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Pharmacy Times
As medication experts, pharmacists can aid in treatment selection and support patients through the process.
The National Institute on Alcohol Abuse and Alcoholism states that alcohol is the most widely used substance in the US. Over 75% of individuals aged 12 and older have reported drinking alcohol at some point in their lives, and nearly 30% of those aged 18 and older engage in binge drinking.1 Binge drinking is defined as consuming 5 or more drinks on a single occasion for men and 4 or more drinks on a single occasion for women. Non binge drinkers and binge drinkers alike are at risk of developing alcohol withdrawal syndrome (AWS) because withdrawal can occur in anyone who drinks regularly, regardless of the amount.1 From these statistics alone, it is obvious that alcohol consumption spans a wide spectrum from low risk to severe alcohol use
disorder (AUD), which is extremely dangerous for the individual and those around them.
AWS and its complications occur when individuals stop or reduce their heavy or constant drinking due to neuroadaptive changes from chronic alcohol use.
Alcohol is a dose-dependent central nervous system depressant that stimulates the γ-aminobutyric acid (GABA)–mediated system, causing disinhibition, euphoria, and sedation, but long-term use leads to increased glutamate and decreased GABA. Abrupt cessation or reduction in alcohol results in a GABA deficit and excess glutamate, causing excitatory symptoms that manifest as tachycardia, anxiety, tremors, sweating, insomnia, seizures, and even hallucinations.2 For these reasons, it is essential to be able to recognize the signs and symptoms at all stages of AW and know how to comprehensively manage them in both outpatient and inpatient settings.
Mary Layton Lancaster, MBA, is a current fourth-year pharmacy student at the Auburn University Harrison College of Pharmacy. She has a strong interest in critical care and is pursuing a residency after graduation.
Marilyn N. Bulloch, PharmD, BCPS, FCCM, SPP, is an associate clinical professor of pharmacy practice at the Auburn University Harrison College of Pharmacy. Her practice site is inpatient acute care at DCH Regional Medical Center in Tuscaloosa, Alabama.
According to the American Society of Addiction Medicine (ASAM), patients at risk of experiencing severe or complicated AW, or those at risk of developing new or worsening signs of withdrawal, may be managed in outpatient settings. Therefore, it is important to offer these individuals preventive pharmacotherapy. For those with mild symptoms, supportive care as well as treatment with carbamazepine (Tegretol XR; Novartis) or gabapentin (Horizant; Azurity Pharmaceuticals) are all appropriate options and are preferred over benzodiazepines.2 They have proven to be as effective as benzodiazepines when used as monotherapy for low-risk patients (eg, younger than 65 years with few coexisting medical conditions experiencing mild anxiety, sweating, and insomnia, but no tremors) and are found to have a lower risk of drug alcohol toxicity and less sedation. These drugs work by decreasing alcohol cravings during withdrawal and decreasing alcohol consumption after withdrawal.2
Per the ASAM, pharmacotherapy is indicated for patients experiencing moderate to severe symptoms of AW.2 Short-term use of benzodiazepines are first line in this patient population, with longer-acting benzodiazepines (eg, lorazepam or chlordiazepoxide) being preferred. Benzodiazepines work to enhance the effects of GABA by increasing neuronal membrane permeability to chloride ions, resulting in hyperpolarization and stabilization.3 Benzodiazepines are rather effective in the treatment of AWS, although their use is contraindicated in conditions such as angle-closure glaucoma and untreated opioid use disorder and should be avoided in those on concomitant opioids or strong CYP3A4 inhibitors.4
The ASAM states that for individuals with a contraindication to benzodiazepines, carbamazepine, gabapentin, or phenobarbital are all appropriate alternatives for monotherapy. Phenobarbital assists in AW by depressing the sensory cortex, decreasing motor activity, and causing drowsiness and sedation. In high doses, it can exhibit antiseizure activity. However, phenobarbital has a narrow therapeutic window and extended half-life and therefore should be reserved for clinicians who are experienced with its use and who can follow up with patients closely.2 There is no antidote to phenobarbital toxicity, which also impacts its utility for AWS in the outpatient setting.3
In addition to their potential role as monotherapy, carbamazepine, gabapentin, and valproic acid may be considered as add-on therapy if treatment with benzodiazepines alone is insufficient.4 Carbamazepine works as an anticonvulsant and mood stabilizer by limiting the influx of sodium ions across the cell membrane, resulting in fewer action potentials.3
According to Barrons et al, in 7 studies (n = 612), carbamazepine demonstrated significant reduction in alcohol withdrawal scores, though no significant difference in efficacy was seen when compared with benzodiazepines.5
Gabapentin modulates the release of excitatory neurotransmitters, which prevents seizures and allows the withdrawal process to be more manageable in the outpatient setting. In a randomized control trial of 90 patients in the community setting, gabapentin significantly increased the number of people with total abstinence, reduced heavy drinking days compared with placebo (27% vs 18.6%; 95% CI, 3.1-34.1; P = .02), and increased total abstinence compared with placebo (18% vs 4%; 95% CI, 1.0-26.7; P = .04).6
Lastly, valproic acid increases the availability of GABA and blocks voltage-dependent sodium channels to suppress neuronal firing, thereby stabilizing mood and preventing seizures.3 Unfortunately, although its pharmacologic mechanism in AWS seems reasonable, there are limited data on the use of valproic acid in AWS in the outpatient setting.
In choosing between carbamazepine, gabapentin, and valproic acid as adjuncts, gabapentin is preferred when there are plans for continued use as part of a patient’s ongoing treatment of AUD because it has been found to improve rates of abstinence and reduce heavy drinking by decreasing cravings.2 Carbamazepine is effective at preventing AW progression, seizures, and delirium. Valproic acid should never be used as monotherapy for the treatment of AWS and should be avoided in women of childbearing potential as well as those with liver disease.2
Additionally, ɑ2-adrenergic agonists (eg, clonidine) can be used as an adjunct therapy to control autonomic hyperactivity and anxiety while β-adrenergic antagonists can be used as an adjunct to control persistent hypertension or tachycardia.2 If symptoms are uncontrolled, increasing the dose of 1 medication is favored before adding adjunct treatment. Patients and caregivers should be counseled to watch for the potential for oversedation and respiratory depression.2 If the patient becomes unstable or presents with more severe signs or symptoms of AWS, such as hallucinations, confusion, or seizures,
a more intensive level of care in the inpatient setting may be warranted.2
Outpatient treatment for alcohol withdrawal is an effective option for many individuals due to its flexibility and their ability to maintain their daily responsibilities. Although treatment with benzodiazepines is a common approach, some patients may not tolerate the class due to adverse effects, coexisting conditions, or concurrent medications. By tailoring treatment plans to individual patients, it is possible to enhance safety and improve outcomes for those undergoing AW in an outpatient setting.
