Professional Documents
Culture Documents
review article
current concepts
disorders must be managed. Care must be support- however, require careful and frequent monitoring
ive and nonjudgmental, yet assertive. with a validated withdrawal-symptom scale such
During detoxification, behavioral interventions as the Clinical Institute Withdrawal Assessment for
for ongoing treatment of these chronic relapsing Alcohol (see the Appendix). The categories on this
disorders may be started. Such interventions should scale are sweating, anxiety, tremor, auditory or vis-
be more sophisticated than simple referral to self- ual disturbances, agitation, nausea and vomiting,
help groups. Effective treatments include contin- tactile disturbances, headache, and orientation. To-
gency management, motivational enhancement, tal symptom scores of more than 15 on this scale
and cognitive therapies.5,6 or a history of withdrawal seizures indicates that
medications should be started at presentation.
Without medication, alcohol-withdrawal symp-
withdrawal from sedatives toms might be expected to peak about 72 hours
(alco hol and benzodiazepines)
after the last use of alcohol, but medications can
clinical presentation and general reduce symptoms within hours. In patients with
management delirium tremens, management with medication
The clinical history often suggests alcohol prob- requires high doses of benzodiazepines (e.g., 5 to
lems, which are seen in 15 to 20 percent of patients 10 mg of diazepam by intravenous injection, repeat-
in primary care and hospitalized patients.7 Since al- ed in two to four hours if seizures occur). Unless
cohol withdrawal can be complicated by seizures delirium is present, medication is typically needed
and delirium and is more severe in persons with for no more than seven days after the last use of al-
more previous episodes of withdrawal or other ill- cohol, although some patients will report withdraw-
nesses, careful evaluation is essential. Such evalua- al symptoms, including sleep problems, for several
tion should include assessment for anemia, throm- more weeks. Protracted symptoms may precipitate
bocytopenia, and elevated liver-enzyme levels.7,8 relapse.16
Specific symptoms during sedative or alcohol with- Withdrawal from benzodiazepines and other
drawal that may dictate pharmacotherapy include sedatives produces more psychomotor and auto-
auditory and tactile disturbances and seizures.
Significant components of the withdrawal syn-
drome after chronic alcohol use reflect reduced neu-
Table 1. Medication Treatment for Alcohol Withdrawal.
rotransmission in type A g-aminobutyric acid path-
ways and enhanced neurotransmission in glutamate Class Examples Effects
(N-methyl-d-aspartate) pathways.9 Seizures during
Benzodiazepines Chlordiazepoxide, diaz- Decreased severity of with-
withdrawal probably result from this altered neuro- (preferably epam, oxazepam, drawal symptoms; re-
biology, but the anticonvulsant medication pheny- long-acting)* lorazepam duced risk of seizures
toin is not an effective treatment for alcohol with- and delirium tremens
drawal.8,10 Benzodiazepines are effective, probably Anticonvulsants Carbamazepine Decreased severity of with-
owing to cross-tolerance with ethanol at the type A drawal symptoms
g-aminobutyric acid receptor, where carbamaze- Adjunctive agents
pine and divalproate are also believed to have their Beta-blockers Atenolol, propranolol Improvement in vital signs;
reduction in craving
main actions.11,12 On the basis of this neurobiol- Alpha-agonists Clonidine Decreased severity of with-
ogy, antagonism at the N-methyl-d-aspartate recep- drawal symptoms
tor is another potential mechanism for relieving
symptoms of alcohol and sedative withdrawal and * Dosing follows one of three strategies. With fixed-dose therapy, a set amount
may be important for reducing the toxic effects from of medication is given at regular intervals (e.g., 50 to 100 mg of chlordiazepox-
ide four times daily), with the dose tapered from day 4 to day 7. With a loading-
repeated episodes of alcohol withdrawal.13 dose strategy, a moderate-to-high dose of a long-acting benzodiazepine (e.g.,
Withdrawal symptoms can be quantified to allow 20 mg of diazepam) is given initially to provide sedation; the level is allowed to
symptom-triggered therapy, in which the patient re- decrease through metabolism. With symptom-triggered therapy, the first dose
of 5 mg of diazepam is given when the score for symptoms is at least 8 on
ceives medication only when symptoms exceed a the Clinical Institute Withdrawal Assessment for Alcohol scale. The severity of
threshold of severity, rather than on a fixed schedule symptoms is measured one hour after this and each subsequent dose of diaz-
(Table 1). This approach is as effective as fixed-dose epam and then at least every eight hours, with the frequency of monitoring in-
creased if symptoms worsen. The dose is adjusted (e.g., from 5 mg of diaz-
therapy but requires significantly less medication epam to 10 mg three times daily) according to the severity of the symptoms.
and leads to a more rapid detoxification.14,15 It does,
nomic nervous system signs than does withdrawal fidence interval, 0.47 to 0.97).20 Thus, a critical issue
from alcohol, and these signs start between 2 and may be the potential effectiveness of anticonvulsant
10 days after abrupt discontinuation. If medications agents for outpatient treatment in more severe as
are used, treatment with anticonvulsant drugs such well as mild-to-moderate alcohol withdrawal.
as carbamazepine will need to be continued for The treatment of benzodiazepine or barbiturate
about two weeks, and the dose of benzodiazepines dependence has involved either tapering dosages
gradually tapered. of the agent of dependence or substituting a longer-
acting benzodiazepine or phenobarbital, with a
pharmacologic treatment gradual reduction in dose over a period of two
Benzodiazepines and Barbiturates weeks. Tables in Smith and Wesson21 provide dos-
Two major reviews of pharmacotherapy for alcohol age equivalents for use in substituting longer-act-
withdrawal concluded that benzodiazepines are the ing for shorter-acting agents.
treatment of choice on the basis of several outcomes,
including the severity of the alcohol-withdrawal syn- Adjuvant Treatments
drome, occurrence of delirium and seizures, adverse Although they may be useful as adjuvant treatments,
effects of the medication, and completion of with- most other agents are unsuitable for use alone dur-
drawal, as well as subsequent entry into rehabilita- ing alcohol withdrawal. The phenothiazines and
tion.8,12 A meta-analysis comparing benzodiaz- haloperidol reduce signs and symptoms of with-
epines with placebo or with an active control drug drawal but are significantly less effective than ben-
included 11 trials, representing a total of 1286 pa- zodiazepines in preventing delirium (difference in
tients.8 There was more often a clinically significant risk, 6.6 cases per 100 patients) and seizures (dif-
reduction of symptoms within two days with benzo- ference in risk, 12.4 seizures per 100 patients)
diazepines than with placebo (common odds ratio, (P<0.01 for both comparisons).22 Beta-adrenergic
3.28; 95 percent confidence interval, 1.30 to 8.28).8 antagonists and clonidine reduce autonomic man-
In addition, in six prospective trials, benzodiaz- ifestations of withdrawal but have no known anti-
epines, particularly longer-acting ones, were more convulsant activity.23,24 Symptoms of early with-
effective than placebo in reducing the incidence of drawal or impeding delirium may be masked by
seizures (risk reduction, 7.7 seizures per 100 pa- propranolol.25 Centrally acting alpha-adrenergic
tients treated; P=0.003) and delirium (risk reduc- agonists such as clonidine ameliorate symptoms
tion, 4.9 cases of delirium per 100 patients treated; in patients with mild-to-moderate withdrawal but
P=0.04).8,10,12,17 However, the potential for abuse probably do not reduce delirium or seizures.26 They
is greater with agents that have a rapid onset of ac- may be used in conjunction with benzodiazepines
tion, including diazepam, alprazolam, and loraz- in patients with coexisting conditions such as cor-
epam, than for those with slower onset of action, onary artery disease. For benzodiazepine withdraw-
such as chlordiazepoxide, oxazepam, and halaze- al, however, they have not found much use even
pam.18 Although phenobarbital has a low potential when low therapeutic doses are discontinued.21
for abuse as compared with other barbiturates and
is used by about 10 percent of substance-abuse pro- Anticonvulsant Agents
grams in the United States, its use is supported by Although phenytoin has no primary role in the treat-
only a few controlled studies. Furthermore, pheno- ment of alcohol-withdrawal symptoms, other anti-
barbital has a poorer safety profile than benzodiaz- convulsant agents, such as carbamazepine, have
epines: it can cause respiratory depression when been in clinical use for this purpose for three dec-
used in high doses or when combined with alcohol, ades.27 Carbamazepine is superior to placebo and
as may happen with outpatients.19 equal in efficacy to phenobarbital and oxazepam for
Other drugs, particularly carbamazepine, do not patients with mild-to-moderate withdrawal symp-
differ significantly from the benzodiazepines in toms.28,29 Carbamazepine has no significant toxic
terms of adverse events (common odds ratio for ad- effects on the blood or the liver when used in seven-
verse events associated with benzodiazepines as day protocols for alcohol withdrawal29,30; it reduces
compared with carbamazepine, 0.67; 95 percent emotional distress better and permits a faster return
confidence interval, 0.34 to 1.32). Dropout rates in to work than does oxazepam.30 Carbamazepine has
the first seven days are slightly lower with benzodi- well-documented anticonvulsant activity and pre-
azepines (common odds ratio, 0.68; 95 percent con- vents alcohol-withdrawal seizures in studies in an-
imals, but data from trials in humans are limited.31 tinuation depend on the half-life of the drug in-
It does not potentiate the central nervous system and volved (Fig. 1). For heroin, symptoms peak within
respiratory depression caused by alcohol, does not 36 to 72 hours and last for 7 to 10 days, whereas for
inhibit memory (which occurs with even small dos- methadone, symptoms peak at 72 to 96 hours but
es of benzodiazepines), and has no potential for last for 14 days or more, and for buprenorphine,
abuse.21 However, dizziness, vomiting, and nausea symptoms are less severe and of shorter dura-
are common side effects, particularly at the initial tion.35,36
dose of 800 mg per day. Carbamazepine has not
been evaluated for treating delirium tremens. treatment
In a recent study of 136 patients with alcohol- Since the use of opiates for detoxification is legally
withdrawal symptoms, patients treated with carba- restricted to inpatient settings and specially licensed
mazepine had fewer protracted symptoms than did outpatient programs, patients in outpatient settings
those receiving lorazepam, five days after the med- more typically receive clonidine or another adrener-
ications were stopped.32 This difference in symp- gic agent. Recent federal initiatives may loosen the
tom levels persisted for a week. Furthermore, re- restrictions on the use of buprenorphine, a partial
lapse to alcohol use during a follow-up period of opioid agonist, for the treatment of opioid with-
three months was less common in the carbamaz- drawal.3,37,38 A summary of pharmacotherapeutic
epine group. Adverse effects such as dizziness and approaches is given in Table 2.
incoordination were also less common in the car-
bamazepine group (7 percent vs. 20 percent). Some Opioid Medications
early studies have suggested that carbamazepine is Substitution of a long-acting, orally active opioid
efficacious in patients undergoing benzodiazepine such as methadone or buprenorphine is the ap-
withdrawal, but the data are less extensive than are proach preferred by most patients. Sublingual bu-
those for alcohol.21,33 prenorphine provides an effective and comfortable
Valproate may also reduce symptoms of alcohol withdrawal and transition from heroin to antagonist
withdrawal. Data have been reported for a total of treatment with naltrexone, and it appears to be su-
approximately 2500 patients. The trials have gen- perior to clonidine in this regard.39,40 Buprenor-
erally been open-label, and not all have reported sei- phine starting at 4 to 16 mg daily is equivalent to
zure rates. Two double-blind, randomized studies methadone starting at 20 to 35 mg daily, and the
have been published, however.32,34 In these trials,
patients treated with 1000 to 1200 mg of valproate
for four to seven days had fewer seizures, dropped
out less frequently, had less severe withdrawal Heroin
symptoms, and used less oxazepam than did con-
Severity of Withdrawal
Abrupt discontinuation
Clonidine alone
Severity of Withdrawal
Clonidine+naltrexone
Buprenorphine+clonidine+
naltrexone
0 5 10 15
Figure 2. Severity and Duration of Opioid-Withdrawal Symptoms with Three Different Treatments after Abrupt Discon-
tinuation on Day 0 of Methadone at a Dose of about 35 mg Daily.
The blue area represents the natural course of such symptoms after abrupt discontinuation of methadone. The yellow
area represents the use of clonidine at 0.1 to 0.2 mg four times per day from days 1 to 7, followed by gradual tapering of
the dose from days 8 to 14. The green area represents the precipitation of opioid withdrawal with use of naltrexone at
12.5 mg on day 1, 25 mg on day 2, and 50 mg on days 3 to 15. Clonidine at 0.1 to 0.2 mg four times daily is also given
from days 1 to 3, with the dose tapered on days 4 and 5. The red area represents abrupt discontinuation of buprenor-
phine from a daily dose of 8 mg (equivalent to 35 mg of methadone) and precipitation of opioid withdrawal using nal-
trexone at 25 mg on day 1 and 50 mg daily on days 2 to 15. Clonidine at 0.1 to 0.2 mg four times daily is also given on day
1, with the dose tapered on days 2 and 3. In patients receiving 35 mg of methadone daily, 8 mg of buprenorphine can be
given without precipitating any withdrawal symptoms; buprenorphine should be started at least two days before naltrex-
one is used to precipitate withdrawal.
high-risk sexual activity or physical abuse. Patients provide extended detoxification to certain patients
found to require additional treatment should be re- with opioid dependence.38 Patients with moderate-
ferred for appropriate services. Referrals are also to-severe withdrawal symptoms, poor social sup-
often indicated to social-work, family-counseling, port, or substantial medical or psychiatric condi-
or other social-service agencies.3 tions that go beyond the depressive symptoms
characteristic of withdrawal should be referred to
referral as compared specialized outpatient or inpatient programs for
with direct treatment withdrawal treatment. Options include outpatient
Direct treatment in an outpatient setting requires detoxification programs such as methadone taper-
daily contact for several days to monitor progress ing for heroin dependence and residential programs
and adjust doses of medication. Such treatment, de- providing both medication management and sup-
livered by generalist physicians, may be appropriate portive housing. Withdrawal management is only
for highly motivated patients with mild withdrawal the first step in long-term treatment; follow-up care
symptoms, as long as their social support systems is always necessary to prevent relapse.
are strong and any coexisting medical or psychiatric Supported by grants (P50-DA12762, K05-DA 0454) from the Na-
tional Institute on Drug Abuse.
conditions are stable. Given the new federal regula- Dr. Kosten reports having been a consultant for Xenova and hav-
tions on the use of buprenorphine in office-based ing received speaker’s fees from Abbott and Schering.
settings, generalist physicians may soon be able to
Range
Category of Scores Examples
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