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Management of Withdrawal Syndromes and Relapse Prevention in Drug and Alcohol Dependence
NORMAN S. MILLER, M.D.,
University of Illinois College of Medicine,
Chicago, Illinois
MARK S. GOLD, M.D.,
University of Florida Brain Institute,
Gainesville, Florida
The primary care physician is in a good position to diagnose, manage and intervene with patients who are undergoing the process of treatment and recovery from alcohol and drug disorders. Medications such as benzodiazepines are effective in the treatment of withdrawal syndromes, and naltrexone and disulfiram can be used to augment relapse prevention. Patients may also participate in psychosocial methods of addiction treatment that can reduce the risk of relapse and improve their psychosocial, health, legal and employment status.
Nearly one half of the patients who visit a family practice have an alcohol or drug disorder. Primary care physicians have an opportunity to intervene at all stages during the course of addictive illness. Each stage can be characterized by types and severity of withdrawal and relapse prevention.1-3 Management of alcohol and drug disorders includes assessment, intervention, prescription of medications, participation in specific addiction treatment strategies and monitoring of recovery.
Pharmacotherapy for Withdrawal Syndromes
In treating alcohol withdrawal, the longer-acting benzodiazepines provide a smoother transition to abstinence than shorter-acting preparations.
Detoxification
Pharmacologic therapies are indicated for use in patients with addictive disorders to prevent life-threatening withdrawal complications such as seizures and delirium tremens, and to increase compliance with psychosocial forms of addiction treatment. Laboratory testing is indicated to assess the type and timing of drugs used addictively and to guide management of withdrawal and recovery.4
Alcohol
Management of alcohol withdrawal is based on the patient's history and current clinical status. The single best predictor of the likelihood of future withdrawal symptoms when alcohol is concerned is the patient's previous history, e.g., the presence or absence of seizures or delirium tremens (Table 1).
Signs and Symptoms of Alcohol and Drug Withdrawal
Drug / Peak period / Duration / Signs / Symptoms
Alcohol / 1 to 3 days / 5 to 7 days / Elevated blood pressure, pulse and temperature, hyperarousal, agitation, restlessness, cutaneous flushing, tremors, diaphoresis, dilated pupils, ataxia, clouding of consciousness, disorientation / Anxiety, panic, paranoid delusions, illusions, visual and auditory hallucinations (often derogatory and intimidating)
Benzodiazepines and other sedative/hypnotics / Short-acting:
2 to 4 days
Long-acting:
4 to 7 days / Short-acting:
4 to 7 days
Long-acting:
7 to 14 days / Increased psychomotor activity, agitation, muscular weakness, tremulousness, hyperpyrexia, diaphoresis, delirium, convulsions, elevated blood pressure, pulse and temperature, tremor of eyelids, tongue and hands / Anxiety, depression, euphoria, incoherent thoughts, hostility, grandiosity, disorientation, tactile, auditory and visual hallucinations, suicidal thoughts
Stimulants (cocaine, amphetamines and derivatives) / 1 to 3 days / 5 to 7 days / Social withdrawal, psychomotor retardation, hypersomnia, hyperphagia / Depression, anhedonia, suicidal thoughts and behavior, paranoid delusions
Opiates (heroin) / 1 to 3 days / 5 to 7 days / Drug seeking, mydriasis, piloerection, diaphoresis, rhinorrhea, lacrimation, diarrhea, insomnia, elevated blood pressure and pulse (mild) / Intense desire for drugs, muscle cramps, arthralgia, anxiety, nausea, vomiting, malaise
PCP/psychedelics / Days to weeks / Days to weeks / Hyperactivity, increased pain threshold, nystagmus, hyperreflexia, hypertension and tachycardia, eyelid retraction (stare), agitation and hyperarousal, dry and erythematous skin, violent and self-destructive behaviors / Anxiety, depression, delusions, auditory and visual hallucinations, memory loss, irritable and angry mood and affect, suicidal thoughts
PCP=phencyclidine.
Alcohol withdrawal may be treated with a pharmacologic agent that exhibits cross-tolerance with alcohol. Agents that are commonly recommended include diazepam (Valium), lorazepam (Ativan), chlordiazepoxide (Limbitrol), clorazepate (Tranxeme) and phenobarbital. The usual initial dosage of diazepam or lorazepam is titrated according to elevations of blood pressure, pulse rate, degree of agitation and presence of delirium. In general, longer-acting preparations such as diazepam or chlordiazepoxide provide a smoother and safer withdrawal than other preparations. Shorter-acting preparations such as lorazepam are indicated when elimination time for benzodiazepines is prolonged, such as in patients with significant liver disease.
A loading dose of a long-acting benzodiazepine such as diazepam or chlordiazepoxide may be given initially, and the dosage may then be tapered. This method is often used in conjunction with a scale for detoxification. It is also used frequently in an inpatient setting. The physician should screen the patient for the presence of other sedating drugs to avoid untoward drug interactions, particularly oversedation. Initial loading doses for diazepam are in the range of 30 to 50 mg. Suggested parameters and dosages are presented in Table 2.
TABLE 2Medications for Alcohol Detoxification
Mild withdrawal / Moderate withdrawal / Severe withdrawal
(delirium tremens)* / Loading-dose method
Diazepam (Valium), 5 to 10 mg orally as needed
or
Lorazepam (Ativan), 1 to 2 mg orally every 4 to 6 hours as needed for 1 to 3 days / Diazepam:
15 to 20 mg orally four times daily on day 1
10 to 20 mg orally four times daily on day 2
5 to 15 mg orally four times daily on day 3
10 mg orally four times daily on day 4
5 mg orally four times daily on day 5
or
Lorazepam:
2 to 4 mg orally four times daily on days 1 and 2
1 to 2 mg orally four times daily on days 3 and 4
1 mg orally twice daily on day 5 / Diazepam, 10 to 25 mg orally as needed every hour while awake until sedation occurs
or
Lorazepam, 1 to 2 mg intravenously as needed every hour while awake for 3 to 5 days (to sedate) / Diazepam, 10 mg, or chlordiazepoxide (Limbitrol), 25 mg, orally every hour Diazepam may be given intravenously
Administer medication when:
Systolic blood pressure:
> 150 mm Hg / Systolic blood pressure: 150 to 200 mm Hg / Systolic blood pressure: > 200 mm Hg
Diastolic blood pressure: > 90 mm Hg / Diastolic blood pressure: 100 to 140 mm Hg / Diastolic blood pressure: > 140 mm Hg
Pulse: > 100 / Pulse: 110 to 140 / Pulse: > 140
Temperature: >37.7°C (100°F) / Temperature: 37.7°C to 38.3°C (100°F to 101°F) / Temperature: > 38.3°C (101°F)
Tremulousness, insomnia, agitation are present / Tremulousness, insomnia, agitation are present / Tremulousness, insomnia, agitation are present
*--Monitoring in an intensive care unit is recommended for cardiac and respiratory function, fluid and nutrition replacement, vital signs and mental status. Restraints are indicated in patients who are confused or agitated to protect the patient from self and others (delirium tremens can be a terrifying and life-threatening state). Thiamine, 100 mg intramuscularly or orally every day for 3 to 7 days, hydration and magnesium replacement may be indicated, according to the severity of the withdrawal state.5,6,10,21
Benzodiazepines and Other Sedative/Hypnotics
The signs and symptoms of benzodiazepine withdrawal are similar to those for withdrawal of other sedative/hypnotics (barbiturates, ethchylorvynol [Placidyl], glutethimide and meprobamate [Equanil]) (Table 1). The management of withdrawal for sedative/hypnotics (barbiturates) is similar to that for benzodiazepines (Table 3).
Benzodiazepine (Barbiturate) Withdrawal
Short-acting detoxification / Long-acting detoxification
7- to 10-day taper:
On day 1, give diazepam (Valium), 10 to 20 mg orally four times daily, and taper until the dosage is 5 to 10 mg orally on last day. Avoid giving the drug "as needed." Adjustments in dosage according to the patient's clinical state may be indicated.
or
7- to 10-day taper:
Calculate barbiturate or benzodiazepine equivalence and give 50 percent of the original dosage; taper (if actual dosage is known before detoxification). Avoid giving the drug "as needed." / 10- to 14-day taper:
On day 1, give diazepam, 10 to 20 mg orally four times daily, and taper until the dosage is 5 to 10 mg orally on last day. Avoid giving the drug "as needed". Adjustments in dosage according to the patient's clinical state may be indicated.
or
10- to 14-day taper:
Calculate barbiturate or benzodiazepine equivalence and give 50 percent of the original dosage; taper (if actual dosage is known before detoxification). Avoid giving the drug "as needed."
Information from references 5 through 8.
Withdrawal from benzodiazepines is not usually marked by significant elevations in blood pressure and pulse as commonly occur in patients undergoing alcohol withdrawal. Furthermore, supplemental doses of sedatives taken as needed are usually not required for changes in vital signs5-8 (Table 3). Since benzodiazepines have cross-tolerance within that drug class as well as with other sedative/hypnotic drugs, benzodiazepines can be substituted for other sedative/hypnotics and vice versa. Equivalent doses can be calculated if the actual doses are known before beginning the tapering process (Table 4).
A long-acting benzodiazepine is more effective than short-acting preparations in suppressing withdrawal symptoms and in producing a gradual and smooth transition to the abstinent state. In general, greater patient compliance and lower morbidity can be expected with the use of the longer-acting benzodiazepines, since withdrawal symptoms are less intense.
A taper over eight to 12 weeks or longer may be indicated in patients who have been taking benzodiazepines for several years (Table 5). The rate of taper can be adjusted according to patient tolerance. The rate of taper is a reduction in dosage of approximately 25 percent per quarter of the withdrawal period (e.g., 25 percent per week for one month).
Stimulants (Cocaine, Amphetamines and Derivatives)
Supportive rather than specific treatment is indicated in patients who are undergoing withdrawal from stimulants. Observation and monitoring for depression and suicidal ideation are advised (Table 1). Since stimulant withdrawal may cause significant irritability, a dosage of 5 to 10 mg of diazepam given orally every six hours on a fixed schedule or as needed for two to three days is recommended in patients with mild to moderate withdrawal symptoms. For severe withdrawal symptoms with persistent depression, therapy may be initiated with antidepressants such as desipramine (Norpramin), at a dosage of 50 mg per day, titrated upward every other day in 50-mg increments until a dosage of 150 to 250 mg per day is attained. The dosage is maintained for three to six months and discontinued by gradually tapering the drug over two weeks.4,9 However, desipramine is not recommended routinely for management of withdrawal.
Drug Dose Conversion* (Equivalent to 60 mg of Diazepam [Valium] and 180 mg of Phenobarbital)
Drug / Dose (mg) / Diazepam
(60 mg)
conversion
factor / Phenobarbital
(180 mg)
conversion
factor
Benzodiazepines
Alprazolam (Xanax)
Chlordiazepoxide (Limbitrol)
Clonazepam (Klonopin)
Flurazepam (Dalmane)
Halazepam (Paxipam)
Lorazepam (Ativan)
Oxazepam (Serax)
Temazepam (Restoril) / 6
150
24
90
240
12
60
60 / 10.0
0.4
2.5
0.6
0.25
5.0
1.0
1.0 / 30.0
1.2
7.5
2.0
0.75
15.0
3.0
3.0
Barbiturates
Butabarbital (Butisol)
Pentobarbital (Nembutal)
Secobarbital (Seconal)
Phenobarbital / 600
600
600
180 / 0.1
0.1
0.1
0.33 / 0.3
0.3
0.3
1.0
Glycerol
Meprobamate (Equanil) / 2,400 / 0.025 / 0.075
Piperideinedione
Glutethimide (Doriden) / 1,500 / 0.04 / 0.12
Quinazoline
Methaqualone / 1,800 / 0.03 / 0.1
NOTE: To find the dose of chlordiazepoxide equivalent to that of diazepam, multiply by 0.4. A dose of 150 mg of chlordiazepoxide is equivalent to a dose of 60 mg of diazepam. A dose of 100 mg is equivalent to a dose of 40 mg, etc.
*--Conversion factor 3 dose=diazepam or phenobarbital dose equivalent. Divide this amount in half to determine starting dosage.
Opiates
Withdrawal symptoms from heroin addiction are predictable and identifiable (Table 1). Management of withdrawal can be accomplished with clonidine (Catapres) or methadone. Patients for whom clonidine is indicated include intranasal heroin users, outpatients and those who are motivated to achieve abstinency. Patients for whom methadone is indicated include intravenous users, inpatients, those who have medical and psychiatric complications and patients with a history of poor compliance when withdrawing from opiates5,9,10 (Table 6). Federal regulations do not allow the use of methadone for detoxification if opiate withdrawal is the primary diagnosis. However, methadone may be used if the primary diagnosis is a medical condition and the secondary condition is withdrawal from opiates.
Phencyclidine and Other Psychedelic Agents
Acute symptoms of withdrawal from psychedelic agents may be diminished or reversed by using therapy with haloperidol (Haldol), 5 to 10 mg intramuscularly or orally every three to six hours as tolerated and needed for behavior control. Lorazepam, 1 to 2 mg intravenously, or diazepam, 5 to 10 mg orally every three to six hours, can also be given as needed. Behavior control may also be indicated (e.g., isolation and restraints).5,9,11
Benzodiazepine Taper
Day / Dosage per day (mg)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 / 10 mg three times daily=30 mg
10 mg three times daily=30 mg
10 mg three times daily=30 mg
5 mg four times daily=20 mg
5 mg four times daily=20 mg
5 mg four times daily=20 mg
5 mg three times daily=15 mg
5 mg three times daily=15 mg
5 mg three times daily=15 mg
5 mg twice daily=10 mg
5 mg twice daily=10 mg
5 mg twice daily=10 mg
5 mg every day=5 mg
5 mg every day=5 mg
5 mg every day=5 mg
Example: Patient taking 12 mg of lorazepam (Ativan) per day=60 mg diazepam (Valium) 3 (50 percent reduction)=30 mg.
Medications for Relapse Prevention
Disulfiram
Disulfiram is a major aversive agent. It has been shown in a randomized, double-blind, placebo-controlled multisite trial12 to be effective as an adjunct to other forms of addiction treatment.
The key components to effective use of disulfiram are overall patient motivation for abstinence and expectation of adverse reactions. Selected patients who have a commitment to working with other treatments for alcoholism may benefit from the addition of disulfiram therapy. The usual dosage of disulfiram is 250 mg per day, or 125 mg per day in patients who experience side effects such as sedation, sexual dysfunction and elevated liver enzymes.12,13