Withdrawal Symptoms

National Institute on Alcohol Abuse and Alcoholism

No. 5 PH 270 August 1989

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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withdrawn.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.

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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.

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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.

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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service * National Institutes of Health

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