Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal in Family Medicine Inpatients

Implementation of a Symptom-Triggered Benzodiazepine Protocol for Alcohol Withdrawal in Family Medicine Inpatients
Hospital Pharmacy
       Volume 44, Number 10, pp 881–887
        2009 Wolters Kluwer Health, Inc.


      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§

 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:

                                                                                                Hospital Pharmacy             881
Implementation 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 2009
Implementation 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            883
Implementation 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 2009
Implementation 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
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-
nale behind using this particular                                                       drawal. JAMA. 1997;278(2):144-151.
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-
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
and the drug levels will decline as      REFERENCES                                     alcohol scale (CIWA-Ar). Br J Addict.
the symptoms of AWS resolve.2            1. National Institute on Alcohol Abuse and     1989;84(11):1353-1357.
     In addition to the nursing staff,   Alcoholism. Twelve month prevalence and        11. Daeppen JB, Gache P, Landry U, et
the role of the pharmacist was cru-      population estimates of DSM-IV alcohol         al. Symptom-triggered vs fixed-schedule
cial to implementing this protocol.      dependence by age, sex, and race-ethinicity;   doses of benzodiazepine for alcohol
                                         United States, 2001-2002. http://www           withdrawal: a randomized treatment
Educating and reassuring the other        trial. Arch Intern Med. 2002;162(10):
clinicians (physicians and nurses)       ces/QuickFacts/AlcoholDependence/abus          1117-1121.
on the safety and effectiveness of       dep2.htm. Accessed September 26, 2008.
                                                                                        12. Roffman JL, Stern TA. Alcohol with-
benzodiazepines, and the limita-         2. Gold J, Nelson LS. Ethanol withdraw-        drawal in the setting of elevated blood
tions and risks of continued phe-        al. In: Flomenbaum NE, Goldfrank LR,           alcohol levels. Prim Care Companion J
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                                                                                               Hospital Pharmacy              885
Implementation 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

                                                                            Hospital Pharmacy       887
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