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Withdrawal Syndromes

Withdrawal Syndromes

Definition

Withdrawal syndrome occurs in drug and alcohol addicted individuals who discontinue or reduce the use of their drug of choice. This process of eliminating drugs and alcohol from the body is known as detoxification. Anxiety, insomnia, nausea, perspiration, body aches, and tremors are just a few of the physical and psychological symptoms of drug and alcohol withdrawal that may occur during detoxification.

Description

Drugs and alcohol affect mood by altering brain chemistry, specifically the production of neurotransmitters. Neurotransmitters are chemicals in the central nervous system that enable nerve impulses to travel through the central nervous system and regulate thought processes, behavior, and emotion. Drugs that temporarily elevate neurotransmitter levels are called stimulants. Drugs that decrease neurotransmitter levels and depress the central nervous system are called depressants; they include opiates and sedative-hypnotic drugs such as alcohol and barbiturates. (There are exceptions: Benzodiazepine elevates the level of an inhibitory neurotransmitter, GABA, therefore it serves as a tranquilizer.)

When drug or alcohol consumption becomes chronic, the body adjusts to the constant presence of the substance by changing its normal production of neurotransmitters. If drug and alcohol use suddenly stops, the body and central nervous system react to the absence of the substance with an array of symptoms known collectively as withdrawal syndrome.

Causes and symptoms

Acute withdrawal syndrome begins within hours of abstinence, and includes a full range of physical and psychological symptoms. More long-term, or subacute, withdrawal symptoms, such as intense drug craving, may occur weeks or months after detoxification has taken place.

Alcohol withdrawal

Alcohol withdrawal syndrome occurs in alcohol-dependent individuals who suddenly stop or dramatically reduce their alcohol intake. The onset of the syndrome is likely to occur within a week, but usually occurs within 24 hours of the individual's last drink, and is triggered when the central nervous system attempts to adjust to the sudden absence of ethyl alcohol in the body. Symptoms may include extreme anxiety, disorientation, hallucinations, sleep disorders, hand tremors, nausea, sweating, seizures, and racing pulse. Delirium tremens (DTs) are an extreme example of withdrawal. In the worst cases, untreated alcohol withdrawal syndrome can result in death. As many as two million Americans may experience symptoms of alcohol withdrawal conditions each year.

Barbiturate withdrawal

Barbiturates are prescribed as anticonvulsants, sedatives, and general anesthetics. They can also mimic some of the characteristics of alcohol intoxication (including euphoria, elation, and uninhibited behavior), which make them candidates for abuse. Commonly abused barbiturates include amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). These drugs depress the respiratory and nervous system functions. Because abusers rapidly build up a tolerance to the effects of the drug, fatal overdose or coma can easily occur. Symptoms of withdrawal syndrome appear 12-20 hours after the last dose; they include anxiety, irritability, elevated heart and respiration rate, muscle pain, nausea, tremors, hallucinations, confusion, and seizures. Death is a possibility if the condition is left untreated. Because barbiturates decrease REM (rapid eye movement) sleep, during which dreaming takes place, withdrawal often results in sleep disruptions such as nightmares, insomnia, or vivid dreaming.

Opiate withdrawal

Opiates are powerfully addictive analgesic drugs that deaden nerve pathways related to pain. Abusers of propoxyphene (Darvon), meperidine (Demerol), percocet (Oxycodone), heroin, morphine, and other powerfully addictive opiates quickly build up a tolerance to the drugs and need progressively larger doses to achieve the desired effect. Stopping or reducing the intake of the drug can cause severe withdrawal symptoms, which begin six to eight hours after the last dosage. Symptoms are flu-like, and include gastrointestinal distress, anxiety, nausea, insomnia, muscle pain, fevers, sweating, and runny nose and eyes.

Stimulant withdrawal

Use of stimulants, such as cocaine, crack, amphetamines, and methamphetamines, cause an increase in neurotransmitters in the central nervous system and produce feelings of alertness and increased energy. This initial "rush" is followed by a longer period of neurotransmitter loss, characterized by depression, lethargy, and a craving for more stimulants sometimes called a rebound effect. When a stimulant-dependent individual abstains from stimulant use, withdrawal symptoms, including depression, fatigue, insomnia, and loss of appetite, reflect this drop in neurotransmitter levels. Withdrawal typically takes one to two weeks.

Diagnosis

A detailed history of the patient's drug or alcohol use taken before detoxification can be helpful in predicting the severity of withdrawal symptoms. Standardized clinical tests, such as the Clinical Institute Withdrawal Assessment for Alcohol, revised, (CIWA-Ar), are used to evaluate the severity of withdrawal symptoms throughout the detoxification procedure.

Treatment

Pharmacologic and medical management is often recommended for withdrawal syndrome. The physical condition of the patient is closely monitored throughout the detoxification procedure.

Alcohol withdrawal

Alcohol withdrawal syndrome can be treated at home or in a hospital or treatment setting. Inpatient treatment is recommended for patients who are at risk for serious withdrawal symptoms or re-intoxication if treated as an outpatient. Withdrawal symptoms are minimized through the administration of cross-tolerant sedatives. Long-acting benzodiazepines, such as diazepam (Valium), chlordiazepoxide (Librium), and lorazepam (Ativan), are the pharmacologic treatments of choice in managing the symptoms of alcohol withdrawal. Drug dosage is adjusted to offset the discomfort of withdrawal, without causing a euphoric effect, and is then gradually decreased as withdrawal symptoms lessen.

Barbiturate withdrawal

Because the risk for seizures and other severe complications is high, barbiturate withdrawal should be monitored in a hospital setting. Patients are given low doses of phenobarbital at a regular interval until mild intoxication is achieved. The dosage amount and frequency is then gradually decreased until withdrawal is complete.

Opiate withdrawal

Two basic treatment approaches are used for managing opiate withdrawal. The first involves treating the symptoms of the withdrawal with appropriate medication. Clondine, an antihypertensive drug, is commonly prescribed to reduce muscle pain and cramping. Other symptom-specific drugs are administered on an as-needed basis.

The second treatment option is to replace the patient's drug of choice with methadone, a long-acting, cross-tolerant opiate that does not normally produce a "high." Doses of methadone are administered every four to six hours. The patient's reaction is closely observed, and dosages are slowly decreased until withdrawal symptoms have disappeared, then dosages are discontinued. Methadone withdrawal can be completed within three weeks. It is important to note that methadone withdrawal treatment differs from a methadone maintenance program, in which patients who are unwilling to give up opiates are prescribed methadone as a legal, long-term substitute for their drug of choice.

Rapid opiate detoxification (ROD) is an emerging treatment option for opiate withdrawal. The ROD method is reported to be faster and to cause less physical discomfort than traditional forms of opiate detoxification. The treatment is typically performed in a hospital or private clinic setting. Naltrexone, an opiate antagonist that blocks opiate receptors and reverses the effects of opiates, is administered to trigger the withdrawal response. Clonidine is given simultaneously to ease the symptoms of withdrawal. The patient is anesthetized throughout the three to four hour procedure, and withdrawal occurs while the patient sleeps. Vital signs are monitored closely and a ventilator may be employed.

In early 2004, a new single injection method for opiate addiction was being tested. It consisted of a slow-release form of buprenorphine and prevented symptoms for an entire month.

Stimulant withdrawal

Because of the depression and dysphoria (feeling of a psychological low) related to stimulant withdrawal, psychological and/or medical management is critical. Treatment may include a regimen of drugs that increase neurotransmitter production.

Prognosis

A closely observed, medically managed detoxification typically results in a safe and tolerable withdrawal experience for the patient. Detoxification is only a short-term solution for obtaining abstinence. An addiction treatment and long-term recovery program is necessary to achieve long-term sobriety. Without such a treatment program, the likelihood of recurrence of abuse and, therefore, the recurrence of withdrawal syndrome is high.

Prevention

After detoxification, alcohol and drug dependent individuals are encouraged to maintain their abstinence through participation in substance abuse treatment or a twelve-step recovery program.

Resources

PERIODICALS

Bayard, Max, et al. "Alcohol Withdrawal Syndrome." American Family Physician March 15, 2004: 1443.

"Single Injection May Relieve Opiate Withdrawal." Alcoholism & Drug Abuse Weekly January 19, 2004: 8.

ORGANIZATIONS

Alcoholics Anonymous. General Service Office. 475 Riverside Drive, New York, NY 10015. (212) 870-3400. http://www.alcoholics-anonymous.org.

National Clearinghouse for Alcohol and Drug Information. Center for Substance Abuse Prevention. P.O. Box 2345, Rockville, MD 20847-2345. (800) 729-6686. http://www.health.org.

National Council on Alcoholism and Drug Dependence. 12 West 21st St., New York, NY 10010. (800) 622-2255. http://www.ncadd.org.

National Institute on Alcohol Abuse and Alcoholism (NIAAA). 6000 Executive Boulevard, Willco Building, Bethesda, Maryland 20892-7003. http://www.niaaa.nih.gov.

KEY TERMS

Analgesics Pain killing drugs that depress respiratory function. Opiates are analgesics.

Antagonist A substance that tends to nullify the action of another.

Benzodiazepines Sedatives used to treat anxiety, epilepsy, and alcohol withdrawal syndrome. Diazepam (Valium), alprazolam (Xanax), and chlordiazepoxide (Librium) are all benzodiazepines.

Cross-tolerant A drug that has the same pharmacological effect as another is considered cross-tolerant. Cross-tolerant drugs are often used in treating withdrawal syndromes.

Detoxification The process of physically eliminating drugs and/or alcohol from the system of a substance-dependent individual.

Dysphoria A depressed and anxious mood state.

Neurotransmitters Chemicals in the brain that affect the nervous system and alter thinking patterns.

Opiates Analgesic, pain killing drugs, such as heroin and morphine that depress the central nervous system.

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Withdrawal Behavior

Withdrawal behavior

Tendency to avoid either unfamiliar persons, locations, or situations.

Withdrawal behavior is characterized by the tendency to avoid the unfamiliar, either people, places, or situations. Though withdrawal, or avoidance, can be the result of a temperamental tendency toward inhibition to unfamiliar events, anxiety over the anticipation of a critical evaluation, or a conditioned avoidant response, often called a phobia , can produce withdrawal. These are three different mechanisms, each of which can mediate withdrawal behavior.

Withdrawal behavior is typically seen in children. The withdrawal or avoidance that is seen in the preschool years is, most of the time, due to a temperamental bias that makes some children uncertain over unfamiliar events. During later childhood , withdrawal or avoidance occurs due to very specific events, like lightening, animals, insects, or foods. At this point, withdrawal is usually not the result of a temperamental bias, but more often is due to conditioning experiences in which the child had a painful or frightening experience in association with the event he avoids.

A small group of children who appear withdrawn may have serious mental illness , including schizophrenia or autism . However, these are relatively rare illnesses and therefore the average child who appears withdrawn will probably not be afflicted with these problems.

Jerome Kagan

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Withdrawal

WITHDRAWAL

This section contains the articles on withdrawal syndromes, each of which describes and discusses withdrawal signs, symptoms, and treatment. The following substances are covered: Alcohol; Benzodiazepines; Cocaine; Nicotine (Tobacco) ; and Nonabused Drugs. For descriptions and discussions of withdrawal from Amphetamines, see Amphetamine ; Anabolic Steroids, see Anabolic Steroids ; Barbiturates, see Barbiturates ; Caffeine, see Caffeine ; Cannabis, see Cannabis, see also Marijuana ; for Heroin, Opiates/Opioids, see Opioid Complications and Withdrawal. For additional information, see also Treatment.

Alcohol

The nervous system undergoes adaptation in response to the chronic consumption of alcohol (ethanol). If consumption is heavy enough (adequate dose) and occurs for a long enough time period (duration), a withdrawal syndrome will ensue following a rapid decrease or sudden cessation of drinking. This occurs in association with readaptation of the nervous system to a drug-free state. The dose and duration of alcohol consumption required to produce a withdrawal syndrome in a given population or even a given individual are difficult to predict, since no well-controlled studies have been conducted (or are likely to be, for ethical reasons). Such studies have been done in animals. The goals of treatment are to relieve discomfort and to prevent complications.

In the nondrinker or social drinker who consumes alcohol to the point of legal intoxication, an acute withdrawal syndrome may ensue ("hang-over"). Symptoms occur in inverse relation to the fall in Blood Alcohol Concentration (BAC). These consist of insomnia, headache, and nausea. Usually no treatment is required and there are no serious consequences of this acute withdrawal. The withdrawal syndrome following chronic long-term alcohol consumption (usually months to years), however, is a more serious disorder.

The natural history of alcohol dependence to the point of requesting or clearly requiring detoxification services is usually fifteen to twenty years. The average age of persons admitted to detoxification units is around 42 years. (That is not to say that persons as young as 20 or as old as 80 do not require detoxification services.) The withdrawal syndrome seen in persons requiring detoxification ranges from a mild degree of discomfort to a potentially life-threatening disorder.

The severity of the withdrawal syndrome is dependent on both the dose and duration of alcohol exposure. This is clearly demonstrated in animal studies (rats) where a severe withdrawal syndrome can be demonstrated following high-level exposure to alcohol in a vapor chamber in as short a time period as a week. Administration of alcohol into the stomach is associated with a longer time period for acquisition of physical dependence. In humans also, the severity of withdrawal depends on the amount of alcohol consumed and the time period during which it has been consumed. For practical purposes this means the amount taken on a daily basis for the weeks and months preceding detoxification. One study of inpatients (who were federal prisoners and narcotic users) demonstrated that the consumption of 442 grams of alcohol or 32 standard drinks (a standard drink being 13.6 gm of alcohol12 oz. of beer, 5 oz. of wine, or 1.5 oz. of liquor) per day for about two months results in a major withdrawal syndrome in all subjects, whereas the consumption of 280 to 377 grams (21 to 28 standard drinks) per day results in a mild syndrome of anxiety and tremor (Isbell et al., 1955). Other studies that involve patients (as opposed to research subjects) have not been able to demonstrate a consistent relationship between recent alcohol consumption and severity of the withdrawal syndrome (Shaw et al., 1981). This in part relates to the lack of accurate recall of exact quantities consumed within a given time period. Furthermore, in the real world there are different patterns of consumption (e.g., some drinkers consume alcohol in a binge pattern, whereas others drink in a more regular pattern), and different drinkers have varying durations of lifetime exposure to alcohol. One drinker may take two or three years to become dependent, another fifteen years, and yet another forty years. In addition, a person who has previously experienced significant alcohol withdrawal may be at higher risk for developing repeat withdrawal, both in terms of the severity of the syndrome and the rate of reacquisition of physical dependence (since it takes a shorter time to become re-addicted). This more rapid reacquisition has been attributed to sensitization (or "kindling") of the central nervous system (Linnoila et al., 1987). Other factors that may be implicated in the severity of the withdrawal syndrome include age, nutritional status, and presence of concurrent physical disorders or illness (e.g., pancreatitis or pneumonia) (Sullivan & Sellers, 1986). Alcoholics are at increased risk for these and other medical disorders.

The symptoms and signs of alcohol withdrawal appear in inverse relation to the elimination of alcohol from the body. Many alcoholics note this phenomenon on a daily basisthey require a drink in the morning to "steady the nerves," to suppress tremor and anxiety. The following are some of the more common symptoms of alcohol withdrawal: anxiety, agitation, restlessness, insomnia, feeling shaky inside, anorexia (loss of appetite), nausea, changes in sensory perception (tactile: skin itchy; auditory: sounds louder; visual: light brighter), headache, and palpitations. Common signs include vomiting, sweating, increase in heart rate, increase in blood pressure, tremor (shakiness of hands and sometimes face, eyelids, and tongue), and seizures. More severe withdrawal is associated with intensification of the above symptoms and signs together with progression to hallucinations (tactile: feeling things that are not there; auditory: hearing things that are not there; visual: seeing things that are not there), disorientation, and confusion (Delirium Tremens, DTs). After stopping alcohol, the more common and milder symptoms usually peak at 12 to 24 hours and have mostly subsided by 48 hours (Sellers & Kalant, 1976). More severe or late withdrawal usually peaks later, 72 to 96 hours, and is potentially life threatening. Less than 5 percent of persons withdrawing from alcohol (depending on how they are selected) are estimated to develop a severe reaction. With appropriate drug treatment, an even lower percentage are estimated to develop a major withdrawal reaction. Under ideal circumstances there should be almost no mortality from this disorder on its own, so overall mortality ought to be similar to that of any concurrent medical disorder.

Assessment of the severity of withdrawal can be accomplished on the basis of clinical experience or with the assistance of various rating instruments. One of the simplest and easiest to administer is the Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar). This consists of ten items that can be scored at frequent intervals (Sullivan et al., 1989). The health-care provider can administer this instrument in less than a minute (see Figure 1).

TREATMENT

Treatment for the alcohol withdrawal syndrome consists of supportive care, general drug treatment, and specific drug treatments. Supportive care consists of reassurance, reality orientation, reduced sensory stimuli (dark, quiet room), attention to fluids, nutrition, physical comforts, body temperature, sleep, rest and positive encouragement toward long-term rehabilitation. The majority of patients can be treated with supportive care alone; however, it is impossible to be able to predict which patients will or will not require more intensive care. General drug treatment includes the B vitamin thiamine, which should be given to all patients. This is given to prevent the brain damage that occurs commonly in alcoholics who are thiamine deficient. Occasionally magnesium may be given if there is a severe deficiency and there are potential cardiac problems. Intravenous fluids may be required in uncommon circumstances.

Specific drug treatments

may also be given to suppress the signs and symptoms of withdrawal. While over a hundred drug treatments have been suggested as useful in the treatment of alcohol withdrawal, very few adequate scientific studies have been conductedthe main reasons being that appropriate studies are difficult to conduct and that many patients do very well with placebo and/or supportive care alone. Nevertheless, appropriate and effective specific treatments are available and consist of drugs belonging to the same general class as alcohol (central nervous system depressants). The drugs of choice are the longer-acting benzodiazepines (usually diazepam [Valium], but others include chlordiazepoxide [Librium], lorazepam [Ativan], and oxazepam [Serax]), or occasionally a long-acting barbiturate like phenobarbital. The specific drug treatment is usually given either before most withdrawal has occurred (substitution or prophylactic treatment) or after significant symptoms and signs manifest themselves (suppressive treatment). The advantages of substitution treatment include the prevention of potential discomfort and the possible prevention of more severe withdrawal. The disadvantages include an unnecessary treatment for some patients. The advantages of suppression treatment include more appropriate titration of dose of medication, according to a given patient's needs. The disadvantages include unnecessary patient discomfort, at least initially, possibly the development of more severe withdrawal, and sometimes drug-seeking behavior from patients and unnecessary drug withholding from staff.

Benzodiazepines have been well demonstrated to prevent complications (Sellers et al., 1983) of serious withdrawal, such as seizures, Hallucinations, and cardiac arrhythmias. In general, high doses of these benzodiazepines (with medium to long half-lives) are provided early in treatment, to cover the patient for the time period of acute withdrawal (usually 24 to 48 hours). Some patients require very large doses of drug (e.g., several hundred milligrams of diazepam) to suppress symptoms and signs. Patients with histories of withdrawal seizures (convulsions) or those that have epilepsy are always treated prophylactically, usually with benzodiazepines and any other anticonvulsant drug (medication) that they are prescribed on a regular basis. Patients who develop hallucinations are given (in addition to benzodiazepines) a phenothiazine (neuroleptic or antipsychotic drug). Typical drugs from this class include haloperidol (Haldol), and chlorpromazine (Thorazine). These drugs are effective in the treatment of hallucinations.

SUMMARY

In summary, alcohol withdrawal syndrome is a constellation of symptoms and signs that accompany the detoxification and readaptation of the nervous system to a drug-free state in chronic users. In most cases, these signs and symptoms are a source of mild discomfort and run a self-limited course. Occasionally, more severe withdrawal occurs or patients have concurrent complications (e.g., seizures). Under these circumstances appropriate drug treatment is mandatory to relieve symptoms and prevent complications.

BIBLIOGRAPHY

Isbell, H., et al. (1955). An experimental study of "rum fits" and delirium tremens. Quarterly Journal of Studies on Alcohol, 16, 1-33.

Linnoila, M., et al. (1987). Alcohol withdrawal and noradrenergic function. Annals of Internal Medicine, 107, 875-889.

Sellers, E. M., & Kalant, H. (1976). Alcohol intoxication and withdrawal. New England Journal of Medicine, 294, 757-762.

Sellers, E. M., et al. (1983). Oral diazepam loading: Simplified treatment of alcohol withdrawal. Clinical Pharmacology and Therapeutics, 34, 822-826.

Shaw, J. M., et al. (1981). Development of optimal tactics for alcohol withdrawal. 1. Assessment and effectiveness of supportive care. Journal of Clinical Psychopharmacology, 1, 382-389.

Sullivan, J. T., & Sellers, E. M. (1986). Treating alcohol, barbiturate, and benzodiazepine withdrawal. Rational Drug Therapy, 20, 1-8.

Sullivan, J. T., et al. (1989). Assessment of alcohol withdrawal: The revised Clinical Institute Withdrawal Assessment Scale for Alcohol (CIWA-Ar). British Journal of Addiction, 84, 1353-1357.

John T. Sullivan

Revised by James T. McDonough, Jr.

Benzodiazepines

Like many other drugs that alter central nervous system (CNS) Neurotransmission, benzodiazepines may produce a withdrawal syndrome when the drugs are abruptly discontinued. These withdrawal symptoms, including increased Anxiety and insomnia, are often the mirror image of the therapeutic effects of the drug. Since the term withdrawal is usually applied to drugs of abuse, these symptoms are sometimes called abstinence syndrome or discontinuance syndrome when associated with benzodiazepines, thereby distinguishing these substances from drugs such as Alcohol, Opioids, Cocaine, and Barbiturates.

ETIOLOGY

Not all patients who take benzodiazepines will experience a discontinuance syndrome when the drug is stopped. Several conditions must be present before the discontinuance syndrome is likely:

  1. Duration of treatment. The benzodiazepine must be taken long enough to produce alterations in the CNS that will predispose to a discontinuance syndrome. When benzodiazepines are taken at therapeutic doses, the range of time that usually produces a discontinuance syndrome is from several weeks to several months. Taking benzodiazepines once or twice during a crisis, or even for several weeks during a prolonged period of stress, ordinarily does not set the stage for discontinuance symptoms.
  2. Dose. The amount of drug taken on a daily or nightly basis is also a critical factor. When higher-than-therapeutic doses are takenfor example, for treatment of panic disorderthen the period required before a discontinuance syndrome may develop is shortened.
  3. Abrupt discontinuance of the benzodiazepine. Discontinuance symptoms arise because the level of drug at the CNS receptor sites is suddenly diminished. Since drug level in the CNS is proportional to the amount circulating throughout the body, an abrupt decline in CNS drug levels occurs when the blood level abruptly drops. Gradual tapering of benzodiazepines usually prevents the appearance or reduces the intensity of discontinuance symptoms.
  4. Type of benzodiazepine. Benzodiazepines are classified into short and long half-life compounds. These terms refer to the time it takes for liver metabolism to remove (clear) benzodiazepines from the body. Short half-life benzodiazepines are cleared very rapidly, usually from 4 to about 16 hours, depending on the drug. In contrast, long half-life benzodiazepines may take anywhere from 24 to 100 or more hours to be cleared. Since the appearance of discontinuance symptoms depends, in part, on the rapidly diminishing blood level of the drug, abrupt cessation of the short half-life benzodiazepines is more likely to produce discontinuance symptoms. Controversy exists about whether other factors that distinguish one benzodiazepine from another are associated with the appearance of a discontinuance syndrome.

MANIFESTATIONS

Virtually all who experience discontinuance symptoms from benzodiazepines describe increased anxiety, restlessness, and difficulty falling asleep. These symptoms may be mild, little more than an annoyance for a few days, or they may be quite severe and even more intense than the symptoms of anxiety or insomnia for which the drugs were initially prescribed. The reappearance of the initial symptom, such as anxiety or insomnia, only in greater severity, is known as the rebound symptom. Rebound symptoms usually occur within hours to days of benzodiazepine discontinuance and then gradually fade. In some cases, however, they may be so intense that the patient resumes taking the benzodiazepine to avoid the discontinuance symptoms themselves. Thus a cycle of benzodiazepine dependence may beginthe patient is taking the drug primarily to treat or prevent rebound discontinuance symptoms from appearing, rather than treating an underlying anxiety or sleep disorder.

Benzodiazepines that are given to induce sleep may also be associated with the development of discontinuance symptoms. Rebound insomnia, the most common discontinuance symptom, typically occurs on the first night and sometimes the second night after discontinuance of short half-life benzodiazepines. Rebound insomnia may be so intense during these nights that the patient may be unwilling to risk another sleepless night and so returns to taking the benzodiazepine hypnotic. Rebound insomnia is less common with long half-life benzodiazepines.

If untreated, rebound symptoms may sometimes persist for many months. When this occurs it is difficult to determine whether the symptoms are still manifestations of discontinuance or are the result of the return of the problems (anxiety, insomnia) for which the drug was originally prescribed. Sometimes new symptoms that did not exist before the patient took benzodiazepine appear after discontinuance; these are termed true withdrawal symptoms, indicating a change in CNS functioning. Usual withdrawal symptoms include headache, anxiety, insomnia, restlessness, depression, irritability, nausea, loss of appetite, gastrointestinal upset, and unsteadiness. Patients may also experience increased sensitivity for sound and smell, difficulty concentrating, and a sense that events are unreal (depersonalization). Unusual withdrawal symptoms include psychosis and seizures.

OCCURRENCE OF SEIZURES

From a medical perspective, the most serious of all discontinuation symptoms is the development of withdrawal seizures. Seizures are generally grand mal in type (tonic-clonic; epileptic) and may threaten the life of the patient. They tend to occur only when higher-than-therapeutic doses are abruptly discontinued.

Withdrawal seizures almost always occur when the patient has been taking other drugs, such as Antidepressants or Antipsychotic agents, together with a benzodiazepine.

COEXISTING PSYCHOPATHOLOGY

Apparently some people are more predisposed to develop the discontinuation syndrome than others. Those who have been previously dependent on benzodiazepines, alcohol, or other Sedative-Hypnotic drugs, such as barbiturates, are more likely to experience discontinuance symptoms after the termination of benzodiazepine therapy. It is especially important, therefore, that such patients never stop taking their benzodiazepines abruptly.

TREATMENT

Although a variety of treatments have been proposed for the discontinuance syndrome, the best approach is to prevent its occurrence. Logically, prevention consists of a very gradual tapering of the benzodiazepine dose, with a firm rule never to discontinue these medications abruptly if they have been taken for more than a few weeks on a regular basis.

Even with gradual tapering, however, some patients may continue to experience rebound or withdrawal symptoms that are sufficiently disturbing to require treatment. Drugs that tend to reduce CNS hyperarousal states, such as anticonvulsants, have sometimes been employed to treat benzodiazepine discontinuance. Alternatively, benzodiazepine treatment is restarted using a long half-life compound that is then very gradually tapered.

CONCLUSION

For the great majority of patients, benzodiazepine discontinuance is a relatively benign and short-lived syndrome; many, if not most, patients have no difficulty. It is generally agreed that the therapeutic benefits of taking benzodiazepines far outweigh any problems with discontinuance when drug treatment is no longer necessary.

BIBLIOGRAPHY

Rickels, K., et al. (1993). Maintenance drug treatment for panic disorders. Archives of General Psychiatry, 50, 61.

Salzman, C. (1991). The APA Benzodiazepine Task Force Report on dependency, toxicity, and abuse. American Journal of Psychiatry, 148, 151-152.

Salzman, C., et al. (1990). American Psychiatric Association Task Force on benzodiazepine dependency, toxicity, and abuse. Washington, DC: American Psychiatric Press.

Carl Salzman

Cocaine

Withdrawal from cocaine was mentioned by H. W. Maier in his 1928 classic Der Kokainismus (Cocaine Addiction), but systematic efforts to describe and understand cocaine withdrawal did not begin until the 1980s, during the most recent epidemic.

The features of withdrawal from depressant drugs such as Alcohol and Opioids are more robust and recognizable than from a stimulant drug such as cocainesince the grossly observable pattern of physiologic disturbances seen in depressant withdrawal syndromes are not observed when a person stops using cocaine. This difference highlights and contrasts depressant withdrawal and stimulant withdrawal, such as is seen with cocaine.

In alcohol withdrawal, for example, the drinker may manifest all or several of the following set of symptoms and signs: tremulousness, elevated pulse and blood pressure, sweatiness, nervousness, and (rarely) seizure. Craving, or desire, for alcohol is typically high during this period, since the drinker knows it will quickly relive the withdrawal symptoms. These symptoms and signs will generally resolve within three to ten days of ceasing the intake of alcohol. Finally, the withdrawal syndrome is reproduceableindividuals tend to experience the same symptoms every time they withdraw from alcohol. Withdrawal from Opiates such as Heroin and Morphine similarly involves physiologic symptoms and signsdiarrhea, gooseflesh, changes in pulse and blood pressure, muscle cramps, stomach cramps, and anxiety.

In the cocaine abuser, the absence of early apparent physiologic symptoms and signs of cocaine withdrawal led to a widely held misperception (among the public and medical professions alike)that cocaine was not an addicting drug. This misperception was based in part on cocaine's lack of a withdrawal syndrome that was as easy to characterize as those associated with alcohol or opioids.

If cocaine withdrawal does not evidence physiologic symptoms and signs, then how can it be recognized? The concept has been advanced that cocaine withdrawal is mediated through the central nervous system, that observable symptoms are limited to subjective states such as depression, lack of energy, agitation, and craving for cocaine. Evidence that neurophysiologic dysfunction may underlie reported symptoms consists of electroencephalogram (EEG) changes, neurohormonal dysregulation, and dopamine-receptor alteration (Satel et al., 1993).

In 1986, Gawin and Kleber were among the first to describe the clinical course of the symptoms following cocaine cessation, and they proposed a three-phase model of cocaine abstinence. Although this triphasic model has gained wide acceptance, other recent data suggest the model may not be applicable in all clinical situations, as will be discussed below.

The triphasic model postulated by F. Gawin and H. Kleber on the basis of interviews with outpatients comprises three phases that occur after cocaine cessation: (1) crash, (2) withdrawal, and (3) extinction. The crash is described as an extreme state of exhaustion that follows a sustained period of cocaine use (binge); it can last between nine hours and four days. The beginning of the crash is marked by craving, irritability, dysphoria, and agitation; the middle is characterized by yearning for sleep; and the late crash by hypersommnolence (excessive sleep). Certain individuals may experience especially severe depressed mood in the early stages of cocaine abstinence and are at risk for suicidal ideation and action at this time. This may be particularly true for those who are struggling with ongoing problems with depression. When alcohol is used with cocaine, depressed mood can intensify. Also alcohol-induced reduction of impulse control, combined with cocaine crash-related despair, creates a high-risk situation for suicide.

As depression and desire for sleep increase, craving subsides. Upon awakening from a lengthy sleep, the individual enters a brief euthymic (normal) period with mild craving. This is followed by a protracted period of milder withdrawal, lasting 1 to 10 weeks, during which time craving reemerges and anhedonia (loss of pleasure) prevails. This is succeeded by an indefinite period of extinction, marked by euthymic mood and episodic craving.

According to the triphasic model, protracted withdrawal is represented by phase 3, thus beginning after two weeks or more. These clinical phenomena are believed to reflect disturbances in central catecholamine (neurotransmitter) function produced by long-term cocaine use. The crash phase, however, can occur even in first-time stimulant usersif their initial episode is of sufficient duration and dose.

Recently, two groups of investigators have observed a mild constellation of subjective features of the post-crash cocaine abstinence syndrome as described by Gawin and Kleber, but without the phases those investigators described. Weddington et al. (1990) documented the absence of cyclic or phasic changes in mood states, cocaine craving, or interrupted sleep in twelve cocaine-dependent inpatients examined during a four-week period. All had abstained from continuous cocaine use within the preceding forty-eight hours. No euthymic window was evident, although subjects reported significantly greater depressed mood than nondrug-using controls at admission. Subjective symptoms of mood, craving, and anxiety displayed a steady and gradual improvement during the course of the study. By the end of week 4, the cocaine users and the nondrug-using controls had comparable scores. Thus, withdrawal had been completed over the course of one month.

Similar subjective findings emerged from a study by Satel and coworkers (1991), in which 22 newly abstinent Cocaine-dependent males were observed during a 21-day hospitalization. Over the 21 days, both subjective and objective ratings of mood and arousal showed gradual improvement. Although all subjects had consumed cocaine within twenty-four hours of admission, some claimed that they had slept prior to admission and thus the crash phase may have been missed in both studies.

The major differences between the triphasic model and the reports made by the two groups of investigators who actually observed cocaine users during withdrawal reside in the euthymic interval, the severity of symptoms, and the time-to-recovery of mood and craving. Nevertheless, all three studies are consistent with at least a mild postcessation syndrome. It may be important that the original conceptualization of the triphasic cocaine withdrawal was derived from observations of outpatients. The subsequent studies involved inpatients, who were largely protected from environmental cues.

Divergent findings with respect to a delineation between acute and protracted withdrawal is related to the difficulty in distinguishing acute cocaine withdrawal symptoms from those that characterize protracted withdrawal. (This distinction is less blurred in alcohol and opiate withdrawal, where the intense physiologic symptoms take place within the first week of ceasing usageand the protracted syndromes, though uncomfortable, are considerably milder.) Conditioned withdrawal symptoms have been documented in opiate users and in alcoholics. These represent actual physiologic correlates of pharmacologic withdrawal (e.g., changes in skin temperature, gooseflesh, diarrhea, and cramps, accompanied by intense craving for the drug) elicited in drug-free individuals after they complete acute withdrawal and are exposed to reminders of drug use (e.g., visual or olfactory cues).

Conceivably, Gawin and Kleber's subjects may have experienced a delineated withdrawal, with a clear transition to a protracted statebecause as outpatients they were constantly exposed to environmental cues and reminders of drug use. In inpatients, symptoms of acute cocaine withdrawal may be less clearly delineated. Constant exposure to cues may intensify a clinically observable acute syndrome, making the acute-protracted distinction easier to recognize. Environmental influences on clinical withdrawal may determine, in part, the severity of the observable manifestations of changes in neuroreceptors and neurotransmitters that accompany chronic cocaine use. Clearly, the behavioral and subjective manifestations are variable.

In addition, it is possible that nonorganic factors play a role in the prolonged psychic distress following termination of the chronic use of cocaine. Indeed, the period of abstinence following heavy drug use is a time when addicts must squarely face the shambles of their livesthe destruction of their families, loss of jobs, financial ruin, insults to health and self-esteem. Cocaine craving during this period is likely triggered by negative mood states as well as a conscious desire to obliterate the psychological pain with more druga return to drug use.

Pharmacologic treatment for the crash phase of withdrawal has received attention, although most treatment centers do not use medicines to help detoxify crashing cocaine addicts. The two major drugs that have been reported useful during the crash phase are bromocriptine and Amantadine. The action of these two drugs is to enhance transmission of the Neurotransmitter dopamine. Indeed, drugs that have this action were specifically chosen by investigators for use in treatment trials, because they assumed such drugs would reverse the reduction in dopamine levels in the brain that normally follows cocaine binging. This reduction is presumed to account for the depression, irritability, agitation, and drug craving during the crash phase.

Pharmacotherapy for detoxifying cocaine addicts becomes especially important when a person is also dependent on alcohol or opioids. Such codependent states are very common. The usual choice for alcohol detoxification is a Benzodiazepine drug (e.g., Librium); for opiate withdrawal, a choice exists for Methadone, Clonidine, Naltrexone, or combinations of these. Important interactions occur between cocaine and other drugs of abuse. For example, cocaine plus alcohol in the body produces a compound called Cocaethylene. This compound produces more intense and longer euphoriabut it also heightens the risk of death, due to cardiac arrythmia. Also, in methadone clinics, cocaine use has been noted to be of epidemic proportion; the opiate methadone mediates the jitteriness and paranoia that often accompanies cocaine use. Some evidence shows that cocaine addicts, who are also dependent on opiates, may have less severe opiate withdrawal than those who do not use cocaine.

Cocaine Craving is the major cause of relapse in individuals trying to attain and sustain abstinence. Such craving is typically most severe in the early stages of withdrawal from cocaine, although, as Gawin and Kleber noted in their model, cocaine addicts are extremely cue-responsive; reminders of drug use in the community (old copping areas, people with whom they used to get high, etc.) can stimulate craving at any stage of abstinence. Thus, people with severe addiction trying to relinquish cocaine must often enter a rehabilitation program with an outpatient phase that lasts from one to two years, at minimum.

Ideally, a heavy cocaine user with good social support and resources could enter an inpatient program to undergo detoxification (when sustained craving is usually at its peak) for a minimum of one week, before beginning outpatient work. Individuals without social support or a stable living situation can often benefit from weeks to months in a residential-treatment setting. Since it appears that the immediate postcessation phase may be milder for inpatients, this might be a way for addicts to experience less distress and to better concentrate on therapy and education. It might also be a period of time when they feel a somewhat greater sense of control over themselvescontrol being especially difficult to achieve when craving for cocaine is high. It is critical to realize, however, that many patients can develop a false sense of control over the addiction because as inpatients they are protected from environmental cues that trigger craving. Thus gradual reintroduction to the ambulatory environment, psychological preparation of the patient for the likely return of craving, and therapy using relapse-prevention techniques (a form of cognitive therapy) are all necessary.

(See also: Amphetamine ; Cocaine )

BIBLIOGRAPHY

Gawin, F. H. (1991). Cocaine addiction: psychology and neuropsychology. Science (March 29), 1580-1585.

Gawin, F. H., & Kleber, H. D. (1986). Abstinence symptomatology and psychiatric diagnosis in chronic cocaine abusers. Archives of General Psychiatry, 43, 107-113.

Maier, H. W. (1928/1987) Der kokainismus (Cocaine Addiction), O. J. Kalant (Trans.). Toronto: Addiction Research Foundation.

Satel, S. L., et al. (1993). Should protracted withdrawal from drugs be included in DSM-IV? American Journal of Psychiatry, 150, 695-701.

Satel, S. L., et al. (1991). Clinical phenomenology and neurobiology of cocaine abstinence: A prospective inpatient study. American Journal of Psychiatry, 148, 1712-1716.

Weddington, W. W., et al. (1990). Changes in mood, craving and sleep during short-term abstinence reported by male cocaine addicts: A controlled residential study. Archives of General Psychiatry, 47, 861-868.

Sally L. Satel

Thomas R. Kosten

Nicotine (Tobacco)

Nicotine is one of the most addicting substances known; indeed, the risk of becoming dependent on nicotine following any tobacco use is higher than the risk of becoming dependent on alcohol, cocaine, or marijuana following any use of those substances. Among multiple drug users, quitting tobacco use is often cited as more difficult than giving up alcohol or cocaine. Most current views of tobacco use include physiological addiction as a factor in the difficult course of achieving smoking cessation.

As with other drugs that result in dependency, nicotine, the active ingredient in tobacco, shares characteristics with other drugs that result in addiction. First, the administration of such drugs alters central nervous system function at specific receptors and often changes structure; in addition increases (up regulation) or decreases (down regulation) in receptor numbers occur. Second, repeated exposure to the drug results in tolerance, and the individual must progressively self-administer higher doses of the drug to obtain the same effects that initially occurred at lower doses. Third, as cellular and neurological functioning adapt to the continuous presence of the drug during tolerance development, a state of physical or physiological dependence is produced so that removal of the drug is accompanied by feelings of dysphoria and an inability to function normally. The individual then needs continued drug intake to function normally. Finally, a hallmark of dependence-producing drugs is that they serve as biological reinforcers for animals, including humans.

NICOTINE TOLERANCE AND DEPENDENCE

Nicotine is the pharmacologic agent that acts on the central nervous system (CNS). Its actions are seen in the brain where it operates on cholinergic receptors. The cigarette is a very fast and effective delivery system and effects occur rapidly after a single inhalation of tobacco smoke. Nicotine quickly crosses the blood-brain barrier and, once in the brain, interacts with brain receptors. Nicotine alters moods and acts on pleasure-seeking receptors in the brain, including dopamine and serotonin. The nicotine alkaloid affects numerous body systems: It raises blood pressure and the heart rate. It also affects the peripheral nervous system (PNS) and both stimulant and depressive effects are observed in cardiovascular, endocrine, gastrointestinal, and skeletal systems.

Initial exposure to nicotine is not a pleasant experience, often causing sickness, intoxication, and disruptions in physiologic functioning. After a period of daily smoking (assumed to be at least a few weeks), the body adapts to nicotine and the unpleasant effects are less pronounced. Tolerance develops and physical dependence occurs. Smokers are free to self-administer the dose of nicotine they desire, and tolerance increases so that the amount of nicotine used per day continues to increase. The level of dependence is strongly related to the dose of nicotine.

As a smoker becomes physically dependent on, that is, addicted to, smoking, the smoker feels normal, comfortable, and effective when taking nicotine, and dysphoric, uncomfortable, and ineffective when deprived of nicotine. The process of dependence development weakens the ability of the person to achieve and sustain even short-term abstinence. Thus, in the nicotine-dependent person, "normal" function depends on nicotine, and the removal of nicotine results in impairment.

NICOTINE WITHDRAWAL SYMPTOMS

The DSM-IV recognizes nicotine dependence as a substance-related disorder, with a well-defined withdrawal syndrome. The potential withdrawal symptoms include dysphoric or depressed mood; insomnia; irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; and increased appetite or weight gain. The severity of the symptoms will depend on the severity of nicotine dependence. Withdrawal symptoms are strongest in the first few days after smoking cessation, and usually diminish within a month, although some smokers may continue to have withdrawal symptoms for many months.

A number of other sequelae accompany smoking cessation. There is evidence that cognitive ability is impaired when smoking cessation is attempted. The cognitive deficits are correlated with disruptions in brain electrophysiologic function. Figure 1 shows that deficits in an arithmetic task follow a similar time course as changes in the brain's electrical activity. These effects begin a few hours after the last cigarette (dose of nicotine), peak during the first few days of abstinence (when smokers trying to quit are most likely to relapse), and mostly subside within a few weeks. Another study of cognitive impairment, using four complex cognitive tasks during withdrawal from smoking in heavy smokers, ex-smokers, and those who had never smoked, assessed ability to perform those tasks; smokers with 12 hours of abstinence had the worst scores on the tasks.

Another symptom associated with withdrawal is craving for cigarettes. Craving is strongly related to the degree of nicotine dependence. Craving may last 6 months which is longer than some of the other symptoms associated with tobacco withdrawal. Craving is a major obstacle to cessation and together with other indicators of nicotine dependence is strongly related to relapse, with the majority of smokers who attempt to quit relapsing within the first week of cessation.

Although the foregoing are universal, albeit with some variation among individuals, some withdrawal symptoms are unique to individuals with specific characteristics. Smokers with a history of major depression, for example, are at some risk of having another depressive episode during the cessation process. Smokers with comorbid disorders such as alcoholism or illicit substance abuse are likely to have more severe withdrawal symptoms as they attempt to address more than one dependency.

The withdrawal syndrome is undoubtedly biologically based; however, behavioral factors have a strong influence on smoking cessation. Cigarette smoking involves a number of rituals that become ingrained into the smoker's daily life, resulting in numerous individual, social, and environmental prompts to smoke. At the individual level, the smoker may associate a cup of coffee, the end of a meal, or watching television as a prompt to light a cigarette. Socially, being with friends or family members who smoke represents other cues to smoke, while presence in a situation where smoking is not allowed may result in powerful negative feelings about smoking cessation. Environmental stimulibeing in bars or other places where the prevalence of smoking is highare likely to reinforce the smoker's desire to smoke. Exposure to any of the cues to smoke may result in relapse.

TREATMENT OF NICOTINE WITHDRAWAL SYMPTOMS

Two pharmacologic approaches, nicotine replacement therapy and drugs to manage symptoms associated with withdrawal, have been taken to reduce nicotine withdrawal symptoms. In addition, behavioral approaches for withdrawal have been tested.

Nicotine replacement therapy.

The purpose of nicotine replacement is to substitute a safer and controllable form of nicotine to the smoker to aid in cessation. Although nicotine replacement delivery systems vary, all attempt to reduce the amount of nicotine available during cessation so that an individual is weaned from nicotine addiction. Two nicotine replacement therapies are available over-the-counter: nicotine polacrilex gum and the transdermal nicotine patch. Two other delivery systems are available through prescriptions: an oral nicotine inhalation system and a nasal nicotine spray. The effectiveness of each of the systems has been well-established in randomized, controlled trials.

Symptom treatment.

A number of drug therapies have been approved to alleviate or reduce some of the discomfort that accompanies smoking cessation. The best known is bupropion (Zyban), which is effective as an antidepressant. Bupriopion, however, is also effective in smokers who have no history of depression; thus, other factors may be involved in the success of this drug in smoking cessation. Another antidepressant, nortriptyline, has also been shown to be useful for smoking cessation. Clonidine, originally used to treat hypertension, appears to be modestly effective in blocking the cravings for nicotine, especially in women. Other pharmacologic therapies are being tested for their value in ameliorating the withdrawal symptoms of cessation. These include mecamylamine, which is thought to block the reinforcing action of nicotine, and anxiolytics and benzodiazepines, which generally lower stress and decrease anxiety.

Behavioral approaches.

Behavioral approaches for preventing relapse have a long history of use in smoking cessation. Behavioral strategies generally focus on the social reinforcers of smoking. The most effective behavioral programs are those that have multiple components. Various behavioral strategies include contracting to quit, with the smoker making a monetary donation if success is not attained; group support, where individuals support each other in their quit attempts; and cognitive restructuring, where smokers are taught to think differently about smoking and cigarettes. Other components include relaxation exercises, coping tactics, visualization and addressing of tempting situations, simple messages to deal with withdrawal symptoms (e.g., deep breathing, delay so the urge will pass, drink water, do something else), and stimulus control (e.g., getting rid of ashtrays, having a smoke-free home). Multicomponent behavioral programs have had much success in helping smokers achieve cessation. Much research suggests that nicotine replacement or pharmacologic approaches without a behavioral component have significantly lower success rates than those with a behavioral component.

SUMMARY

Nicotine is a very addictive drug that affects the central nervous system. Its use results in tolerance and dependence, so that the user feels most normal when using tobacco. A clear nicotine withdrawal syndrome is known; smokers attempting cessation may have dysphoria, insomnia, irritability, anxiety, difficulty concentrating, restlessness, decreased heart rate, and increased appetite. Further, cognitive ability is somewhat impaired during cessation, strong craving for the drug is present, and powerful behavioral cues make cessation difficult. New approaches to the withdrawal syndrome include the administration of nicotine in a safer delivery system that can be tapered over time, and drugs to counter the unpleasant symptoms of withdrawal. Along with behavioral treatment, such pharmacologic tools may assist the smoker in achieving cessation.

BIBLIOGRAPHY

American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association.

Balfour, D. J., & Ridley, D. L. (2000). The effects of nicotine on neural pathways implicated in depression: A factor in nicotine addiction? Pharmacology, Biochemistry, & Behavior, 66, 79-85.

Benowitz, N. L. (1999). Nicotine addiction. Primary Care: Clinics in Office Practice, 26, 611-631.

Ghatan, P. H., Ingvar, M., Eriksson L., Stone-Elander, S., Serrander, M., Ekberg, K., & Wharen, J. (1998). Cerebral effects of nicotine during cognition in smokers and non-smokers. Psychopharmacology, 136, 179-189.

Hall, S. M., Reus, V. I., MuÑoz, R. F., Sees, K. L., Humfleet, G., Hartz, D. T., Frederick, S., & Triffleman, E. (1998). Nortriptyline and cognitive-behavioral therapy in the treatment of cigarette smoking. Archives of General Psychiatry, 55, 683-690.

Henningfield, J. E. (1995). Nicotine medications for smoking cessation. New England Journal of Medicine, 333, 1196-1203.

Hughes, J. R., Goldstein, M. G., Hurt, R. D., & Shiffman, S. (1999). Recent advances in the pharmacotherapy of smoking. Journal of the American Medical Association, 281, 72-76.

Snyder, F. R., Davis, F. C., & Henningfield, J. E. (1989). The tobacco withdrawal syndrome: Performance assessed on a computerized test battery. Drug and Alcohol Dependence, 23, 259-266.

Sziraki, I., Sershen, H., Benuck, M., Lipovac, M., Hashim, A., Cooper, T. B., & Lajtha, A. (1999). The effect of cotinine on nicotine- and cocaine-induced dopamine release in the nucleus accumbens. Neurochemical Research, 24, 1471-1478.

U.S. Department of Health and Human Services (1988). The health consequences of smoking. Nicotine addiction. A report of the surgeon general. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health. DHHS Publication No. (CDC) 88-8406.

U.S. Department of Health and Human Services. (1989). Reducing the health consequences of smoking. 25 years of progress. A report of the surgeon general. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. DHHS Publication No. (CDC) 89-8411.

U.S. Department of Health and Human Services (1990). The health benefits of smoking cessation. A report of the surgeon general. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. DHHS Publication No. (CDC) 90-8416.

Jack E. Henningfield

Leslie M. Schutt

Revised by Beti Thompson

Nonabused Drugs

Although drug withdrawal is often considered synonymous with matters relating to drug abuse, a number of drugs which have no abuse potential and are prescribed for medical illness are associated with clear symptoms of withdrawal when their use is abruptly discontinued. The symptoms do not necessarily indicate drug dependence, a syndrome that has several features, including tolerance, inability to control drug use, and continued drug use despite deleterious effects.

CARDIOVASCULAR DRUGS

Beta-Adrenergic Blockers.

These drugs are taken by many people to treat hypertension (high blood pressure), angina pectoris (chest pain from heart muscle deprived of oxygen), heart arrhythmias following heart attack, and for migraine headache. The mechanism for each of these effects is related to the drug occupying the beta-adrenergic receptors in the blood vessels and the heart. When a patient abruptly stops taking a beta blocker, particularly when angina pectoris is the symptom being treated, a marked increase in the frequency and/or severity of angina pectoris may occur. This occurs within the first few days of discontinuing the beta blocker; it may be prevented by slowly decreasing the drug dose over several days before completely stopping the drug. The discontinuation symptom is probably related to an increased sensitivity of the beta receptor for the body's own hormones Norepinephrine and epinephrine, when its antagonist, the beta blocker, is suddenly removed. The withdrawal syndrome disappears in a few days, consistent with the time required for beta-adrenegic receptor reregulation.

Clonidine.

This drug is used for hypertension and to treat withdrawal from opiate narcotics. Its mechanism of effect is stimulation of alpha (type 2)-adrenergic receptors in the central nervous system, which results in decreased stimulation of nerves that release norepinephrine and epinephrine in blood vessels. When Clonidine is abruptly stopped, blood pressure increases to well above baseline levels and may become dangerously high. This occurs within one to two days after stopping the drug and is prevented by slowly (over several days) decreasing the drug dose before stopping it completely. This may be due to a "rebound" over-stimulation of norepinephrine and epinephrine releasing nerves in blood vessels. This rebound hypertension disappears within a few days, again consistent with the time required for alpha-adrenergic receptor reregulation.

Nitroglycerinand Other Nitrates.

These drugs are taken to treat angina pectoris. They cause the relaxation of blood vessels by the activation of an intracellular enzyme, guanylyl cyclase, which catalyzes formation of cyclic GMP (guanosine monophosphate). The coronary arteries (blood vessels which supply heart muscles) relax when exposed to nitrates. If the coronary arteries are blocked by atherosclerosis, causing insufficient blood supply to the heart, angina pectoris can occur. Relaxation of these arteries improves blood supply to the heart and the chest pain rapidly disappears. When nitrates are taken continuously for relief of chest pain, then abruptly discontinued, rebound angina pectoris which is more frequent or more severe than the angina experienced pretreatment may occur. This begins within a few hours of the last nitrate dose and in a time course consistent with the metabolism and removal of the nitrate drug from the body. If the nitrate dose is slowly decreased before discontinuation, the rebound angina may be prevented. The mechanism for this withdrawal syndrome is not certain, however, it is probably related to loss of the chronic activation of guanyl cyclase during nitrate therapy and abnormal regulation of the contractile apparatus in the blood vessel muscle, leading it to have rebound contraction.

NEUROPSYCHOPHARMACOLOGICAL DRUGS

Antidepressants.

These drugs are used to treat major depressive illnesses; therefore they are frequently administered daily for periods of weeks or months. Abrupt discontinuation of any of the major classes of Antidepressants may result in discontinuation reactions. Antidepressants vary in their ability to cause reactions, and reactions are more common after abrupt discontinuation and longer courses of treatment. Common symptoms include gastrointestinal problems like nausea, abdominal pain, and diarrhea. In addition, some patients complain of a flulike illness consisting of weakness, chills, fatigue, headaches, and muscle aches. Central nervous system dysfunction characterized by difficulty falling asleep, anxiety, vivid dreams or nightmares, or jitteriness can also occur, as can such affective symptoms as irritability and low mood. Symptoms usually start a few days after termination of the antidepressant and continue anywhere between one day and three weeks. The mechanism of withdrawal may result from up-regulation and increased sensitivity of the muscarinic receptor, which is blocked by these drugs. During chronic heterocyclic-antidepressant treatment, muscarinic-receptor sensitivity increases. When receptor blockade is suddenly stopped, over-activity of these receptors in the digestive tract and brain causes the withdrawal symptoms.

Withdrawal symptoms of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) can be particularly deceptive and therefore problematic because some of the symptoms are like those an individual experiences with a relapse of depression. In such instances, individuals may be at risk of being prescribed even more anti-depressants. This cycle of drug treatment is a significant problem, especially since many government agencies have stepped up efforts to treat depression and managed care plans are increasingly turning to antidepressants as a treatment for depression. However, SSRIs have several distinct discontinuation symptoms, including dizziness and such sensory abnormalities as electric shocklike sensations, numbness, and paraesthesia. The symptoms typically go away the day after antidepressant treatment has resumed, unlike a true depressive relapse, which takes longer. Therefore, with care, a misdiagnosis of a relapse of a psychiatric illness can often be avoided. In addition, to reduce the risk of withdrawal symptoms, some physicians have recommended that antidepressants be gradually reduced over a four week period rather than abruptly discontinued.

Monoamine Oxidase Inhibitor (MAOI) antidepressants drugs interfere with the enzymatic breakdown of Neurotransmitters (such as norepinephrine) in the brain. Sudden discontinuation after high chronic dosing has been associated with psychosis and deliriumconsisting of visual hallucinations as well as mental confusion. Milder symptoms consisting of anxiety, vivid dreaming, or nightmares may also occur. The exact mechanism of withdrawal has not been well studied, but it may relate to the way nerve cells regulate the release of neurotransmitters in the brain. Presynaptic receptors serve to provide a message to nerve cells about how much neurotransmitter is present in the synapsethe space between two nerve cells where messages, in the form of neurotransmitters, flow between cells. When activated, these types of receptors (present on the surface of the nerve cell releasing the message) inhibit any further release of neurotransmitters. As a result of treatment with MAOI, decreases in the number of presynaptic receptors occur, resulting in larger amounts of neurotransmitter being released before the cell shuts down release. The increase in the amount of neurotransmitter may result in withdrawal symptoms that abate over a period of days after discontinuation.

Major Tranquilizers.

Neuroleptic agents are commonly used in psychiatric practice for the treatment of psychotic disorders such as schizophrenia. These agents all block brain dopaminergic receptorsthe basis for their effectiveness in treating psychotic illness. These agents also inhibit emesis (vomiting), which is caused by dopaminergic blockade in the brain as it affects the perception and initiation of vomiting. Chronic blockade results in increased numbers of these receptors. The abrupt discontinuation of this class of drugs results in nausea, vomiting, and headaches. The antipsychotic and antiparkinsonian effects of neuroleptics are also still present for a prolonged period. According to some research, it is not known whether the prolonged effects of neuroleptic drugs in humans are due to the continued presence of drug in brain tissue or to long-lasting, drug-induced physiologic changes.

Clozapine is in a class of atypical antipsychotic drugs associated with discontinuation symptoms. Although atypical antipsychotics may be different from other neuroleptic drugs, there are also significant differences among these drugs in their effects on the receptors of the central nervous system. Clozapine interacts with a wide range of neurotransmitter receptors, especially serotonin receptors. Common discontinuation symptoms of clozapine include delusions, hallucinations, hostility, and paranoia. The underlying mechanism of these symptoms is thought to be cholinergic supersensitivity.

OTHER DRUGS

Baclofen.

As a muscle relaxant, this drug is used to treat muscle spasticity associated with certain paralytic states. It acts as an agonist (mimic) of the inhibitory neurotransmitter in the spinal cord, Gamma-Aminobutyric Acid (GABA). Therefore baclofen inhibits excitatory neural pathways, which are modulated by GABA and which ultimately stimulate skeletal muscles to contract. This is a rather selective effect as there are two types of GABA receptors and pathways, GABA-A and GABA-B, of which baclofen only acts on GABA-B receptors. When baclofen is used to treat muscle spasm, the excitatory pathways of the spine are chronically modulated and inhibited. When baclofen is abruptly discontinued, this inhibition is released and, within a few hours as is consistent with the rate of disappearance of baclofen, the excitatory pathways reboundprobably due to a transient unregulated state. The symptoms experienced by a person suddenly discontinuing baclofen may include auditory and visual hallucinations, severe anxiety, increased heart rate and blood pressure, and generalized seizures. Such clinical symptoms are consistent with the impaired modulation of neural-excitatory pathways. When baclofen dosage is gradually reduced before discontinuation, these symptoms either do not occur or are attenuated, indicating that the inhibitory/excitatory-neural-pathway balance, which has been disturbed by the excessive inhibitory modulus of baclofen, has the capacity to reregulate over a few days.

Corticosteroids.

The drug prednisone will be discussed specifically; however, the biological changes that result in withdrawal phenomena after discontinuation of long-term prednisone treatment hold for all members of the glucocorticoid group. When, for example, a significant dose (5-10 mg daily) of prednisone is taken for a period of several weeks, a series of feedback regulatory events occurs resulting in the patient becoming functionally adrenally insufficient. Specifically, in mimicking the endogenous corticosterone cortisol, prednisone signals the pituitary gland to stop the synthesis and release of the adrenocorticotrophic hormone (ACTH) and, perhaps, the hypothalamus to stop the release of the corticotropin-releasing hormone (CRH). ACTH release from the pituitary, which normally stimulates the adrenal glands to produce corticosterones and which is modulated by the hypothalamic CRH, is blocked by the drug prednisone when ingested in the above dose or greater. Not only does adrenal production of cortisol decrease but also the adrenal glands atrophy.

When prednisone therapy is abruptly discontinued, the atrophic adrenal glands no longer respond to ACTH stimulation, so the patient has symptoms of adrenal insufficiency. Clinically, this is manifested by fatigue, weakness, electrolyte imbalance, and the lack of many bodily responses to stress. If an individual remains in this state for more than a few hours, severe illness and death can be expected. When the adrenal glands become atrophic during long-term prednisone treatment, if the prednisone is to be discontinued, it must be done with slowly decreasing doses over many weeks to permit the adrenal glands sufficient time to regrow to their normal size under the influence of ACTH stimulation and to have sufficient stores of the body's own cortisol to respond to stress in a physiologically appropriate manner.

COMPARISONS WITH DRUGS OF ABUSE

Alcohol is one of the most common drugs of abuse. If alcohol withdrawal is used as a basis for comparison, marked similarity in effect is noted when considering the cardiovascular drugs (beta-blockers, clonidine, nitrates) and baclofen. Alcohol, a nonspecific central nervous system depressant, leads to an ill-defined reregulated state, allowing habituated individuals some level of functionduring their chronic alcohol-induced depressive state. Abrupt cessation of alcohol consumption results in loss of the depressive state, with a rebound state of psychic and physical excitation. This is not unlike the cardiovascular drugs and baclofen; there, the withdrawal syndrome is the clinical manifestation of a neural- or cellular-regulatory system that has reached a new homeostatic state under the influence of the drug and the sudden drug removal leaves insufficient time for physiological reregulation. In the case of corticosteroids, the reverse of this mechanism occurs. Here, the physiological regulation which has occurred during prednisone therapy leads to loss of the capacity to have a physiological response, instead of an over-response.

Human physiology is characterized by the coordinated and finely tuned operation of multiple messaging systems, exhibiting both positive and negative feedback regulation, with multiple levels of control. All the drugs mentioned exert both their desired and undesired effects by interfering with these systems. In the drug-treated individual, homeostasis is maintained by counteracting some of the drug effects at the cellular level. Such adaptation is not without cost. The sudden discontinuation of a drug to which the system has adapted results in a period of disequilibrium between the affected messaging systems. The disturbed physiology is expressed by specific withdrawal symptoms.

(See also: Anabolic Steroids ; Withdrawal: Alcohol )

BIBLIOGRAPHY

Berecz, R.; Glaub, T.; Kellermann, M.;de la Rubia, A.; Llerena, A.; & Degrell, I. (2000) Clozapine withdrawal symptoms after change to sertindole in a schizophrenic patient. Pharmacopsychiatry, 33, 42-44.

Byyny, R. L. (1976). Withdrawal from glucocorticoid therapy. New England Journal of Medicine, 295, 30-32.

Cederbaum, J. M., & Schleifer, L. S. (1990). Drugs for Parkinson's disease, spasticity, and acute muscle spasms. In A. G. Goodman et al. (Eds.), Goodman & Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

Durst, R; Teitelbaum, A; Katz, G;&Knobler, HY (1999). Withdrawal from clozapine: The "rebound phenomenon." Israel Journal of Psychiatry and Related Sciences, 36, 122-128.

Goldstein, J. M. (1999). Quetiapine fumarate (Seroquel (R)): A new atypical antipsychotic. Drugs of Today, 35, 193-210.

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Darrell R. Abernethy

Paolo DePetrillo

Revised by Patricia Ohlenroth

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withdrawal

with·draw·al / wi[voicedth]ˈdrôl; wi[unvoicedth]-/ • n. the action of withdrawing something: the withdrawal of legal aid. ∎  an act of taking money out of an account. ∎  a sum of money withdrawn from an account: a $30,000 cash withdrawal. ∎  the action of ceasing to participate in an activity: the Soviet withdrawal from Afghanistan. ∎  the process of ceasing to take an addictive drug. ∎  coitus interruptus. PHRASES: withdrawal symptoms the unpleasant physical reaction that accompanies the process of ceasing to take an addictive drug.

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withdrawal symptoms

withdrawal symptoms the feeling of being depressed by the absence of something; literally, the unpleasant physical reaction that accompanies the process of ceasing to take an addictive drug.

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withdrawal

withdrawal (with-draw-ăl) n.
1. (social withdrawal) the removal of one's interest from one's surroundings.

2. see coitus (interruptus).

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withdrawal symptoms

withdrawal symptoms pl. n. see dependence.

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withdrawal

withdrawaldenial, dial, espial, Lyall, mistrial, myall, Niall, phial, trial, vial, viol •sundial •knawel, withdrawal •avowal, Baden-Powell, bowel, disembowel, dowel, Howell, Powell, rowel, towel, trowel, vowel •semivowel •bestowal, koel, Lowell, Noel •loyal, royal, viceroyal •accrual, construal, crewel, cruel, dual, duel, fuel, gruel, jewel, newel, renewal, reviewal •eschewal •artefactual (US artifactual), contractual, factual, tactual •perpetual •aspectual, effectual, intellectual •conceptual, perceptual •contextual, textual •habitual, ritual •conflictual • instinctual • spiritual •mutual • punctual • virtual • casual •audio-visual, televisual, visual •usual • gradual • individual •menstrual • actual •asexual, bisexual, heterosexual, homosexual, psychosexual, sexual, transsexual, unisexual •accentual, conventual, eventual •Samuel •annual, biannual, Emanuel, Emmanuel, manual •Lemuel •consensual, sensual •continual

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