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analysis.17-25 Despite the heterogeneity of these data, when
the studies were separated based on AWS severity, more
meaningful conclusions on the roles PHB can play in mildto-moderate and severe AWS were formed. This heterogeneity prevented both performing a meta-analysis to evaluate
the effect of PHB in treatment of AWS and providing a strong
recommendation for PHB in specific patients.
PHB is a reasonable adjunctive agent in patients who are
not responsive to BZDs alone. The addition of a weightbased or dose-escalation protocol was associated with
improved outcomes, including need for ICU admission and
reduction in BZD doses, and was well tolerated. The methods in these studies seem to be relatively easily translated
into an institutional guideline for PHB administration in
patients not responding to BZD monotherapy. Data suggest
that approximately 75% of patients with severe AWS require
intubation to protect their airway due to a decreased Glasgow
coma score.34 Therefore, front-loading of PHB may be preferred to prevent progression of AWS symptoms. Historically,
clinicians have been hesitant to use higher doses of barbiturates; however, the doses provided in this trial are similar to
the doses patients received in other studies.22,23,27 BZDs were
administered following the loading dose of PHB, which may
increase the risk of respiratory depression and sedative
effects.6,40,41 Although the studies were not specifically powered to evaluate safety outcomes, this regimen appeared to
be safe as no adverse effects related to PHB were reported.
As there is no comparison between a dose escalation, route
of administration, or a single-dose approach to administering
PHB, institutional preference and comfort with administration of these approaches would be an appropriate deciding
factor until this comparison has been performed.
It is difficult to offer a recommendation for PHB monotherapy given the limited data available in the studies evaluated. PHB does appear to be as effective and safe as other
GABA agonists (eg, gabapentin and valproate).
Administration of PHB seems to have a relatively linear relationship with regard to expected serum levels, which may be
a potential target for future studies. Frequently, the symptoms of patients who present to the ED or a psychiatric facility with mild-to-moderate AWS may be controlled using
PHB without requiring hospital admission. A chief concern
when discharging patients who present with AWS from the
ED is that the patient may progress to severe AWS symptoms
(ie, seizure or DT) following discharge and either require
readmission or experience irreversible neurological damage.6,42 As the elimination half-life of PHB may be between
5 and 6 days, patients who receive PHB in the ED should not
require a prescription for a BZD or barbiturate at discharge
and would be at decreased risk for failing treatment.43

Future Studies
We believe that future directions for studying the utility of
PHB therapy should include the creation of studies solely

Hospital Pharmacy 52(9)
evaluating PHB and BZDs (ie, no other adjunctive treatments used) and dose-finding studies for appropriate dosing
and routes of administration of PHB as monotherapy, as well
as adjunctive therapy to BZDs. AWS literature, especially in
severe AWS, has commonly included many medications in
addition to the primary medication of evaluation in the study.
Due to the lack of standardization of institutional protocols
and lack of available guidelines for therapy in these patients,
many individual medications and classes of medications are
used for control of AWS symptoms. As previously mentioned, there have been no studies comparing different dosing strategies of PHB to one another. Although it is likely
that specific patients may benefit from individualized PHB
dosing, closer identification of the safety of PHB use in addition to BZDs needs to be evaluated. Future studies involving
PHB should target a clinically relevant, objective end point
related to AWS such as time to resolution of symptoms. Of
utmost importance remains the ability to identify patients at
risk for AWS and those early on in their AWS symptomatology to prevent progression to more severe AWS.

Conclusions
In conclusion, PHB may have a role in AWS treatment alongside BZDs or as monotherapy; however, there is not enough
evidence to recommend a general, nonindividualized regimen based on AWS severity at this time. The most favorable
results for patients with severe AWS or mild-to-moderate
AWS who presented to the hospital were seen when PHB
was administered using an early and aggressively dosed
strategy. Patients with severe AWS who received PHB
required less escalation of their care, and those with mild-tomoderate AWS spent less time in the ED and did not require
further care following discharge. To better delineate the role
of PHB, clinical trials of adequate size and appropriate
design should be conducted. Specific areas of investigation
include front-loading PHB in various severities of AWS and
head-to-head comparisons between adjuvant therapies in
patients with resistant AWS already admitted to the ICU.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

References
1. National Institute of Alcohol Abuse and Alcoholism. http://
pubs.niaaa.nih.gov/publications/AlcoholFacts&Stats/Alcohol
Facts&Stats.htm. Accessed October 27, 2016.
2. U.S. alcohol epidemiologic data reference manual, volume 9.
http://pubs.niaaa.nih.gov/publications/NEDS&NIS-DRM9/
NEDS&NIS-DRM9.pdf. Accessed October 27, 2016.

http://pubs.niaaa.nih.gov/publications/AlcoholFacts&Stats/Alcohol Facts&Stats.htm http://pubs.niaaa.nih.gov/publications/AlcoholFacts&Stats/Alcohol Facts&Stats.htm http://pubs.niaaa.nih.gov/publications/AlcoholFacts&Stats/Alcohol Facts&Stats.htm http://pubs.niaaa.nih.gov/publications/NEDS&NIS-DRM9/NEDS&NIS-DRM9.pdf http://pubs.niaaa.nih.gov/publications/NEDS&NIS-DRM9/NEDS&NIS-DRM9.pdf

Table of Contents for the Digital Edition of Hospital Pharmacy - October 2017