Gabapentin Use in Acute Alcohol Withdrawal Management Christopher Wilming, PharmD; Mariah Alford, PharmD; and Lynnette Klaus, PharmD, BCPS Gabapentin’s anxiolytic and sedative properties along with its overall safety profile suggest that it may be a viable adjuvant to lorazepam in the management of acute alcohol withdrawal. Dr. Wilming is a he prevalence of alcohol dependence in frequent medical supervision for acute alcohol PGY-1 Pharmacy Practice Resident, the U.S. represents a significant public withdrawal, especially in patients at high risk Dr. Alford is a Thealth concern. Alcohol use disorder for seizure or DTs because morbidity and mor- General Medicine (AUD) is estimated to affect 6.7% of Americans tality risk is increased.7 Clinical Pharmacist, and Dr. Klaus is an and is the fourth leading preventable cause of Benzodiazepines remain the standard of care Associate Chief of death.1 Men and women who have served in for management of moderate-to-severe symp- Acute Care Pharmacy the military are at an even higher risk of ex- toms of AWS. Strong evidence supports the use and PGY-1 Acute Care Residency Director, cessive alcohol use. More than 20% of service of benzodiazepines to reduce withdrawal se- all at the VA Portland members report binge drinking every week.2 verity, incidence of delirium, and seizures in Health Care System in This risk is further exacerbated in veterans who AWS by enhancing GABA activity.8 However, Oregon. Correspondence: have experienced active combat or who have the adverse effect (AE) burden associated with Dr. Wilming comorbid health conditions, such as posttrau- benzodiazepines can be a major limitation (christopher.wilming matic stress disorder.3 throughout care. Benzodiazepines also may be @va.gov) limited in their use in select patient popula- BACKGROUND tions, such as in older adults or patients who Individuals that regularly consume excessive present with hepatic dysfunction due to the amounts of alcohol can develop acute alco- risk of increased AEs or metabolite accumula- hol withdrawal syndrome (AWS) after abrupt tion.6 A high dosing requirement of benzodi- discontinuation or significant reduction of al- azepine for symptom management can lead to cohol intake. Patients admitted for acute alco- oversedation to the point of requiring intuba- hol withdrawal may experience complicated tion, increasing length of stay in the intensive courses of treatment and extended lengths of care unit (ICU), and the risk of nosocomial hospitalization.4,5 Cessation from chronic alco- infections.9 hol intake elicits a pathophysiologic response Anticonvulsants, such as carbamazepine, from increased N-methyl-d-aspartate recep- valproic acid, and gabapentin, have shown to tor activity and decreased γ-aminobutyric acid be superior to placebo and equal in efficacy to (GABA) receptor function. benzodiazepines for symptom management in Autonomic and psychomotor hyperactiv- mild-to-moderate alcohol withdrawal in both ity disturbances, such as anxiety, nausea, trem- inpatient and outpatient settings.6-8 However, ors, diaphoresis, and tachycardia, may occur these agents are not recommended as first- as early as 6 to 8 hours after cessation of use. line monotherapy due to the limited number Within 48 to 72 hours of alcohol cessation, pa- of randomized trials supporting their efficacy tients may be at an increased risk of experienc- over benzodiazepines in preventing severe ing tonic-clonic seizures, visual and auditory symptoms of withdrawal, such as seizures or hallucinations, and delirium tremens (DTs), delirium.10-12 Nonetheless, the mechanism which may be accompanied by signs of extreme of action of anticonvulsants may help raise autonomic hyperactivity and agitation.6 Pa- seizure threshold in patients and provide a tients hospitalized within acute settings require benzodiazepine-sparing effect by enhancing 40 • FEDERAL PRACTITIONER • MARCH 2018 mdedge.com/fedprac GABAergic activity and lowering neuronal TABLE 1 Baseline Characteristics excitability.13 Gabapentin makes an attractive agent for Characteristics Group 1 (n = 55) Group 2 (n = 46) clinical use because of its anxiolytic and seda- tive properties that can be used to potentially Age, mean (SD), y 59.1 (11.8) 58.0 (10.2) target symptoms analogous with AWS when the use of benzodiazepines becomes a safety con- Sex, male 96% 98% cern. Although similar in chemical structure, gabapentin is not metabolized to GABA and Race, white 98% 91% does not directly interact with the receptor. Gabapentin may increase GABA concentra- Weight, mean (SD), kg 88.3 (26.4) 85.0 (16.9) tions by direct synthesis of GABA and indi- rectly through interaction with voltage-gated BMI, mean (SD), kg/m2 28.4 (8.8) 27.7 (6.5) calcium channels.13 In addition to its overall safety profile, gabapentin may be a viable ad- Serum creatinine, mean (SD), mg/dL 0.9 (1.0) 1.0 (0.6) juvant because emerging data may suggest a potential role in the management of acute Creatinine clearance, mean (SD), 2 123 (57) 104 (40) alcohol withdrawal.12,14,15 mL/min/1.73 m Patients with BAL taken 56% 43% Gabapentin for Alcohol Withdrawal at at admission VAPORHCS BAL at admission, mean (SD), g/dL 0.16 (1.4) 0.20 (1.4) Although not currently included in the alcohol withdrawal protocol at Veterans Affairs Port- History of alcohol withdrawal seizures 13% 0% land Health Care System (VAPORHCS), gaba- pentin has been added to the standard of care History of substance abuse in select patients per the discretion of the at- (excluding alcohol, tobacco, and 27% 26% tending physician. Anecdotal reports of patients marijuana) experiencing milder symptoms and less ben- Active opiate prescription 20% 35% zodiazepine administration have facilitated use Active sedative hypnotic of gabapentin in alcohol withdrawal manage- 5% 9% prescription ment at VAPORHCS. However, routine use of gabapentin is not consistent among all patients Abbreviation: BAL, blood alcohol level; BMI, body mass index. treated for acute alcohol withdrawal, and dos- ing schedules of gabapentin seem highly vari- able. Standard symptom management for acute adjunct for the treatment of alcohol withdrawal alcohol withdrawal should be consistent for has the potential to reduce benzodiazepine re- all affected individuals, using evidence-based quirements and minimize AEs, a thorough eval- medicine in order to achieve optimal outcomes uation of the treatment should be conducted and improve harm reduction. before its practice is incorporated into the cur- The objective of this quality assurance/qual- rent standard of care. ity improvement (QA/QI) project was to assess the amount of lorazepam required for symp- METHODS tom management in acute alcohol withdrawal The following QA/QI project was approved when gabapentin is used as an adjunct to treat- locally by the VAPORHCS associate chief of ment and to evaluate the impact on symptom staff/Office of Research and Development and management using the Clinical Institute With- is considered to be nonresearch VHA opera- drawal Assessment for Alcohol scale, revised tions activity and exempt from an institutional version (CIWA-Ar) in patients admitted to the review board committee review. This project ICU and general medicine wards for acute al- was a single-center, retrospective chart review cohol withdrawal at VAPORHCS.16 If a possible of patients admitted to the ICU and general mdedge.com/fedprac MARCH 2018 • FEDERAL PRACTITIONER • 41 MANAGING ALCOHOL WITHDRAWAL TABLE 2 Lorazepam Dosage on CIWA-Ar Protocola ondary endpoints included rate of the CIWA-Ar score reduction, time to protocol discontinu- Lorazepam, mg ation, as well as incidence and onset of peak Groups Patients, No. Average SD Min Max delirium scores during hospitalization. Cumu- lative CIWA-Ar scores over 24 hours were av- Group 1 55 7.9 8.2 0.5 48.0 eraged per patient per day while on CIWA-Ar protocol. Peak CIWA-Ar scores per patient per Group 2 46 5.5 8.7 0.0 41.0 day on the protocol also were collected. Time to aAverage daily dose of gabapentin: 948 mg. protocol termination was determined by date of order for discontinuation or by date when scor- ing had ceased and protocol order was inadver- medicine wards at VAPORHCS with acute alco- tently continued. Peak Intensive Care Delirium hol withdrawal. The CIWA-Ar protocol order Screening Checklist (ICDSC) scores were col- sets between January 1, 2014 and December 31, lected for patients admitted to the ICU.18 Day of 2015, were retrieved through the Computerized peak ICDSC scores also were evaluated. Patient Record System (CPRS) at VAPORHCS. Patients with an alcohol withdrawal pro- Statistical Analysis tocol order set who received gabapentin with The sample size for this analysis was deter- or without lorazepam during hospitalization mined by the number of patients identified were identified for chart review. Patients were who met the inclusion criteria and did not meet eligible for review if they were aged ≥ 18 years any of the exclusion criteria. Power was not with a primary or secondary diagnosis of acute calculated to estimate sample size needed to alcohol withdrawal and had a CIWA-Ar pro- determine statistical significance. One hun- tocol order set placed during hospitalization. dred patients treated for alcohol withdrawal Patients must have been administered gaba- was established as the target sample size for this pentin, lorazepam, or both while the CIWA- project. Descriptive statistics were performed to Ar protocol was active. Patients with an active analyze patient baseline characteristics and pri- outpatient