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608
glutamate on N-methyl-d-aspartate (NMDA) receptors.6-9
Chronic ingestion of ethanol causes downregulation of
GABAA receptors, upregulation of NMDA receptors,
decreased GABA release, and increased glutamate production. If ethanol is not present, the disequilibrium due to the
lack of sufficient inhibitory neurotransmitter activity leads to
the manifestation of clinical signs and symptoms of AWS.5,8,9
Alcohol abuse and withdrawal are associated with an
increased risk for medical comorbidities (eg, infections, cardiopulmonary insufficiency, cardiac arrhythmia, bleeding
disorders, need for mechanical ventilation). Withdrawal also
leads to longer, more complicated hospital and intensive care
unit (ICU) lengths of stays (LOS).10-12 Signs and symptoms
of AW may occur within 8 hours after the last ingestion of
ethanol but often appear after several days and reach peak
intensity after 24 to 72 hours.3-5 Numerous medications in
combination or as monotherapy are used for treatment of
AW, including α-adrenergic agonists, barbiturates, benzodiazepines (BZDs), β-blockers, butyrophenones, carbamazepine, dexmedetomidine, gabapentin, propofol, and valproic
acid.13-31 The primary goals of pharmacologic management
of AWS are to minimize symptom severity and prevent major
complications.6,7 The ideal agent should be cross-tolerant
with alcohol. It should have a rapid onset, wide margin of
safety, metabolism independent of liver function, low potential for abuse, and provide sedative, anxiolytic, and anticonvulsant effects without causing respiratory depression.6-9
Benzodiazepines have most of the properties of an ideal
agent (rapid onset, wide margin of safety, and provide sedative, anxiolytic, and anticonvulsant effects without causing
significant respiratory depression); thus, they have emerged
as the cornerstone of AWS management. When symptomtriggered dosing of BZDs using a validated scale, such as the
revised Clinical Institute Withdrawal Assessment for Alcohol
(CIWA-Ar) scale,32 was compared with fixed schedule dosing alongside supportive care, symptom-triggered dosing
demonstrated decreased BZD requirements, decreased time
spent on mechanical ventilation, and decreased ICU
LOS.6,22,33-35 However, in milder cases of AWS for which
patients may be candidates for discharge from the ED rather
than admission to the hospital, discharge with a medication
with a longer half-life may prove beneficial.6,21,22 In patients
with a history of AW and more severe cases of AWS,
decreased GABAA receptor sensitivity to GABA and GABA
agonists may cause BZD monotherapy to be ineffective.36
Patients may experience increased occurrence of morbidity,
mortality, and severe adverse effects (eg, respiratory depression, ICU delirium, and oversedation) as doses of BZDs are
escalated to manage resistant AW.14,37 Adjunctive agents or
alternatives to BZDs may reduce these effects.13-15
Phenobarbital (PHB) has been studied for patients across
the continuum of AWS over the last 40 years and offers
potential advantages to BZDs.17-31 PHB exerts its effects in
as few as 5 minutes with parenteral administration. With oral
administration, absorption from the gastrointestinal tract is
Hospital Pharmacy 52(9)
rapid and effects may be seen in 20 to 60 minutes. Barbiturates
bind to the GABA receptor at a different binding site than
BZDs, increasing the time the GABA-mediated chloride
channels remain open by mimicking the stimulation provided by chronic alcohol use. Through a secondary, additive
mechanism, barbiturates also may inhibit the excitatory
NMDA receptor and reduce neuroexcitation commonly seen
with AW. Respiratory depression, hypotension, and central
nervous system depression may occur with supratherapeutic
dosing, and severe hepatic impairment can develop after
chronic, prolonged use.38
The objective of this systematic review was to evaluate
PHB use with and without concomitant BZD therapy according to indication, dosing, and patient outcomes.
Materials and Methods
Search Strategy and Selection Criteria
Studies were retrieved from the PubMed, Cochrane Controlled
Trial Registry, and Scopus databases from 1950 through
February 2017 to address the question, "Does use of PHB in
adult patients at risk for developing AWS affect clinical outcomes compared to nonuse of PHB?" Controlled and observational studies were considered for inclusion. The search
strategy used was ["phenobarbital" or "barbiturate"] and
["alcohol withdrawal" or "delirium tremens."] References
from the bibliographies of the studies retrieved from the literature search were reviewed to identify additional studies.
After these initial studies were selected, additional studies
that cited a selected study were reviewed for potential inclusion. Studies written in languages other than English and
those presented solely as abstracts at scientific conferences
were not considered for inclusion. Case studies were excluded
due to the lack of rigor.30,31 This systematic review was registered with PROSPERO (CRD42017056990).
Study Selection
Two authors (Drayton A. Hammond & Jordan M. Rowe)
independently reviewed the abstracts for all studies. A
study was considered eligible for inclusion if patients
received PHB for treatment of AWS of any severity and
clinical outcomes (ie, BZD usage, location-specific lengths
of stay, symptomatology, and adverse events) were evaluated. When relevant data for our review were unavailable,
original study authors were contacted for further details
whenever possible.
Data Extraction
Data extracted from the identified studies included study
design, inclusion and exclusion criteria, clinical setting,
patient population, number of study participants, age, severity of illness, receipt and dosing of PHB and comparator
Table of Contents for the Digital Edition of Hospital Pharmacy - October 2017
Pharmacists and Medical Missions
Current FDA-Related Drug Information
Summaries of Safety Labeling Changes Approved By FDA- Boxed Warnings Highlights April-June 2017
Pharmaceutical Pipeline Update
Cholesterol Ester Transfer Protein Inhibitor Review
Formulary Drug Review
Ocrelizumab
Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review
Development of a Pharmacy Technician–Driven Program to Improve Vaccination Rates at an Academic Medical Center
Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin for Venous Thromboembolism Prophylaxis in Hemodialysis Patients
Multilayer Model of Pharmacy Participation in the Antimicrobial Stewardship Program at a Large Academic Medical Center
Impact of Inpatient Automatic Therapeutic Substitutions on Postdischarge Medication Prescribing
Impact of Respiratory Viral Panel Polymerase Chain Reaction Assay Turnaround Time on Length of Stay and Antibiotic Use in Patients With Respiratory Viral Illnesses
Administration of Injectable Vitamin K Orally
Hospital Pharmacy - October 2017 - 577
Hospital Pharmacy - October 2017 - 578
Hospital Pharmacy - October 2017 - 579
Hospital Pharmacy - October 2017 - 580
Hospital Pharmacy - October 2017 - 581
Hospital Pharmacy - October 2017 - 582
Hospital Pharmacy - October 2017 - 583
Hospital Pharmacy - October 2017 - 584
Hospital Pharmacy - October 2017 - 585
Hospital Pharmacy - October 2017 - 586
Hospital Pharmacy - October 2017 - 587
Hospital Pharmacy - October 2017 - 588
Hospital Pharmacy - October 2017 - Pharmacists and Medical Missions
Hospital Pharmacy - October 2017 - Current FDA-Related Drug Information
Hospital Pharmacy - October 2017 - Summaries of Safety Labeling Changes Approved By FDA- Boxed Warnings Highlights April-June 2017
Hospital Pharmacy - October 2017 - 592
Hospital Pharmacy - October 2017 - Pharmaceutical Pipeline Update
Hospital Pharmacy - October 2017 - Cholesterol Ester Transfer Protein Inhibitor Review
Hospital Pharmacy - October 2017 - 595
Hospital Pharmacy - October 2017 - Formulary Drug Review
Hospital Pharmacy - October 2017 - Ocrelizumab
Hospital Pharmacy - October 2017 - 598
Hospital Pharmacy - October 2017 - 599
Hospital Pharmacy - October 2017 - 600
Hospital Pharmacy - October 2017 - 601
Hospital Pharmacy - October 2017 - 602
Hospital Pharmacy - October 2017 - 603
Hospital Pharmacy - October 2017 - 604
Hospital Pharmacy - October 2017 - Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review
Hospital Pharmacy - October 2017 - 606
Hospital Pharmacy - October 2017 - 607
Hospital Pharmacy - October 2017 - 608
Hospital Pharmacy - October 2017 - 609
Hospital Pharmacy - October 2017 - 610
Hospital Pharmacy - October 2017 - 611
Hospital Pharmacy - October 2017 - 612
Hospital Pharmacy - October 2017 - 613
Hospital Pharmacy - October 2017 - 614
Hospital Pharmacy - October 2017 - Development of a Pharmacy Technician–Driven Program to Improve Vaccination Rates at an Academic Medical Center
Hospital Pharmacy - October 2017 - 616
Hospital Pharmacy - October 2017 - 617
Hospital Pharmacy - October 2017 - 618
Hospital Pharmacy - October 2017 - 619
Hospital Pharmacy - October 2017 - 620
Hospital Pharmacy - October 2017 - Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin for Venous Thromboembolism Prophylaxis in Hemodialysis Patients
Hospital Pharmacy - October 2017 - 622
Hospital Pharmacy - October 2017 - 623
Hospital Pharmacy - October 2017 - 624
Hospital Pharmacy - October 2017 - 625
Hospital Pharmacy - October 2017 - Multilayer Model of Pharmacy Participation in the Antimicrobial Stewardship Program at a Large Academic Medical Center
Hospital Pharmacy - October 2017 - 627
Hospital Pharmacy - October 2017 - 628
Hospital Pharmacy - October 2017 - 629
Hospital Pharmacy - October 2017 - 630
Hospital Pharmacy - October 2017 - 631
Hospital Pharmacy - October 2017 - 632
Hospital Pharmacy - October 2017 - Impact of Inpatient Automatic Therapeutic Substitutions on Postdischarge Medication Prescribing
Hospital Pharmacy - October 2017 - 634
Hospital Pharmacy - October 2017 - 635
Hospital Pharmacy - October 2017 - 636
Hospital Pharmacy - October 2017 - 637
Hospital Pharmacy - October 2017 - Impact of Respiratory Viral Panel Polymerase Chain Reaction Assay Turnaround Time on Length of Stay and Antibiotic Use in Patients With Respiratory Viral Illnesses
Hospital Pharmacy - October 2017 - 639
Hospital Pharmacy - October 2017 - 640
Hospital Pharmacy - October 2017 - 641
Hospital Pharmacy - October 2017 - 642
Hospital Pharmacy - October 2017 - Administration of Injectable Vitamin K Orally
Hospital Pharmacy - October 2017 - 644
Hospital Pharmacy - October 2017 - 645
Hospital Pharmacy - October 2017 - 646
Hospital Pharmacy - October 2017 - 647
Hospital Pharmacy - October 2017 - 648
Hospital Pharmacy - October 2017 - 649
Hospital Pharmacy - October 2017 - 650
Hospital Pharmacy - October 2017 - 651
Hospital Pharmacy - October 2017 - 652
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