Table 1.

Evidence for Phenobarbital in Alcohol Withdrawal Syndrome.

Study authors, type, and quality	Setting and severity	Sample size	PB dosing	Comparator	BZD dosing	Efficacy and safety outcome(s)
Concomitant BZD therapy
Rosenson et al.17 Prospective, randomized, double-blind, placebo-controlled trial Good quality	ED then admitted to the hospital Severe AWS	N = 102 (n = 51 PB and n = 51 placebo)	10 mg/kg IV x1	Placebo	Yes Symptom-guided LZ-based AWS protocol	PB: decreased ICU admission (8% vs 25%, 17% difference, 95% CI 4-32%) PB: decreased continuous infusion LZ (4% vs 31%, 27% difference, 95% CI, 14-41%) PB: decreased total LZ requirements (26 mg vs 49 mg, difference 23 mg, 95% CI, 7-40 mg) PB: no adverse effects No difference in ICU or hospital LOS No difference in admission to other locations in the hospital
Duby et al.18 Retrospective, cohort study Fair quality	ICU Severe AWS	N = 135 (n = 65 preguideline: physician preference and n = 70 postguideline: protocol of escalating doses of BZD and PB to RASS goal of -2 to 0)	Escalating doses (route unknown) of 60 mg, 120 mg, and 240 mg after max DZ (120 mg) based on RASS Median PB doses in both groups was 0	Physician preference (no protocol)	Escalating doses based on RASS (max 120 mg DZ)	Post-guideline care associated with: Decreased ICU LOS (9.6 d vs 5.2 d, P = .0004) Decreased ventilator days (5.6 d vs 1.31 d, P < .0001) Decreased DZ (319 mg vs 93 mg, P = .002) Decreased sedation time (10.8 d vs 3.5 d, P < .001) Decreased need for continuous sedation (33 [55%] vs 18 [24%], P < .001) Decreased intubation (13 [22%] vs 4 [5%], P < .001)
Gold et al.19 Retrospective, cohort study Fair quality	ICU Severe AWS	N = 95 (n = 54 DZ ± PB preguideline, n = 41 DZ ± PB post-guideline)	Escalating IV doses (65 mg, 130 mg, 260 mg)	No protocol for intermittent DZ	Yes Escalating doses of DZ to max of 150 mg/dose	Symptom-guided DZ ± PB for adequate sedation associated with decreased complications Post-guideline: Increased max individual dose DZ (32 mg vs 86 mg; P = .001), total DZ (248 mg vs 562 mg; P = .001), and PB use (17% vs 58%; P = .01) Post-guideline: Decreased mechanical ventilation (47% vs 22%; P = .008) Post-guideline: reduction in mechanical ventilation rate (21.9% vs 47.3%, P = .008) Post-guideline: ICU LOS and total amount of BZD received correlated (r = .48, P = .008) No difference in ICU LOS or nosocomial complications between groups
Gashlin et al.20 Retrospective, cohort study Fair quality	Hospitalized, non-ICU Mild-to-moderate AWS	N = 28 (n = 7 PB, n = 21 BZD)	PB (65 mg IV ×1, then 130 mg IV ×1, then 260 mg IV until AWS symptom resolution) Median PB dose 455 mg (IQR: 309-618) or 6.3 mg/kg (IQR: 3.5-10.3)	BZD	BZD (DZ 20 mg PO or equivalent dose of LZ; doses reduced for age and liver dysfunction)	No difference in percentage of CIWA-Ar scores <10 at 24 hours between PB and BZD (28.6% vs 23.8%, P = .588) Reduction in cumulative BZD dose in DZ equivalents in PB group [25 mg (IQR: 20-226) vs 326 mg (160-550), P = .02] No difference in intubation requirement (14.3% vs 4.8%) or ICU admission (14.3% vs 19%)
No concomitant BZD therapy
Hendey et al.21 Prospective, randomized, double-blind trial Good quality	ED (only 6 patients admitted to the hospital) Mild-to-moderate AWS	N = 44 (n = 25 PB, n = 19 LZ)	260 mg IV ×1, 130 mg IV thereafter at physician’s discretion) Mean PB dose 509 mg (range: 260-910)	LZ	2 mg IV as needed + CDP PO as needed Mean LZ dose 4.2 mg (range: 2-8)	PB and LZ both reduced the average CIWA-Ar score from baseline to discharge (15.0 to 5.4 and 16.8 to 4.2, P < .0001) More doses of PB given (2.9 doses (range: 1-6) vs 2.1 doses (1-4), P = .03) No difference in hospital admission rate (12% vs 16%, P = .8) No difference in ED LOS (267 m vs 256 m, P = .8)
Young et al.22 Prospective, uncontrolled trial Fair quality	ED (only 5 patients admitted to hospital) Mild-to-moderate AWS	N = 62 PB	260 mg IV ×1 then 130 mg IV until clinical end point of light sedation or adverse effect noted	None	None	Safe discharge from ED was achieved in 92% of patients Average ED LOS was 3 h, 47 min No discharged patients returned to ED during the following week Adverse effect in 6% of patients (none were admitted to hospital): 1 hypotension, 1 ataxia, 2 lethargy after final bolus doses
Hjermø et al.23 Retrospective, cohort study Poor quality	Psychiatric department in 2 hospitals Mild-to-moderate AWS	N = 194 106 PB (n = 53 PB at hospital 1, n = 53 PB at hospital 2) n = 88 DZ at hospital 2	100-200 mg PO or IV up to 4 times/h	DZ + carbamazepine 200 mg TID (41% of patients)	10-20 mg IV up to 4 times/h + CDP as needed to achieve sleep	No difference in hospital LOS (PB hospital 1: 5.85 ± 6.3 d, PB hospital 2: 5.30 ± 2.6 d, DZ hospital 2: 6.64 ± 4.2 d) No difference in rate of ICU admission (16%, 9%, 14%) Adverse effect in 1 PB patient: respiratory depression
Rosenthal et al.24 Prospective, randomized trial Poor quality	Inpatient detoxification unit Mild-to-moderate AWS	N = 42 patients (unknown how many each of PB and valproate)	PB (Day 1: 60 mg PO QID; Day 2: 60 mg PO TID; Day 3: 60 mg PO BID; Day 4: 30 mg PO ×1)	Valproate + PB 60 mg PO as needed for breakthrough AWS symptoms	Unknown	Both decreased AWS symptoms (P < .00001) PB group: more frequent use of as-needed PB (39 doses vs 20 doses, P < .05)
Mariani et al.25 Prospective, randomized trial Poor quality	Inpatient detoxification unit Mild-to-moderate AWS	N = 21 (n = 10 PB, n = 11 GP)	PB (Day 1: 60 mg PO QID; Day 2: 60 mg PO TID; Day 3: 60 mg PO BID; Day 4: 30 mg PO BID PB 60 mg PO PRN breakthrough AWS symptoms)	GP (Day 1: 1200 mg PO ×1, 600 mg PO BID for 2400 mg; Day 2: 600 TID; Day 3: 600 BID; Day 4: 600 ×1) and PB PRN	None	No difference in treatment failure (PB 38% vs GP 29%, P = .70) – 3+ PB as needed doses, intolerable adverse effect, or left against medical advice No difference in requirement for as-needed PB (38% vs 57%, P = .45)

Note. AWS = alcohol withdrawal syndrome; BID = twice daily; BZD = benzodiazepine; CDP = chlordiazepoxide; CI = confidence interval; CIWA-Ar = clinical institute withdrawal assessment score, revised; DZ = diazepam; ED = emergency department; GP = gabapentin; ICU = intensive care unit; IQR = interquartile range; IV = intravenous; LOS = length of stay; LZ = lorazepam; PO = by mouth; PB = phenobarbital; QID = 4 times daily; TID = 3 times daily; RASS = Richmond Agitation and Sedation Scale; PRN = as needed.