients delirious due to overmedication with BZDs are more likely to be obtunded or sedated; bedside electroencephalography is the best test to determine the cause of delirium but may not be readily available and requires patients to be cooperative; BZDs can cause respiratory depression, especially in patients taking other medications (eg, opioids); all BZDs are effective for preventing seizures, but CD appears to be slightly more effective; longer-acting BZDs (eg, CD, diazepam) are preferable as symptoms are less likely to recur between doses; patients tolerate the experience better and need less frequent reassessment; however, longer-acting BZDs are cleared more slowly and erratically, especially in patients with hepatic impairment; short-acting BZDs that do not need hepatic transformation (lorazepam and oxazepam) may be more appropriate for patients who are elderly, have known liver disease, or have other severe acute medical illness; they need more frequent dosing and reassessment and are more likely to experience symptoms during treatment; only lorazepam and diazepam are available parenterally

Dosing of BZDs: a standardized assessment is performed and BZD is dosed based on severity; Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar), measures nausea, vomiting, tremor, sweats, anxiety, agitation, hallucinations and disturbances (tactile, auditory, visual), and disorientation; a score of 0 to 8 is no or mild withdrawal, 9 to 20 is moderate, and >20 is severe; a patient with moderate AWS can be given 1 mg of lorazepam, 5 mg of diazepam, or 25 mg of chlordiazepoxide and reassessed after 4 hr, but higher doses and more frequent reassessment may be needed for scores of 13 to 19; patients with severe AWS need larger doses and hourly reassessment; this approach works well for hospitalized patients but requires waiting for symptoms to begin until medication can be given; AWS is a relapsing-recurring condition, and patients tend to have repeated episodes; in such cases, it may be possible to predict the course based on previous episodes; previously used treatments and their effectiveness can be checked and recommendations made based on that

Phenobarbital: a long-acting barbiturate introduced in 1912 that was commonly prescribed as an anxiolytic until BZDs were introduced; until the early 2000s, it was used to treat epilepsy, but has now largely been replaced; barbiturates have a similar side effect profile as BZDs but with a significantly higher risk for lethality and overdose; they inhibit neurons without any limit and have more of the good and bad effects of BZDs; they can be used to treat patients who do not respond to BZDs; BZD-resistant AWS is defined as severe AWS that does not respond to 20 mg of lorazepam, 100 mg of diazepam, or 500 mg of CD within 24 hr; for such patients, a loading dose of 130 or 260 mg of phenobarbital followed by additional intravenous boluses every 30 min can be given until mild sedation occurs; patients should be in the ICU or a medical unit and need frequent monitoring; phenobarbital has a half-life of ≈100 hr, and patients may reach mild sedation with only the loading dose; if symptoms reappear, redosing can be done or BZD can be tried (rarely needed); some clinicians have proposed using it as a first-line treatment for AWS since retreatment or reassessment for AWS is often unnecessary; however, reassessment for sedation and other effects of phenobarbital is still needed, and patients may continue to be impaired for ≥1 wk

Gabapentin: affects cation rather than anion channels; has some inhibitory effect on glutamate but does not mimic GABA; does not reduce risk for seizures or delirium tremens but does offer symptomatic relief from AWS comparable to BZDs; patients who are given gabapentin in hospital require a lower total dose of BZDs; carries lower risk than BZDs but can be sedating for some people and can cause motor impairment or affect one’s ability to drive; however, it is safer than BZD as an outpatient medication as patients are less likely to have adverse outcomes if they drink alcohol while taking it; may be appropriate for low-risk patients; the speaker recommends 600 mg thrice daily for 2 days, then 300 mg twice daily for 2 days

Carbamazepine: has a similar mechanism of action to gabapentin and similar benefits and drawbacks; does not reduce the risk for seizures or DT but can decrease the total amount of BZDs given; the speaker uses it only if the patient is already taking gabapentin or has had a prior bad reaction to it; can cause liver injury, Stevens-Johnson syndrome, toxic epidermal necrolysis, and blood cell dyscrasias

Other agents: no compelling evidence exists to recommend α-2 adrenergic agonists; β-blockers may mask the severity of AWS by masking hypertension and tachycardia while not addressing the risk for seizures or DT (not preferrable but may be used to manage severely abnormal vital signs); propofol is commonly used to manage agitation in ICU patients, but not enough evidence exists to recommend it on a routine basis; no evidence exists for baclofen or nitrous oxide; antipsychotic medications are recommended against as they do not treat hallucinations in AWS, and lower the seizure threshold

Readings

Ahmed S, Bachu R, Kotapati P, et al. Use of gabapentin in the treatment of substance use and psychiatric disorders: A systematic review. Front Psychiatry. 2019;10:228. Published 2019 May 7. doi:10.3389/fpsyt.2019.00228; Becker HC, Mulholland PJ. Neurochemical mechanisms of alcohol withdrawal. Handb Clin Neurol. 2014;125:133-156. doi:10.1016/B978-0-444-62619-6.00009-4; Dharavath RN, Pina-Leblanc C, Tang VM, et al. GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential. Front Neural Circuits. 2023;17:1218737. Published 2023 Oct 20. doi:10.3389/fncir.2023.1218737; Jesse S, Bråthen G, Ferrara M, et al. Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurol Scand. 2017;135(1):4-16. doi:10.1111/ane.12671; Malone D, Costin BN, MacElroy D, et al. Phenobarbital versus benzodiazepines in alcohol withdrawal syndrome. Neuropsychopharmacol Rep. 2023;43(4):532-541. doi:10.1002/npr2.12347; Melkonian A, Patel R, Magh A, et al. Assessment of a Hospital-Wide CIWA-Ar Protocol for Management of Alcohol Withdrawal Syndrome. Mayo Clin Proc Innov Qual Outcomes. 2019;3(3):344-349. Published 2019 Aug 23. doi:10.1016/j.mayocpiqo.2019.06.005; Steel TL, Malte CA, Bradley KA, et al. Benzodiazepine Treatment and Hospital Course of Medical Inpatients With Alcohol Withdrawal Syndrome in the Veterans Health Administration. Mayo Clin Proc Innov Qual Outcomes. 2022;6(2):126-136. Published 2022 Feb 15. doi:10.1016/j.mayocpiqo.2021.11.010; Wang A, Park A, Albert R, et al. Iatrogenic delirium in patients on symptom-triggered alcohol withdrawal protocol: A case series. Cureus. 2021;13(6):e15373. Published 2021 Jun 1. doi:10.7759/cureus.15373; Wolf C, Curry A, Nacht J, et al. Management of alcohol withdrawal in the emergency department: Current perspectives. Open Access Emerg Med. 2020;12:53-65. Published 2020 Mar 19. doi:10.2147/OAEM.S235288.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Miller's lecture contains information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Miller was recorded at 2023 IPPS Psychiatry Post Graduate Fall Symposium, held on October 13, 2023, in Coralville, IA, and presented by the Iowa Psychiatric Physicians Society. For information about upcoming CME activities from this presenter, please visit Iowapsychiatry.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

PS531601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.