Drugs of abuse are generally classified into seven groups (Table 1). Physicaql dependence may produce a variety of withdrawal signs and symptoms (abstinence syndrome), depending on the drug involved. The severity of the syndrome ranges from life-threatening delirium trements, as seen with central nervous system depressants, to the complete absence of signs and symptoms, as seen with hallucinogens. 
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This article discusses the pharmacologic management of acute abstinence syndrome, with an emphasis on the pharmacologic approaches that have stood the test of time and are of practical use to family physicians.
Alcohol abstinence syndrome is divided into several stages (Table 2), depending on the degree of physical dependence. The symptoms range in severity from mild sympathetic nervous system hyperactivity (mild tremor, nervousness and tachycardia) to full-blown delirium tremens.
The majority of patients do not require pharmacologic management; however, for those who do, the following approach can be used. [2-4] A multivitamin table containing zinc is given once or twice a day. The zinc is thought to ensure continued
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functioning of the alcohol dehydrogenase system. Folic acid, 1 mg orally, is given daily to correct any folate deficiency. An intramascular injection of thiamine, 100 mg, is administered at the time of admission. This dose is followed by 100 mg orally once or twice a day for three to five days. To preevent precipitation of Wernicke-Korsakoff syndrome, the intramascular injection of thiamine should be given before administration of a glucose load.
The serum magnesium level should be determined in patients with a history of withdrawal seizures and in those who are malnourished. Magnesium deficiency, in the presence of good renal function, can be corrected by administration of a 50 percent solution of magnesium sulfate, 2 mL intramuscularly every six hours for 48 hours. Magnesium sulfate can be given intravenously, if an intravenous line is required; intramuscular injection of magnesium can be uncomfortable. Although oral magnesium supplements are available, magnesium is not adequately absorbed from the gastrointestinal tract to rapidly correct significant deficits.
Serum calcium levels should also be measured, Hypocalcemia can be corrected by administering a 10 percent calcium gluconate solution until the serum calcium level rises above 7.5 mg per dL (1.88 mmol per L). No more than 10 mL is usually required. Hypophosphatemia can be corrected by adding 20 to 40 mmol of potassium phosphate to each liter of intravenous fluid.
Most alcoholic patients are initially overhydrated and thus do not require parenteral hydration. Patients usually experience diuresis during the first two days of detoxification and may lose up to 2 kg (4.4 lb) of body weight. Patients with excessive vomiting, however, may be dehydrated and require fluid replacement, as well as acid-base balance monitoring. [3,5-7]
Pharmacologic management of the alcohol abstinence syndrome involves two basic principles: (1) substitution of another sedative-hypnotic agent for alcohol, such as a benzodiazepine or barbiturate, and (2) gradual tapering of the dose. Substitution of another sedative-hypnotic for alcohol is based on the principle of cross-tolerance.
Chlordiazepoxide (Librium), a long-acting benzodiazepine, is the drug most commonly used for detoxification. It should be given initially in doses of 50 to 100 mg orally every four to six hours as needed, and then tapered as tolerated over the next four to five days. Tapering can be done by decreasing the dose, increasing the dosing interval, or both. Extra doses can be given as needed for withdrawal symptoms, and doses can be withheld if the patient becomes oversedated. Diazepam (Valium), another benzodiazepine with a long half-life, is also very effective. The initial dose of diazepam is 15 to 30 mg orally every four to six hours as needed. The adequacy of management can be judged by the heart rate (less than 100 per minute), the blood pressure (less than 150/100 mm Hg), and the degree of tremor, agitation an insomnia.
In elderly patients and patients with severe liver dysfunction, the daily benzodiazepine dosage should be reduced. Alternatively, a shorter-acting agent, such as lorazepam (Ativan), can be used. The initial dose of lorazepam is 4 to 5 mg orally every four hours or 2 mg intramuscularly or sublingually every four hours.
Most benzodiazepines are erratically absorbed following intramuscular administration. Therefore, intramuscular injection of benzodiazepines, other than lorazepam, should not be used. The medication can, of course, be given intravenously when necessary. [2,5,8]
Barbiturates, especially the long-acting agents such as phenobarbital, are alternatives to benzodiazepines. Phenobarbital is started in a dose of 60 to 120 mg every six hours and then tapered as tolerated over four to five days. [2,5,8]
Nausea and vomiting can usually be controlled by giving the patient ice chips followed by small amounts of juice. When this is not effective, promethazine (Phenergan), 25 to 50 mg orally, intramuscularly or by suppository, can be given every six hours as needed. [2,5,8]
For patients with alcoholic hallucinosis (visual hallucinations with an otherwise relatively clear sensorium), haloperidol (Haldol) can be given (1 to 2 mg orally every four hours) in conjunction with benzodiazepines for as long as needed to control symptoms. [2,5,8]
Patients may have withdrawal seizures in the first 48 hours after their last drink; rarely, seizures start after 96 hours. In patients without a history of withdrawal syndrome or idiopathic seizures, the probability of withdrawal seizures is so low that anticonvulsant prophylaxis is unwarranted. Seizures can usually be prevented, even in patients with a history of withdrawal seizures, by liberal use of benzodiazepines and correction of magnesium deficiency.
In patients with a previous history of seizures, a loading dose of phenytoin (Dilantin), 15 mg per kg intravenously followed by 100 mg orally every eight hours, can be administered as prophylaxis for four to five days. However, in most cases, benzodiazepines alone are effective in preventing withdrawal seizures. Patients who develop seizures but have no prior history of withdrawal seizures should undergo a complete neurologic work-up. In the rare patient who develops status epilepticus during withdrawal, diazepam should be administered by slow intravenous push, 5 to 20 mg.
Delirium tremens is a medical emergency. The mortality rate without medical care is 20 to 40 percent, and a small percentage of patients die despite good medical care. Patients with delirium tremens should be admitted to an intensive care unit where respiratory and circulatory support are available. Intravenous access should be established, and fluid and electrolyte disturbances corrected. Patients should not be restrained but should be sedated sufficiently to prevent them from harming themselves. This can usually be accomplished with a slow infusion of chlordiazepoxide, 12.5 mg per minute, or diazepam, 2.5 mg per minute. [3,8]
BARBITURATES, BARBITURATE-LIKE DRUGS,
MEPROBAMATE AND CHLORAL HYDRATE
Barbiturates include a large group of sedative-hypnotics that have varied half-lives, ranging from ultra-short (thiopental [Pentothal], methohexital [Brevital]) to long-acting (mephobarbital [Mebaral], phenobarbital). The short-acting barbiturates (pentobarbital [Nembutal] and secobarbital [Seconal]) and the intermediate-acting barbiturates (amobarbital [Amytal], aprobarbital [Alurate], butabarbital [Barbased, Butisol, etc.], butalbital [Barbased, Butisol, etc.], butalbital [present in Axotal, Esgic, Fiorinal]) are the most likely to be abused. Agents containing butalbital are commonly prescribed for headaches, and as a result it is commonly abused. 
Some barbiturate-like drugs have limited medical use today. For example, methaqualone (Quaalude) is no longer legal in the United States.  Meprobamate (Equanil, Miltown) is an older sedative that is not ordinarily recommended for use in medicine today. However, it is still available by prescription. 
Chloral hydrate is an older hypnotic that was once used in elderly patients because it did not cause the persistent effects seen with other agents. It does, however, produce adverse side effects (epigastric distress, nausea, flatulence) that make it undesirable, which led to its replacement by benzodiazepines. 
The abstinence syndrome associated with barbiturates and similar drugs resembles that seen with alcohol. Symptoms include restlessness, tremors, tachycardia, anxiety, insomnia, hyperpyrexia and hyperactive reflexes. Psychoses and generalized seizures may occur. Seizures from withdrawal of the long-acting drugs may occur up to one week after the last use and may be the first sign of withdrawal. 
Treatment of abstinence syndrome requires estimating the usual daily dose of the abused drug (from the patient's history), stabilizing the patient at an equivalent phenobarbital dose (Table 3), and then tapering the dose as tolerated over four to 10 days, depending on the half-life of the abused drug. For example, in a patient who has been taking 1,200 mg per day of secobarbital, the initial daily detoxification
Dose Equivalents for Phenobarbital (30 mg), Chlordiazepoxide (25 mg) or Diazepam (10 mg)
toxification dose of phenobarbital would be 360 mg (calculated by using the formula 1,200 X 30 / 100). Phenobarbital would be given orally as 90 mg every six hours. The maximum daily dose of phenobarbital should not exceed 500 mg. [8,10] In patients taking multiple drugs, the equivalents of each drug are added to calculate the initial daily dosage of phenobarbital.
The pentobarbital challenge test has been used when the usual daily dosage cannot be estimated: 200 mg of pentobarbital are given orally, and the patient's mental state is assessed in one hour. The patient's condition at the end of the hour determines the estimated initial daily dosage of pentobarbital (Table 4). If a patient is asleep but arousable, no detoxification medication is needed. Conversely, if at the end of the hour a patient shows no sign of being affected by the drug, the equivalent daily dosage of pentobarbital is estimated to be between 1,000 and 1,200 mg. This amount of phenobarbital, which is given in four divided doses daily and then tapered. [8,10]
Chlordiazepoxide and diazepam are
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good alternatives to phenobarbital. Equivalent daily doses for either can be estimated as shown in Table 3.
Benzodiazepines are available as short-acting agents (temazepam [Restoril], triazolam [Halcion]), intermediate-acting agents (alprazolam [Xanax], lorazepam, oxazepam [Serax]) and long-acting agents (chlordiazepoxide, chlorazepate [Tranxene], diazepam, flurazepam [Dalmane], halazepam [Paxipam], prazepam [Centrax], clonazepam [Klonopin]).  Alprazolam has recently become widely prescribed, and thus patients with withdrawal symptoms from this agent are being seen with increasing frequency. In general, benzodiazepines with a shorter half-life have more intense withdrawal syndromes.
Three abstinence syndromes are associated with benzodiazepine use: high-dose, short-duration use; low-dose, long-duration use, and high-dose, long-duration use. 
The high-dose, short-duration abstinence syndrome is similar to barbiturate abstinence syndrome. Symptoms include intense anxiety, insomnia, sensitivity to light and sound, and irritability. Symptoms may progress to tremulousness, diaphoresis, muscle twitching, tachycardia, elevated blood pressure, confusion, psychosis, hyperpyrexia and seizures. The onset of symptoms varies from a few hours to several days, depending on the half-life of the drug. Symptoms peak in two to four days for short-acting benzodiazepines and in five to six days for long-acting agents. With long-acting agents, seizures can occur up to a week after the last dose. [11,12]
The low-dose, long-duration abstinence syndrome may occur in patients who have received therapeutic doses of a benzodiazepine for more than a few months. Symptoms include many of the minor symptoms of the high-dose, short-duration abstinence syndrome, such as anxiety, insomnia, sensitivity to light and sound, muscle spasm and irritability. Psychosis occasionally occurs. Panic attacks are an extremely troublesome symptom. Disturbing nightmares may also occur. These symptoms may wax and wane, gradually decreasing in intensity, for six to 12 months, making it difficult for many patients to discontinue benzodiazepine use. [11,13]
The high-dose, long-duration abstinence syndrome is characterized in the first fewdays by a barbiturate-like abstinence syndrome, which is then followed by several months of symptoms of the low-dose, long-duration abstinence syndrome. 
There are two other syndromes that follow discontinuation of benzodiazepines. The first is a rebound phenomenon that occurs after discontinuation of short-term, low-dose benzodiazepine use. The rebound phenomenon consists of exacerbation of the original symptoms (anxiety, insomnia) and lasts only a day or two. With the second syndrome, the original symptoms recur after cessation of benzodiazepine use. Unlike the rebound phenomenon, the symptoms persist and do not fluctuate and ameliorate. No symptoms develop other than those that were present before benzodiazepine therapy. 
For many patients, treatment of benzodiazepine abstinence syndrome is simply not adequate. The intensity of the symptoms, coupled with the protracted course, makes treatment difficult. Because withdrawal symptoms tend to be worse with the short-acting benzodiazepines, patients should be switched to, and stabilized on, one of the long-acting agents, such as chlordiazepoxide or diazepam. The dose of the long-acting benzodiazepine is then tapered over a period of time.
Patients addicted to therapeutic doses can try outpatient detoxification. Typically, the dose is tapered over six to 12 weeks. However, many patients cannot tolerate the withdrawal symptoms and must be admitted for inpatient detoxification. Inpatient detoxification from the short-acting or intermediate-acting benzodiazepines may take up to seven days; detoxification from the long-acting agents may take up to 14 days. The main goals of benzodiazepine detoxification are to make patients comfortable and prevent psychosis and seizures. [1,14]
Equivalent doses are used when switching a patient from a short-acting benzodiazepine to a long-acting agent. For example, 25 mg of chlordiazepoxide is equivalent to 15 mg of clorazepate, flurazepam or temazepam; to 10 mg of diazepam, oxazepam or prazepam; to 4 mg of clonazepam; to 2 mg of lorazepam, and to 1 mg of alprazolam. [1,14]
Propranolol (Inderal), 20 mg every six hours, can be added on the third to the fifth day to mollify tachycardia, increased blood pressure and anxiety. After two weeks, propranolol is given only as needed. Frequently, benzodiazepine dependence occurs as part of a polysubstance dependence. Withdrawal from alcohol or other drugs must be treated concomittantly.
The symptoms of opioid abstinence syndrome include rhinorrhea, lacrimation, yawning, chills, goose pimples, hyperventilation, hypothermia, mydriasis, muscle aches and spasms, bone pain, vomiting, diarrhea, anxiety and hostility. Goose pimples give the skin the appearance of gooseflesh, from which we get the expression "quitting cold turkey." The expression "kicking the habit" probably comes from the movements that result from muscle spasms.
The opioid abstinence syndrome, unlike that of CNS depressants, is not life-threatening.  The onset, intensity and duration of withdrawal symptoms are related to the half-life of the abused drug. With morphine and heroin, withdrawal signs and symptoms start within six to 10 hours after the last dose, peak in 36 to 48 hours and then gradually subside. At sometime after the last dose, opioid addicts may fall into a tossing, restless sleep, known as the "yen," from which they awaken several hours later even more miserable than they were before. By five days, most of the effects have disappeared. With long-acting drugs, such as methadone, the abstinence syndrome may not peak for several days and may last as long as two weeks. Because the methadone abstinence syndrome has a longer course, the symptoms may be less severe, but they are still uncomfortable. 
A transient, explosive abstinence syndrome can inadvertently be precipitated by the administration of naloxone (Narcan) or other antagonist. Within five minutes of injection of the antagonist, withdrawal signs and symptoms appear. They peak in 10 to 20 minutes and subside in about one hour. [1,8]
Several approaches are available for opioid detoxification. Classically, methadone has been the agent of choice. The dose of the abused drug is converted to a daily methadone equivalent; 1 mg of methadone is equivalent to 1 to 2 mg of heroin, 3 to 4 mg of morphine, 0.5 mg of meperidine (Demerol). Methadone is given orally in divided doses twice a day and tapered over four to five days. Alternatively, the dose of the abused drug itself can be tapered. Detoxification from methadone, because of its long half-life, is probably best done by tapering the methadone itself over the weeks. [1,8]
When the daily opioid dose is uncertain, a 10-mg dose of methadone is given orally and its effects assessed over 30 to 60 minutes. If withdrawal symptoms are not suppressed, an additional 10-mg dose is given, and the patient is again observed. This process is repeated until withdrawal is suppressed. A similar dose is administered 12 hours later. Methadone is then given twice daily and tapered over five to 14 days, depending on the half-life of the abused drug. Serious overdoses may occur in addicts who have not used opioid drugs for a while whose tolerance has been reduced. 
Currently, the detoxification agent of choice is the [alpha.sub.2]-receptor agonist clonidine (Catapres), which decreases sympathetic nervous system hyperactivity during withdrawal. Clonidine is especially effective when it is combined with a benzodiazepine such as chlordiazepoxide. For detoxification from most opioid agents, clonidine is initially given in a dose of 0.1 to 0.2 mg orally every four to six hours for four to five days. With long-acting opioids such as methadone, clonidine may have to be continued for two weeks, and tapering may be required to prevent rebound hypertension. Chlordiazepoxide is also given; the dose is 25 to 50 mg every four to six hours as needed.
Transdermal clonidine patches are believed to promote a smoother withdrawal. Patches are available in three sizes that deliver doses equivalent to the twice-daily oral doses of 0.1, 0.2 and 0.3 mg. Because of the time required to reach a therapeutic blood level with transdermal administration, a 0.2-mg loading dose should be given. Oral clonidine, 0.1 to 0.2 mg every six hours, should then be given for the first 24 hours. The patches can be left in place up to seven days. Hypotension may be a problem. Treatment should be modified as required to keep the systolic blood pressure above 90 mm Hg. [1,8,15]
Promethazine, 25 to 50 mg every four to six hours as needed, can be given for nausea or vomiting; loperamide (Imodium), two capsules initially followed by one capsule as needed (not to exceed eight in 24 hours), can be given for diarrhea. Ibuprofen (Mortin), 400 mg every four hours as needed, can be given for pain. 
Opioid detoxification in pregnant patients remains controversial. Fetal death sometimes occurs. Traditionally, the recommended method has been to switch the patient from her opioid of choice to an equivalent methadone dose, and then gradually taper the methadone to a maintenance dose of 20 mg per day. Both the mother and infant are detoxified after delivery. If detoxification must be done sooner, it should be accomplished after the first trimester. Fetal monitoring is essential. [1,8]
Outpatient detoxification from opioid drugs is prohibited by federal statute. Prescriptions can be written daily for up to three days while arrangements for inpatient treatment are made. 
The CNS stimulant abstinence syndrome (such as that associated with withdrawal from amphetamines or cocaine) is fairly mild and consists of negativism, pessimism, lack of patience, irritability, sleepiness, hunger, fatigue, anhedonia, depression and intense carving. [1,8,15] Management of the CNS stimulant abstinence syndrome, for the most part, consists of reassurance that the symptoms will pass. Drug therapy is usually not required.
In recent years, several studies have suggested that pharmacologic intervention might decrease the relapse rate following cocaine detoxification. Dopamine precursos (tyrosine, tryptophan, levodopa [Dopar, Laradopa], carbidopa [Lodosyn]) have been used in an attempt to raise dopamine concentrations in the brain, and dopamine concentrations in the brain, and dopamine agonists (amantadine [Symmetrel], bromocriptine [Parlodel]) have been used to decrease drug craving. Tricyclic antidepressants (desipramine [Norpramine], pertofrane [Imipramine, Janimine, Tofranil]) have been used in an attempt to reduce depression and drug craving. Evidence that these measures are clinically effective is not sufficiently strong to recommend their routine use at this time. Bromocriptine, 1.25 mg as needed, is sometimes used in the first few days of treatment when episodes of craving are so intense that the patient may leave the hospital against medical advice. It appears to be effective for this purpose. [1,8,16-22]
Phencyclidine (PCP) was developed by the pharmaceutical industry in the 1950s for use as an anesthetic. Because of bizarre symptoms, use was discontinued in humans in 1965. However, PCP is still made in illicit laboratories. A large number of PCP analogs have been produced in this manner. [1,2,3]
Acute withdrawal symptoms following cessation of PCP use include nervousness, anxiety and depression. These symptoms, when they occur, are mild. Pharmacologic detoxification is not required; however, the persistence of PCP's effects (hallucinations, delusions) may require the use of haloperidol and a benzodiazepine for a period of time. [9,23,24]
The cannabinoids include marijuana (the dried folowering tops and stems of the hemp plant) and hashish (a resinous extract of the hemp plant). The main psychoactive substance in this group is delta-9-tetrahydrocannabinol (THC). 
A mild abstinence syndrome consisting of irritability, restlessness, nervousness, decreased appetite, insomnia, mild tremor, slightly increased body temperature and chills has been reported after chronic, high-dose use. In reality, acute cannabinoid abstinence syndrome is rarely seen. [9,25] Most abusers have lethargy, apathy and difficulty concentrating. Because of its mild nature, cannabinoid abstinence syndrome does not require pharmacologic treatment. 
The hallucinogens consist of a wide variety of agents. LSD or "acid" (lysergic acid diethylamide), MDMA or "ecstacy" (3,4-methylenedioxymethamphetamine) and MDEA or "Eve" (3,4-methylenedioxyethamphetamine) are currently popular drugs of abuse among adolescents and young adults. Hallucinogens are not associated with an abstinence syndrome; therefore, detoxification is not required. [1,9]
An abstinence syndrome consisting of hallucinations, abdominal cramps, chills and delirium tremens has been reported with heavy, chronic inhalation of solvents. However, this syndrome has not been reported with nitrites or nitrous oxide. 
Detoxification is rarely required for the solvent and aerosol abstinence syndrome. Because of the lack of nitrite and nitrous oxide abstinence syndromes, detoxification from these agents is not required. 
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H. THOMAS MILHORN, JR. M.D., PH.D. is professor of family medicine, professor of physiology and biophysics, and associate professor of psychiatry and human behavior at the University of Mississippi School of Medicine, Jackson. He is certified in addiction medicine by the American Society of Addiction Medicine.
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