9 - Treatment of Physical Dependence on Barbiturates, Benzodiazepines, and other Sedative-Hypnotics

Editors: Shader, Richard I.

Title: Manual of Psychiatric Therapeutics, 3rd Edition

Copyright 2003 Lippincott Williams & Wilkins

> Table of Contents > 9 - Treatment of Physical Dependence on Barbiturates, Benzodiazepines, and other Sedative-Hypnotics

9

Treatment of Physical Dependence on Barbiturates, Benzodiazepines, and other Sedative-Hypnotics

Richard I. Shader

Domenic A. Ciraulo

David J. Greenblatt

I. General Information

The number of persons who abuse prescription drugs in the United States is estimated to be about 2% to 4%. Although the stereotypic drug abuser is portrayed as an inner city male, data suggest that whites, particularly those with psychiatric disorders and those between the ages of 18 and 25 years, are more likely to abuse prescribed agents intentionally. Unintentional misuse is more common among the elderly than it is among the young. Nevertheless, concern about physical dependence on sedative-hypnotic agents among both older persons and those of middle age, the age cohorts in which indefinite use of sleeping pills is most common, is widespread.

However, as the overall data on prescription drug abuse might lead one to expect, the population that most often seeks or is required to obtain treatment for a drug habit of downs or downers is adolescents and young adults. Short-acting and intermediate-acting barbiturates; benzodiazepines, including flunitrazepam or Rohypnol; other sedative-hypnotics, including -hydroxybutyrate; and alcohol are used by this younger cohort as mood modifiers, either alone or in combination with cocaine, amphetamines, or opioids. Usage alone rarely applies to the benzodiazepines. In the jargon of this cohort, such illicit drugs are commonly referred to according to the colors of their capsules as follows: yellow jackets, red birds, red devils, rainbows, and blue heavens (Table 9.1). Such street names go in and out of fashion. Some names refer to any agent with central nervous system depressant properties.

Although United States pharmaceutical companies have discontinued the manufacture and sale of some sedative-hypnotics (e.g., methaqualone, glutethimide, halazepam, prazepam) or some dosage strengths or they have temporarily withdrawn some from the market (e.g., some oral barbiturates), many licit forms remain. Others in the illicit market either appear as imports from other countries or as illegally manufactured street drugs.

Dependence is a general term used to describe the subjective sensation of a perceived need for regular doses of a drug. Dependence on a substance is usually present when the following characteristics exist: (a) a strong desire or need to continue with the drug or its substitutes, which is sometimes called craving ; (b) a tendency to increase the dose that is usually related to tolerance; (c) psychic dependence, which is sometimes associated with drug-seeking behavior or the need to have the drug available at all times; and (d) physical dependence. Emphasizing that the presence of craving does not predict physical dependence (strong craving may exist without tolerance or dependence) is important, nor does the presence of the first three characteristics necessarily imply the fourth. Physical dependence refers to abstinence or withdrawal symptoms that appear when a drug is abruptly stopped. This is a physiologic phenomenon that does not imply abuse or addiction. Therefore, discussions of the general concept of drug dependence need to include more descriptive specificities of the characteristics of the particular syndrome and of the patients. Table 9.2 compares these properties among classes of central nervous system depressants (see also Chapters 3, 10, and 14).

When patients reporting or suspected of physical dependence are initially seen by a clinician, they must be medically evaluated for symptoms and signs of overdose, intoxication, or abstinence. An accurate history, which is often difficult to obtain, is invaluable; questioning the patient or other informants about

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the amount of drug taken, the time of ingestion of the last dose, and the chronicity of use is important. In addition, knowledge of the events leading to the referral or admission; of what environmental supports are available; of any history of prior or current psychiatric or drug-related problems; and of whether alcohol or stimulants, such as cocaine or amphetamines, were also recently ingested is helpful. The patient's motivation should be assessed; examining carefully the realistic quality of his or her plans is also useful.

TABLE 9.1. SEDATIVE-HYPNOTICS: STREET NAMES OF SOME COMMONLY ABUSED FORMS

Generic Name Trade Name Street Name
Amobarbitala Amytal Blue angels, blue birds, blue devils, blue dolls, blue clouds, blue heavens, blue tips, blue velvet
Amobarbital and secobarbitalb Tuinal Double trouble, rainbows, reds and blues, tooies, tuie
Chloral hydrate Noctec Chorals, coral, green frog, mickey finn
Ethchlorvynol Placidyl Pickles, Mr. Green Jeans
Methaqualonec Q, quads, ludes, 714s, sopers
Pentobarbital Nembutal Nembiesd, nemmies, nimbies, yellows, yellow bullets, yellow jackets
Secobarbital Seconal Marshmallow redse, Mexican reds, reds, red bullets, red devils, redbirds, seggy, seccy
Flunitrazepam Rohypnol Circles, forget-me drug, forget pill, forget-me pill, La Rocha, pingus, reynolds, rib, roach-2, robutal, rochas dos, roche, roofies, rope, rophies, rophy, ropies, roples, row-shay, ruffies, ruffles,
-Hydroxybutyrate Xyremf Cherry meth, easy lab, everclear, G.B., gamma oh, Georgia homeboy, great hormones at bedtime, grievous bodily harm, jib, liquid E, liquid ecstasy, liquid X, max, salt water, scoop, sleep-500, soap, somatomax
Nonspecific (class) terms Depressants, especially barbiturates Bambs, bank bandit pills, barbs, barbies, block busters, busters, downers, downie, drowsy high, gangster pills, goofers, gorilla pills, green dragons, idiot pills, lay back, mother's little helper, Mighty Joe Young, peanut, peter, phennies, phenos, stoppers, stumbler, tranq, ups and downs
aThe formulation of amobarbital that is legally available in the United States in 2001 is for i.v. use.
bTemporarily withdrawn, but reintroduced in late 1991 in 100 and 200 mg oral forms.
cNo longer legally manufactured in the United States.
dAn orange-and-white 50 mg capsule is also manufactured.
eCurrently manufactured as an orange pulvule.
fProposed name; not currently marketed in the United States.

Among sedative-hypnotic drugs, pentobarbital, secobarbital, and methaqualone are disproportionately abused; meprobamate and the benzodiazepines are abused less often, even though they are widely available. As was noted above, methaqualone is no longer available as a licit drug in the United States. However, it remains available as a street drug in some areas of the

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country, and overdose victims are seen in emergency departments (see Chapter 3). The barbiturates provide a paradigm for discussing the difficulties that clinicians encounter when treating persons dependent on any of these agents.

TABLE 9.2. COMPARATIVE UNWANTED PROPERTIES a OF VARIOUS CENTRAL NERVOUS SYSTEM DEPRESSANTS

Drug Abstinence or Withdrawal Syndrome (after 3 mo) Therapeutic Dose Tolerance Psychologic Dependence (at Therapeutic Doses) Physical Dependence (at Supra-Therapeutic Doses)
Barbiturates and barbiturate-like drugs +++ ++ + +++
Benzodiazepines + + ++ ++
Alcohol (ethanol) +++ ++ ++ +++
Opioids ++++ +++ ++++ ++++
aVariation exists within each class.
Increased number of + represents an increased degree.

II. Medical Evaluation

A. Abstinence (the Withdrawal Syndrome)

The character of a person's physical dependence results in part from the type of drug ingested, its dose, the length of time it was used, and whether that use was continuous or intermittent. Physical dependence does not usually develop with short-term usage at therapeutic dosages; it may develop when therapeutic dosages are ingested over months or years. Physical dependence may develop sooner if large doses are consumed at a steady or escalating rate. Thus, persons taking nightly doses of 200 mg of a short-acting barbiturate rarely become physically dependent. Routine ingestion of 400 mg per day of pentobarbital or secobarbital can lead to tolerance development and mild withdrawal symptoms after a period of 90 days. Persons consuming 600 to 800 mg per day of either drug for 35 to 120 days may have grand mal seizures upon withdrawal, even though they usually do not show symptoms of delirium. Table 9.3 illustrates the relationship between the barbiturate dosage level and the intensity of physical dependence.

TABLE 9.3. RELATIONSHIP OF DOSAGE OF SECOBARBITAL OR PENTOBARBITAL TO ABSTINENCE MANIFESTATIONSa

Daily Dose (mg) Duration of Ingestion (d) Percentage of Patients Showing
Convulsions Delirium Minor Symptoms
200 365 0 0 0
400 90 0 0 5.5
600 35-57 11 0 50
800 42-57 20 0 100
900-2,200 32-144 78 75 100
aData derived from 61 patients.
From Wikler A. Diagnosis and treatment of drug dependence of the barbiturate type. Am J Psychiatry 1968;125:758-765, with permission.

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Table 9.4 summarizes the doses of sedative-hypnotic drugs that reportedly can lead to physical dependence. Remembering that documented experience with nonbarbiturate sedative-hypnotics is limited and is largely anecdotal is important.

The syndrome of barbiturate abstinence is similar to that which is seen after alcohol withdrawal (see Chapter 12); it is characterized by tremulousness; anxiety; insomnia; anorexia; nausea; vomiting; sweating; postural hypotension; tendon hyperreflexia; excessive sensitivity to light and sound; and, in some cases, convulsions and delirium (Table 9.5). Some authors also include progression to hyperpyrexia, electrolyte abnormalities, cardiovascular collapse, and death in this list. The character and intensity of the withdrawal state should differentiate this state from that of a return of anxiety symptoms or from a temporary rebound state after drug discontinuation.

The examining clinician must carefully separate subjective symptoms from those that have been verified by the physical examination. The abstinence syndrome, if it occurs, usually begins 16 to 72 hours after the cessation of drug intake. Typically, the onset of abstinence symptoms is related to the elimination half-life of the particular drug. Grand mal convulsions, when they occur, generally are noted 3 to 7 days after drug cessation, usually as single episodes but occasionally in multiple bursts. (Note: Convulsions after longer-acting benzodiazepine use tend to come later in the abstinence syndrome.) Convulsions may be accompanied by a loss of consciousness and cyanosis and occasionally by progression to delirium. When delirium is present, it most often begins between the fourth and sixth days with fluctuating consciousness, visual and auditory hallucinations, unsystematized delusions, mood fluctuations, restlessness, insomnia, fever, and hyperreflexia with marked blepharospasm. Delirious patients often have no understanding of their situation. They may be combative and difficult to manage. Physical restraints may be required to protect both the patient and staff (see Chapter 26). The intensity of the withdrawal syndrome lessens gradually, and almost all of the symptoms are gone by 2 weeks after the cessation of drug intake.

Electroencephalographic examination of patients with increased barbiturate blood levels sometimes reveals a spiky pattern with abnormal fast activity. Photic stimulation can produce occasional paroxysmal bursts of activity. During abstinence, the electroencephalogram can become distinctly abnormal. One early report found that 12% of abstinent patients had paroxysmal activity without photic stimulation; two-thirds showed paroxysmal activity with photic stimulation.

TABLE 9.4. EXAMPLES OF DOSAGE AND DURATION ASSOCIATED WITH WITHDRAWAL SYMPTOMS FROM SEDATIVE-HYPNOTICSa

Generic Name Dose (g) Duration (mo)
Ethchlorvynolb 2-4 7-8
Glutethimidec 2.5 3
5 0.5
Methaqualonec 0.6-0.9 1
Meprobamate 2.4 1.3
3.2-6.4 9
Chlordiazepoxide 0.3-0.6 5-6
Diazepam 0.1-1.5 Several
aData derived from case reports.
bUsually over four times the therapeutic dose.
cNot legally available in the United States.

TABLE 9.5. BARBITURATE ABSTINENCE (WITHDRAWAL) SYNDROMEa

Clinical Phenomenon Frequency (%) Time of Onset Duration (d) Remarks
Apprehension 100 1st day 3-14 Vague uneasiness or fear of impending catastrophe
Muscle weakness 100 1st day 3-14 Evident on mildest exertion
Tremors 100 1st day 3-14 Coarse, rhythmic, non-patterned; evident during voluntary movement and subsiding at rest
Postural faintness 100 1st day 3-14 Evident on sitting or standing suddenly; associated with marked fall in systolic and diastolic blood pressure and with pronounced tachycardia
Anorexia 100 1st day 3-14 Usually associated with repeated vomiting
Twitches 100 1st day 3-14 Myoclonic muscle contractions or spasmodic jerking of one or more extremities; sometimes bizarre patterned movements
Seizuresb 80 2nd-3rd day 8 Up to a total of four grand mal episodes, with loss of consciousness and postconvulsive stupor
Psychoses or deliriumb 60 3rd-8th day 3-14 Usually resemble delirium tremens ; occasionally resemble schizophrenia or Korsakoff syndrome; acute panic states may occur
aSeen after abrupt withdrawal in 19 persons exposed to experimental addiction to secobarbital or pentobarbital using chronic intoxication at dose levels of 0.8-2.2 g/d p.o. for 6 wk or more.
bFour persons developed seizures without subsequent psychosis one exhibited delirium without antecedent seizures, and three escaped both seizures and delirium.
From Wikler A. Diagnosis and treatment of drug dependence of the barbiturate type. Am J Psychiatry 1968;125:758-765, with permission.

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B. Intoxication

Intoxicated patients range in appearance from those who are sleeping but are easily aroused to those who are alert, with fine lateral nystagmus as the only sign of recent use. Drowsiness, slurred speech, coarse nystagmus, hyporeflexia, and ataxia characterize moderate intoxication. Intoxicated patients may be aggressive, uncooperative, or even violent.

C. Overdose

The treatment of an overdose of sedative-hypnotics is reviewed in Chapter 3.

III. Detoxification: Assessment and Management

When assessing a patient for detoxification, the clinician must carefully examine (a) the context of the patient's admission, (b) the events leading to admission, (c) the availability of social supports, (d) the purpose for which the patient used the drug, (e) the patient's past history of drug detoxification, (f) the patient's expectation of difficulties without the drug, and (g) the realistic quality of the patient's plans and motivations. Objective validation of the recency and quantity of drug exposure based on a plasma barbiturate measurement may be highly desirable or even essential. Urine drug screening may also be helpful. From this assessment, an attentive clinician may foresee some of the problems that may arise after the detoxification regimen is begun. Similarly, careful assessment may allow the clinician to recognize patients who may be taking multiple drugs. Because multiple-drug users may be taking drugs with different elimination rates (half-lives), knowing what the patient has taken facilitates making decisions about which detoxification to undertake first.

Detoxification of a person as either an inpatient or an outpatient is possible. Although hospitalization offers more safety and control, particularly when the reliability of the patient is uncertain, outpatient care may be the only means of engaging the patient in treatment. A stable environment and strong motivation may permit withdrawal to take place without excessively disturbing the patient's daily life routines. Detoxification must not be carried out perfunctorily. Information about the actual amounts and types of drugs taken is frequently unavailable to the treating clinician, or the information that is available may be unreliable; close observation of the patient's responses and conducting a thorough physical examination are essential. Individuals respond differently to medication. What may be an adequate withdrawal schedule for one person can heavily sedate another.

With any form of drug detoxification, the patient should be informed at the outset that this is an uncomfortable procedure that is often accompanied by malaise, anxiety, increased heart rate, shakiness, insomnia, and nightmares. Nightmares may at times be so distressing that the patients will interrupt the drug withdrawal to suppress their nightmares by taking more drugs. Some complain of anorexia, nausea, and mild abdominal cramps. The clinician must separate these from the symptoms of other physical ailments. The insomnia from sedative-hypnotic detoxification or withdrawal may last for weeks, and it is associated with a dream rebound ( REM rebound ), in which the patient has many anxious nightmarish dreams.

A. Initiation of a Planned Withdrawal

Three methods for withdrawing patients from barbiturates are available. The first two rely on an estimation of the patient's level of drug requirement, based either on estimated equivalencies to phenobarbital or on the results of a pentobarbital challenge test. The third method uses a loading dose of phenobarbital to achieve sedation and mild toxicity.

  • Test dose (pentobarbital challenge test). The patient is given 200 mg of pentobarbital orally, and changes in the neurologic examination are assessed after 1 hour. Table 9.6 presents possible findings on the physical examination, the associated degree of tolerance, and the estimates of 24-hour pentobarbital requirements. If no physical changes are observed after 1 hour, the level of the habit is probably above 1,200 mg per day of pentobarbital. The test is then repeated 3 to 4 hours later, using 300 mg of pentobarbital. No response to the 300 mg dose suggests a habit above 1,600 mg per day.

    TABLE 9.6. CLINICAL RESPONSE PATTERNS TO TEST DOSE OF 200 mg OF PENTOBARBITAL GIVEN ORALLY: RELATIONSHIP TO TOLERANCE

    Patient's Condition 1 h After Test Dose Degree of Tolerance Estimated 24-h Pentobarbital Requirement (mg)
    Asleep but arousable None or minimal None
    Drowsy, slurred speech; coarse nystagmus; ataxia; marked intoxication Definite 400-600
    Comfortable; fine lateral nystagmusis only sign of intoxication Marked 800
    No signs of drug effects; perhaps persisting signs of abstinence; no intoxication Extreme 1,000-1,200 or more

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    After 2 to 3 days of stabilization, either phenobarbital or pentobarbital can be used for withdrawal, but the course of withdrawal is often smoother with phenobarbital, because it causes fewer variations of the blood barbiturate level. The estimated daily requirement of pentobarbital is divided into four equal doses and is administered orally every 4 to 6 hours. Smaller total doses of phenobarbital, usually one-third of the amount of pentobarbital, are required due to its longer duration of action. Phenobarbital is given orally in equally divided amounts every 8 hours. Both the pentobarbital and the phenobarbital can be reduced at a rate of one-tenth the starting dose per day (e.g., an initial daily dose of 600 mg of pentobarbital would be decreased by 60 mg per day; the equivalent 200 mg of phenobarbital would be lowered by 20 mg per day). Reducing the dosage at this slow rate typically results in a minimal and tolerable withdrawal syndrome.

    Stabilization doses of 500 to 600 mg per day of either phenobarbital or pentobarbital should rarely be exceeded. The risk-to-benefit ratio above this range is not favorable.

  • Phenobarbital equivalents. Another technique for determining the baseline level of drug that is required daily was developed for outpatients who have refused admission but who nonetheless seek detoxification. Table 9.7 gives the empirically established amounts of phenobarbital that correspond to some of the abused drugs. With this method, knowing the names and quantities of the drugs that are frequently abused (Table 9.1) becomes important. By totaling the number of daily hypnotic doses that are reported and calculating their equivalent, the clinician can estimate the patient's initial requirement for phenobarbital. After 2 to 3 days of stabilization, the dose is divided on an every-8-hour schedule and is tapered, with a total daily decrement of about 10%. Many clinicians are reluctant to use this procedure because of the possibility that a patient may misuse the prescribed amounts. Another problem with this approach is that drug histories are frequently unreliable; moreover, some drug-seeking patients may exaggerate the amounts they have been using. In instances of mixed sedative abuse or when alcohol is also used, thus complicating the clinical presentation, the calculation of equivalencies is also likely to be inexact. In these patients, the challenge test or a loading-dose strategy is more appropriate. Furthermore, some argue that, when the phenobarbital-equivalents procedure is used in outpatients, the risks to the patient and the medicolegal risks from seizures, automobile accidents, or cardiac arrhythmias are too high.

    TABLE 9.7. ESTIMATED OR APPROXIMATE PHENOBARBITAL SUBSTITUTION WITHDRAWAL DOSAGE EQUIVALENCIES FOR SOME SEDATIVE-HYPNOTIC AGENTS

    Generic Name Dosage (mg)
    Phenobarbital 30
    Pentobarbital 100
    Secobarbital 100
    Chloral hydrate 500
    Meprobamate 200
    Alprazolam 1
    Chlordiazepoxide 25
    Clonazepam 0.5
    Clorazepate 15
    Diazepam 5
    Estazolam 2
    Flurazepam 15-30
    Lorazepam 1
    Oxazepam 15-30
    Quazepam 15
    Temazepam 15-30
    Triazolam 0.25
    Zaleplon 10
    Zolpidem 10

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    When withdrawal is impending, the patient may be given a single intramuscular loading dose of 100 to 200 mg of phenobarbital. The first oral dose is then begun after the patient has gone several hours without significant physical signs of intoxication.

  • Loading dose. A third approach to detoxification involves an oral loading dose of phenobarbital; the clinician then tries to reach the level of early sedation and toxicity by adding further increments of phenobarbital (i.e., titrating up to this level). Usually a dose of 120 mg (smaller amounts [e.g., 40 mg] are advocated by some clinicians) is given every hour until the patient becomes dysarthric, ataxic, sedated, or labile or until the individual shows nystagmus. Typically, three of these findings are considered sufficient for determining that the intoxication threshold has been reached. Reaching this level may take 15 to 20 hours; thus, this method is best reserved for hospital situations or for those in which the patient can be confined and can be continuously supervised by trained personnel. Some clinicians have found that an accumulated initial dose with this method ranges from 1,300 to 1,500 mg. The phenobarbital is then slowly eliminated, and the resulting withdrawal is quite mild. Patients requiring 500 mg per day or less of phenobarbital usually do not require intervention other than support and observation.

B. Mixed Physical Dependence ( Addiction )

When a patient is dependent on both an opioid and a barbiturate or a barbiturate-like sedative-hypnotic, the best approach is to withdraw the hypnotic gradually while maintaining the opioid at a constant level (e.g., methadone, usually 20 mg per day, if the patient has verifiable opioid dependence). Decreasing both drugs at once is possible, but this simultaneous weaning occasionally complicates the clinical picture. Some barbiturates (or meprobamate) may induce the metabolism of methadone (see Chapter 29), as may other drugs, such as carbamazepine and phenytoin. Restabilizing the methadone concentrations in the blood and tissues after the discontinuation of the barbiturate or barbiturate-like drug may take time.

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A person withdrawing from opioids (see Chapter 10) usually has dilated reactive pupils; an elevated pulse rate, blood pressure, and respirations; muscle aches and twitches; and tremulousness, nausea, vomiting, diarrhea, tearing, runny nose, yawning, restlessness, chills, and gooseflesh ( cold turkey ). By carefully examining the patient's eyes; pulse; blood pressure, both while lying and standing; reflexes, including the blink reflex; and mental status, separating one withdrawal syndrome from the other should be possible. Nonetheless, an accurate clinical distinction is often difficult. Although opioid withdrawal is uncomfortable, it rarely leads to convulsions, and it is not lethal. Abstinence from a sedative-hypnotic clearly is more dangerous.

C. Psychologic Adjuncts

Psychologic interventions may be helpful in both acute withdrawal and in the longer term treatment of underlying or withdrawal-related anxiety. Several general principles can be derived from studies of benzodiazepine-dependent patients, even though the number of such studies is small. Most clinicians recommend frequent contact with the patient during the withdrawal phase. For inpatients, daily contact is recommended; once-weekly or twice-weekly appointments and telephone availability are appropriate for most outpatients. The clinician, both through discussion and written materials, should provide the patient with information about the nature of the withdrawal syndrome and the distinctions between withdrawal symptoms and a return of underlying anxieties. Success rates are usually highest in patients who are able to develop alternative coping skills that help them to achieve a sense of control over their worries, stresses, and drug cravings. With this in mind, offering patients at least one trial for determining their own rate of withdrawal through setting their own targets may be helpful. The goals should be flexible, and they should be reviewed with the clinician. One strategy is suggesting that the first dosage reduction may be set by omitting the dose the patient feels that he or she least needs. In some instances, the omission of a full dose is not tolerated, and a partial reduction may be chosen instead.

Many clinicians recommend the use of a diary to help patients distinguish between withdrawal symptoms and anxiety and to help them see what situational stresses or precipitants trigger or augment their anxiety or promote an urge to return to drug taking. This approach can increase a patient's sense of mastery over his or her anxiety. Discussing the diary entries with the patient may alert the clinician to maladaptive coping strategies or to compensatory increases in alcohol consumption. Other cognitive-behavioral approaches (e.g., relaxation training, systematic desensitization, graded in vivo exposure, and cognitive restructuring) have been proposed as additional adjuncts.

IV. Benzodiazepine Dependence

In recent years, considerable media and regulatory attention has been paid to benzodiazepine dependence (see Chapters 3 and 14). Contrary to what would be expected from popular reports, actual physical dependence on benzodiazepines is not a common problem when benzodiazepines are taken at their therapeutic doses. Dependence at therapeutic doses is infrequent, and it is rarely seen in patients who have taken benzodiazepines for less than 3 months. When dependence does develop on therapeutic dosing regimens, it is most likely idiosyncratic, although a personal or family history of sedative-hypnotic or alcohol abuse or misuse may be more common in those who develop it. Based on clinical experience, some clinicians argue that diazepam, alprazolam, and lorazepam have a higher abuse potential than clonazepam, chlordiazepoxide, clorazepate, and oxazepam. (Note: No credible scientific evidence supports this impression.) In general, patients who gradually taper the dosage of any benzodiazepine at the time of drug discontinuation will reveal minimal withdrawal symptoms. When symptoms do appear, they most likely reflect a return of the original anxiety disorder for which the benzodiazepines were prescribed. In general, if dependence and withdrawal do occur, the patient has likely exceeded the therapeutic dose by at least a factor of 2 or 3 for 1 month or more.

The clinical presentation of benzodiazepine withdrawal is basically identical to that which is seen with barbiturates and other sedative-hypnotics. Some clinicians

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believe, however, that hyperacusis (sensitivity to sound), photophobia (sensitivity to light), myoclonic jerks, and urinary incontinence in an apparently alert patient are seen more frequently in benzodiazepine withdrawal than in barbiturate withdrawal. Withdrawal can be treated with barbiturate substitution as reviewed above; by reinstituting the prediscontinuation dose of benzodiazepine and beginning a gradual tapering of the dosage (usually a 10% to 20% reduction every second or third day); or by substituting a longer-acting benzodiazepine, such as clonazepam, and then beginning the tapering strategy.

What is sometimes improperly called interdose dependence (i.e., withdrawal symptoms, such as anxiety symptoms and tachycardia) is sometimes reported by patients taking shorter-acting benzodiazepines at widely spaced dosing intervals. Decreasing the dosage interval while maintaining the same total daily dose is an appropriate corrective strategy. An alternative is increasing the 24-hour dosage to ensure that the patient remains above the minimum therapeutic concentration at all times a strategy that may unfortunately result in a greater likelihood of dependence over time. A sustained-release form of alprazolam might obviate the occurrence of interdose withdrawal symptomatology.

For patients who do not adequately respond to tapering or substitution, covering the final stages of the withdrawal with oral carbamazepine (100 to 300 mg per day for the last 5 to 10 days) may prove beneficial. The latter strategy is supported by anecdotal case reports, small-sample uncontrolled studies, and at least one animal model study.

The oral administration of other anticonvulsants is another option that may be used to ease patient discomfort during a planned withdrawal from benzodiazepines. Some clinicians believe that gabapentin use reduces somatic complaints and improves sleep, although the specific withdrawal symptoms (e.g., hyperacusis) may not be alleviated. A common regimen reflects the typical anticonvulsant range for gabapentin (900 to 3,600 mg per day). A more aggressive regimen involves a higher maximum dose (e.g., 5,400 mg per day). Gabapentin is then tapered after the benzodiazepine has been discontinued. Divalproex sodium (500 to 2,500 mg per day) has been used in a similar manner. Antidepressants (e.g., trazodone [100 to 500 mg per day], nefazodone [200 to 600 mg per day]) have also been used successfully by some clinicians. Unfortunately, the limited number of published observations for these anticonvulsants and antidepressants is insufficient for providing the evidence that is needed for strongly recommending their use.

Because some patients forget to tell their clinicians that they are taking benzodiazepines, alcohol, or other sedative-hypnotics, specific inquiry before surgery or hospitalization is essential to avoid the complications of withdrawal during recovery or the possible confusion of withdrawal symptoms with the underlying disorder or some other untoward reaction.

V. Flunitrazepam

Flunitrazepam is a benzodiazepine hypnotic that is not marketed in the United States. However, it is imported illegally into this country, especially from Central and South America. It has received wide publicity as a date rape drug, because of reported cases of individuals who have unknowingly ingested the drug with alcohol, which renders the victim sedated, unable to resist sexual activity, and often amnestic for the assault. That flunitrazepam is unique among benzodiazepines in producing this effect is unlikely; clonazepam, for example, is sometimes sold as roofies (so-called because of the trade name for flunitrazepam, Rohypnol; see Table 9.1 for some other common street names). Withdrawal syndromes, including seizures, have been reported in individuals abusing flunitrazepam.

A related drug, -hydroxybutyrate (GHB), is abused for its sedative effects; liquid GHB combined with alcohol has also been linked to sexual assaults. Some street names for GHB are given in Table 9.1. GHB is now available in the United States under the trade name Xyrem for the treatment of narcolepsy. GHB is easily synthesized from -butyrolactone or 1,4-butanediol, which has increased the illegal access to GHB. GHB can produce the abstinence syndrome characteristic of sedative-hypnotics, although some authorities believe that it is

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milder than that which is induced by barbiturates, alcohol, or benzodiazepines. The abstinence syndrome most commonly presents with anxiety and insomnia, although more severe symptoms may also occur. The recommended treatment is stabilization on benzodiazepines, followed by gradual tapering. Complicating the assessment is the difficulty that one may have in distinguishing acute intoxication from withdrawal. At low doses, GHB appears to be a central nervous system depressant; at higher doses, it is excitatory and it may even induce seizures. This reflects the complexity of the pharmacologic actions of GHB, which are different than those of drugs that act on the -aminobutyric acid A receptor. GHB naturally occurs in the body, where it acts as a neuromodulator or neurotransmitter. A GHB receptor has been identified, but the drug's actions affect many neurotransmitter systems, including the dopamine, serotonin, opioid, and -aminobutyric acid B receptors.

VI. Zolpidem

This is an imidazopyridine hypnotic that has a rapid onset of action. Although some studies suggest that its abuse potential may be lower than that of the benzodiazepine hypnotics, instances of abuse and physiologic dependence have been reported. At the present time, it is the most commonly prescribed hypnotic in the United States. Zaleplon is a pyrazolopyrimidine hypnotic that has a short duration of action, thus allowing patients to take the medication in the middle of the night as long as they are able to avoid activities for at least 4 hours. Little or no psychomotor impairment appears to be present the following day, and some studies have found no evidence of rebound insomnia or withdrawal when the drug is taken in prescribed doses. When dependence with zolpidem or zaleplon develops, treatment of the abstinence syndrome should follow the guidelines for benzodiazepine withdrawal.

VII. Longer Term Treatment

Treatment of patients with sedative-hypnotic dependency must be individualized. In general, most patients develop their dependence either as part of a problem with polysubstance abuse or in the context of their treatment for a medical condition, such as chronic pain or a psychiatric condition.

The authors' impression is that many of the latter group of patients do not fare well in standard drug or alcohol abuse treatment programs. Treatment must be directed not only at their problem of dependence but also at their underlying medical or psychiatric problem. In some cases, this is easily accomplished; for example, Fiorinal could be replaced by a nonsteroidal antiinflammatory agent in some patients with chronic headache or by an antidepressant (e.g., venlafaxine XR). A -adrenergic receptor antagonist could be substituted for a benzodiazepine in a chronically anxious patient. Often, however, the situation is sufficiently complex that individual psychotherapy or cognitive-behavioral therapy is also needed.

Unfortunately, many polysubstance-abusing patients who begin detoxification from sedative-hypnotic agents do not complete their course of treatment, and some of those who do quickly return to a drug-dependent state. Discussions with barbiturate and other sedative-hypnotic abusers often reveal that their use of drugs substitutes or compensates for unsatisfying or unpredictable relationships. A common theme is the avoidance of interpersonal frustration. Some constrict their relationships, avoiding strong ties; others evolve tortuous associations. Their treatment, if it is successful, often requires involvement in some form of a 12-step program modeled after Alcoholics Anonymous; individually tailored combinations of individual, group, and cognitive-behavioral therapies (e.g., social skills training); and, when appropriate, psychotropic medications other than sedative-hypnotics (see Chapter 11).

For some patients, especially licensed health care practitioners, contingency contracting is an effective therapeutic adjunct. Upon entering a treatment program, a contract is generated and signed that outlines the program the patient must follow; it includes monitoring by an appropriate agency (e.g., a state medical society in the case of a physician). If the patient does not comply with the contract or shows evidence of relapse (e.g., a verified positive urine screen), the appropriate licensing board is notified and the practitioner's license is suspended or revoked.

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Inpatient detoxification and rehabilitation programs may be necessary when complicated detoxification strategies are anticipated (e.g., in patients with significant medical or psychiatric impairment). Inpatient care may also be important for patients who would have to return to environments that could not support abstinence. However, one must remember that substance abuse disorders are often chronic disorders and that inpatient care per se is rarely sufficient. Inpatient treatment should be followed by one of the longer-term outpatient treatment plans noted above.

ADDITIONAL READING

Addolorato G, Caputo F, Capristo E, et al. A case of gamma-hydroxybutyric acid withdrawal syndrome during alcohol addiction treatment: utility of diazepam administration. Clin Neuropharmacol 1999;22:60-62.

Bonnet U, Banger M, Leweke FM, et al. Treatment of alcohol withdrawal syndrome with gabapentin. Pharmacopsychiatry 1999;32:107-109.

Ciraulo DA, Nace EP. Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addictions 2000;9:276-284.

Ciraulo DA, Sarid-Segal O. Sedative-, hypnotic-, or anxiolytic-related abuse. In: Sadock BJ, Sadock VA, eds. Comprehensive textbook of psychiatry, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:1071-1085.

Crockford D, White WD, Campbell B. Gabapentin use in benzodiazepine dependence and detoxification. Can J Psychiatry 2001;46:287.

Dodes LM, Khantzian EJ. Psychotherapy and chemical dependence. In: Ciraulo DC, Shader RI, eds. Clinical manual of chemical dependence. Washington, D.C.: American Psychiatric Press, 1991:345-358.

Dooley M, Plosker GL. Zaleplon: a review of its use in the treatment of insomnia. Drugs 2000;60:413-445.

Dyer JE, Roth B, Hyma BA. Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 2001;37:147-153.

Harris JT, Roache JD, Thornton JE. A role for valproate in the treatment of sedative-hypnotic withdrawal and for relapse prevention. Alcohol Alcoholism 2000;35:319-323.

Marlatt GA, George WH. Relapse prevention: introduction and overview of the model. Br J Addict 1984;79:261-273.

McElroy SL, Keck PE Jr, Lawrence JM. Treatment of panic disorder and benzodiazepine withdrawal with valproate. J Neuropsychiatry Clin Neurosci 1991;3:232-233.

Moroz G, Rosenbaum JF. Efficacy, safety, and gradual discontinuation of clonazepam in panic disorder: a placebo-controlled, multicenter study using optimized dosages. J Clin Psychiatry 1999;60:604-612.

Myrick H, Brady KT, Malcolm R. Divalproex in the treatment of alcohol withdrawal. Am J Drug Alcohol Abuse 2000;26:155-160.

Nelson J, Chouinard G. Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal. Canadian Society for Clinical Pharmacology. Can J Clin Pharmacol 1999;6:69-83.

Nicholson KL, Balster RL. GHB: a new and novel drug of abuse. Drug Alcohol Depend 2001;63:1-22.

Pages KP, Ries RK. Use of anticonvulsants in benzodiazepine withdrawal. Am J Addict 1998;7:198-204.

Pollack MH, Mathews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry 1998;155:992-993.

Rickels K, Schweizer E, Garcia Espana F, et al. Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome. Psychopharmacology 1999;141:1-5.

Spiegel DA. Psychological strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol 1999;19:17S-22S.

Volpicelli JR, Pettinati HM, McLellan AT, O'Brien CP. Combining medication and pyschosocial treatment for addiction: the BRENDA approach. New York: Guilford Press, 2001.



Manual of Psychiatric Therapeutics Paperback
Manual of Psychiatric Therapeutics: Practical Psychopharmacology and Psychiatry (Little, Browns Paperback Book Series)
ISBN: 0316782203
EAN: 2147483647
Year: 2002
Pages: 37

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