By Georgeanna Rechner-Neven, PharmD, BCPS, BCCCP

Clinical Pharmacy Specialist, Medical and Neurosciences Intensive Care Units, Rush University Medical Center, Chicago

The 2019 National Survey on Drug Use and Health found that 25.8% of people older than 18 years of age engaged in binge drinking in the previous month and 6.3% engaged in heavy alcohol use.1 A similar survey in 2019 found that 14.5 million people older than 12 years of age had an alcohol use disorder (AUD). In addition, there has been an increase of 210,000 alcohol-related visits to the emergency department (ED) between 2006 and 2014. Approximately 2% to 7% of hospitalized patients with a history of heavy alcohol use will develop moderate to severe alcohol withdrawal syndrome (AWS).2 Unfortunately, the COVID-19 pandemic has further increased alcohol consumption and the potential for AUD.3

Chronic alcohol use causes a downregulation of inhibitory γ-aminobutyric acid receptor A (GABAA) and an upregulation of excitatory N-methyl-D-aspartate (NMDA) receptors.2 The sudden discontinuation of alcohol use then will cause an imbalance between inhibitory and excitatory neurotransmitters, leading to symptoms of AWS: sweating, tachycardia, tremor, insomnia, nausea, hallucinations, agitation, anxiety, seizures, and delirium. Benzodiazepines are GABAergic and, therefore, recommended first-line as prophylaxis and treatment for AWS, seizures, and alcohol-related delirium. However, some patients develop resistant alcohol withdrawal and, despite high doses of benzodiazepines, continue to have severe withdrawal symptoms. In addition, benzodiazepines have the potential to cause oversedation and respiratory depression, leading to escalation in level of care, possible need for mechanical ventilation, increased length of stay (LOS), and delirium. In an effort to lessen benzodiazepine exposure while providing sufficient AWS treatment, adjunctive therapies have been explored targeting both GABAA and NMDA receptors. The following is a brief review of these therapies in the management of AWS patients.

PHENOBARBITAL

Phenobarbital stimulates GABAA receptors and inhibits NMDA receptors, thereby acting at the primary receptors responsible for AWS.4 Phenobarbital has a long half-life (50 to 120 hours), which can allow for a self-tapering effect; however, it takes a prolonged time to reach steady-state without the use of a loading dose. Side effects of concern are hepatotoxicity, respiratory depression, sedation, hypotension, and bradycardia, especially with intravenous (IV) administration. Severe allergic reactions to phenobarbital and other aromatic anticonvulsants (e.g., phenytoin, carbamazepine, oxcarbazepine) also have been documented, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN).

A prospective, randomized, double-blind trial was conducted in the ED of a university-affiliated community hospital comparing phenobarbital to lorazepam plus chlordiazepoxide for mild to moderate AWS.5 Patients with severe alcohol withdrawal were excluded because of their inability to provide informed consent. Patients also were excluded if they had other medical illness at presentation, were allergic to the study medications, or were pregnant. A modified Clinical Institute Withdrawal Assessment (CIWA) score was used and assessed every 30 minutes in the ED, on discharge from the ED or admission, and at 48 hours.

Intravenous phenobarbital was given as an initial 260-mg dose followed by 130-mg doses with the interval determined by the physician; on discharge, patients who received phenobarbital were given placebo pills. Intravenous lorazepam was given in 2-mg doses, with the frequency again at the discretion of the physician, and oral chlordiazepoxide pills were provided on discharge. The 48-hour reassessment also included evaluation of medication compliance and relapse with alcohol.

Forty-four patients were randomized to receive phenobarbital plus placebo (n = 25) or lorazepam plus chlordiazepoxide (n = 19).5 The mean length of ED stay was approximately 4.5 hours in each group, and three patients in each group required inpatient hospitalization. While in the ED, patients in the phenobarbital group received one to six doses, with a mean of 2.9 doses, while patients in the lorazepam group received one to four doses, with a mean of 2.1 doses.

Each group had a significant reduction in modified CIWA scores upon discharge. Less than half of patients in each group returned to the ED for the 48-hour follow up; however, of those 18 patients, there was not a significant increase in CIWA score, and there was a 100% compliance in oral medication use. The authors concluded a phenobarbital-based regimen in the ED may be beneficial for patients with mild to moderate AWS where the risk of benzodiazepine misuse is high, compliance to outpatient medications is poor, or there is a risk of being lost to follow up.

Another prospective, randomized, double-blind, placebo-controlled study was conducted in the ED for patients with AWS and likely need for inpatient admission.6 Notable exclusion criteria were allergies to study medications as well as allergies to carbamazepine or phenytoin, admission for reasons other than alcohol withdrawal, or pregnancy. Informed consent was waived initially for patients who were either intoxicated or presented with altered mental status; this study, therefore, included patients with severe alcohol withdrawal. All patients received symptom-guided lorazepam and either one dose of IV phenobarbital 10 mg/kg over 30 minutes or placebo.

One hundred ninety-eight patients received study medication; however, only 102 patients, divided evenly between the two groups, were included in the final analysis.6 The primary reasons for exclusion were admitting diagnosis other than alcohol withdrawal (n = 49), discharge from the ED (n = 26), and declined consent (n = 18). Patients who received phenobarbital were less likely to be admitted to the intensive care unit (ICU), while there was no difference in the rate of admission to a general floor or telemetry unit. Once admitted, patients did not require escalation in level of care. Fewer continuous infusions of lorazepam were needed, and the cumulative lorazepam dose also was less in the phenobarbital group. The authors concluded phenobarbital given as a large one-time dose may be beneficial for patients with severe alcohol withdrawal and may prevent ICU admission, although total hospital LOS was not decreased.

A retrospective cohort study of 120 patients admitted to a medical ICU for the prevention or treatment of AWS received either lorazepam according to the institutional Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) protocol (n = 60) or scheduled phenobarbital (n = 60) with lorazepam as needed for agitation based on risk of developing delirium tremens (DT).7 Patients were excluded from the study if they were treated with the lorazepam protocol alone for more than 24 hours before starting the phenobarbital protocol, were treated for less than 24 hours, received phenobarbital as an outpatient medication, or were pregnant.

Approximately half the patients in each group had a history of withdrawal seizures or DT.7 Although not statistically significant, fewer patients in the CIWA-Ar based group presented in active withdrawal or DT compared to patients in the phenobarbital group (20 vs. 28, respectively). However, patients receiving the phenobarbital protocol left the ICU two days earlier, were discharged from the hospital 2.6 days earlier, required less mechanical ventilation, and used less dexmedetomidine for agitation while not mechanically ventilated. The authors also noted less frequent nursing assessment was required for patients in the phenobarbital protocol, given the CIWA-Ar based protocol required assessments from every eight hours to every 10 minutes.

DEXMEDETOMIDINE

Dexmedetomidine is a centrally acting α2-agonist administered as a continuous infusion that can be used to manage agitation in patients with AWS.4 Given the lack of activity at either GABAA or NMDA receptors, benzodiazepines should be given to prevent seizure and DT. Dexmedetomidine does not cause significant respiratory depression and has been used in non-mechanically ventilated patients. Side effects of concern are hypotension and bradycardia.

A randomized, double-blind, placebo-controlled, dose range study compared dexmedetomidine 1.2 mcg/kg/hr and 0.4 mcg/kg/hr to placebo in addition to symptom-based lorazepam in patients admitted to the ICU with severe AWS.8 Notably, patients were excluded if they required benzodiazepines for other indications, had second- or third-degree heart block, or had active myocardial ischemia. Study medications were continued for five days or until patients were no longer in withdrawal.

Twenty-four patients were evenly randomized to receive dexmedetomidine 1.2 mcg/kg/hr, 0.4 mcg/kg/hr, or placebo.8 Although baseline characteristics were similar between the three groups, there was a higher Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) III score in the lower dose dexmedetomidine group. There also was a higher-than-expected proportion of patients requiring mechanical ventilation on initiation of dexmedetomidine or placebo (50% and 37.5%, respectively). The mean duration of infusion was 61 hours in the dexmedetomidine group and 70 hours in the placebo group. Fifty percent of patients receiving dexmedetomidine needed to have the infusion dose held or reduced because of hypotension and/or bradycardia, and two patients received less than 25% of the 1.2 mcg/kg/hr goal infusion rate within the first 24 hours of the study. Within the first 24 hours, there was a significant reduction in cumulative lorazepam administered in patients receiving dexmedetomidine; however, there was no difference in cumulative lorazepam administered at seven days. There was no statistical difference in ICU or hospital LOS. The authors concluded that dexmedetomidine, even at low doses, may help decrease benzodiazepine requirements while maintaining symptom management even though this did not affect LOS.

A retrospective, multi-center cohort study evaluated the association between symptom-based benzodiazepines with or without dexmedetomidine and the duration of ICU admission.9 This study excluded patients who were admitted to the ICU for reasons other than alcohol withdrawal, required intubation, transferred from an outside hospital, or were started on dexmedetomidine after one hour of ICU admission. Analysis was controlled for age, gender, BMI, admission CIWA score, and pre-ICU LOS, and also was stratified based on severity of AWS (i.e., mild, moderate, and severe). None of the patients received phenobarbital, clonidine, or dexmedetomidine monotherapy. After adjustment, patients receiving dexmedetomidine and benzodiazepines had a significantly longer ICU LOS of 43 hours, which remained significant for all strata of AWS severity. The authors specifically selected ICU LOS as the primary outcome rather than cumulative benzodiazepine exposure to assess resource utilization. Given the increased ICU LOS, the authors recommended further evaluation and protocolization of dexmedetomidine for AWS.

A retrospective cohort study was conducted evaluating patients admitted to the ICU receiving symptom-based management with and without the use of dexmedetomidine.10 Major exclusion criteria were patients requiring intubation on hospital or ICU admission and a history of seizures. Propensity score matching was used to minimize selection bias, since dexmedetomidine was used at the provider’s discretion and initially was found to be used in more patients with severe AWS. After propensity score matching, 55 patients were included in each group. The primary outcome was change in CIWA-Ar score (initial score on ICU admission minus the mean CIWA-Ar score for the length of ICU stay); this was not significant between the two groups.

Interestingly, the dexmedetomidine group had significantly longer ICU LOS, cumulative benzodiazepine requirements, and use of restraints. The need for mechanical ventilation and incidence of seizures also were higher in the dexmedetomidine group, athough this was not significant. Given the retrospective nature and lack of protocolized dexmedetomidine use in AWS, it is difficult to determine if there were patient characteristics that may have contributed to increased ICU LOS, need for mechanical ventilation, and increased benzodiazepine use in the dexmedetomidine group.

KETAMINE

Ketamine is an NMDA receptor antagonist that also does not cause significant respiratory depression at low doses.4 Concurrent benzodiazepines should be given for GABAA stimulation, similar to their use with dexmedetomidine. Notable side effects include hypertension, tachycardia, and emergence reactions. The American Society of Addiction Medicine did not include ketamine as an adjunctive medication in the most recent guideline; however, it did note further research is warranted.

A retrospective review was completed to assess the safety and efficacy of 23 patients receiving ketamine for severe alcohol withdrawal.11 Institutional practice used sedation assessment in the ICU rather than the Withdrawal Assessment Scale, which was reserved for assessment of floor patients. Approximately half of the patients were initially admitted to the floor and transferred to the ICU for alcohol withdrawal management. Continuous infusion ketamine was initiated with an average dose of 0.2 mg/kg/hr and duration of 55.8 hours; one-third of the patients received an initial bolus of 0.3 mg/kg. Approximately half of the patients received additional adjunctive medications (i.e., dexmedetomidine, phenobarbital, propofol, and haloperidol) while on ketamine. There was a decrease in diazepam equivalent dosage after the initiation of ketamine, but this was not statistically significant. Eight patients required mechanical ventilation (six for the management of alcohol withdrawal and six before ketamine was initiated).

The authors concluded it was difficult to determine if the decrease in benzodiazepine use after ketamine initiation was due to ketamine or the other adjunctive agents administered. The use of other adjunctive medications also may indicate insufficient dosing of ketamine.

A retrospective cohort study was conducted to evaluate the use of continuous infusion ketamine as an adjunct to symptom-based diazepam treatment for patients admitted to the ICU for DT.12 A DT guideline was created so that on diagnosis, ketamine was administered with an optional initial bolus of 0.3 mg/kg followed by an infusion of 0.15 mg/kg/hr to 0.3 mg/kg/hr, which continued until delirium resolved. Patients were not required to be mechanically ventilated to receive ketamine.

All patients were diagnosed with DT; however, the majority of patients were admitted to the ICU primarily for reasons other than alcohol withdrawal.12 Intensive care unit LOS was significantly shorter after ketamine guideline implementation compared to pre-guideline (5.7 days vs. 11.2 days, respectively). Hospital LOS also was significantly shorter (12.5 days vs. 16.6 days), cumulative diazepam equivalence dose was significantly less, and there were significantly fewer intubations (10 vs. 22) with a ketamine protocol. The authors did note one patient receiving ketamine became oversedated, which resolved after dose adjustment. The mean ketamine infusion rate was 0.19 mg/kg/hr, which continued for an average of 47 hours. The authors concluded ketamine adjunctive therapy may reduce cumulative benzodiazepine use and, thus, may decrease delirium and LOS.

GABAPENTIN

Gabapentin antagonizes the α2-δ1-subunit of voltage-gated calcium channels, decreasing the release of excitatory neurotransmitters.4 Gabapentin is renally eliminated and will accumulate in patients with reduced renal function, thereby increasing the risk of side effects, including sedation and dizziness. There also is a potential for misuse when continued in the outpatient setting. Gabapentin has been studied in the management of outpatient AWS and may increase abstinence while patients are being treated for AUD.

A single-center, retrospective cohort study evaluated the use of a high-intensity lorazepam protocol tapered over five days with symptom-based lorazepam for breakthrough agitation with and without high-dose gabapentin for patients presenting to the ED with severe AWS or major risk factors for developing severe AWS.13 The high-dose gabapentin protocol was a loading dose of 800 mg followed by 600 mg three times per day. Patients needed to have a calculated creatinine clearance of 60 mL/min or greater, remained on gabapentin throughout their hospital stay, and were discharged with prescriptions for continued use. Propensity score matching was performed to minimize selection bias for patients receiving gabapentin, and ultimately 50 patients were included in each group.

The majority of patients in each group were admitted to an ICU stepdown service, with some being admitted directly to the general medical floor and a smaller portion in the ICU.13 Approximately one-third of patients received the initial loading dose; only one patient discontinued use of gabapentin while hospitalized, and gabapentin was continued as an outpatient in three-quarters of patients. The gabapentin group used significantly less lorazepam and had a significantly shorter length of hospital stay by 1.4 days. At day 3 of hospitalization, the gabapentin group had a significantly lower maximum and mean CIWA-Ar score compared to benzodiazepines alone. A greater proportion of patients receiving benzodiazepines alone had hypotension, oversedation, and CAM-ICU positivity, although these were not statistically significant. There was no significant difference in other adjunctive medications used between the two groups, with clonidine and haloperidol used in the majority of patients. The authors concluded that the initiation of gabapentin early in the course of treatment for severe AWS reduced benzodiazepine exposure and may have allowed for early hospital discharge.

CONCLUSION

Although benzodiazepines are the mainstay of prevention and treatment of AWS, adjunct medications are used increasingly, with the goal of reducing cumulative benzodiazepine exposure and decreasing both hospital and ICU admission and LOS. The wide variety of studies presented here and within the larger body of literature suggests the need for well-designed prospective trials. Until then, developing institutional guidelines for the use of the adjunct therapies presented here can improve the management of severe and refractory AWS.

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