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National Institute on Alcohol Abuse and Alcoholism No.
5 PH 270 August 1989
Alcohol Withdrawal Syndrome
The alcohol withdrawal syndrome is a cluster of symptoms
observed in persons who stop drinking alcohol following continuous and
heavy consumption. Milder forms of the syndrome include tremulousness,
seizures, and hallucinations, typically occurring within 6-48 hours after
the last drink. A more serious syndrome, delirium tremens (DTs), involves
profound confusion, hallucinations, and severe autonomic nervous system
overactivity, typically beginning between 48 and 96 hours after the last
drink (Victor 1983). Estimates vary on the incidence of serious consequences
of alcohol withdrawal. Regardless of actual incidence, recent evidence
suggests that it may be important to treat everyone who is suffering from
alcohol withdrawal.
In a classic study that has shaped our understanding
of alcohol withdrawal for many years, Isbell et al. (1955) found that
alcohol-related seizures occur only after stopping heavy drinking. In
a recent study that looked primarily at seizures, Ng et al. (1988) challenged
Isbell's concept and reported that the risk of first seizure is related
to current alcohol use rather than to withdrawal. They concluded, based
on self-reports given retrospectively by seizure patients, that the relationship
of alcohol use to seizures is causal and dose-dependent. However, emerging
neurophysiological findings lend support to Isbell's interpretation of
withdrawal.
In the central nervous system, ethanol (in concentrations
high enough to intoxicate humans) interferes with the processes that tell
certain nerve cells to activate or become excited (Hoffman et al. 1989;
Lovinger et al. 1989). It also enhances those processes that tell certain
nerve cells to be restrained (Suzdak et al. 1986). Thus, ethanol acts
as a nonspecific biochemical inhibitor of activity in the central nervous
system. During withdrawal, a person's central nervous system experiences
a reversal of this effect: Excitatory processes are enhanced while inhibitory
processes are reduced (Morrow et al. 1988). Such changes can result in
overactivation of the central nervous system when alcohol is withdrawn.
Clinical researchers have measured this overactivation
in patients (Linnoila et al. 1987). Even patients with moderately severe
alcohol withdrawal can experience sympathetic nervous system overactivity
and increased production of the adrenal hormones cortisol and norepinephrine.
Both of these hormones can be toxic to nerve cells. Moreover, cortisol
can specifically damage neurons in the hippocampus (Sapolsky et al. 1986)--a
part of the brain that is thought to be particularly important for memory
and control of affective states. Thus, repeated untreated alcohol withdrawals
may lead to direct damage to the hippocampus.
Ballenger and Post (1978) did a retrospective chart
review that led them to postulate that repeated inadequately treated withdrawals
could produce future withdrawals of increased severity. These authors
suggested that this phenomenon may be analogous to kindling as described
in the animal literature. In kindling, repeated, weak (subthreshold),
electrical or pharmacological stimulation of certain parts of the central
nervous system leads to increased sensitivity; an animal eventually exhibits
behavioral changes (including seizures) that are more severe on each occasion.
The implication is that repeated untreated withdrawals from alcohol have
a cumulative effect and create more serious future withdrawals. Only a
minority of chronic alcoholics develop a seizure disorder, so an inherited
vulnerability may be involved. Many investigators (e.g., Linnoila et al.
1987) now believe that chronic alcoholics who cannot maintain abstinence
should receive pharm acotherapy to control withdrawal symptoms, thereby
reducing the potential for further seizures and brain damage.
In a recent review of pharmacological treatments
for alcohol intoxication, withdrawal, and dependence, Liskow and Goodwin
(1987) concluded that the drugs of choice for treating withdrawal are
the benzodiazepines--e.g., the longer-acting benzodiazepines chlordiazepoxide
(Librium) and diazepam (Valium) or the shorter-acting benzodiazepines
oxazepam (Serax) and lorazepam (Ativan).
Physicians traditionally have used benzodiazepines
by administering decreasing doses over the period of alcohol withdrawal.
Rosenbloom (1988) recommends this approach, suggesting the use of intermediate
half-life benzodiazepines (such as lorazepam), or even shorter half-life
drugs (such as midazolam), because these drugs do not linger in the system
and allow for doses to be easily titrated to the parent's response. However,
Sellers et al. (1983) introduced a different approach. At the start of
treatment, doses of diazepam are given every 1 to 2 hours until withdrawal
symptoms abate. Because diazepam has a long half-life and produces a psychoactive
metabolite (desmethyldiazepam) with an even longer half-life, there is
usually no need for further medication. This strategy, called "loading
dose," simplifies treatment, protects against seizures, and eliminates
possible reinforcement of drug-seeking behavior in parents who otherwise
might receive additional medication for relief of symptoms.
Other agents, such as the beta-blocker propranolol
(Sellers et al. 1977), the beta-blocker atenolol in combination with oxazepam
(Kraus et al. 1985), and the alpha-2-adrenoreceptor agonist clonidine
(Manhem et al. 1985; Robinson et al. 1989), have been tested and shown
to alleviate some symptoms of the withdrawal syndrome, but there is no
clear evidence of their efficacy in preventing seizures (Liskow and Goodwin
1987). Potential drugs for future use are calcium channel blockers (Koppi
et al. 1987) and carbamazepine, which are now in the early stages of evaluation
(Butler & Messiha 1986).
Most clinicians use medications to diminish the symptoms
of alcohol withdrawal. However, Whitfield et al. (1978) reported success
with nondrug detoxification of a group of ambulatory patients with uncomplicated
alcoholism. The treatment consisted of screening and providing extensive
social support during withdrawal. The authors concluded that nondrug detoxification
offers a reduced need for medical staff, a shortened detoxification period,
and no sedative interference with a patient's alertness for participating
in an alcohol treatment program.
Several researchers have developed scales for assessing
the severity of the alcohol withdrawal syndrome: the Total Severity Assessment
and Selected Severity Assessment (Gross et al. 1973), the Abstinence Symptom
Evaluation Scale (Knott et al. 1981), and the Clinical Institute Withdrawal
Assessment Scale [CIWA] (Shaw et al. 1981) Originally developed as research
tools for studying treatment efficacy, such scales are now finding clinical
use. Foy et al. (1988) demonstrated that a modified version of the CIWA
can assist in guiding treatment and predicting patients at risk for severe
alcohol withdrawal. Such scales also may be helpful when monitoring the
adequacy of a loading dose of medication. However, rating procedures are
not infallible, and an occasional patient will have a more severe reaction
than the scale predicts. Rating procedures cannot replace the clinical
judgment of medical staff.
One final point deserves mention. A recent study
by Hayashida et al. (1989) compared outpatient with inpatient detoxification.
The research concluded that outpatient medical detoxification is "an effective,
safe, and low-cost treatment for patients with mild-to-moderate symptoms
of alcohol withdrawal." However, the data from this study indicate that
inpatient detoxification was more effective than outpatient detoxification:
At the 6-month followup those treated as inpatients reported significantly
greater improvement in their drinking behavior, despite having been measured
as more impaired than the outpatient group at the time of admission. This
point is not emphasized in the report. Whereas outpatient detoxification
may be cheaper for some alcoholics, it is not clear to what extent serious
comorbidities, which may be undetected outside a hospital setting, may
lead to more severe and expensive problems later.
Alcohol Withdrawal Syndrome-- A Commentary by
NIAAA Director Enoch Gordis, M.D.
A variety of techniques exist for managing alcohol withdrawal,
some that involve pharmacotherapy with sedatives and some that do not.
Based on current literature, it appears that it is probably safe to treat
mild withdrawal without drugs. However, research on treating alcohol withdrawal
is just beginning to accumulate. Recent research findings show a potential
for central nervous system damage to patients who experience repeated
withdrawals and suggest that all patients exhibiting alcohol withdrawal
symptoms receive pharmacotherapy. As evidence increases, it may well be
that pharmacotherapy becomes the recommended choice in all withdrawal
cases. Therefore, it is vital that clinicians keep abreast of the literature
to ensure that their patients receive the most up-to-date care.
When using sedatives to treat alcohol withdrawal,
understanding the relative advantages and disadvantages of different drug
administration techniques is important. Administering an initial dose
of a long-acting benzodiazepine, like diazepam, with repeated doses every
2 hours until symptoms subside, then stopping the drug, simplifies treatment
and frees patients and staff to focus on the recovery process, not drug
dosage schedules. However, this method could cause problems if sedation
is found to complicate an existing medical condition, such as chronic
obstructive pulmonary disease, because the drugs, or their metabolites,
remain in the body for several days. On the other hand, by giving repeated
doses of a short-acting benzodiazepine (e.g., oxazepam), probably for
several days, if complications to medical conditions are found, the drugs
can be easily stopped due to their rapid elimination by the body. But
this regimen is less easily managed because medication must be given around
the clock, and it could result in the patient and staff attending to the
drug-taking regimen rather than to recovery.
In deciding which drug administration technique to
use for individual patients, there is no substitute for a thorough medical
evaluation. There is a welcome trend toward using the CIWA and other clinical
scales for measuring withdrawal syndrome severity and for guiding drug
treatment decisions; their use should be encouraged. However, no scaling
instrument is infallible. Withdrawal severity scales should be used to
complement, not replace, a thorough clinical evaluation of the patient's
medical status.
References
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133: 1-14, 1978. * BUTLER, D. and Messiha, F.S. Alcohol Withdrawal
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3(2): 113-129, 1986. * FOY, A,; March, S.; and Drinkwater, V. Use
of an objective clinical scale in the assessment and management of alcohol
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and Hall, C.P. Comparative effectiveness and costs of inpatient and outpatient
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NOTE: The following ERRATA appeared in Alcohol Alert
No. 8. It is shown here for clarity.
ERRATA: Dr. M. Hayashida has notified NIAAA that
Alcohol Alert No. 5, entitled "Alcohol Withdrawal Syndrome," contained
incorrect information about his study comparing the effectiveness and
costs of inpatient and outpatient detoxification (Hayashida, M.; Alterman,
A.; McLellan, A.; et al. Comparative effectiveness and costs of inpatient
and outpatient detoxification of patients with mild-to-moderate alcohol
withdrawal syndrome. New England Journal of Medicine 320(6): 358-365,1989).
The last paragraph of the Alert erroneously reported that data from the
study provide evidence that inpatient detoxification was more effective
than outpatient detoxification. However, an accurate interpretation of
the study would have suggested that some significant differences were
noted between the two groups at a 1-month followup, favoring inpatient
detoxification (a group that was more impaired by some drinking measures
at admission), but that no differences were observed at a 6-month followup.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service * National Institutes of Health
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