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Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal
A Randomized Treatment Trial
Jean-Bernard Daeppen, MD;
Pascal Gache, MD;
Ulrika Landry, BA;
Eva Sekera, MD;
Verena Schweizer, MD;
Stéphane Gloor, PhD;
Bertrand Yersin, MD
Arch Intern Med. 2002;162:1117-1121.
ABSTRACT
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Background In alcohol withdrawal, fixed doses of benzodiazepine are generally recommended
as a first-line pharmacologic approach. This study determines the benefits
of an individualized treatment regimen on the quantity of benzodiazepine administered
and the duration of its use during alcohol withdrawal treatment.
Methods We conducted a prospective, randomized, double-blind, controlled trial
including 117 consecutive patients with alcohol dependence, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, entering an alcohol treatment program at both the Lausanne
and Geneva university hospitals, Switzerland. Patients were randomized into
2 groups: (1) 56 were treated with oxazepam in response to the development
of signs of alcohol withdrawal (symptom-triggered); and (2) 61 were treated
with oxazepam every 6 hours with additional doses as needed (fixed-schedule).
The administration of oxazepam in group 1 and additional oxazepam in group
2 was determined using a standardized measure of alcohol withdrawal. The main
outcome measures were the total amount and duration of treatment with oxazepam,
the incidence of complications, and the comfort level.
Results A total of 22 patients (39%) in the symptom-triggered group were treated
with oxazepam vs 100% in the fixed-schedule group (P<.001).
The mean oxazepam dose administered in the symptom-triggered group was 37.5
mg compared with 231.4 mg in the fixed-schedule group (P<.001). The mean duration of oxazepam treatment was 20.0 hours
in the symptom-triggered group vs 62.7 hours in the fixed-schedule group (P<.001). Withdrawal complications were limited to a
single episode of seizures in the symptom-triggered group. There were no differences
in the measures of comfort between the 2 groups.
Conclusions Symptom-triggered benzodiazepine treatment for alcohol withdrawal is
safe, comfortable, and associated with a decrease in the quantity of medication
and duration of treatment.
INTRODUCTION
AN IMPORTANT advance in the last 3 decades has been the use of benzodiazepines
to treat alcohol withdrawal. In the late 1960s, the comparison of chlordiazepoxide
with placebo and 3 other drugs established the therapeutic efficacy of benzodiazepines
for alcohol withdrawal.1 Recent meta-analyses
concluded that benzodiazepines are recommended over most nonbenzodiazepine
sedative-hypnotic agents because they have better efficacy, a greater margin
of safety, and lower potential of abuse.2-3
Although withdrawal severity varies greatly, and the amount of medication
needed to control symptoms can also vary significantly, benzodiazepines are
generally administered on a predetermined dosing schedule for 3 to 5 days
for all patients. This is in contrast with numerous observations indicating
that the pharmacologic treatment of alcohol withdrawal should allow for a
degree of individualization. A personal adaptation of medication dosage is
now possible, using questionnaires that evaluate the occurrence and intensity
of alcohol withdrawal. One of these instruments, the revised Clinical Institute
Withdrawal Assessment for Alcohol scale (CIWA-Ar),4
is a 10-item scoring system that measures the severity of alcohol withdrawal,
monitors the clinical course, and identifies patients at risk of complications
such as seizures and delirium.
Since an individual monitoring system of alcohol withdrawal has become
available, the characteristics of pharmacologic treatments adapted to each
individual have been evaluated. Retrospective evaluation of admissions in
a general hospital suggests that monitoring withdrawal symptoms using the
CIWA-Ar allows for a reduction in duration and intensity of benzodiazepine
treatment.5 A single controlled trial demonstrated
an important reduction in the duration of treatment and quantity of benzodiazepines
administered during alcohol withdrawal. Saitz and colleagues6
randomized 101 alcohol-dependent patients admitted to a treatment unit to
either symptom-triggered or fixed-schedule chlordiazepoxide treatment. The
individualized regimen was associated with a reduction in the duration (68
hours vs 9 hours) and intensity (425 mg vs 100 mg of chlordiazepoxide) of
treatment without difference in the incidence of complications.6
However, as Mayo-Smith2 notes, only 1
controlled trial confirms the reduction in medication use associated with
individualized doses of benzodiazepines for treatment of alcohol withdrawal.
The major aim of the present study is to reassess the extent of the benefits
of an individualized regimen of benzodiazepines for treatment of alcohol withdrawal.
Secondary objectives are to verify that the benefits of individualized benzodiazepine
therapy persist even in patients with severe alcohol-withdrawal histories
and individuals at elevated risk of alcohol withdrawal because of recent alcohol
use at the time of admission in treatment.
METHODS
PARTICIPANTS
Between August 19, 1999, and October 3, 2000, consecutive patients admitted
to the alcohol treatment inpatient program, the 12-bed clinic "Vallon" affiliated
with the Lausanne University Hospital and the 10-bed clinic "Petit Beaulieu"
of the Geneva University Hospital, were considered for study inclusion. On
a weekly basis, staff organization required that study inclusion be interrupted
when 2 patients from the given institution were included; thus, no more than
4 patients were included from any given week. Exclusion criteria were (1)
last alcoholic beverage intake more than 72 hours prior to admission; (2)
daily use of medication for treatment of alcohol withdrawal for the 30 days
prior to admission (ie, benzodiazepines, barbiturates, or clomethiazole);
(3) major cognitive, psychiatric, or medical comorbidity; (4) opiate or stimulant
dependence; and/or (5) no fluency in French. The ethics committees of the
departments of internal medicine at Lausanne and Geneva university medical
schools approved the study protocol.
ASSESSMENTS
A history, physical examination, and blood tests for  -glutamyltransferase,
red blood cell volume, and blood alcohol concentration were done at admission.
Levels of carbohydrate-deficient transferrin (CDT) were also checked, which
is a biological marker suggestive of heavy alcohol use (>60 g of alcohol per
day) for the past 15 days.7 Eligible patients
were personally interviewed by trained research assistants to assess their
demographic characteristics, medical comorbidities (using the Charlson scale8), use of any prescribed drugs during the last 30 days,
use of any illegal drugs, and Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria of alcohol dependence using questions adapted from the French
version of the Diagnostic Interview for Genetic Studies (DIGS).9
The interviewer also solicited a detailed history of alcohol use over the
week, month, and year preceding admission10
and a measure of alcohol dependence severity using the Severity of Alcohol
Dependence Questionnaire.11
Finally, subjects' comfort level during the first 3 days of treatment
was estimated retrospectively at treatment day 3: well-being was assessed
using 4 questions adapted from the well-being schedule12
and 3 dimensions adapted from the health-related, quality-of-life, Medical
Outcomes Study 36-Item Short-Form Health Survey (MOS-SF-36)13
questionnaire. Alcohol withdrawal was assessed using the CIWA-Ar, a validated,
reliable measure of the current severity of alcohol withdrawal consisting
of 10 items, scored from 0 (no withdrawal) to 67 (maximum withdrawal severity).4 The fixed-schedule regimen of oxazepam was determined
according to the guidelines of the American Society of Addiction Medicine
(30 mg every 6 hours for 4 doses, then 15 mg every 6 hours for 8 doses).2 We used 15-mg oxazepam tablets in our study regimen
because they are frequently used for the oral treatment of alcohol withdrawal
in Europe. We could have used 10-mg diazepam or 25-mg chlordiazepoxide instead.
INTERVENTION GROUPS
A pharmacist not involved in other aspects of the trial randomly assigned
eligible patients in clusters of 10 subjects to either the symptom-triggered
group or the fixed-schedule group. The allocation was generated using a program
running on Excel (Microsoft Inc, Redmond, Wash). Oxazepam and placebo (mannitol)
were manufactured in capsules of similar appearance. During the trial, each
patient was allocated an identification number. A safety-sealed envelope labeled
with the patient's identification number contained the code of randomization
for each individual. Physicians, nurses, research assistants, and patients
were blinded to treatment assignment throughout the trial. The evidence of
successful blinding among the staff was assessed on the third day of the protocol
by asking the nurse in charge to guess whether the patient was assigned to
the symptom-triggered group or the fixed-schedule group. Data analyses indicated
that 65 of 117 patients (55.5%) were attributed to the wrong group, with a
similar rate of incorrect guesses in both groups. Subjects in the fixed-schedule
group received oxazepam every 6 hours, 4 doses of 30 mg each, and then 8 doses
of 15 mg each. Half an hour after taking each capsule, subjects with CIWA-Ar
scores between 8 and 15 received 15 mg of oxazepam, and those with CIWA-Ar
score higher than 15 received 30 mg of oxazepam. The CIWA-Ar scores were monitored,
and additional oxazepam doses were administered every half hour as long as
CIWA-Ar scores remained at 8 or higher ("as-needed" medication). Fixed-schedule
doses were not administered when subjects were sleeping or were somnolent.
The symptom-triggered group received placebo every 6 hours, 4 doses of 30
mg each followed by 8 doses of 15 mg each. Half an hour after taking each
capsule, subjects with CIWA-Ar scores between 8 and 15 received 15 mg of oxazepam,
while those with CIWA-Ar scores higher than 15 received 30 mg of oxazepam.
The CIWA-Ar scores were monitored, and additional oxazepam doses were administered
every half hour as long as CIWA-Ar scores remained at 8 or higher (as-needed
medication). Subjects were observed for symptoms of withdrawal for 48 hours
after study completion.
STATISTICAL ANALYSIS
Analyses were performed using SPSS (Chicago, Ill) for Windows. The Mann-Whitney
test was used to compare duration of treatment and medication doses that were
not normally distributed. Independent-sample t tests
were used to compare normally distributed continuous variables, and  2 tests were used to compare categorical variables. Two-tailed P values were obtained from all tests. With the hypothesis
of a medium effect size d (d = 0.5 SE), where d illustrates the difference
in the total quantity of oxazepam between the symptom-triggered group and
the fixed-schedule group, the trial was designed to have a 90% probability
obtaining significant differences between groups with an  (type I error)
of 5%.
RESULTS
Eight of the 251 consecutive patients admitted in the treatment program
who were asked to participate declined the offer, resulting in 243 individuals
evaluated for study inclusion. Forty-four subjects (18.1%) who did not have
any alcoholic beverage within 72 hours preceding admission were excluded,
as were 42 (17.3%) who had used benzodiazepines daily for the last 30 days.
Another 31 (12.7%) were excluded because 12 were undergoing methadone maintenance
therapy, 4 had used barbiturates on a regular basis, 13 had major psychiatric
or medical comorbidity, and 2 did not speak French. Among the 126 patients
randomized, 4 exited the program within the first 3 days, 3 had exclusion
criteria apparent only after randomization, 1 had somnolence, and 1 had several
falls. These exclusions left valid data for 117 patients. The mean ±
SD age of these subjects was 46.6 ± 9.52 years; 90 (76.9%) were men;
40 (34.2%) were married; 21 (17.9%) were single; 56 (47.9%) were separated,
divorced, or widowed; and 111 (94.9%) were white, while 6 (5.1%) were from
other ethnic groups.
Patients were randomized into 2 groups: symptom-triggered (n = 56) and
fixed-schedule (n = 61) oxazepam administration. To verify that the withdrawal
treatment characteristics did not reflect preexisting group differences, we
compared demographic characteristics and alcohol use history between the groups
(Table 1), which were similar
at intake in age, sex ratio, ethnic makeup, marital status, and employment.
There was no group difference in medical comorbidity assessed with the Charlson
scale. Table 1 underscores group
similarities in (1) alcohol use over the 7-day and 30-day periods preceding
admission, (2) blood alcohol concentration, (3) biological markers of recent
heavy alcohol intake (-glutamyltransferase, carbohydrate-deficient
transferrin, and red blood cell volume), (4) severity of alcohol dependence
(assessed by the number of DSM-IV dependence criteria
endorsed), and (5) withdrawal history (the number of DSM-IV alcohol withdrawal criteria, findings of the Severity of Alcohol Dependence
Questionnaire, and the proportion of patients reporting a former history of
major alcohol withdrawal [seizures, hallucinations, or delirium tremens]).
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Table 1. Comparison of Demographic Characteristics and Alcohol Use
History by Treatment Group*
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Considering group similarities in demography, alcohol use, and alcohol
withdrawal history, we found that the symptom-triggered treatment approach
resulted in a significant reduction in duration and quantity of oxazepam used
during alcohol withdrawal (Table 2). The symptom-triggered group used 6 times less oxazepam than the fixed-schedule
group and also experienced markedly shorter duration of treatment. This important
difference between groups resulted in part from the fact that only 22 (39%)
of the patients in the symptom-triggered group used oxazepam at all, compared
with 100% in the fixed-schedule group. However, it is important to note that
the group differences persisted after excluding individuals who did not require
any oxazepam in the symptom-triggered group. Indeed, although not reported
in the tables, after excluding individuals who did not require any oxazepam
treatment (CIWA-Ar score was always lower than 8 in 34 [61%] patients in the
symptom-triggered group), we found that the mean ± SD quantity of oxazepam
administered to the 22 treated patients was 95.4 ± 107.7 mg, which
was significantly less than the 231.4 ± 29.4 mg registered in the fixed-schedule
group (Mann-Whitney, z = 5.84; P<.001).
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Table 2. Comparison of Treatment Outcomes by Treatment Group*
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To explore whether the individualized benzodiazepine regimen also offered
benefits in the subgroup with a history of severe alcohol withdrawal (seizures,
hallucinations, or delirium tremens), analyses were repeated in the 19 subjects
with such history (not reported in the tables). The results indicated a trend
toward less total oxazepam used (94.1 ± 137.2 mg vs 240.0 ±
34.95 mg; Mann-Whitney, z = 1.83; P = .07) and a reduction in treatment duration (22.7 ± 26.68
hours vs 62.1 ± 6.18 hours; Mann-Whitney, z
= 2.87; P = .004) in the symptom-triggered group
compared with the fixed-schedule group.
While the symptom-triggered regimen was associated with a reduction
in the intensity and duration of oxazepam use, it is important to examine
whether treatment reduction was associated with a change in safety, withdrawal
intensity, and/or comfort. Regarding safety, Table 2 indicates that a single patient experienced an episode of
seizure, while no hallucinations or delirium tremens were registered. The
intensity of the withdrawal symptoms assessed by the CIWA-Ar indicated that
symptom-triggered group mean scores were generally higher at days 1, 2, and
3, with a larger proportion of patients with CIWA-Ar scores of 8 or higher
than in the fixed-schedule group. Higher CIWA-Ar scores might have been associated
with more anxiety, nervousness, and a decrease in comfort. Therefore, to explore
whether the symptom-triggered regimen might be detrimental to comfort, at
day 3 we evaluated well-being and health-related quality of life over the
3 days of detoxification (Table 2).
There were no treatment group differences in health concerns, anxiety, energy,
or depression (well-being schedule), similar findings of vitality and energy,
and a higher level of physical functioning during detoxification in the symptom-triggered
group than in the fixed-schedule group (adapted from the MOS-SF-36). To verify
that the measures of well-being and health-related quality of life did not
reflect preexisting group differences, we conducted further analyses (not
reported) that indicated similar scores between groups for the 4 questions
of the well-being schedule and the 3 dimensions of the MOS-SF-36 evaluated
over the 30 days preceding admission.
COMMENT
The data reported offer strong support to the hypothesis that for many
patients withdrawing from alcohol, symptom-triggered therapy can shorten detoxification
time and avoid unnecessary medications without decrease in safety or comfort.
Anecdotally, the nursing staff involved in the study preferred to have an
objective scale to guide their medication dosing and decided to pursue the
symptom-triggered regimen after completion of the study. While the results
presented confirm an important reduction in the duration and intensity of
benzodiazepine treatment, the study by Saitz and colleagues6
and the present data differed in the magnitude of the reduction (7 times vs
3 times for treatment duration and 4 times vs 6 times for medication quantity,
respectively). Differences between the 2 studies' results were probably due
to variations in the protocol of administration of "as-needed" medication.
By excluding patients without recent alcohol intake and focusing on subjects
at risk to develop alcohol withdrawal symptoms, the present study adds precision
to the importance of the benefits of the symptom-triggered regimen. Including
patients with seizures or severe withdrawal histories adds potential for generalizing
from the results reported by Saitz and colleagues, confirming the benefit
of a symptom-triggered regimen for the numerous patients with these complications.
In the present study, 60.3% of the patients withdrawing from alcohol
did not require any oxazepam (symptom-triggered group), suggesting that, even
in a sample of individuals with severe alcohol problems, most patients did
not require any pharmacologic treatment for alcohol withdrawal. This result
extends over prior research demonstrating that among 203 problem drinkers
admitted to a general hospital, 46% demonstrated no significant withdrawal
symptoms requiring pharmacologic treatment.14
Although these results may have wide applicability in treating patients
withdrawing from alcohol, it is important to recognize some limitations in
the generalizablity of the findings. First, these subjects were in alcohol
detoxification units, and the results may not hold true for other settings,
such as general hospitals, where withdrawal occurs less frequently. Second,
the sample consisted mostly of white men; the findings might not apply to
women or nonwhites. Finally, although efforts were made to optimize the accuracy
of the data, information on quantity and frequency of alcohol use and severity
of alcohol use disorders relied solely on the subjects' estimates and recollections.
AUTHOR INFORMATION
Accepted for publication September 25, 2001.
This study was financially supported by Wyeth AG, Zug, Switzerland.
Corresponding author and reprints: Jean-Bernard Daeppen, MD, Alcohol
Treatment Center, Mont-Paisible 16, CHUV-1011 Lausanne, Switzerland (e-mail: jean-bernard.daeppen{at}inst.hospvd.ch).
From the Alcohol Treatment Centers, Lausanne (Drs Daeppen, Schweizer,
Gloor, and Yersin and Ms Landry) and Geneva (Drs Gache and Sekera), Switzerland.
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