Is gabapentin worth a shot? Gabapentin as adjunct treatment for acute alcohol withdrawal

Aileen C. Scheibner, PharmD PGY1 Pharmacy Resident

Department of Pharmacotherapy Services, University Health System Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center UT Health San Antonio

February 24, 2020 and February 28, 2020

Learning Objectives:

1. Describe the pathophysiology of acute alcohol withdrawal symptoms2. Explain the mechanism by which benzodiazepines and gabapentin provide alcohol withdrawal

symptomatic relief3. Provide an evidence-based recommendation regarding the use of gabapentin as adjunct therapy

with benzodiazepines for the treatment of alcohol withdrawal in hospitalized patients

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ASSESSMENT QUESTIONS

Is gabapentin worth a shot? Gabapentin as adjunct treatment for acute alcohol withdrawal

Aileen C. Scheibner, PharmD PGY1 Pharmacy Resident

February 24, 2020 and February 28, 2020

1) Alcohol withdrawal symptoms are caused by:

a) An increase in glutamatergic signaling b) A decrease in dopaminergic signaling c) An increase in GABAergic signaling d) A decrease in serotoninergic signaling

2) Benzodiazepines and gabapentin may help alleviate symptoms of alcohol withdrawal by: a) Activating the NMDA receptor b) Activating the GABA receptor c) Directly inhibiting the D2 receptor in the nucleus accumbens d) Directly activating the D2 receptor in the nucleus accumbens

3) True or false: In prospective trials, high dose gabapentin tapers have been proven efficacious in reducing CIWA-Ar scores and total benzodiazepine amounts (mg) when added to standard-of-care benzodiazepines for hospitalized patients experiencing acute alcohol withdrawal

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez2@uhs-sa.com. ***

Faculty (Speaker) Disclosure: Aileen Scheibner has indicated she has no relevant personal or financial relationships to disclose relative to the content of his presentation.

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BACKGROUND

ALCOHOL USE DISORDER (AUD)

Definition Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-V) defines AUD: 1

Two or more of the following within the past 12-months:

o Drinking more or longer than planned o Desire to stop drinking but could not o A lot of time spent drinking or

recovering from drinking o Could not think about anything else

besides drinking o Drinking impacted activities of daily

living o Continued drinking despite

interference with relationship (family or friends)

o Would drink rather than participate in hobbies

o Would participate in risky behavior after drinking

o Would continue to drink despite detrimental effects on health

o Increasing number of drinks to achieve same effect as than before with less drinks

o Experience alcohol withdrawal when effects of alcohol were wearing off

Chronic/excessive consumption Chronic alcohol consumption typically defined as those with an AUD

Excessive alcohol consumption:2

Binge drinking: o Women: four or more drinks on one occasion o Men: five or more drinks on one occasion

Heavy drinking: o Women: eight or more drinks per week o Men: 15 or more drinks per week

Alcohol use by a pregnant woman or anyone younger than 21 years

ALCOHOL WITHDRAWAL (AW) DEFINITION

DSM-V defines alcohol withdrawal:1 Cessation of heavy and prolonged alcohol consumption Two or more of the following signs/symptoms:

o Hyperactive autonomic system o Hand tremor o Difficulty sleeping o Nausea and/or vomiting

o Hallucinations or illusions o Agitation o Anxiety o Generalized tonic-clonic seizures

Signs/symptoms impacting daily life (social or occupational impairment) Signs/symptoms not attributable to another cause

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PATHOPHYSIOLOGY

Gamma-aminobutyric acid (GABA) and glutamate3,4,5 GABA: inhibitory neurotransmitter Glutamate: excitatory neurotransmitter Imbalance leads to symptoms of withdrawal (Figure 1) Associated withdrawal symptom: seizures

Catecholamines3

Decreased α2 adrenergic receptor activity on the presynaptic neurons during alcohol withdrawal o Decreased inhibition of catecholamine release

Associated withdrawal symptoms: tachycardia, hypertension, tremor

A) Acute alcohol consumption B) Chronic alcohol consumption C) Alcohol withdrawal

= GABA = GABA receptor = glutamate = NMDA receptor

Figure 1. GABA and glutamate neuronal signaling in alcohol withdrawal3,4,5

(A) GABA acitvity is increased leading to supressed post-synaptic NMDA receptor activity (B) Upregulation of glutamate neurotransmission and NMDA receptor function to maintain balance with

GABA activity (C) Sudden decrease in GABA activy with glutamate activity remaining elevated

GABA: gamma-aminobutyric acid, NMDA: N-methyl-D-aspartate

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Dopamine and endogenous opioids (β-endorphins)3,6,7

β-endorphins increase dopamine release in nucleus accumbens (Figure 2) Chronic alcohol use → decreased dopamine D2 receptors Increase in dopamine neurotransmission leads to withdrawal symptoms Associated withdrawal symptoms: hallucinations, depressive symptoms (agitation, cognition

deficits)

= β-endorphin

= GABA

= Dopamine

Figure 2. Dopamine release in the nucleus accumbens in response to alcohol consumption7

Dopamine release is inhibited by GABA neurotransmission. Alcohol stimulates the release of BE. BE inhibit the release of GABA. By inhibiting the inhibitory signals, alcohol increases dopamine release. BE: β-endorphins; GABA: gamma-aminobutyric acid

SIGNS AND SYMPTOMS

Table 1. Four categories of alcohol withdrawal symptoms5 Dysautonomic Motor Hypervigilance Psychiatric

Tachycardia Tachypnea Mydriasis Hypertension Hyperthermia Diaphoresis Nausea Diarrhea

Tremor Seizure Ataxia Visual Hyperreflexia Slurred speech

Insomnia Agitation Irritability Confusion Temporal and spacial

disorientation

Delusions Delirium Hallucinations Persecution Anxiety Dysphoria Disinhibition

Minor symptoms Mild dysautonomic, motor, and hypervigilant symptoms9

Tachycardia Hypertension

Insomnia Craving alcohol

Mild tremor Irritability

Major symptoms Moderate to severe dysautonomic, motor, psychiatric, and hypervigilant symptoms9

Tachycardia Hypertension Diaphoresis

Fever Insomnia Hyperreflexia

Tremor Pronounced irritability and anxiety Hallucinations

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Complicated/severe symptoms Alcohol withdrawal seizures5

Onset: 6-72 hours after alcohol reduction or cessation Incidence: 10% of all patients experiencing alcohol withdrawal

Delirium tremens (DT) also known as alcohol withdrawal delirum

Onset: 48-72 hours after alcohol reduction or cessation;5,10 may occur up to 14 days later7 Incidence: 5-20% of all patients experiencing alcohol withdrawal5

o History of DT → 2.6 mes increased risk compared to no history of DT Mortality:

o Without treatment: 10%5 o With treatment: < 1-2%3 o Associated with cardiovascular (arrhythmias, myocardial infarctions), metabolic,

infectious (aspiration pneumonia), or traumatic (self harm) complications4,11 Defined by DSM-V criteria for alcohol withdrawal and delirium1,10

o DSM-V criteria for delirium: Reduced ability to focus Reduced awareness Change from baseline mentation Additional cognitive disturbances (memory deficit, language, perception)

o Not explained by another medical condition or substance Symptoms:12

o Delirium o Psychosis o Hallucinations

o Hyperthermia o Seizure o Coma

o Uncontrolled hypertension

Commonly associated with severe autonomic symptoms (tremor, nausea, sweating, irregular heart rate)12

Onset of symptoms

Peak withdrawal symptoms are experienced within the first 24-36 hours in 80% of patients (Figure 3)6

Figure 3. Onset of alcohol withdrawal symptoms3,4,6,8

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ALCOHOL WITHDRAWAL ASSESSMENT Clinical Institute of Withdrawal Assessment for Alcohol (CIWA-Ar) (Appendix A)

Validated in hospitalized, non-intensive care unit (ICU) patients13-15 Score range: 0-67 points Subjective scoring may lead to inter-rater variability

o Classification of severity based on CIWA-Ar varies by institution o Generally recognized scores:3,13,14,16

RECOMMENDED THERAPY

Management strategies

Table 2. Commonly utilized medication regimens for the treatment of alcohol withdrawal Fixed-dose regimen Front-loading Symptom-triggered

Benzodiazepine regimen17

Administered regardless of symptom severity

Initially at higher regular interval doses, then tapered off

Administration and dose based on symptom severity scored by a withdrawal rating scale (CIWA-Ar)

Benefits3,4,12

Compared to symptom-triggered: Longer duration of

therapy Larger total doses

Decreases alcohol withdrawal symptom progression

Decreases incidence of seizures

Compared to fixed-dose regimen: Decreased total

benzodiazepine use Decreased treatment

duration

Consider use12 History complicated alcohol withdrawal

History complicated alcohol withdrawal

No history complicated alcohol withdrawal

Supportive care Monitor fluid status and correct fluid depletion12 Thiamine (vitamin B1) supplementation to prevent Wernicke’s encephalopathy (WE)5,12,18

Provide thiamine prior to glucose to prevent precipitation of WE Folate (vitamin B9) supplementation to reduce risk of seizures5

Folate overdose may cause neurotoxicity, do not exceed 500 mg per day Magnesium (Mg) supplementation5,19

Mixed evidence supporting routine administration during acute alcohol withdrawal Theoretical benefits:

o Mg is co-factor for thiamine-dependent enzymes o Acts as a competitor of glutamate on NMDA receptor binding sites o May reduce benzodiazepine use

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Choice of pharmacologic therapy Ideal therapy would be a substitute agent for alcohol that has the following properties:12

Rapid-acting Long half-life Simple metabolism (ideally minimal

hepatic metabolism)

Suppresses desire to consume alcohol Does not interact with alcohol No potential for abuse No cognitive or motor impairment

Standard of care Sedative hypnotics (benzodiazepines and barbiturates, Table 3) ± adjunct medications (Appendix B)10

Reduce duration of symptoms, complications, and mortality, compared to neuroleptic agents (haloperidol, chlorpromazine)

Evidence does not support superiority of either benzodiazepines or barbiturates o Benzodiazepines preferred over barbiturates by experts due to shorter half-life, fewer

drug-drug interactions, and barbiturates’ narrow therapeutic window

Table 3. Sedative hypnotics used for the management of acute alcohol withdrawal Medication (class) MOA in AW Route Pharmacokinetics Considerations*

Chlordiazepoxide3,12,20

(benzodiazepine) Benzodiazepine class effect: Binds GABAA

receptors on the post-synaptic neurons enhancing GABA neuronal transmission leading to hyperpolarization of the post-synaptic neuron

Overall decreases CNS hyperactivity

PO O: intermediate M: hepatic phase I t1/2: 5-30 hrs

Long-acting metabolites, t1/2= 30-200 hrs

Diazepam3,12,20

(benzodiazepine) PO, IM,

IV O: rapid M: hepatic phase I t1/2: 30-80 hrs

Quick onset Long-acting

metabolites, t1/2= 30-100 hrs

Lorazepam3,20

(benzodiazepine) PO, IM,

IV O: intermediate M: hepatic phase II t1/2: 10-20 hrs

Midazolam3,12,20

(benzodiazepine) PO, IM,

IV O: intermediate M: hepatic hydroxylation t1/2: 2-6 hrs

Active metabolite

Oxazepam12

(benzodiazepine) PO O: slow/intermediate

M: hepatic and gut t1/2: 2-6 hrs

Phenobarbital18 (barbiturate)

Binds GABA receptors at alternative binding site

Inhibit NMDA receptor activity

IV, PO O: PO ≥ 60 minutes, IV 5 minutes M: hepatic phase I t1/2: ~80 hrs Protein binding: 48%

Dose-dependent respiratory depression

*all medications listed have anticonvulsant activity AW: alcohol withdrawal, CNS: central nervous system, GABA: gamma-aminobutyric acid, Hr: hour, IM: intramuscular, IV: intravenous, M: metabolism, MOA: mechanism of action, N/A: not applicable, NMDA: N-methyl-D-aspartate, O: oral onset, PO: oral, t1/2: elimination half-life

Benzodiazepines Considerations3,12

Metabolism: o Phase II (glucuronidation) preferred over phase I (oxidation) o Active versus inactive metabolites

Half-life: long half-life allows for self-taper (preferred) Lipophilicity: higher lipophilicity quicker onset but quicker redistribution Route of administration: multiple routes preferred (oral and IM/IV) if patient is agitated Superiority of one benzodiazepine over another has not been demonstrated

o Lorazepam frequently used due to phase II metabolism

Concerns6,21-23

Abuse potential Interactions with CNS depressants, opioids, and alcohol Additive respiratory depression Risk of benzodiazepine induced delirium Increased alcohol cravings19 Increased early relapse to alcohol20

Alternative and/or adjunct medications (Appendix B) Neuroleptic agents (haloperidol, chlorpromazine)10

Not recommended as single agent therapy When compared to sedative-hypnotics:

o Higher mortality o Longer duration of delirium o More complications (lower seizure threshold, hypotension, prolong QTc)

Alcohol (beverages and IV ethanol) not recommended3,16 No controlled trials Concerns with ethanol infusions:

o Inconsistent pharmacokinetics o Narrow therapeutic window o Risk of extravasation

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GABAPENTIN FOR ALCOHOL WITHDRAWAL PHARMACOKINETICS AND PHARMACODYNAMICS

Mechanism of action Binds to the α2δ subunit of voltage-gated calcium channels and increases the concentration and rate of synthesis of GABA24 Pharmacokinetics

Absorption25

Dose-dependent bioavailability (F) Dose (mg) F (%)

900 60 1200 47 2400 34 3600 33 4800 27

Distribution25,26

Protein binding: < 3% Volume of distribution = 0.65-1.04 L/kg,

mean 58 L Partition coefficient = 0.8

Metabolism25,26

No known metabolites, no induction/inhibition/autoinduction of liver enzymes

Elimination25-27

Urine excretion proportional to creatinine clearance Renal clearance = 76-81% Half-life = 5-7 hrs

Dose Effective dose for outpatient alcohol withdrawal: 900-1800 mg/day28-30

ADVERSE EFFECTS25

BENEFITS/ADVANTAGES25-26

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INPATIENT MANAGEMENT WITH GABAPENTIN AS SINGLE AGENT Bonnet, et al. Alcohol Alcohol. 2010;45(2):143-145.31

Design: open label trial, gabapentin 800 mg load then stratification into “responders” and “non-responders” (N = 37)

o Responders (n = 27) received additional gabapentin doses (3200 mg day 1, 2400 mg day 2, then tapered by 400 mg per day)

o Non-responders (n = 10) received hospital standard of care (clomethiazole or clonazepam)

Conclusion: gabapentin not effective at decreasing 2-hr CIWA-Ar if baseline CIWA-Ar ≥ 20 Bonnet, et al. J Clin Psychopharmacol. 2003;23(5):514-519.32

Design: placebo-controlled trial, gabapentin 400 mg every 6 hours Population: baseline moderate to severe withdrawal (N = 61) Conclusion: gabapentin was no better than placebo in the amount of rescue medication

(clomethiazole) administered within first 24 hours or in reducing withdrawal severity scores within the first 48 hours

CLINICAL QUESTION Should gabapentin be used as adjunct therapy with benzodiazepines for the management of

alcohol withdrawal in hospitalized patients?

EVIDENCE

CONSIDERATIONS

Concomitant benzodiazepine dose and duration

Duration of hospital length of stay

Use of additional adjunct therapies

Incidence of DT and seizures

Overall severity and duration of withdrawal symptoms

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LITERATURE REVIEW

Levine AR, Carrasquillo L, Mueller J, et al. High-Dose Gabapentin for the Treatment of Severe Alcohol Withdrawal Syndrome: A Retrospective Cohort Analysis. Pharmacotherapy. 2019; 39(9):881-888.33

Objective Determine if scheduled gabapentin reduces benzodiazepine requirements, AW symptoms, and hospital LOS when used as adjunct therapy to lorazepam

Design Retrospective cohort study Population Academic medical center (single site)

Included: adults (≥ 18 years), severe AW ED admits managed by the institution’s AW protocol Severe AW defined by:

Max CIWA-Ar ≥ 20 OR Max CIWA-Ar ≥ 15 AND major risk factors for severe AW (hx DT, sz, and/or evidence

of hyperadrenergic response) Excluded: left against medical advice

Intervention Control: institution AW protocol (described below) High intensity lorazepam taper over 5 days Break through agitation treated with lorazepam PRN per CIWA-Ar Recommended haloperidol for severe agitation or aggression Recommended clonidine for persistent hypertension and tachycardia

Treatment: gabapentin initiated within the first 48-hours + institution’s AW protocol Optional one-time gabapentin 800 mg loading dose 600 mg Q8H during

hospitalization and continued outpatient Outcomes Primary: mean lorazepam-equivalents administered during hospitalization

Secondary: mean daily lorazepam-equivalents, mean and max CIWA-Ar score, AEs, hospital disposition at discharge, time to lower level of care, hospital LOS

Analysis Categorical variables Pearson χ2 test; continuous variables multiple t-tests Groups were propensity score matched regression model identified variables used in prognostic score for matching treatment and control groups

Results

Baseline characteristics, N = 100

Treatment (n = 50) Control (n = 50) ICU, n (%) 7 (14) 4 (8)

ICU step-down, n (%) 33 (66) 41 (82) Age in years, mean ± SD 49.6 ± 10.7 51.3 ± 11.1

Male, n (%) 40 (80) 40 (80) Caucasian, n (%) 45 (90) 39 (78)

Mean BAL ± SD, mg/dL 259 ± 137 251 ± 109 Mean Day 1 CIWA-Ar ± SD 10.7 ± 4.2 10.8 ± 4.2 Mean max CIWA-AR ± SD 21.6 ± 4.8 22.9± 5.8 History of seizures, n (%) 12 (24) 10 (20)

History of delirium tremens, n (%) 1 (2) 1 (2) AW as admitting diagnosis, n (%) 44 (88) 42 (84)

Primary outcome

Treatment# Control# P-value Total lorazepam-equivalents amount,

mg 88.5 ± 35.6 109.5 ± 53.4 0.023*

Secondary outcomes Treatment# Control# P-value

Hospital LOS, days

6 ± 2.6 7.4 ± 4 0.034*

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Results continued

Secondary outcomes continued Day 2 daily lorazepam-equivalents,

mg 23.1 ± 11.7 29 ± 13.8 0.027*

Day 3 CIWA-Ar 7.7 ± 3.9 (Max 12.6 ± 6.1)

10.1 ± 4.7 (Max 16 ± 7)

0.010* (0.016)*

Time to lower level of care, days 3.6 ± 1.33 4.9 ± 2.67 0.011* AEs, n (%):

Oxygen saturation < 92% RASS score < -1

Respiratory rate < 10 bpm CAM-ICU positive

Requiring higher level of care

18 (36) 10 (20) 9 (18)

11 (22) 9 (18)

24 (48) 17 (34) 9 (18)

15 (30) 7 (14)

NS NS NS NS NS

Discharged home, n (%) 44 (88) 33 (66) 0.009*

Authors’ conclusion

Gabapentin as adjunct therapy to standard-of-care lorazepam decreased AW symptoms and benzodiazepine exposure

Reviewer’s critiques

Positives: Assessed adverse events (sedation) Propensity score matching of groups

Critiques: Retrospective study design Optional gabapentin load (36% of treatment group received) Additional concomitant medications used for AWS

o No description of dose or frequency (difficult to compare groups) Did not account for gabapentin use prior to hospital admission

*statistically significant, #mean ± SD or n AE: adverse events, AW: alcohol withdrawal, BAL: blood alcohol level, bpm: breaths per minute, CIWA-Ar: Clinical Institute of Withdrawal Assessment for Alcohol, DT: delirium tremens, ED: emergency department, hx: history, ICU: intensive care unit, n: population size, NS: not statistically significant, PRN: as-needed, RASS: Richmond Agitation-Sedation Scale, QxH: every x hours, SD: standard deviation, sz: seizure

Andaluz A, DeMoss D, Claassen C, et al. Fixed-dose gabapentin augmentation in the treatment of alcohol withdrawal syndrome: a retrospective, open-label study. Am J Drug Alcohol Abuse. 2020; 46(1):49-57.34

Objective Assess if the addition of a fixed-dose gabapentin protocol to standard, symptom-based lorazepam treatment decreases benzodiazepine requirements

Design Retrospective, open-label cohort study Population Large public hospital (single site)

Adults (≥ 18 years) undergoing treatment for AW in the ED or inpatient psychiatric Included: enrolled in institution’s AW protocol Excluded: pre-existing epileptic or sz disorder, missing CIWA-Ar scores, highest CIWA-Ar = 0

Intervention Assignment to group based on provider preference AW treatment terminated when CIWA-Ar ≤ 3 or after 96 hours Control: institution symptom-based lorazepam protocol based on CIWA-Ar Treatment: high-dose gabapentin taper in addition to institution symptom-based lorazepam protocol based on CIWA-Ar

Gabapentin taper Day 1 900 mg × 1 dose, then 600 mg Q6H × 2 doses Day 2 600 mg three times daily Day 3 600 mg twice daily Day 4 600 mg once daily

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Outcomes Primary: average CIWA-Ar score/hr, average lorazepam dose/hr Secondary: time in the AW protocol, average lorazepam dose in mild to moderate AW

Analysis Linear regression models used to identify variables corrected for in mixed model analysis Lorazepam analysis: non-parametric data Wilcoxon-Mann-Whitney test

o Only included patients that received lorazepam Symptom analysis: non-parametric data unclear statistical test

o Included entire population Results

Baseline characteristics, N = 982 Treatment (n = 515) Control (n = 467)

Mean age ± SD, yrs 42.4 ± 11.4 38.3 ± 12.4 Male, n (%) 345 (67) 280 (60)

Caucasian, n (%) 438 (85) 331 (70.9) Home lorazepam, n (%) 71 (13.8) 53 (11.3)

Home gabapentin, n (%) 123 (23.9) 17 (3.6) Mean highest CIWA-Ar ± SD 7.9 ± 6 6.1 ± 5.1

First CIWA-Ar = 0, n (%) 109 (21.2) 147 (31.5) Lorazepam never administered, n (%) 243 (47.2) 278 (59.5)

Average lorazepam, mg/day 2.8 1.2 Mean time in protocol, hours ± SD 59.5 ± 33.3 63 ± 34.2

Primary outcomes: Average total lorazepam use/hour (n = 461): NS

Adjusted for age, race, home gabapentin, first CIWA-Ar score Average CIWA-Ar score/hour (n = 982): NS

Adjusted for age, race, home gabapentin, O2 saturation, first CIWA-Ar score Secondary outcome: Time on protocol:

All: patients that stayed on treatment protocol > 35 hrs and were in the treatment group achieved a CIWA-Ar < 3 faster than those in the control group (NS)

Highest CIWA-Ar 9-15: treatment group achieved a CIWA-Ar < 3 faster than those in the control group (NS)

Highest CIWA-Ar >15: control group achieved a CIWA-Ar < 3 faster than those in the treatment group (NS)

Authors’ conclusion

Fixed-taper gabapentin did not provide additional benefit compared to symptom-triggered lorazepam alone in the treatment of AW

Reviewer’s critiques

Positives: Standardized gabapentin dose Statistically controlled for home gabapentin use

Critiques: Retrospective Non-randomized group assignment (selection bias) Additional adjunct medications not documented No assessment of renal function Unclear statistical analyses used Overall mild alcohol withdrawal (average highest CIWA-Ar < 10)

AW: alcohol withdrawal, CIWA-Ar: Clinical Institute of Withdrawal Assessment for Alcohol, ED: emergency department, MV: multivariate, n: population size, NS: not statistically significant, Q6H: every 6 hours, SD: standard deviation, sz: seizure

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Morrison M, Udeh E, Burak M. Retrospective analysis of a gabapentin high dose taper compared to lorazepam in acute inpatient alcohol withdrawal. Am J Drug Alcohol Abuse. 2019; 45(4):385-391.

Objective Assess if the addition of high-dose gabapentin to standard treatment of alcohol withdrawal effects benzodiazepine requirements

Design Retrospective cohort study Population Academic medical center (single site)

Included: adults ≥ 18 years, baseline CIWA-Ar score ≥ 6, on institution’s AW protocol Excluded: BAL > 80 mg/dL, CrCl < 30 mL/min, taking > 900 mg/day gabapentin prior to admit, received < 3 days gabapentin while inpatient

Intervention Control: hospital’s AW protocol Lorazepam primary medication for alcohol withdrawal

o Continuous infusion, scheduled, PRN per CIWA-Ar Treatment: gabapentin AW protocol

Gabapentin taper based on age + PRN CIWA-Ar lorazepam High dose gabapentin taper

≥ 65 years old < 65 years old 800 mg loading dose then 1200 mg loading dose then

600 mg Q8H × 6 doses 800 mg Q8H × 6 doses 400 mg Q8H × 3 doses 600 mg Q8H × 3 doses 200 mg Q8H × 3 doses 400 mg Q8H × 3 doses

200 mg Q12H × 2 doses 400 mg Q12H × 2 doses 200 mg Q24H × 1 dose 400 mg Q24H × 1 dose

Outcomes Primary: difference in daily lorazepam usage (mg) between pre- and post- gabapentin

protocol implementation Secondary: hospital LOS, ICU LOS, rapid responses, delirium positive days (per CAM-ICU assessment), transfers to a higher level of care

Statistics A priori power analysis: N = 94 patients with n = 47 patients/group 80% power, α = 0.05 to show a relative difference of 25% reduction in mean daily lorazepam use

Student’s t-test for normally distributed continuous variables Mann-Whitney U test for non-normally distributed continuous variables Fisher’s exact test for categorical variables

Results Baseline characteristics, N = 100

Treatment (n = 50) Control (n= 50) ICU, n (%) 12 (24) 15 (30)

Age in years, mean ± SD 47.08 ± 11.97 47.26 ± 10.21 Male, n (%) 39 (78) 45 (90)

Caucasian, n (%) 37 (74) 35 (70) Adjunct medications used$ 21 (42) 27 (54)

Baseline CIWA-Ar ± SD 9.90 ± 3.56 9.98 ± 4.51 Max CIWA-Ar ± SD# 17.68 ± 6.67 21.82 ± 10.09

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Results continued

Univariate primary outcome Treatment Control P-value Daily lorazepam equivalents (mg),

median [IQR] 6.52 [3.84,11.65] 9.48 [5.58,28.46] 0.024*

Univariate secondary outcomes Treatment (n= 50) Control (n= 50) P-value

LOS in days, mean ± SD 7.04 ± 4.59 9.92 ± 7.33 0.021* ICU LOS in days, median [IQR] 0 [0,0.25] 0 [0,4.25] NS

Rapid responses, n (%) 2 (4) 4 (8) NS CAM-ICU days, median [IQR] 0 [0-2.25] 0 [0-3.50] NS

Transfers to higher level of care, n (%)

17 (34) 20 (40) NS

ICU subgroup analysis Treatment (n = 15) Control (n = 12) P-value

ICU days, mean ± SD 5.42 ± 2.91 9.40 ± 5.10 0.018* CAM-ICU positive days, mean ± SD 3.92 ± 2.50 7.53 ± 5.36 0.031*

Multivariate analysis: gabapentin is not an independent predictor of benzodiazepine use

Dependent variable: daily lorazepam equivalent usage Independent variables: gabapentin use, ICU days, patient age, max CIWA-Ar score

Authors’ conclusion

Gabapentin taper decreases daily lorazepam use, hospital LOS, ICU LOS, and delirium positive days when combined with PRN CIWA-Ar lorazepam for AW

Reviewer’s critiques

Disagree with the authors’ conclusion Gabapentin as an independent factor did not reduce benzodiazepine exposure as

demonstrated by the results of the multivariate analysis Positives:

Exclusion criteria o Accounted for prior gabapentin use o Accounted for patients with no AW symptoms

Standardized gabapentin dosing Critiques:

Retrospective o Treatment group and control group selected from different time points

Excluded patients that died during hospital stay Undefined dose and duration of additional adjunct medications Non-standard lorazepam equivalence used

$ clonidine, guanfacine, or dexmedetomidine,*statistically significant, #statistically significant p-value = 0.019 AW: alcohol withdrawal, BAL: blood alcohol level, CAM-ICU: Confusion Assessment Method for the ICU, CIWA-Ar: Clinical Institute of Withdrawal Assessment for Alcohol, CrCl: creatinine clearance, ICU: intensive care unit, IQR: interquartile range, LOS: length of stay, n:population size, NS: not statistically significant, PRN: as needed, QxH: every x hours, SD: standard deviation

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LITERATURE SUMMARY

Table 4. Study comparison Levine, et al. Andaluz, et al. Morrison, et al.

AW severity Most severe AW Day 1 CIWA-Ar: 10-11 Max CIWA-Ar: 21-23

Least severe AW No baseline CIWA

requirements Max CIWA-Ar: 6-7

Baseline CIWA-Ar: ~10 Max day 1 CIWA-Ar: ~ 17-

20

ICU patients 11/100 None 27/100 Gabapentin dose Fixed dose (1800 mg/day)

± initial load (800 mg) Four-day taper Initial dose: 2100 mg/24 hr

Five-day taper Initial dose: 2800 mg/24 hr

Benzodiazepine protocol used

Lorazepam taper delivered over 5 days + PRN doses

PRN lorazepam per CIWA-Ar: Score 0-8: no lorazepam Score 9-15:2 mg Q2H PRN Score >15: 2 mg Q1H PRN

Lorazepam CI, scheduled, or PRN per CIWA-Ar

Efficacy outcomes

Gabapentin decreased benzodiazepine exposure, LOS, AW symptoms

No difference in benzodiazepine exposure or AW symptoms

Gabapentin decreased hospital LOS and ICU LOS

MV: gabapentin not an independent predictor of benzodiazepine use

Safety outcomes No difference in sedation Not assessed No difference in number of rapid responses or transfers to higher level of care

Kidney function > 60 mL/min Not documented > 30 mL/min Admitting

diagnosis = AW, n Treatment = 44/50 Control = 42/50

Not documented 100/100

Additional adjunct medications

Many in treatment and control group

Dose and duration not provided

Not documented Treatment: 42% Control: 54% Dose and duration not

provided AW: alcohol withdrawal, CI: continuous infusion, CIWA-Ar: Clinical Institute of Withdrawal Assessment for Alcohol, ICU: intensive care unit, MV: multivariate, PRN: as needed, QxH: every x hours

CONCLUSION Weak evidence suggests gabapentin may be beneficial (decreased benzodiazepine exposure, LOS, and symptom severity) for the inpatient management of acute alcohol withdrawal.

RECOMMENDATIONS Do not advocate for gabapentin as adjunct therapy to benzodiazepines

Consider use if: The patient will continue gabapentin outpatient for AUD The patient takes gabapentin at home or has another indication for gabapentin

Avoid use if: There are concerns about renal function Assessment of neurological function is required The patient is experiencing mild AW

REFERENCES

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

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APPENDICES

Appendix A. Clinical Institute of Withdrawal Assessment for Alcohol (CIWA-Ar) The total score is a sum of the scores in each of the ten categories.14

Appendix B: Alternative and/or adjunct pharmacologic agents studied for the management of acute alcohol withdrawal Medication (class) MOA in AW Route Pharmacokinetics Additional considerations

Clonidine6

(α2-adrenergic agonist, antihypertensive)

Decreases norepinephrine release via α2-adrenergic receptor agonist activity

PO, IV, transdermal

F: 70-80%; M: hepatic, t1/2: 13 hrs; PB: 40%

Risk of QT interval prolongation Risk of hypotension

Dexmedetomidine6,36 (α2-adrenergic agonist,

sedative)

Decreases norepinephrine release via α2 -adrenergic receptor agonist activity

IV O: 5-10 min; M: hepatic; PB: 94%

Eight times the specificity for the α2 -adrenergic receptor compared to clonidine

Risk of bradycardia

Propofol6,12,36

(sedative)

NMDA receptor antagonist activity GABAA agonist activity Overall CNS depression

IV O: 30 sec; M: hepatic; t1/2: 40 min

Provides anticonvulsant activity Lipophilic, accumulates in tissues with prolonged use Patient must be intubated (respiratory depression)

Baclofen3,36 (skeletal muscle

relaxant)

GABAB receptor agonist IV, PO F: 74%; M: 15% hepatic; t1/2: 4-6 hrs

Very low-quality evidence studying the efficacy and safety in AW

May lower seizure threshold

Carbamazepine6,36 (antiepileptic)

Stabilizes neuronal Na channels, thus reducing firing frequency

Potentiates GABA receptors Inhibits glutamate release

PO F: 100%, M: phase II hepatic; t1/2: 25 hrs; PB: 55%

Risk of agranulocytosis or aplastic anemia Provides anticonvulsant activity Many drug-drug interactions

Valproic acid6,36

(antiepileptic)

Increase turnover of GABA Inhibit NMDA receptors Overall enhances levels of GABA

PO, IV F: 90%; M: phase II hepatic; t1/2: 6-16 hrs

Provides anticonvulsant activity

Topiramate36

(antiepileptic)

Increases GABAA receptor-mediated inhibitory activity

PO F: 80%; M: not extensive; t1/2: 19-23 hrs; PB: 15-41%

Provides anticonvulsant activity

Haloperidol12,36

(1st generation antipsychotic#)

Nonselective blockade of postsynaptic D2 receptors in the brain

PO, IM, IV O: IM 30 min, IV 3-20 minutes; M: hepatic; t1/2: 14-40 hrs; PB: 88-93%

Only use as adjunct therapy; management of hallucinations and delirium

Risk of QT prolongation Does not prevent worsening of withdrawal symptoms

Chlorpromazine36

(1st generation antipsychotic#)

Blocks post-synaptic mesolimbic dopaminergic receptors

Strong α-adrenergic blocking effects

PO, IV, IM O: IM 15 min, PO 30-60 min; M: hepatic; t1/2: 30 hrs; PB: 92-97%

Only use as adjunct therapy for management of hallucinations and delirium

Thioridazine36 (1st generation antipsychotic#)

Blocks post-synaptic mesolimbic dopaminergic receptors

PO F: 25%- 33%, M: hepatic; t1/2: 5-27 hrs

Only use as adjunct therapy; management of hallucinations and delirium

# neuroleptic agent, AW: alcohol withdrawal, CNS: central nervous system, F: bioavailability, GABA: gamma-aminobutyric acid, hr: hour, IM: intramuscular, IV: intravenous, M: metabolism, min: minutes, MOA: mechanism of action, NMDA: N-methyl-D-aspartate, O: onset, PB: protein binding, PO: oral, t1/2: elimination half-life