Written by: Elizabeth Stulpin, MD (NUEM PGY-1) Edited by: Kevin Dyer, MD (NUEM PGY-2) Expert Commentary by: Erin Lareau, MD
Alcohol related ED visits are an all too common occurrence and are only becoming more frequent. Between 2006 and 2014, the number of ED visits involving alcohol consumption increased by over 60 percent. This has led us to our current estimated 1.2 million hospital admissions per year related to alcohol abuse, with about 500,000 of those requiring greater attention for acute withdrawal.
Alcohol withdrawal can be treated with an innumerable combination of medications and dosages, with symptom dosed benzodiazepines currently the treatment of choice. However, with increasing visits for withdrawal and increasing doses needed to control symptoms, adverse effects of benzodiazepines can also be seen, such as paradoxical agitation, propylene glycol toxicity from increasing doses of lorazepam (lactic acidosis, AKI) and respiratory depression requiring intubation. Some patients are also resistant to benzodiazepine therapy, showing no symptomatic relief despite increasing doses. These factors have led to a pendulum swing back to the age before benzodiazepines, when phenobarbital was a first line treatment for treating alcohol withdrawal.
Benefits of Phenobarbital:
Reaching for phenobarbital instead of the syringe or tablet of lorazepam, diazepam, or chlordiazepoxide is an attractive option for many reasons. From its mechanism to pharmacokinetics to side effects, phenobarbital as a monotherapy can take some guesswork out of treatment. At the same time, patient outcomes are shown to be similar or improved when compared to benzodiazepines.
Mechanism:
The underlying cause of alcohol withdrawal is multifactorial. With chronic alcohol use, inhibitory GABA receptors are down regulated, while excitatory glutamate and NMDA receptors are upregulated. When the inhibitory effect of alcohol is suddenly removed, an excessive excitatory state is produced, resulting in the typical symptoms of tremulousness, anxiety, tachycardia, among others. Like benzodiazepines, phenobarbital targets GABA receptors to decrease excitatory tone, but does so more effectively since it does not rely on the presence of endogenous GABA hormone. At the same time, phenobarbital also down regulates glutamate signaling, leading to a more comprehensive approach to treating withdrawal.
Pharmacokinetics:
Besides its mechanism of action (MOA), one of the most attractive features of phenobarbital therapy is its simple pharmacology. Not only can it be given IV, IM or PO with almost 100 percent bioavailability in each route, the drug level in the body is extremely predictable. A linear relationship exists between the cumulative weight based dose and the resulting plasma concentration, which allows providers to reliably achieve the target dose range while avoiding levels at which toxicity would occur. This is in contrast to benzodiazepines, where metabolism and clinical response vary greatly among patients, and drug levels are nearly impossible to predict when periodically dosing with different doses at nonstandard points of time.
Another added benefit of phenobarbital is its length of action. Whereas the half-life of lorazepam is 14 to 20 hours, phenobarbital has a half-life of 80 to 120 hours. This allows for titration of medication over the patient’s hospital stay and an auto-tapering effect that can prevent rebound symptoms for days after, one of the main benefits of using chlordiazepoxide.
Patient outcomes:
The superior molecular characteristics and MOA of phenobarbital carry over to patient outcomes as well. Since the 1970s, phenobarbital monotherapy has been shown to be as safe, and as or more effective than benzodiazepines. With renewed focus on phenobarbital, more recent studies have been conducted that corroborate this claim. In the past few years, phenobarbital has been shown to have similar or improved outcomes when compared to benzodiazepines in terms of ICU stay and overall length of hospital stay. Additionally, patients treated with phenobarbital monotherapy have been seen to have decreased rates of delirium, decreased need for additional PRN sedation and lower rates of leaving against medical advice.
With regards to the most feared outcome, respiratory depression, phenobarbital has also held its own. Patients treated with phenobarbital have shown to have similar or even reduced rates of intubation, possibly due to the predictable linear relationship between drug dosing and plasma concentration as discussed previously. Secondly, the therapeutic range of phenobarbital is quite large. While the therapeutic dose hovers around 5 to 25mg/kg of total body weight, the toxic dose requiring intubation is often greater than 40mg/kg.
Phenobarbital was also shown to be effective in patients whose symptoms were refractory to benzodiazepines, possibly due to its different mechanism and lack of dependence on endogenous GABA.
What now?
So now you want to give phenobarbital a try, what now?
The most commonly seen dosing regimen is a loading dose, followed by IV or PO titration to the patient’s therapeutic level based on symptoms.
The IV loading dose is often set at 10mg/kg ideal body weight, infused over 30 minutes to achieve a serum level of about 15ug/mL. Similar to treatment with benzodiazepines, treatment is then symptom based. Repeat infusions or pills of 130mg are given every 15 minutes, with a total upper limit of 20 to 30mg/kg. Unlike benzodiazepine therapy where steadily increasing doses are used to control agitation, phenobarbital’s standard dosing takes some of the guesswork out of treatment for providers. Once symptoms have been appropriately managed, the patient may require additional PRN doses of phenobarbital, but the slow auto-tapering effect of the drug should prevent acute decompensation.
Take Home Points:
Phenobarbital is a safe and effective method to combat the symptoms of alcohol withdrawal.
Start low and go slow! If the patient has received benzodiazepines already, phenobarbital will act synergistically, and high doses may increase the risk of respiratory depression.
Remain aware of the cumulative phenobarbital dose to prevent reaching levels at which toxicity would occur.
Talk to your pharmacist about using phenobarbital for your next case of alcohol withdrawal!
Expert Commentary
This is a wonderful review of current treatment strategies for alcohol withdrawal in the ED. To broaden and emphasize some of your main concepts:
Alcohol related ED visits are extremely common. ED patients with alcohol related chief complaints are high risk for traumatic, medical, psychiatric and toxicologic problems that can easily be missed if providers are not vigilant.
Some patients may present to the ED with chief complaints that are medical or psychiatric in nature, but are directly associated with an underlying alcohol use disorder, making their management even more challenging.
Patients with unhealthy alcohol use may present to the ED with intoxication, withdrawal, seizures, agitation/psychosis, falls, traumatic injuries, gastritis/ GI bleeding, liver disease, cardiac disease, depression and anxiety. Many have concurrent social challenges including domestic violence and homelessness.
When a patient with an alcohol use disorder presents in acute withdrawal, there are multiple treatment strategies to use for symptom relief. Benzodiazepines are widely used and effective, though often require repeat doses to obtain maximal effect. Phenobarbital loading is a wonderful alternative with similar outcomes and simplified, standard dosing, as noted by the pharmacokinetics you reviewed.
My personal clinical practice is to preferentially use phenobarbital for high risk patients who present for alcohol withdrawal symptoms, and who have not already received IV benzodiazepines. Those at high risk for complications from alcohol withdrawal may have a history of:
withdrawal seizures
hallucinations
delirium tremens
abuse of multiple substances
recent admission (ICU or floor) for severe alcohol withdrawal.Phenobarbital loading is also effective for patients who are not responding to high dose IV pushes of benzodiazepines, as an alternative to starting continuous infusions. Anecdotally, I have spared patients such as this from requiring intensive care admission for withdrawal by using this pathway, though I have not found any research to support that this is a widespread phenomenon. Because serum phenobarbital levels can be checked for maintenance of a therapeutic range, severe withdrawal requiring multiple repeat doses can be directed in a more simplified way. For those with more mild symptoms, PO or IV benzodiazepines continue to be appropriate and have good effect.
Be sure to screen your patients presenting with alcohol intoxication or withdrawal for other emergent medical conditions, including traumatic, medical and psychiatric. Similarly, think about alcohol abuse and withdrawal in patients presenting for other problems, but who exhibit abnormal vital signs, abnormal neurologic exam or an insufficient response to treatment. Ask yourself:
Are there signs of trauma?
Are there other intoxicants?
Does this medical patient have untreated alcohol withdrawal? Is there tremor, hypertension and tachycardia that is not otherwise explained?
Are there vital sign abnormalities in the intoxicated patient? Can they be explained by intoxication? By withdrawal? If the answer is no, be sure you have appropriately treated for dehydration, alcoholic ketoacidosis and/or alcohol withdrawal. Then look for concomitant disease.
Was this patient trying to hurt themselves? Do they have underlying psychiatric disease? Are they in treatment? Do they need further resources?
Even a single conversation may be a life changing intervention for someone with an underlying alcohol use disorder!
References:
UpToDate article on “Risky Drinking and Alcohol Use Disorder” https://www.uptodate.com/contents/risky-drinking-and-alcohol-use-disorder-epidemiology-pathogenesis-clinical-manifestations-course-assessment-and-diagnosis?search=risky-drinking-and-alcohol-use-&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed on 2/09/2020.
Hammond, D, et al. “Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review.” Hospital Pharmacy 2017;52(9):607-616
Erin Lareau
Assistant Professor
Department of Emergency Medicine
Feinberg School of Medicine
Northwestern University
How to Cite This Post
[Peer-Reviewed, Web Publication] Stulpin, E, Dyer, K. (2020, May 25). Alcohol Related ED Visits [NUEM Blog. Expert Commentary by Lareau, E]. Retrieved from https://www.nuemblog.com/blog/etoh
References
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