Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal in Family Medicine Inpatients
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Hospital Pharmacy
Volume 44, Number 10, pp 881–887
2009 Wolters Kluwer Health, Inc.
FEATURED ARTICLE
Implementation of a Symptom-Triggered
Benzodiazepine Protocol for Alcohol
Withdrawal in Family Medicine Inpatients
Sharon See, PharmD, BCPS*, Sarah Nosal, MD†, Wendy Brooks Barr, MD, MPH, MSCE‡, Robert Schiller, MD§
Abstract
Purpose: The purpose of this pilot study was to review the implementation of symptom-triggered benzodiazepine
therapy and evaluate the feasibility and outcomes as compared with a previous hospital standard of fixed-dose phe-
nobarbital protocol for alcohol withdrawal on a family medicine service.
Methods: This retrospective chart review of 46 patients’ medical records was performed on admissions to the fam-
ily medicine service occurring between February and October of 2005 compared with February and October of
2006. Included in the study were adults who were suffering from alcohol withdrawal symptoms (AWS), who admit-
ted to heavy daily alcohol intake, who were intoxicated on admission, and who had a history of AWS and/or histo-
ry of AWS-related seizures. The Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar) was
used to evaluate the impact of individualized symptom-triggered therapy on outcome measurements utilizing symp-
tom-triggered benzodiazepine therapy compared with the previous hospital standard using a fixed-dose phenobar-
bital protocol.
Results: One hundred percent of the patients in the phenobarbital group required drug compared with 38% in the
benzodiazepine group (P < 0.001). Fewer patients (9.5%) in the benzodiazepine group left the hospital against med-
ical advice (AMA), while 36% of patients in the phenobarbital group left AMA (P = 0.045). There was no signifi-
cant difference in length of stay or the number of days on the protocol.
Conclusion: The results of the pilot study demonstrated that symptom-triggered therapy using benzodiazepines
resulted in better outcomes than fixed-dosing phenobarbital. Importantly, most patients in the benzodiazepine group
required no drug administration.
Key Words—alcohol withdrawal, benzodiazepines, symptom-triggered therapy
Hosp Pharm—2009;44:881–887
INTRODUCTION that results in the development of most significant complications of
Alcohol dependence is a major minor or major withdrawal symp- alcohol withdrawal, seizures and
health problem in the United toms. Minor withdrawal symp- delirium tremens, typically occur
States, affecting approximately 8 toms, including tremor, hyperten- within 48 to 96 hours from the last
million Americans.1 Alcohol with- sion, diaphoresis, and tachycardia, drink.2 Although AWS in the gener-
drawal syndrome (AWS) is defined occur in about 6 to 12 hours, often al US population is rare and usual-
as the discontinuation or reduction while the patient still has a mea- ly mild, symptoms of alcohol with-
of prolonged, heavy alcohol use surable blood alcohol level. The drawal relate proportionately to
*Associate Clinical Professor, St. John’s University College of Pharmacy and Allied Health Professions, Jamaica, NY; Clinical Fac-
ulty, The Institute for Family Health, New York, NY; †Family Physician, Urban Horizons Family Practice, Bronx, NY; ‡Research
Director, The Institute for Family Health, New York, NY; Assistant Professor of Family and Social Medicine, Albert Einstein Col-
lege of Medicine, Yeshiva University, Bronx, NY; §Chair, Alfred and Gail Engelberg Department of Family Medicine, The Insti-
tute for Family Health; Senior Vice President Medical Affairs, Institute for Urban Health, Albert Einstein College of Medicine,
Yeshiva University Bronx, NY. Corresponding author: Sharon See, PharmD, BCPS, St. John’s University College of Pharmacy and
Allied Health Professions, 8000 Utopia Parkway, Jamaica, NY 11439; phone: 212-844-1955; e-mail: sees@stjohns.edu.
Hospital Pharmacy 881Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal
the amount of alcohol intake and azepines for the treatment of AWS that it does not provide additive
the duration of a patient’s recent are diazepam (Valium), chlordia- CNS suppression when taken with
drinking habit. According to a zepoxide (Librium), and loraze- alcohol and has an established
recent analysis, patients who con- pam (Ativan). Diazepam, a longer- record as an antiepileptic drug.2,8
sume more alcohol (more than 10 acting agent, has a rapid onset, can Routine magnesium replacement is
drinks/week) are more likely to be easily titrated with loading not recommended because it has
report withdrawal symptoms.3 To doses, and provides a smooth with- not been shown to have any effect
avoid the lethal stages of AWS, drawal due to its long half-life (48 on severity of alcohol withdrawal
clinicians must be vigilant during to 72 hours) and active metabolite symptoms, seizures, or delirium.9
this critical 6- to 96-hour window. (desmethyldiazepam) but has the Although there is a lack of
The American Society of potential to cause excess sedation well-designed, prospective trials
Addiction Medicine lists 3 goals in elderly patients or patients with demonstrating the efficacy of phe-
for detoxification of alcohol and hepatic dysfunction due to im- nobarbital for AWS, our institu-
other substances: “to provide a paired clearance. Similarly, chlor- tion continues to use it as a prima-
safe withdrawal from the drug(s) diazepoxide is also long acting, has ry therapeutic agent.7 The ratio-
of dependence and enable the active metabolites (desmethylchlor- nale for the use of phenobarbital is
patient to become drug-free,” “to diazepoxide and demoxepam), and that it is cross-tolerant with alco-
provide a withdrawal that is hu- may cause oversedation in elderly hol; has a long duration of action;
mane and thus protects the pa- patients or patients with hepatic can be administered orally, intra-
tient’s dignity,” and “to prepare the dysfunction. Its onset, however, is muscularly (IM), and intravenous-
patient for ongoing treatment of slower than diazepam.8 Lorazepam ly (IV); is relatively inexpensive;
his or her dependence on alcohol may be a better pharmacologic and has a low potential for abuse.
or other drugs.”4 choice for these patients because it Despite these advantageous char-
To accomplish these goals, sev- does not have active metabolites acteristics, phenobarbital has a less
eral agents have been administered and undergoes oxidation. Howev- desirable safety profile than benzo-
to patients to manage the manifes- er, oversedation during the loading diazepines. It may produce over-
tations of AWS. These agents in- phase with lorazepam may occur sedation, hypotension, and respira-
clude barbiturates, benzodiaze- because peak sedation may not oc- tory depression, and lacks clinical
pines, beta-adrenergic blockers, cur for 10 to 20 minutes compared data from controlled, comparative
carbamazepine, clonidine, magne- to minutes with diazepam. trials to support its use as a prima-
sium, and neuroleptic agents. The Adrenergic agents such as beta- ry agent for alcohol withdrawal.
ideal agent should be cross-tolerant blockers and clonidine are some- Furthermore, hepatic enzyme induc-
with alcohol. It should have seda- times used to control the autonom- tion occurs with extended pheno-
tive, anxiolytic, and anticonvulsant ic symptoms of alcohol withdrawal, barbital use and may create the po-
activity; a rapid onset and long such as elevated blood pressure. tential for multiple drug interactions.5
duration of action; a wide margin They are generally not recom- Controversy exists over the best
of safety; metabolism independent mended as sole treatment for alco- dosing regimen for patients suf-
of liver function; and a low poten- hol withdrawal because they do fering from AWS. Patients are either
tial for abuse.5 not treat the underlying mecha- given regular “around the clock”
Benzodiazepines are the stan- nisms of alcohol withdrawal and doses of agents, also known as the
dard of care for the pharmacologic may mask signs of delirium or “fixed-dose” regimen or patients
management of alcohol withdraw- other markers of withdrawal.2,7 are individually assessed with the
al. Benzodiazepines have been Carbamazepine has been shown to Clinical Institute Withdrawal As-
shown to be superior to placebo in be effective for alcohol withdrawal sessment for Alcohol Scale, Revised
treating alcohol withdrawal symp- symptoms. When compared with (CIWA-Ar) tool and given doses
toms as well as seizures and deliri- benzodiazepines, carbamazepine based on an elevated objective
um.6 A meta-analysis showed that, has been shown to be equally effec- score, also known as the symptom-
compared with placebo, benzodi- tive for alcohol withdrawal and to triggered approach. The CIWA-Ar
azepines reduced withdrawal se- be helpful with secondary out- is a validated 10-item scale that as-
verity, incidence of delirium (P = comes such as anxiety and depres- sesses the severity of alcohol with-
0.04), and seizures (P = 0.003).7 sion. Carbamazepine offers an drawal and aids in monitoring
The most commonly used benzodi- advantage over benzodiazepines in response to treatment (see Appen-
882 Volume 44, October 2009Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal
dix A).10 Unlike fixed-dose regi- had a contraindication to benzodi- ucated the nursing staff and clini-
mens, symptom triggered therapy azepines or hypersensitivity to ben- cians on the rationale and details
allows for drug administration zodiazepines were excluded from of how to implement the CIWA-
when needed by the patients, as the study. The objective of the Ar protocol via designated train-
opposed to administering drug study was to evaluate newly imple- ing sessions, teaching afternoons,
when there may be no need or ben- mented symptom-triggered thera- and constant reinforcement and
efit.7 The main advantage to the py using the CIWA-Ar scale, evalu- encouragement while on the med-
symptom-triggered approach is ate the impact of individualized ical floor.
that much less medication is used symptom-triggered therapy on out-
to achieve the same withdrawal come measurements, and compare Statistical Analysis
state. Daeppen et al11 performed a symptom-triggered benzodiazepine Data were analyzed with Stata
prospective, double-blind, random- therapy to a previous hospital stan- Statistical Software: Release 8
ized, controlled-treatment trial to dard using phenobarbital in a (College Station, TX: StataCorp
study the benefits of an individual- fixed-dose protocol. 10 A retrospec- LP) using chi-square, Fisher exact,
ized treatment regimen on the tive chart review of patients receiving and t tests where appropriate.
quantity of benzodiazepines admin- the symptom-triggered benzodiaze-
istered and the duration of its use pine protocol during the period of RESULTS
during alcohol withdrawal treat- February to October 2006 was A total of 46 patients qualified
ment.11 The authors compared ox- compared with patients who were for inclusion in this pilot study. The
azepam given either on a fixed dose treated with fixed-dose phenobar- baseline characteristics between groups
or as a symptom-triggered schedule bital during the period of February were similar, with a majority of pa-
using the CIWA-Ar assessment tool. to October 2005. The outcome tients having a history of alcohol
The symptom-triggered oxazepam measurements included quantity of abuse or dependence (80%) (see
patients required less drug (37.5 ± medication used, duration of drug Table 1). Of the 21 patients in the
81.7 mg) and were on the protocol treatment, inpatient length of stay, benzodiazepine group, 2 patients
for less time (20 ± 24.45 hours) number and type of withdrawal- received lorazepam, while the rest
than the fixed-dose group (231 ± related complications experienced, received diazepam. Patients in the
29.43 mg and 62.7 ± 5.44 hours, and adverse effects experienced. phenobarbital group received a
respectively). Adverse events were determined by mean dose of 663 mg (standard
Based on the evidence in the a retrospective chart review. Our deviation [SD] 834 mg), while pa-
literature, the continued use of protocol used oral diazepam or tients in the benzodiazepine group
fixed-dose prescribing with pheno- lorazepam, and IM lorazepam if received a mean dose of diazepam
barbital needed to be evaluated the patient could not tolerate any- 14 mg (SD 36 mg) and lorazepam
and possibly replaced with the thing by mouth (see Appendix B). 0.86 mg (SD 2.72 mg). Important-
CIWA-Ar tool using benzodi- Hospital policy did not allow for ly, 62% of patients on the benzo-
azepines. The goal of this study IV administration of benzodiaze- diazepine symptom-triggered pro-
was to investigate the introduction pines on the general medical floor. tocol did not require any drug,
of this symptom-based treatment Nurses assessed each patient using whereas 100% of patients in the
protocol in a limited inpatient set- the CIWA-Ar tool and documented phenobarbital group received a
ting operated by the family medi- the patient’s score. Patients received drug (P < 0.001). This means that
cine department. diazepam 10 mg or lorazepam 2 if these patients had received the
mg orally when CIWA-Ar scores previous hospital standard of
METHODS demonstrated that patients were fixed-dose phenobarbital, they
This was a retrospective study exhibiting mild withdrawal (CIWA- would all have received at least 5
of hospitalized patients admitted Ar score 10 to 20). Doses were days of drug whether or not they
to the family medicine unit who doubled when scores exceeded 20. had symptoms. The length of stay
were older than 18 years of age The primary investigator (See) was similar in both groups. The
and suffering from AWS, admitted and a medical resident collected phenobarbital group trended to-
to heavy daily alcohol intake, were the study data. The study methods ward being on the protocol longer
intoxicated at admission, and had and design were approved by the than the benzodiazepine group
a history of AWS and/or history of hospital’s Institutional Review (3.12 vs 2.57 days; P = 0.25). Addi-
AWS-related seizures. Patients who Board. The clinical pharmacist ed- tionally, 36% of patients in the
Hospital Pharmacy 883Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal
Table 1. Baseline Demographics increase his CIWA-Ar score and
thus was given medication.
Demographics Phenobarbital (n = 25) Benzodiazepine (n = 21) As with any new protocol, vari-
ous questions were raised during the
Male 92% (23) 90% (19)
pilot study. First, clinicians inquired
Age (years) (mean) 47 (range, 36 to 63) 51 (range, 26 to 78) about what to do if the patient pre-
Race sented with a positive blood alcohol
Caucasian 16 % (4) 24% (5) level. Patients with chronic alcohol
African American 40 % (10) 24% (5) dependence can still go into alcohol
Other 28% (7) 24% (5) withdrawal despite the presence of
alcohol in the blood. An acute
Unknown 16% (4) 29% (6)
decline in their blood alcohol con-
Detoxification history 68% (17) 43% (9) tent can precipitate withdrawal.12 It
History of alcohol 72% (18) 29% (6) was recommended to order the
withdrawal symptoms symptom-triggered protocol as per
History of alcoholic seizures 60% (15) 33% (7) usual procedure. The second ques-
Daily alcohol intake (drinks) 17 (4 to 40) 21 (6 to 40) tion was what to do with a patient
Intoxicated on admission 20% (5) 29% (6) who was on clonazepam at home
Hours since last drink (mean) 23 (range, 0 to 96) 36 (range, 4 to 168)
for anxiety. Due to the concern of
benzodiazepine withdrawal, clona-
zepam was continued and the ben-
phenobarbital fixed-dose group Additionally, patients in this group zodiazepine-symptom triggered pro-
left the hospital against medical left against medical advice less often tocol was used as usual to prevent
advice (AMA), while only 9.5% of than those in the fixed-dose pheno- alcohol withdrawal symptoms.
patients in the benzodiazepine barbital group. While not statistically The phenobarbital patients
group left AMA (P = 0.045). No significant, there was a trend toward were sicker at baseline as defined by
patient experienced any adverse e- decreased length of stay and days on the presence of detoxification histo-
vents in the benzodiazepine group, protocol in the symptom-triggered ry, history of alcohol withdrawal
while 7 of 12 patients in the phe- benzodiazepine group. symptoms, and seizures. Inadequate
nobarbital group had adverse Limitations of this study in- treatment for alcohol withdrawal
events (P < 0.001). These included clude a small sample size and a ret- symptoms may have contributed to
1 case each of hyponatremia, rospective design using a historical the large number of patients who
arrhythmia, chest pain, diabetic ke- control. Incomplete data were found left AMA. In addition, patients
toacidosis, severe detoxification in the charts, which could have may have received phenobarbital
symptoms, nausea and vomiting, affected the statistical analysis. In in the emergency department
and nonsustained ventricular tachy- addition, there were some cases in before arriving on the family med-
cardia that required transfer to the which the CIWA-Ar protocol was icine floor. This may have skewed
coronary care unit. incorrectly used. Specifically, in the results of the study.
some patients, the protocol was One of the major concerns
DISCUSSION continued despite the fact that the with implementing this type of
The pilot study demonstrated protocol could have been stopped protocol is the ability of nurses to
that symptom-triggered therapy because the patient was no longer carry out the protocol. The CIWA-
using benzodiazepines resulted in at risk of AWS. This meant that Ar assessment tool requires that
better outcomes than those pa- nurses continued to assess the nurses go through the 10 assess-
tients on fixed-dose phenobarbital. patients and presumably, the scores ment questions to determine a
The most significant finding in the were not high enough to require patient’s CIWA-Ar score. This
pilot was that almost two-thirds of any drug. It was also noted that nurse-driven protocol requires that
patients in the symptom-triggered occasionally the incorrect dose was all nurses are educated on the
group did not require any drug. given according to the score. Both rationale and method of activating
Avoiding unneeded sedatives may of these types of misuse could be this protocol. The clinical pharma-
render the patient more able to par- attributed to user error. In 1 case, cist in-serviced all of the nurses on
ticipate in other necessary treatments. a patient feigned symptoms to the family medicine inpatient ser-
884 Volume 44, October 2009Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal
vice. Each nurse was given a hand- in overcoming their reluctance and Nelson LS, eds. Goldfrank’s Toxicologic
out that included the rationale for changing their practice patterns. Emergencies. 8th ed. New York, NY: The
McGraw-Hill Companies Inc; 2006:
using symptom-triggered protocols 1167-1175.
and benzodiazepines and an ex- CONCLUSION 3. Caetano R, Clark CL, Greenfield TK.
ample of how to use the protocol. This pilot study demonstrated Prevalence, trends, and incidence of alco-
Prior to the pilot study, nurses that a symptom-triggered alcohol hol withdrawal symptoms: analysis of
expressed concern that this assess- withdrawal protocol using benzodi- general population and clinical samples.
ment would be too time-intensive. azepines could be successfully im- Alcohol Health Res World. 1998;22
(1):73-79.
Nurses should be able to conduct plemented on an inpatient adult
the CIWA-Ar assessment in less than medicine service operated by fami- 4. Kasser CL, Geller A, Howell E,
Wartenberg A. Principles of detoxifica-
2 minutes.10 This was confirmed ly physicians. The data revealed a tion. In: Graham AW, Schultz TK, eds.
during the pilot. Nurses were re- trend toward less medication use, Priniciples of Addiction Medicine. 2nd
minded that they were already doing decrease in duration of treatment ed. Chevy Chase, MD: American Society
this assessment, except that now it and length of stay, and a significant of Addiction Medicine Inc; 1998:423-
had to be documented to determine difference in adverse events com- 430.
a score. In addition, nurses were pared with patients on fixed-dose 5. Rodgers JE, Crouch MA. Phenobarbi-
tal for alcohol withdrawal syndrome.
reassured that this assessment tool phenobarbital. The most notable re- Am J Health Syst Pharm. 1999;56(2):
was validated, reproducible, and sult of this study is that over two- 175-178.
reliable.10 It was found that once the thirds of patients in the symptom- 6. Ntais C, Pakos E, Kyzas P, Ioannidis
nurses understood the rationale triggered benzodiazepine group JP. Benzodiazepines for alcohol with-
behind the protocol, they were able required no drug. Based upon this drawal. Cochrane Database Syst Rev.
to implement the protocol with min- study, the fixed-dose protocol at 2005;(3): CD005063.
imal problems. our institution was replaced sys- 7. Mayo-Smith MF. Pharmacological man-
The nurses were also unfamil- tem-wide with the CIWA-Ar proto- agement of alcohol withdrawal. A meta-
analysis and evidence-based practice
iar and initially uncomfortable col, and became fully implemented guideline. American Society of Addiction
with giving diazepam 10 mg until in the hospital computerized physi- Medicine Working Group on Pharmaco-
the pharmacist explained the ratio- cian order entry system. logical Management of Alcohol With-
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dose and medication. The goal of ACKNOWLEDGEMENTS 8. McKeon A, Frye MA, Delanty N. The
treating alcohol withdrawal is to The authors want to acknowl- alcohol withdrawal syndrome. J Neurol
sedate the patient while ensuring edge Mary Ann Howland, PharmD, Neurosurg Psychiatry. 2008;79(8):854-
862.
normal vital signs.2 Diazepam is a DABAT, FAACT, Clinical Professor
9. Wilson A, Vulcano B. A double-blind,
rapid-acting benzodiazepine that of Pharmacy, St. John’s University placebo-controlled trial of magnesium
has an active metabolite with a College of Pharmacy and Allied sulfate in the ethanol withdrawal syn-
long half-life ensuring a smooth Health Professions; Consultant, drome. Alcohol Clin Exp Res. 1984;
taper as the alcohol levels decrease New York City Poison Control 8(6):542-545.
during the patient’s stay. This Center; Consultant, Bellevue Hos- 10. Sullivan JT, Sykora K, Schneiderman
“autotitration” allows the clinician pital Emergency Department. J, Naranjo CA, Sellers EM. Assessment
to administer 1 dose of diazepam of alcohol withdrawal: the revised clini-
cal institute withdrawal assessment for
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Hospital Pharmacy 885Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal Appendix A. The Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-AR)8 886 Volume 44, October 2009
Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal
Appendix B. Order Sheet
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