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Creator: University of Florida College of Pharmacy
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Publication Date: October 2004
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BENZODIAZEPINES FOR THE
TREATMENT OF DELIRIUM
TREMENS


Nancy Borja, Pharm.D. Candidate



Introduction
Delirium Tremens (DT), or alcohol with-
drawal delirium, is one of three clinical stages
manifested by patients experiencing alcohol with-
drawal. It is considered the most severe stage and
usually occurs within 3 to 5 days following the dis-
continuation of alcohol. About 5% of patients ex-
periencing alcohol withdrawal will progress to DT.2
DSM-IV diagnostic criteria for alcohol
withdrawal delirium include: (1) disturbance of
consciousness with reduced ability to focus, sus-
tain, or shift attention; (2) a change in cognition or
the development of a perceptual disturbance that
cannot otherwise be explained; (3) disturbance de-
velops in a short period and tends to fluctuate dur-
ing the day; (4) evidence from the history, physical
examination, or laboratory findings that symptoms
developed during or shortly after a withdrawal syn-
drome.3 Mortality rates for DT have been estimated
to range from 1% 5%. Patients most often die
from cardiac arrhythmias, respiratory arrest, severe
dehydration, hyperthermia, or circulatory collapse.4
This article will review the role and use of benzodi-
azepines in treating alcohol withdrawal delirium.


Guidelines for Treatment
The American Society of Addiction Medi-
cine has prepared guidelines to ensure appropriate
treatment of alcohol withdrawal. The guideline
identifies three goals of treatment for detoxification
of alcohol and other substances: (1) to provide a
safe withdrawal from the drugs) of dependence
and enable the patient to become drug-free; (2) to
provide a withdrawal that is humane and thus pro-
tects the patient's dignity; and (3) to prepare the pa-
tient for ongoing treatment of his or her depend-
ence on alcohol or other drugs. 4
Benzodiazepines (BZD) are the drug of choice
for DT.5 They exhibit cross-tolerance with alcohol
and act directly on the gamma-amino butyric acid
(GABA) system, thus, fostering a withdrawal that
satisfies the tenets set forth by the American Soci-
ety of Addiction Medicine. Other benefits include
their anticonvulsant activity and favorable safety
profile in patients with adequate cardiorespiratory
reserve.
Additional drug therapy for DT includes the use
of thiamine (100 mg)2 to prevent Wernicke-
Korsakoff syndrome and vitamin supplementation,
including a minimum of 1 mg of folate. 1,5

rI,. .fil


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PharmaNote Volume 20, Issue 1 October 2004


PharmaNote


VOLUME 20, ISSUE 1 OCTOBER 2004


INSIDE THIS ISSUE:
BENZODIAZEPINES FOR THE TREATMENT
OF DELIRIUM TREMENS
INDEX FOR VOLUME 19 (OCT. 2003-SEP. 2004)


PharmaNote


Volume 20, Issue 1 October 2004








Table 1. Pharmacokinetics of Benzodiazepines

Onset of Active Route of ad-
Drug Half life action (oral) Metabolites ministration
Diazepam (Valium) 20-80 hours Rapid Yes oral/IV

Lorazepam (Ativan) 10-20 hours Intermediate None oral/IV/IM

Midazolam (Versed) 2-5 hours 1- 5 minutes (IV only) None IV

Chlordiazepoxide (Librium) 5-30 hours Intermediate Yes Oral/IV

Note: Duration of action depends on rate and extent of absorption and patient characteristics. Rapid onset =within 15 minutes, Intermediate = 15-30 minutes.
Abbreviations: IV intravenous, IM intramuscular.


Pharmacokinetics
Benzodiazepines are metabolized hepati-
cally to active and/or inactive metabolites that are
eliminated really. When initiating a BZD it is im-
portant to consider the route of elimination,
whether there are active metabolites, half-lives of
the parent drug and any active metabolites, and the
onset and duration of action.5 Water solubility is
also an important consideration when initiating
treatment. Diazepam and lorazepam lie on opposite
ends of the spectrum in this regard; diazepam is the
most lipophilic BDZ while lorazepam has an oc-
tanol:water partition coefficient much less than di-
azepam. Lipophilicity alone, however, does not de-
termine efficacy. For instance, lorazepam is the
least lipophilic BZD, yet has an onset of action of 2
to 5 minutes when administered parenterally. Phar-
macokinetics for different benzodiazepines are pre-
sented in Table 1.1 The elimination half-lives of
BZDs and their metabolites are prolonged in geri-
atric patients and those with liver disease. Hepatic
function must be considered early in the DT treat-
ment algorithm, since alcohol abuse is the precursor
to DT. However, because there is poor correlation
between the severity of hepatic disease and drug
disposition, there are no formal dosing recommen-
dations in this population.
Lorazepam has theoretical advantages over
other BZDs since it does not have active metabo-
lites.5 Furthermore, it undergoes glucuronidation
and has an intermediate half-life, which minimize
the potential for accumulation in patients with he-
patic disease. Due to its shorter half-life and route
of metabolism, there is less concern with prolonged


sedation in elderly patients. On the other hand,
some have suggested that drugs with a longer half-
life might be preferred due to "smoother" with-
drawal. Unlike other BZDs, lorazepam possesses
anti-emetic properties, which may minimize nausea
associated with withdrawal. Chlordiazepoxide, a
long-acting BZD, was once considered the BZD of
choice for DT. However, its active metabolites can
accumulate after several days of therapy, making
prolonged sedation a concern.

Clinical Trials
Data regarding the use of benzodiazepines in
DT appeared in the literature in the late 1950s, yet
there is no consensus on which agent or dosing
regimen is preferred. Clinical trials of BZDs have
evaluated diverse endpoints such as mortality, dura-
tion of delirium, time required to control agitation,
and adequate control of delirium. Table 2 summa-
rizes the results of prospective trials evaluating dif-
ferent agents in reducing the duration of alcohol
withdrawal delirium.1317 A meta analysis found that
benzodiazepines reduce withdrawal severity, the
incidence of delirium, and seizures. Compared with
neuroleptics, BZDs may improve survival.6 P-
adrenergic antagonists, clonidine, and neuroleptics
were found to ameliorate withdrawal severity and
can be considered useful adjuncts. Phenothiazines
ameliorate withdrawal but are less effective than
benzodiazepines in reducing delirium or seizures.
The following conclusions can be made based on a
limited number of controlled clinical trials; (1)
agents with rapid onset control agitation more
quickly; (2) agents with a long duration of action
provide a smooth treatment course with less break-


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Table 2. Prospective Controlled Trials Reporting Duration of Delirium in Patients With Alcohol Withdrawal
Patients,
Study Intervention ROA No. Duration, h P Value
Friedhoff and Zitrin13 Chlorpromazine IM/PO 15 192 < .05

Paraldehyde 16 144

Thomas and Freedman14 Promazine PO 17 96 0.04

Paraldehyde PO 22 74

Golbert et al.15 Promazine PO 5 134 NS

Paraldehyde/ chloral
11 <24
hydrate

Kaim and Klett16 Perphenazine IM/PO 46 77.9 > .2

Pentobarbital IM/PO 41 80

Paraldehyde IM/PO 55 78.4

Chlordiazepoxide IM/PO 46 74

Thompson et al.1 Paraldehyde Rectal 17 57 > .05

Diazepam IV 17 55

ROA= route of administration, IM= intramuscular, PO= oral, h= hours, NS= not significant.


through symptoms; (3) when there is concern re-
garding prolonged sedation, such as in patients who
are elderly, who have substantial liver disease or
other serious concomitant medical illness, agents
with shorter duration of activity may be associated
with a lower risk; and (4) the cost of different ben-
zodiazepines varies considerably.
Neuroleptic agents such as promazine and
chlorpromazine are not as effective as BZDs for the
treatment of DT.6 P-adrenergic antagonists have not
been adequately studied in patients with DTs. 6 A
randomized, controlled clinical trial comparing
transdermal clonidine with chlordiazepoxide in al-
cohol withdrawal concluded that clonidine was an
effective treatment for alcohol withdrawal syn-
drome, 1 but it has not been evaluated in patients
that have progressed to DT. Finally, Malcolm et al
compared the effects of carbamazepine and loraze-
pam in ambulatory patients with alcohol with-


rharmaNote 0


drawal.12 Carbamazepine was superior in prevent-
ing rebound withdrawal symptoms and reducing
post-treatment drinking. However, carbamazepine
has not been evaluated for the treatment of DT.

Dosing and Administration
When using BZDs in the acute setting, the par-
enteral route is preferred since the onset of action is
more rapid. It is important to administer the chosen
BZD slowly to avoid respiratory depression, hy-
potension, bradycardia, or cardiac arrest.2 The dose
selected should be individualized and titrated to
achieve light somnolence, which should serve as
the therapeutic endpoint. Examples of medication
regimens used to treat DTs include: (1) diazepam 5
mg IV (2.5 mg/min), which can be repeated a sec-
ond time in 5-10 minutes, with 10 mg given as a
third and fourth dose (5-10 minutes apart) up to a
max of 20 mg if needed; (2) lorazepam 1 to 4 mg


Volume 20, Issue 1 October 2004


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harma"ote








Table 3. Drug Interactions and the Effect on Benzodiazepines


Drug/ Drug Class
Macrolide ABX
Antifungals
Cimetidine

Levodopa

Phenytoin

Carbamazepine


Antacids
Digoxin


Effect on BZD
Decreased clearance of BZD


Increased plasma concentration of BZD
Increased plasma concentration of BZD

Decreased control of parkinsonian symptoms


Decreased PHT concentrations


Decreased plasma concentration of BZD
Decreased rate of GI absorption for BZD
Increased plasma half-life of digoxin


IV every 5-15 minutes; or (3) lorazepam 1 to 40 mg
IM every 30 to 60 minutes until calm, then every
hour as needed to maintain light somnolence.6 For
patients requiring large doses, frequent redosing, or
extended treatment, BZDs can be administered by
continuous infusion, often in the intensive care unit
setting. For instance, lorazepam can be started at 1
mg/hr and titrated to the desired effect.
Once the patient is stabilized, he/she can be
converted to the oral form. Two commonly used
dosing practices are the fixed-dose schedule and the
symptom-triggered schedule.5 In a fixed-dose
model, benzodiazepines are given at specific time
intervals and as needed based on the patient's with-
drawal symptoms. Symptom-triggered regimens are
more cost-effective because they use less total
medication. The benzodiazepine is administered
based on the Clinical Institute Withdrawal Assess-
ment for Alcohol (CIWA-Ar) score. The CIWA-Ar
scale is an assessment tool, which quantifies the se-
verity of alcohol withdrawal syndrome and also
helps treat and monitor patients. Also, symptom-
triggered therapy is associated with a shorter course
of therapy. 47

Adverse effects
Adverse effects of BZD treatment have not
been systematically collected in this population.
However, these agents are generally well tolerated
when an appropriate starting dose is selected and
titrated cautiously. The following should be consid-
ered when evaluating the tolerability of BZD for
this indication: 1) it is the adverse effect profile (i.e.
somnolence) that serves as the therapeutic end-


point, 2) patients often are incoherent, 3) the toxic-
ity of alcohol and BZDs overlap. In general, the
most common adverse effects seen with BDZs are
respiratory depression and sedation. Other reported
effects include hypotension, confusion, dizziness,
akathisia, unsteadiness, headache, depression, dis-
orientation, amnesia, dermatitis, rash, weight gain/
loss, nausea, changes in appetite, weakness, nasal
congestion, hyperventilation, and apnea. 9

Drug Interactions
Concomitant use of benzodiazepines with CNS-
depressant drugs can enhance CNS effects such as
increased sedation or respiratory depression of ei-
ther agent.8 Table 3 lists the drug classes and their
effect when used in combinations with BZDs.

Cost
Table 4 depicts the average retail cost of the
parenteral form of diazepam, lorazepam and mida-
zolam at 3 pharmacies in Gainesville, FL. Because
these patients often require large doses for an ex-
tended period of time (i.e., several days), these dif-
ferences become amplified.

Summary
Benzodiazepines are the drug class of
choice for the treatment of DT. They cross-react
with alcohol and act directly on the GABA system.
They are beneficial in reducing agitation, prevent-
ing seizures, and providing sedation in this popula-
tion. While BZDs are considered the drug of
choice, there is a lack of consensus regarding which
agent in the class and what dose is the most effec-


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PharmaNote Volume 20, Issue 1 October 2004


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Volume 20, Issue I October 2004









Table 4. Retail Cost*

Drug Cost ($)

Lorazepam 2 mg/ml (10 ml vial) 30.41

Diazepam 5 mg/ml (10 ml vial) 13.02

Midazolam 1 mg/ml (20 ml vial) 18.73

*Cost reflects average cost from 3 retail pharmacies in Gainesville, FL.

tive. Given the high rate of complications when
DTs is treated inadequately, this is certainly an area
worthy of further investigation.


References
1. Newman J, Terris D, et al. Trends in the Management of Alcohol
Withdrawal Syndrome. Laryngoscope 1995;105:1-7.
2. Sachse, Donna. Emergency. Delirium tremens. Am J Nurs
2000;100:41-2.
3. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition. Washington, DC:
American Psychiatric Association; 1994.
4. Bayard et al. Alcohol Withdrawal Syndrome. American Family
Physician 2004; 69;1443-1450.
5. Erwin et al. Delirium Tremens. Southern Medical Journal 1998;
91:425-432.
6. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of
alcohol withdrawal delirium: an evidence-based practice guide-
line. Arch Intern Med 2004;164:1405-12.
7. Daeppen J, Gache P, et al. Symptom-triggered vs fixed-schedule
doses of benzodiazepine for alcohol withdrawal: A randomized
treatment trial. Arch Internal Med 2002; 162: 1117- 1121.
8. Lorazepam Drug Monograph. Clinical Pharmacology Online
2004. Gold Standard Multimedia.
9. Benzodiazepines. AHFS Drug Information 2003.
10. Hoey L, Nahum A, Vance-Bryan K. A prospective evaluation of
benzodiazepine guidelines in the management of patients
hospitalized for alcohol withdrawal. Pharmacotherapy 1994;
14:579-585.
11. Baumgartner G, Rowen R. Transdermal clonidine versus
chlordiazepoxide in alcohol withdrawal: A randomized,
controlled clinical trial. Southern Medical Journal 1991;
84:312-321.
12. Malcolm et al. The effects of carbamazepine and loraze-
pam on single versus multiple previous alcohol withdraw-
als in an outpatient randomized trial. J Gen Intern Med
2002;17:349-355.
13. Friedhoff AJ and Zitrin A. A comparison of the effects
of paraldehyde and chlorpromazine in delirium tremens. N
Y State J Med 1959;59:1060-3.
14. Thomas DW and Freedman DX. Treatment of the alcohol
withdrawal syndrome. comparison of promazine and par-
aldehyde. JAMA 1964;188:316-8.
15. Golbert TM, Sanz CJ, Rose HD, Leitschuh TH.
Comparative evaluation of treatments of alcohol with-


drawal syndromes. JAMA 1967;201:99-102.
16. Kaim SC amd Klett CJ. Treatment of delirium tremens. A
comparative evaluation of four drugs. Q J Stud Alcohol
1972;33:1065-72.
17. Thompson WL, Johnson AD, Maddrey WL. Diazepam
and paraldehyde for treatment of severe delirium tremens.
A controlled trial. Ann Intern Med 1975;82:175-80.





Labeling Changes

As of July 2004, the product labeling for
all atypical antipsychotics on the market
in the United States include a warning
section cautioning prescribers regarding
the association between these agents and
hyperglycemia. Hyperglycemia, in some
cases extreme and associated with
ketoacidosis, hyperosmolar coma or
death, has been reported in patients
treated with all atypical antipsychotics.

Topiramate (Topamax, Ortho-McNeil)
is now indicated for the prophylaxis of
migraine in adults. The recommended
starting dosage is 25 mg in the evening
during week 1, 25 mg in the morning and
in the evening during week 2, 25 mg in
the morning and 50 mg in the evening
during week 3, and 50 mg in the morning
and in the evening during week 4; the
recommended maintenance dose is 100
mg/day in two divided doses. A
precaution was added concerning an
association between the concomitant use
of topiramate and valproic acid and
hyperammonemia. The signs and
symptoms of hyperammonemia abate
after discontinuation of either drug.

Fondaparinux sodium (Arixtra,
Organon Sanofi-Synthelabo): the
contraindication for use in patients
weighing less than 50 kg has been
narrowed to those needing prophylactic
therapy and undergoing hip-fracture or
hip- or knee-replacement surgery.


PharmaNote Volume 20, Issue 1 October 2004


PharmaNote


Volume 20, Issue I October 2004








New Drug Approvals

* The FDA rejected the New Drug
Application submitted by AstraZeneca
requesting approval of ximelagatran
(Exanta) for the prevention of strokes
in patients with atrial fibrillation,
prevention of venous thromboembolism
in patients undergoing knee replacement
therapy and long-term secondary
prevention of venous thromboembolism
following standard treatment. The FDA
cited concerns regarding the long-term
safety of Exanta, specifically hepatic
and cardiac safety.

* Insulin glulisine (Apidra, Aventis
Pharma) was approved by the FDA in
April 2004. Apidra is a rapid-acting
insulin similar to insulin aspart
(NovoLog). It should be administered
within 15 minutes before or 20 minutes
after starting a meal.





Index for Volume 18
October 2002 September 2003


Issue (Page)


Aminoglycosides
Acute Bacterial Rhinosinusitis
Social Anxiety Disorder

B-C-D
Crestor
Cialis

E-F-G-H-I-J
Eletriptan
Ethinyl estradiol/levonorgestrel
Exanta
Fluoxetine/olanzapine


Jun. '04 (01)
Mar. '04 (01)
May '04 (01)


Oct. '03 (01)
Jan. '04 (01)


Jun. '04 (05)
Dec. '03 (01)
Apr. '04 (01)
Aug. '04 (01)


K-L-M-N
Ketek
Lyme Disease
Memantine
Namenda


O-P-Q-R
Olanzapine/fluoxetine
Relpax
Restless Legs Sysndrome
Acute Bacterial Rhinosinusitis
Rosuvastatin

S-T-U-V
Seasonale
Social Anxiety Disorder
Symbyax
Tadalafil
Telithromycin
Uncomplicated UTIs in a Drug
Resistant Era

W-X-Y-Z
Ximelagatran


Sep. '04 (01)
Aug. '04 (06)
Feb. '04 (01)
Feb. '04 (01)


Aug. '04 (01)
Jun. '04 (05)
Jul. '04 (01)
Mar. '04 (01)
Oct. '03 (01)


Dec. '03 (01)
May '04 (01)
Aug. '04 (01)
Jan. '04 (01)
Sep. 04 (01)
Nov. '03 (01)



Apr. '04 (01)


U U U


~
PharmaNote Volume 20, Issue 1 October 2004


Topic


The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.


PharmaNote


Volume 20, Issue I October 2004




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