Chapter 11Pharmacotherapy for Substance Use Disorders

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DOI: 10.1176/appi.books.9781585622825.239082

Manual of Clinical Psychopharmacology >

Chapter 11. Pharmacotherapy for Substance Use Disorders

INTRODUCTION

Drug therapies for patients with substance use disorders are sometimes necessary or useful, but

they are rarely sufficient to cure the disorder. If illicit drugs are overused by a patient with major

depression to reduce psychic pain, by a patient with mania manifested as overactivity and

uncontrolled hedonism, or by a patient with some other comorbid major Axis I disorder,

appropriate drug therapy for the underlying major psychiatric condition can be very helpful.

Unfortunately, some patients with clear syndromes (e.g., depression, bipolar disorder, or

schizophrenia) continue to abuse illicit drugs even when the syndromes are in full or partial

remission, though others show improvement in both conditions with appropriate drug therapy.

Specific drug therapies are, however, available for some aspects of chemical dependence.

Medications are useful for ameliorating withdrawal symptoms caused by physical dependence on

sedative or opiate drugs. Either methadone or L- -acetylmethadol (LAAM), as maintenance therapy,

is a longer-acting, more manageable, less dangerous drug than heroin and can be given indefinitely

in an attempt to replace heroin. Naltrexone, an opiate antagonist, can also be given indefinitely to

prevent the patient from obtaining euphoria from heroin and has been found to be useful in the

maintenance therapy of alcoholism. Disulfiram (Antabuse) is sometimes used in treating chronic

alcoholism to ensure that patients will become unpleasantly sick if they were to consume alcohol.

Some classes of illicit drugs, of course, do not cause any serious degree of physical dependence.

These include cannabis, inhalants, and the hallucinogens (e.g., lysergic acid diethylamide [LSD]

and mescaline). Withdrawal symptoms are also seldom seen with phencyclidine (PCP) use. Such

drugs can be abruptly discontinued, even in heavy and frequent users. Nevertheless, a drug therapy

that would decrease or stop the use of these agents might well be clinically useful. Drug

dependence syndromes for which drug therapies are sometimes or regularly useful involve

stimulants, opiates, sedative-hypnotics, and alcohol.

A large variety of interesting, even promising, drug therapies for various substance use disorders

have been proposed and studied, but the basic, approved, and available drug therapies have

changed very little. The situation is exciting, frustrating, and, even sometimes, irritating. However,

there is general agreement that a variety of psychosocial approaches to substance use disorders,

especially opiate, cocaine, and alcohol dependence, are effective, probably more so than most

available or even potential drug therapies. There is also agreement that drug therapies must be

used in the context of psychosocial treatments, including 12-step and compulsory aspects of

treatment.

The only new drug to be approved for the treatment of alcoholism in more than a decade is

acamprosate (Campral). Acamprosate was approved by the U.S. Food and Drug Administration

(FDA) in 2004 but has been used in Europe since the early 1990s.

On the basis of published evidence, buprenorphine, a mixed opiate agonist-antagonist, appears to

be effective both in opiate detoxification and as a maintenance treatment potentially superior to

methadone, particularly if it is allowed to be used without all the legalistic complications

surrounding the use of methadone and LAAM. Buprenorphine was approved for the maintenance

treatment of opiate dependence in 2002. It is currently available in 2-mg and 8-mg sublingual

tablets (Subutex) and in an injection form (Buprenex). Buprenorphine is also available in

combination with naloxone (Suboxone) in sublingual tablets (2 mg buprenorphine/0.5 mg naloxone

and 8 mg buprenorphine/2 mg naloxone).Print: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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A number of drug therapies (e.g., tricyclic antidepressants [TCAs]) were found to be better than

placebo in the treatment of cocaine users in early controlled studies but not effective in many other

similar controlled studies. Old drugs in new bottles (e.g., disulfiram for cocaine abuse) and totally

new approaches (e.g., antibodies against cocaine) wait in the wings.

The only other relatively solid advance in the pharmacotherapy of substance use disorders is the

handful of well-controlled studies showing that patients with substance use disorders and major

depression can benefit from standard antidepressants without being forced to become drug free

first.

DRUG TESTING

A variety of sensitive assays are available to monitor and test for illicit drug use. The most common

of these are urine drug screens that evaluate the “NIDA 5,” which are the five classes of drugs

typically evaluated in federal drug testing programs: cannabinoids, opiates, cocaine, amphetamine,

and PCP. Many labs are also equipped to evaluate benzodiazepines, barbiturates, hallucinogens,

and inhalants.

Urine drug screens are the least intrusive tests, and they are inexpensive and, typically, quite

reliable. The cost for in-office tests range from about $5 to $50 dollars. Urine drug screens can be

influenced by abstaining before the drug screen and primarily detect drugs taken within 7 days of

the test. However, chronic cannabis use up to 12 weeks before a urine drug screen can be detected

by the screen, while a single use a few days before the test might be picked up. Saliva tests are

usually processed in a laboratory and tend to be more expensive ($20–$100) than urine drug

screens. Salivary tests are capable of detecting very recent use (the past hour or so) that may be

missed in a urine test. Like urine tests, they primarily pick up drugs that have been used in the

previous 3 days. Serum blood screens are the most sensitive assays and the most expensive. For

most drugs, a serum assay is best at detecting drug use in the previous 3-7 days. Other types of

tests include hair assays, which can detect most drugs that have been used in the previous 90 days,

and patch or sweat tests, which are neither very accurate nor convenient. In most offices, a urine

drug screen offers the best combination of convenience, cost, and reliability.

STIMULANTS

Stimulants, including cocaine, amphetamine, and their various forms, are among the most common

drugs of abuse in the United States. The U.S. National Institute on Drug Abuse (NIDA) estimates

that at least 1%–2% of the population currently abuses cocaine but that rates of amphetamine

abuse are lower. Stimulant overdose or abuse represents a fairly common reason for emergency

room (ER) visits and hospitalization in urban settings. When a patient who is dependent on

stimulants is hospitalized, stimulant administration should be stopped abruptly. No tapered

withdrawal is necessary. Patients who have been taking stimulants in large amounts (e.g., more

than 50 mg of D-amphetamine or several doses of cocaine a day) often have a withdrawal

syndrome consisting of depression, fatigue, hyperphagia, and hypersomnia. In unstable individuals,

this rebound depression can reach serious clinical proportions for a few days and may persist for

weeks, usually in less severe form.

A variety of drugs, mainly dopaminergic or noradrenergic drugs (desipramine, amantadine,

bromocriptine, bupropion), but even fluoxetine, have been tried in cocaine withdrawal or as

possible longer-term treatments, but with no consistent effect. Imipramine, desipramine, and

venlafaxine have shown “promising results” in treating depressed cocaine-dependent patients,

reducing both depressive symptoms and cocaine use, but the full value of these controlled but

preliminary studies does not yet constitute a clear, valid guide for the use of such drugs in patients

with major depression who use cocaine.

Carbamazepine has been used, without success, in an attempt to reduce brain stimulation caused

by cocaine. Calcium channel blockers have been tried as a way to improve brain blood flow in

cocaine users, but this work is only in the preliminary stages.

Disulfiram (Antabuse) has been resurrected from its declining use in treating chronic alcoholism,Print: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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because it inhibits dopamine- -hydroxylase, thereby raising brain cocaine and dopamine levels.

One might imagine that this effect would only make the cocaine “high” better and longer, but

disulfiram seems to increase anxiety, paranoia, and dysphoria when cocaine is taken. Several small

studies have shown reduction in cocaine use, perhaps secondary to subjects’ fear of using alcohol

to modulate cocaine-induced agitation. In one study the reduction in cocaine use in the disulfiram

group occurred even in patients who disclaimed prior use of alcohol (Petrakis et al. 2000). The

dosage of disulfiram used appears to be 250 mg/day. It is unclear how safe this therapy will be in

the long run if patients drink alcohol despite warnings and get severe reactions.

Other investigational approaches include ecopipam, a dopamine1 receptor blocker, and citicoline,

previously used in treating neurological disorders to repair damaged cell membranes. Even aspirin

has been used to prevent platelet aggregation and improve brain blood flow and, in one study, to

improve neuropsychological function (O’Leary and Weiss 2000).

As noted earlier, a cocaine “vaccine”—a large antibody that binds cocaine in body fluids—is being

developed. Animal experiments suggest this approach might have promise.

Any or all of these potential therapies should be combined with appropriate addiction-focused

psychotherapies (Najavits and Weiss 1994).

Amphetamine abuse, even the relatively recent advent of “crack”-style D-methamphetamine (“ice”)

inhalation, has not stimulated any new pharmacotherapy—either conceptually or

empirically—though treatments useful for cocaine use would likely be effective for “speed” use.

The issue of abuse can be a problem with medically prescribable stimulants. If the patient has a

clinical depression that responds uniquely to stimulants or clearly has adult

attention-deficit/hyperactivity disorder and takes moderate doses in a stable manner to produce

socially responsible functioning, stimulant use can be therapeutically helpful (see Chapter 8:

“Stimulants”). If the patient takes stimulants in large doses for euphoriant purposes or pushes the

dosage to the point that paranoia or other serious symptoms develop, prescribing stimulants is

obviously contraindicated.

OPIATES

Detoxification

Opiates include heroin, the most common street narcotic, and its variants. In addition, this large

class includes commonly used therapeutic agents such as morphine, codeine, methadone, and other

prescription narcotic analgesics. Abstinence symptoms can begin as early as 6 hours after the last

dose of heroin or other short-acting opiate. Withdrawal symptoms include anxiety, insomnia,

yawning, sweating, and rhinorrhea, followed by dilated pupils, tremor, gooseflesh, chills, anorexia,

and muscle cramps. About a day after the last dose, pulse, blood pressure, respiration, and

temperature may all increase, and diarrhea, nausea, and vomiting can occur. The syndrome,

untreated, peaks at 2–3 days and resolves within about 10 days, although mild variable complaints

may persist for weeks.

Because a great deal of street heroin is so weak, some illicit heroin users may not have developed

true physical dependence. In addition, both street and medical users of opiates, with or without

real physical dependence, often consciously or unconsciously exaggerate their withdrawal distress

in an effort to obtain more opiate medication from the physician. For these reasons, the drug

treatment of the withdrawal syndrome should be based on objective signs of opiate withdrawal, not

on subjective complaints. These signs are listed in Table 11–1.

Table 11–1. Objective opiate withdrawal signs

1. Pulse 10 bpm or more over baseline or more than 90 if no history of tachycardia and baseline unknown

(baseline: vital-sign values 1 hour after receiving 10 mg of methadone)

2. Systolic blood pressure 10 mm Hg or more above baseline or greater than 160/95 in nonhypertensive

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3. Dilated pupils
4. Gooseflesh, sweating, rhinorrhea, or lacrimation

Methadone, a long-acting opiate, is used to treat withdrawal because of its superior

pharmacokinetics (a long half-life). A short-acting drug like morphine would have to be given every

few hours to block withdrawal, whereas methadone accomplishes this when given only twice a day.

The initial methadone dose should be 10 mg orally, in liquid or crushed tablet form, so as to blind

the patient to that dosage and subsequent dosages during detoxification. The patient should be

evaluated every 4 hours, and an additional 10 mg of methadone should be administered if at least

two of the four criteria in Table 11–1 are met. Unless the patient is being withdrawn from

high-dose methadone maintenance therapy, no more than 40 mg of methadone should be required

in the first 24 hours.

The total dose of methadone given in the first 24 hours should be considered the stabilization dose.

This dose is then given the next day in two divided doses (e.g., 15 mg at 8:00 A.M. and 8:00 P.M.) in

crushed or liquid form. It should be consumed under the direct observation of a staff member to

avoid illicit diversion. The stabilization dose should then be reduced by 5 mg/day until the patient

is completely withdrawn from the drug. A patient who is physically dependent on sedative drugs

and opiates should continue taking the stabilization methadone dose without tapering until he or

she is completely withdrawn from the sedative drug.

An alternative pharmacological approach to the management of opiate withdrawal has been used

for the last few years at some centers. This approach involves the use of the nonopiate

antihypertensive drug clonidine, which is mainly an 2-adrenergic agonist. It can suppress both

objective and subjective symptoms of opiate withdrawal. In beginning clonidine treatment, the

method of Kleber et al. (1985) is worth following: an initial dose of 0.1 mg of clonidine should be

given to assess the patient’s tolerance of this approach. Hypotension, dizziness, sedation, and dry

mouth are common adverse effects. If the initial dose is tolerated well by the patient, doses of

0.1–0.2 mg every 8 hours can be given during the early phases of opiate withdrawal, with increases

to as high as 0.2–0.4 mg every 8 hours after 2–3 days. Blood pressure should be checked before

each dose, and the dose should not be given if blood pressure is less than 85/55. Amelioration of

withdrawal symptoms reaches a peak 2 or 3 hours after each dose. Muscle aches, irritability, and

insomnia are not well suppressed by clonidine.

In one inpatient study of the use of clonidine in the detoxification of patients withdrawing from

maintenance methadone, an average dosage of about 1 mg/day of clonidine was required for the

first 8 days the patients were withdrawing from methadone. In a study using clonidine in

outpatient detoxification, the medication was begun at 0.1 mg every 4–6 hours as needed, and the

dose was increased to 0.2 mg every 4–6 hours, with a maximum dosage of 1.2 mg/day (average

maximum total daily dose was 0.8 mg). Some variation of these dosing strategies could be used if a

methadone detoxification program is to be avoided.

Physicians interested in using this approach should carefully read the article by Kosten et al.

(1989) or consult with a local program where this approach is being actively used.

Outpatient use of clonidine for opiate detoxification has generally met with much less success than

has use in inpatient studies. Clonidine (Catapres) is available in 0.1-mg, 0.2-mg, and 0.3-mg

tablets, as well as in transdermal patches that may be administered weekly.

Three interlocking developments are taking place in the area of opiate detoxification. One is the

investigational and sometimes routine off-label use of buprenorphine, the mixed opiate

agonist-antagonist, instead of methadone to speed the detoxification process (Umbricht et al.

1999). Another, sometimes combined with buprenorphine or with anesthesia, is the use of the

opiate antagonists naltrexone or naloxone to precipitate rapid, severe abstinence of short duration,

leaving the patient no longer physically dependent on (or having tolerance for) opiates after a day

or two. The third is, of course, the use of outpatient or day hospital settings to carry out old or

newer forms of withdrawal at less expense.Print: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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Neither buprenorphine-assisted withdrawal nor very rapid antagonist withdrawal is a procedure to

be undertaken outside a specialized treatment facility.

Maintenance

For many years, methadone maintenance has been available in major urban areas in specially

licensed clinics as a replacement therapy for heroin or other illicit opiates for confirmed addicts

who have failed to stay drug free after detoxification. The dose adjustment varies from program to

program; dosages as high as 80 mg/day are used in some clinics; it now has been repeatedly

shown that a dosage of 60 mg/day provides much better long-term results than lower maintenance

dosages.

Patients usually take the drug once a day at the clinic under direct supervision and have their urine

samples checked for other illicit drug use. If the patient is drug free and doing generally well,

take-home doses are often allowed so that the patient takes the methadone dose at the clinic only

every other day. The drug is often dispensed in a fruit drink to avoid intravenous misuse of the

alternate-day dose taken at home. Although this regimen would appear to provide a popular and

useful alternative for confirmed opiate addicts, patients often drop out of methadone maintenance

programs after weeks or months of participation.

Over the years it has become ever clearer that the purpose of methadone maintenance and related

programs is not to gradually wean all patients off methadone entirely over weeks or months, but to

stabilize the patients so they can improve their psychosocial adjustment or, at least, not have to

resort to criminal activity to obtain heroin. Concomitantly, “dirty” urine samples showing that the

patient is using other abusable drugs have become issues for counseling, not reasons to throw the

patient out of the methadone program.

LAAM is even longer acting than methadone and is effective even if administered only three times a

week. This feature eliminates the complications of daily clinic visits and the potential diversion of

take-home doses. LAAM was approved by the FDA for the treatment of opiate dependence in 1993

but is still not widely used.

Either methadone or LAAM is intended to avert withdrawal symptoms and to abolish craving for

opiates in heroin-addicted individuals. Either agent is also supposed to provide so high a level of

tolerance to opiates that self-administration of street heroin or other illicit morphinelike drugs will

no longer cause euphoria.

Maintenance methadone is stabilizing for some opiate addicts, but it does not completely suppress

drug-seeking behavior, even for heroin; patients in methadone programs often continue to get in

trouble with other drugs of abuse, especially alcohol and cocaine. Maintenance therapy, even

coupled with good support programs, cannot solve the multiple problems of many heroin users.

Maintenance methadone is a specialized modality in which psychiatrists cannot get involved in the

ordinary course of practice. Consider the plight of the psychiatrist involved in caring for an

opiate-dependent patient who is seeking, or claims to be seeking, admission to a detoxification

program but has an admission date that is several days off. What can or should the physician do? It

is illegal to prescribe opiates to sustain an addiction. The best procedure is to consult with the

detoxification program staff as to how to proceed. It is our understanding of U.S. Drug Enforcement

Administration (DEA) regulations that a physician is allowed to dispense daily doses of an opiate

each day for up to three successive days to avert acute withdrawal while awaiting a planned

admission for detoxification. In addition, physicians may provide maintenance treatment to an

addict “who is hospitalized for medical conditions other than addiction and who requires temporary

maintenance during the critical period of his [or her] hospitalization or whose enrollment in an

approved program has been verified” (AHFS Drug Information 2003, p. 2040). Physicians should

check with their local DEA office before embarking on such an enterprise. It is legal to prescribe

opiates for prolonged periods outside a methadone clinic if the patient has bona fide chronic pain of

substantial degree. Before getting into such a situation, the physician should certainly obtain a

consultation from a pain specialist or refer the patient to a pain clinic.Print: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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Another available maintenance treatment is the opiate antagonist naltrexone (ReVia). This drug is

similar to naloxone (Narcan), the opiate antagonist that has long been available for treating opiate

overdose. However, naltrexone is much longer acting and is available in oral form. Either drug

could, in theory, be given orally in large daily doses to create a chronic blockade of opiate

receptors, which would reliably block the euphoriant effects of heroin or other morphinelike drugs.

Naloxone is too weak and short acting orally to be usable. Naltrexone is adequate for the purpose,

but it has been even less popular with opiate addicts than methadone has. However, now that

naltrexone has become available to the clinician, it may perhaps find a useful niche in the

long-term maintenance treatment of some opiate-addicted individuals, particularly those who are

highly motivated. The problem, of course, is that naltrexone is as easy as disulfiram to circumvent.

An opiate addict needs to simply hold the dose of naltrexone for 2 or 3 days and then inject heroin

to experience the full effects of the drug. For the moment, however, naltrexone is still a drug to be

used mainly in special programs and not by general psychiatrists, unless they are asked to take

over the care of a patient who has already been stabilized by being given naltrexone in a specialty

program. The usual dosage of naltrexone for maintenance treatment of opiate addiction is 50

mg/day. It can be given three times a week (100 mg, 100 mg, then 150 mg), but gastrointestinal

side effects are more common with that regimen.

Buprenorphine (Subutex; Suboxone [buprenorphine and naloxone]), a mixed agonist-antagonist,

was approved by the FDA in 2002 as an alternative to methadone for maintenance treatment of

opiate addiction. The drug is given usually at dosages of 6–20 mg/day, with a target dosage of

around 16 mg/day. Buprenorphine is taken sublingually to avoid excessive drug destruction in the

liver, which occurs if the drug is taken as an ordinary pill and swallowed. This sublingual form,

which is said to be the most widely used analgesic in many European countries, has been placed by

the DEA in Schedule III.

Buprenorphine is a good analgesic, but so are many other opiates and mixed agonist-antagonists

(e.g., pentazocine). However, when buprenorphine was tested for abuse liability in humans by

Jasinski et al. (1978) at NIDA’s Addiction Research Center, it proved to be well tolerated and to

elicit very mild dependence and withdrawal symptoms, even after prolonged high-dose

administration.

Buprenorphine can substitute for other opiates and can block opiate-induced euphoria. Testing for

periods of several weeks with opiate-addicted individuals has suggested that the drug is much

more acceptable to patients than is naltrexone, perhaps because of the former’s mild euphoriant

effect. It decreases illicit drug use, as measured by urine screens, as effectively as methadone—not

completely, but substantially. Studies of buprenorphine in opiate withdrawal suggest that it is

equivalent in efficacy to methadone and superior to other drugs, such as clonidine (Janiri et al.

1994).

Withdrawing patients from maintenance buprenorphine is much easier than withdrawing them from

methadone. The drug is already in pharmacies, in vials. It may become the first reasonably good

maintenance therapy for chronic opiate users that could be prescribed in ordinary hospitals, clinics,

and doctors’ offices and dispensed in ordinary pharmacies. Such availability would avoid the bad

side of methadone clinics: the massing of a lot of street users all in one clinic to “re-infect” each

other.

Another change, in process, is in our attitude toward the treatment of depression in methadone

patients and other substance users. In a study by Nunes and colleagues (1998), imipramine was

superior to placebo in decreasing depression in methadone-maintained patients with coexisting

primary major depression. There was also some concomitant decrease in illicit drug use.

Anyone contemplating using psychiatric drugs to treat Axis I disorders in methadone clinic patients

should be aware of potential drug-drug interactions. Carbamazepine, but not valproic acid or

lithium, enhances hepatic metabolism and lowers methadone blood levels, perhaps justifying an

increase in the daily methadone dose. Fluvoxamine, however, blocks methadone metabolism and

raises the blood level (which will fall again if the fluvoxamine is discontinued).Print: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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In general, selective serotonin reuptake inhibitors (SSRIs) or other newer antidepressants that can

be taken once a day and do not need much dose adjustment are easier for patients with depression

and substance use disorders. With other agents, these patients are likely to be undercompliant and

not experience improvement or to raise their dosages unilaterally and induce toxicity. One of us has

seen such an outpatient become delirious after 5 days of taking amitriptyline; because the

prescribed dosage (50 mg) did not give rapid relief, the patient took 500 mg/day.

SEDATIVES AND HYPNOTICS

Detoxification

Over the past 50 years, the problem of sedative addiction (physical and psychological dependence)

shifted from being almost completely an abuse of short- or intermediate-acting barbiturates (e.g.,

amobarbital, pentobarbital, secobarbital) to being an abuse of newer hypnotics (glutethimide,

methaqualone) and, most recently, benzodiazepines (e.g., diazepam, alprazolam). All these agents

(and alcohol) produce cross-tolerance—that is, physical withdrawal symptoms in a patient who is

dependent on any one of these drugs can be relieved by an adequate dose of another. The time

course of withdrawal symptoms differs with the half-lives of the drugs involved, beginning within

12–16 hours after the last dose of a short-acting agent (e.g., amobarbital, alprazolam) and perhaps

2–5 days after the last dose of diazepam.

Early withdrawal symptoms include anxiety, restlessness, agitation, nausea, vomiting, and fatigue.

Later, weakness develops, often with abdominal cramps, plus tachycardia, postural hypotension,

hyperreflexia, and gross resting tremor. Insomnia and nightmares may occur. Peak symptoms,

including grand mal seizures in some instances, occur at about 1–3 days after the last dose of

short-acting drugs (amobarbital, lorazepam, alprazolam) and 5–10 days after the last dose of

long-acting drugs (diazepam, clorazepate). Of patients who have seizures, about half develop

delirium with disorientation, anxiety, and visual hallucinations. Even without seizures, patients in

benzodiazepine withdrawal may be mildly confused, perceive lights as being too bright and sounds

as too loud, become mildly paranoid, and feel depersonalized.

Sedative withdrawal, particularly from barbiturates, can be fatal once it has progressed to delirium

and is not readily reversible then. For this reason, withdrawal from sedative dependence should be

considered a medical emergency, and patients presenting in withdrawal should be treated as

emergency patients. Withdrawal syndromes from benzodiazepines may be less severe. In contrast,

opiate withdrawal symptoms are rarely life-threatening and always reversible if an opiate is given.

There are current regimens that use a long-acting sedative, such as phenobarbital,

chlordiazepoxide, or diazepam, to ameliorate withdrawal from sedatives. In previous years, the

most commonly recommended regimen involved using the short-acting barbiturate pentobarbital

(Nembutal) to establish the degree of dependence and then converting the patient to the

longer-acting phenobarbital for the real detoxification phase. This regimen, the pentobarbital

tolerance test (see next section), is very rarely used now; the favored regimen is treatment of

sedative dependence with a taper of a long-acting benzodiazepine.

Pentobarbital Tolerance Test

Once the patient is no longer sedated or intoxicated and is showing early withdrawal symptoms,

pentobarbital 200 mg po should be given and the patient should be observed 1 hour later for signs

of sedative intoxication. If the patient is asleep at that point, it is likely that no detoxification is

necessary, because the patient has almost no tolerance to the drug. A patient who has nystagmus,

slurred speech, ataxia, or sedation 1 hour after the initial 200-mg dose has probably been taking

less than the equivalent of 800 mg of pentobarbital a day. This patient can then be stabilized on

100–200 mg of pentobarbital every 6 hours, depending on the degree of sedation induced by the

initial 200-mg test dose.

The patient who shows no response to the initial 200-mg test dose requires more than 800 mg/day.

In determining the needed dose, the patient should be given 100 mg every 2 hours until he or shePrint: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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shows signs of intoxication (sedation) or until a total dose of 500 mg of pentobarbital in 6 hours

has been given. The total dose given in the first 6 hours (300–500 mg) is the patient’s 6-hour

requirement, and this dose can be given every 6 hours and gradually tapered by 100 mg/day.

However, it is better to calculate the initial 24-hour requirement (four times the initial 6-hour dose)

and convert it to phenobarbital at 30 mg for each 100 mg of pentobarbital (e.g., 300 mg/day of

phenobarbital for 1,000 mg/day of pentobarbital). The daily phenobarbital dose needed should be

divided into thirds and given every 8 hours for the first 48 hours. After 2 days, the phenobarbital

dose should be decreased by 30 mg/day until the patient is totally withdrawn. Obviously, if the

patient appears oversedated on the calculated dose, it could be slightly reduced; it could be slightly

increased in the face of continuing objective signs of withdrawal.

This program should be used with patients with patterns of serious sedative abuse who have been

taking doses large enough to lead to frequent sedative intoxication with behavioral consequences

(e.g., falls, ataxia, fights, job loss, car accidents) or with patients who combine moderate doses of a

prescribed benzodiazepine (e.g., 30 mg/day of diazepam) with excessive alcohol intake.

BENZODIAZEPINES

For the more common psychiatric patient who has probably become physically dependent on a

prescribed benzodiazepine at moderate doses taken for more than a year, the benzodiazepine dose

can be gradually decreased while the patient is followed as an outpatient, if the patient can tolerate

such a program. There are reports that in panic patients who have responded to relatively higher

dosages (e.g., 6 mg/day) of alprazolam, reduction in dosage at a rate of 0.5 mg every week to 2

mg/day is generally well tolerated. Further reduction below 2 mg/day at this rate of

discontinuation will cause patients considerable discomfort. At or below 2 mg/day, a more gradual

reduction—0.25 mg/day every week—is recommended.

A shift from short-acting benzodiazepines, such as lorazepam or alprazolam, to longer-acting ones

like clonazepam can be tried if tapering of the shorter-acting drug leads to uncomfortable

symptoms. For patients with such discomfort, it is not clear whether rapid inpatient withdrawal is

required, but that approach seems legitimate if outpatient withdrawal is poorly tolerated. It may be

that slow withdrawal over weeks produces more discomfort than would a rapid, systematic

inpatient regimen. Even with systematic inpatient withdrawal, however, there is a significant risk

of relapse. A study by Joughin et al. (1991) found that most patients with long-term

benzodiazepine dependence did not fare well even after successful inpatient detoxification. Only

38% of patients studied had had a “good” outcome in 6-month follow-up, and many had relapsed

or encountered other difficulties, including suicide. Elderly patients and those with concurrent

depressive symptoms fared particularly poorly. The authors concluded that for some patients,

maintenance benzodiazepine therapy might be preferable to withdrawal.

Herman et al. (1987) reported good results in shifting patients from alprazolam to clonazepam.

They substituted 1 mg of clonazepam abruptly for every 2 mg of alprazolam and allowed patients to

take extra doses of alprazolam as needed during the first week they were receiving clonazepam.

Patients stabilized on clonazepam could then be withdrawn more easily from the longer-acting

drug. Animal studies (Galpern et al. 1991) suggested that clonazepam probably has a risk for

dependence and tolerance problems similar to that of other benzodiazepines but that its long

half-life may make for a smoother withdrawal. Still, we have seen patients who had difficulty in

withdrawing from clonazepam.

Carbamazepine has also been used, with mixed results, to facilitate withdrawal from alprazolam

and other short-acting benzodiazepines. Patients given carbamazepine at dosages of 200–800

mg/day, initiated before a benzodiazepine taper, showed longer benzodiazepine abstinence after

the taper than did patients treated concurrently with placebo (Schweizer et al. 1991). Likewise,

geriatric patients who failed to respond to previous tapers of alprazolam were able to achieve

success when the taper was initiated with concurrent carbamazepine use (Swantek et al. 1991).

However, it has been difficult to demonstrate that the withdrawal is any less severe in patientsPrint: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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using carbamazepine as an adjunct in benzodiazepine withdrawal, and not all studies have found a

robust effect for this regimen. It is important to keep in mind that carbamazepine may induce

cytochrome P450 3A3/4 and other P450 enzymes in the liver, thus lowering alprazolam plasma

levels and intensifying withdrawal symptoms. Some clinicians use valproate instead.

Another issue that warrants attention is that mild benzodiazepine withdrawal symptoms should be

looked for more carefully in patients who have been admitted to psychiatric hospitals and whose

prior sedative benzodiazepine medication was abruptly stopped. A few patients appear to become

quite uncomfortable and to have typical withdrawal symptoms after discontinuation of dosages as

low as 5 mg/day of diazepam or 30 mg/day of flurazepam if the dosages were taken regularly for

many years. Withdrawal symptoms in such patients can last for weeks. Physicians may forget that

sedative withdrawal may be occurring when a depressed or schizophrenic patient begins to get

more agitated, and they may be painfully surprised and discomfited when the patient suddenly has

a grand mal seizure.

There is a real question as to whether outpatients receiving long-term regular benzodiazepine

therapy for anxiety—say clonazepam 0.5 mg tid and 1 mg hs—need to be firmly tapered off the drug

over their objections. If they have a history of a substance use disorder and have been stable while

taking such a dose for months or even years, does the chronic use of prescribed drug put them at

significant risk of relapse into serious substance abuse? Physicians who see “ordinary” psychiatric

outpatients outside of specialized drug abuse programs are sometimes not aware of their patients’

history of past substance abuse. Physicians actively treating patients with serious substance use

disorders are often horrified if patients are given maintenance benzodiazepines for chronic anxiety

disorder.

The published literature is mixed. Expert opinion is generally against using benzodiazepines in

patients with substance use disorders, but clinical reports on the adverse effects of such

prescribing are lacking. On the basis of guesswork and of experience supervising residents treating

such patients, we surmise that soon after alcohol, sedative, or other detoxification, patients may be

at much increased risk of returning to substance abuse if they are prescribed benzodiazepines, but

a bit later they may use such sedative drugs sensibly and with benefit.

Some patients with substance use disorders probably have anxiety disorders of such severity that

they will relapse rapidly into taking whatever is available to relieve their discomfort; some of these

patients may do better on prescribed, well-monitored sedatives than on illicit drugs (Mueller et al.

1996). Any physician regularly prescribing maintenance benzodiazepines to a large number of

patients with substance use disorders needs to document the reasons for his or her prescribing in

detail in each case and to get outside consultations to forestall accusations of substandard practice.

ALCOHOL

Ethyl alcohol is a short-acting sedative drug that produces withdrawal syndromes similar to those

caused by barbiturates. The symptoms and signs of withdrawal are the same as those described in

the “Detoxification” subsection of “Sedatives and Hypnotics” in this chapter, with the caveat that

alcoholic patients may be either very slightly dependent physically but in trouble with alcohol for

other reasons or malnourished and/or medically quite ill. Because alcoholism programs tend to

treat large numbers of patients, they usually choose a “standard” detoxification program—a

program that is standard for a given institution but that may differ substantially from one facility to

another. Kings County Hospital in Brooklyn used paraldehyde routinely and successfully for many

years; other sites have used phenobarbital, diazepam, or even an antipsychotic such as

perphenazine or prochlorperazine for alcohol detoxification. McLean Hospital has used

chlordiazepoxide in alcohol detoxification for at least 15 years; it may be a good choice because it

has a long half-life and may be less euphoriant than diazepam. Because of the risk of Wernicke’s

syndrome in alcoholic patients, thiamine 100 mg po or im must be given on admission. Thereafter,

for 1 month, 50 mg/day is given. Folate 1 mg/day po is also a common component of the alcohol

detoxification regimen. Chlordiazepoxide is initiated at a maximum of 200 mg/day for the first 2

days, and then the dosage is reduced by approximately 25% per day to zero, with extra dosesPrint: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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given intramuscularly or orally on a prn basis if the withdrawal symptoms are not adequately

controlled.

An alternative and perhaps simpler approach, developed by Sellers et al. (1983) (Table 11–2), for

alcoholic patients in withdrawal is to administer diazepam in 20-mg doses every 1–2 hours until

withdrawal symptoms are relieved. Medication is then stopped. Detoxification was reported to

proceed comfortably without further drug treatment once this loading dose of a long-acting

benzodiazepine has achieved symptom suppression.

Table 11–2. Pharmacological strategies for acute detoxification of alcohol alone

Dosage regimen

Agent Fixed

Flexible

diazepam 10–20 mg q 4–6 hours x 2–3 days, then decrease by

25% per day

5–10 mg q 1–2 hours per DBP,

pulse > 100

chlordiazepoxide 25–50 mg q 4–6 hours x 2 days, then decrease by

25% per day

25–50 mg q 1–2 hours per DBP,

pulse > 100

clonidine 0.1–0.2 mg q 4–6 hours x 2 days, then decrease by

25%–33% per day

Titrate to BP and pulse

Note. BP = blood pressure; DBP = diastolic blood pressure; q = every.

Because only about 5% of alcohol-dependent patients are subject to serious withdrawal, some

detoxification centers do not use pharmacological strategies at all. In some hospital settings,

patients without a history of complicated withdrawal are observed, and the dosing of

benzodiazepines is titrated to physiological parameters. A dose of 5–10 mg of diazepam or 25–50

mg of chlordiazepoxide may be given every hour when the diastolic blood pressure or pulse is

greater than 100.

Some clinicians have adopted lorazepam as the drug of choice in detoxifying alcoholic patients

because it undergoes glucuronidation, has no active metabolites, and has an intermediate half-life.

Therefore, patients with alcoholic liver disease might be at less risk of developing toxicity from

detoxification with lorazepam than from detoxification with other benzodiazepines. On the other

hand, the shorter half-life of lorazepam may be less than ideal for achieving smooth withdrawal.

Unfortunately, no controlled studies have ever compared the advantages and disadvantages of

various benzodiazepines in alcohol detoxification (Bird and Makela 1994), and there is no evidence

for or against the routine use of lorazepam as a first-line agent in the treatment of alcohol

withdrawal.

Clonidine has also become popular in some settings for decreasing the discomfort associated with

alcohol withdrawal. In one study, transdermal clonidine was as well tolerated and as effective as

chlordiazepoxide in the treatment of acute alcohol withdrawal (Baumgartner and Rowen 1991).

Clonidine decreases the hypertension, tachycardia, and tremulousness associated with withdrawal.

However, it does not prevent seizures or delirium tremens in the rarer instance of complicated

withdrawal. Vital signs need to be monitored regularly with this drug. Typical oral dosages average

0.4–0.6 mg/day in two to four divided doses. Clonidine is also available in a transcutaneous patch.

Each clonidine patch lasts approximately 1 week and delivers a fixed dose of 0.1–0.3 mg/day,

depending on the strength of the patch. Patches, however, do not allow for the day-to-day

adjustments in dose that are often required in detoxification.

Phenytoin (Dilantin) is sometimes added in patients with a history of withdrawal seizures or in

patients unable to give an adequate history. The very rare patient who develops delirium tremens

despite the above regimens should be transferred to a major medical hospital for treatment.

Outpatient detoxification has been carried out in patients with adequate motivation and an

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become more common than inpatient detoxification. For outpatient detoxification, chlordiazepoxide

25 mg taken every 4 hours, or less often if not needed, is probably reasonable for the first day, with

tapering thereafter. For very tremulous patients who have to be handled as outpatients,

chlordiazepoxide 100 mg im initially may be indicated. In this situation, the drug’s slow absorption

from the tissues is an asset rather than the liability it is in treating psychiatric conditions in which

rapid sedation is desired.

As in opiate withdrawal and maintenance treatment, the general psychiatrist will often be well

advised to refer patients to specialized alcoholism programs for at least the management of

detoxification and possible medical or neurological complications.

Maintenance Treatment

Most alcoholism programs rely for maintenance treatment mainly on Alcoholics Anonymous plus

other educational, psychotherapeutic, and psychosocial modalities. Disulfiram (Antabuse) is

sometimes prescribed (or recommended). McLean Hospital has used a daily dose of 125 mg for

occasional patients with chronic alcoholism. If the disulfiram is taken daily and alcohol is ingested,

the following symptoms appear in this general order: flushing, sweating, palpitations, dyspnea,

hyperventilation, tachycardia, hypotension, nausea, and vomiting. These events are usually

followed by drowsiness and are usually gone after the patient has slept for a period.

Diphenhydramine 50 mg parenterally may be helpful in cases of severe disulfiram-alcohol

reactions. Hypotension, shock, and arrhythmias are treated symptomatically. Oxygen is useful in

respiratory distress. Hypokalemia may occur. Severe reactions require emergency treatment in a

medical setting.

Obviously, willingness to take disulfiram, and thereby to commit oneself to not ingesting alcohol or

suffering unpleasant effects if one drinks, is a test of motivation to remain abstinent. It is still,

after all these years, not firmly established that the drug is more than a test of motivation or of

compliance with therapy. Long-acting injectable or implantable disulfiram preparations have been

tested abroad, but they are not available in this country.

Patients whose motivation to remain abstinent at all costs while taking disulfiram is questionable

or weak should not be prescribed disulfiram. In fact, doubts about the utility of disulfiram have

probably led to the gradual decrease in its use in alcohol treatment programs over the years.

Disulfiram can cause side effects such as fatigue, a metallic taste, impotence (rarely), toxic

psychosis (even more rarely), and a severe, occasionally fatal toxic hepatitis (very rarely). The

last-named side effect comes early in treatment, usually within 2–8 weeks after disulfiram is

begun, and is the basis for a labeling recommendation that liver function tests be carried out before

disulfiram is begun and again after about 8 weeks of treatment. Disulfiram is a potent inhibitor of

cytochrome P450 enzymes and can substantially raise the levels of phenytoin, oral anticoagulants,

and other drugs.

Metronidazole (Flagyl) has mild disulfiram-like properties and can cause adverse effects when

alcohol is taken with it. Studies of the use of metronidazole in alcoholism have been generally

negative.

Naltrexone joined disulfiram as a strategy for the maintenance treatment of alcoholism in the early

1990s. Volpicelli et al. (1992) found that naltrexone 50 mg/day was twice as effective as placebo

in preventing relapse from alcohol in a 12-week period. In a similar study, which also incorporated

either supportive therapy or coping skills and relapse-prevention approaches, naltrexone was

superior to placebo; it worked best when combined with supportive therapy (O’Malley et al. 1992).

Naltrexone appears to modify the reinforcing effects of alcohol through its effect on endogenous

opioids (Swift 1995). Further naltrexone studies have yielded mixed results; still, the drug, at

dosages of approximately 50 mg/day, is an option for the maintenance treatment of alcohol

dependence.

Naltrexone does not stop alcohol consumption entirely, but it appears to significantly decrease thePrint: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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likelihood that one drink will lead to uncontrolled binge drinking. In patients who respond well to

the drug and are doing well by 3–6 months, discontinuing the drug and continuing other

psychosocial treatments seems reasonable. Patients doing badly by 3 months while taking

naltrexone are unlikely to improve significantly with longer treatment. However, experience with

opiate users taking naltrexone suggests that prolonged treatment over 1 or more years may well be

safe if the patient (or the doctor) feels more secure continuing the drug.

Naltrexone tends to be well tolerated at 50 mg/day. However, a number of side effects are common

with this drug (Table 11–3). At least 10% of patients experience gastrointestinal side effects,

including nausea, vomiting, anorexia, constipation, and abdominal pain. The gastrointestinal

disturbance tends to attenuate with time and may be reduced by the patient’s avoiding taking the

drug on an empty stomach. Central nervous system (CNS) side effects such as nervousness,

headache, somnolence, insomnia, and agitation are also fairly common. Lowering the dose and

avoiding the drug at bedtime often help with the CNS symptoms. Joint pain and muscle pain occur

in about 10% of patients, and increases in hepatic enzymes, rashes, and chills have also been

reported at rates higher than those with placebo.

Table 11–3. Common side effects of naltrexone therapy

Gastrointestinal CNS

Nausea and vomiting Nervousness

Abdominal pain and cramping Agitation

Constipation Headaches

Heartburn Insomnia

Hepatic enzyme elevation Somnolence

Anorexia

Musculoskeletal

Joint pain

Muscle soreness

Note. CNS = central nervous system.

An alternative maintenance treatment for chronic alcoholism, acamprosate (Campral), has been

studied extensively in Europe and was approved in the United States in 2004. Its mechanism of

action is unclear. The drug is a taurine analog that reduces alcohol intake in animal models of

alcoholism, reduces symptoms of alcohol withdrawal in humans, and, as a chronic treatment,

reduces relapse drinking and alcohol craving at a dosage of up to 3,000 mg/day (Sass et al. 1996;

Swift 1998). In three of four multicenter U.S. trials, acamprosate was effective in maintaining

abstinence in patients who were abstinent at the start of treatment. The failed trial occurred in

polysubstance abusers. In contrast, the nearly 20 positive European studies had not required

abstinence or detoxification, and this may account for the difference from earlier studies. The

combination of acamprosate and naltrexone might be more effective than either drug alone

(Carmen et al. 2004). The main side effects seem to be diarrhea and headache. However, the drug

is well tolerated overall. The target dose is 666 mg given three times daily. Although the divided

dosing presents a compliance challenge, many patients have been able to stick with a long-term

maintenance program. There are no significant drug interactions with benzodiazepines, naltrexone,

or disulfiram.

There was previously much interest in the potential application of serotonin (5-hydroxytryptamine;

5-HT) agonists and reuptake blockers to the management and treatment of patients with alcohol

abuse or alcoholism. The rationale for their use stemmed from a number of observations in

animals: in rats that are genetically bred to preferentially drink alcohol rather than water, alcohol

consumption is reduced by the administration of L-tryptophan and SSRIs (e.g., fluoxetine), but not

by the administration of noradrenergic TCAs (Naranjo and Sellers 1985). Abnormalities in the 5-HT

receptors 5 HT1B, 5-HT2, and 5-HT3 have been implicated in some cases of alcoholism (MurphyPrint: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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1990). In early studies of heavy social drinkers, zimelidine, an SSRI that was once available in

Europe, significantly increased the interval between bouts of consumption. However, subjects had

only about 10 drinks fewer per bout, suggesting that this strategy will be only adjunctive at best.

The mechanism of action may involve increasing satiety rather than acting via classical aversive or

reinforcement mechanisms. The nausea-producing effects of the SSRIs also do not explain their

effects on alcohol consumption. The SSRIs are not currently being pursued by pharmaceutical

concerns in the United States as a treatment for alcoholism.

However, there is evidence that major depressive disorder coexisting with alcohol dependence can

and probably should be treated with an antidepressant. Mason et al. (1996) and McGrath et al.

(1996) showed that TCAs produce significant improvement in depression in active alcoholic

patients and decrease alcohol consumption at the same time. Cornelius et al. (1997) showed

similar results in a placebo-controlled study of fluoxetine. For many years, most clinicians believed

that alcoholic patients should be abstinent for at least 4 weeks (and still be depressed) before

receiving a drug therapy for their depression. A study by Greenfield et al. (1998) casts serious

doubt on this belief. They found that all alcoholic patients hospitalized for detoxification who had a

recent major depressive diagnosis relapsed into drinking, two-thirds within a month after discharge

from the hospital. None had been prescribed antidepressants, in accordance with the practice of the

time. This study was completed prior to the publication of the articles showing a positive effect of

antidepressants in nonsober depressed alcoholic patients. These two bodies of data combine to

encourage the use of antidepressants in treating depressed alcoholic patients even if patients are

or are likely to be drinking.

It has been evident for some time that pharmacotherapy and psychosocial therapies should be

coordinated in treating patients with substance use disorders. The old caveat that sobriety must

precede antidepressant therapy appears to be dubious. The clinician is better advised to work on

the substance abuse and the non-substance-related psychiatric disorder concurrently (Weiss

2003). The SSRIs may not suppress drinking directly, but they, and other newer drugs, may be

easier to use and therefore more effective (acceptable) in treating depressed alcoholic patients

than the TCAs.

Obviously, if a patient has psychiatric disorder that will respond to pharmacotherapy, such as major

depression, in addition to alcoholism, the second disorder should be treated appropriately. The

treatment of episodic or chronic residual anxiety symptoms after detoxification is a problem. The

use of benzodiazepines is usually frowned upon, probably correctly. (The case could be made,

however, that chlordiazepoxide could be considered the sedative equivalent of methadone and

might be able to be taken at a stable, controlled rate, whereas alcohol, if used to control anxiety,

leads to uncontrolled use.) Nonabusable alternatives to sedative benzodiazepines in the treatment

of anxious, abstinent alcoholic patients include propranolol, clonidine, hydroxyzine, TCAs, atypical

antipsychotics, buspirone, SSRIs, and serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g.,

venlafaxine).

CANNABIS

Cannabis use continues to be quite prevalent in the United States: 5% of the population are current

users of the drug. The resin of the marijuana plant, -9-tetrahydrocannabinol (THC), results in the

acute intoxication state. Symptoms of cannabis intoxication include behavioral or psychological

changes such as euphoria, anxiety, impaired judgment, increased appetite, dry mouth, and

increased heart rate. Motor skills and coordination are frequently affected. Rare instances of

cannabis-induced delirium and psychosis have been reported (Tunving 1985).

Medications are rarely required for the treatment of cannabis intoxication. The most common

symptom requiring intervention is severe anxiety. This anxiety can usually be managed by modest

amounts of oral benzodiazepines such as lorazepam, 1 mg every 4 hours. Often, one or two doses is

an amount sufficient to control the anxiety. Likewise, if psychotic symptoms are present, one or

two doses of haloperidol 2–5 mg po will control these symptoms, which have occasionally been

reported in frequent users of high-potency cannabis.Print: Chapter 11. Pharmacotherapy for Substance Use Disorders http://www.psychiatryonline.com/popup.aspx?aID=239085&print=yes…

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States of withdrawal from long-term cannabis dependence are quite uncommon except in chronic

daily users of high-potency or high-dose cannabis. The withdrawal state can include mild insomnia,

irritability, tremor, and nausea. These symptoms usually do not require treatment. The treatment of

choice for long-term dependence is a combination of education, drug counseling, and support

programs.

HALLUCINOGENS

The hallucinogens include LSD, mescaline, psilocybin, and related drugs whose principal effects are

increased perceptual sensitivity, derealization, visual illusions, and hallucinations. Occasionally,

these perceptual changes are associated with a frank panic reaction (called a “bad trip”),

depression, or paranoid ideation. The symptoms of hallucinogen intoxication usually begin 1 hour

after the last dose and typically last 8–12 hours. LSD use is still apparently more common in the

western United States than in other parts of the country, and it is used by young males more than

by other demographic groups.

Time and a calm, supportive environment enable patients who are in the midst of a hallucinogenic

hallucinosis associated with panic to be talked down. Benzodiazepines such as diazepam 10–20 mg

po will decrease the anxiety and commonly contribute to the patient’s being able to sleep off the

effects of the hallucinogen. Antipsychotics have also been used, but they are rarely necessary.

Low-potency antipsychotics should probably be avoided, because their anticholinergic effects can

exacerbate the hallucinosis. Haloperidol 5–10 mg im or po is preferred over other antipsychotics,

but there are no controlled studies to support this common clinical practice. For recurrent

hallucinosis (flashbacks), benzodiazepines may be as useful as antipsychotics.

Withdrawal states for chronic hallucinogen use are very rarely reported, and no detoxification is

necessary. Chronic hallucinogen use is best managed through psychosocial interventions such as

drug counseling and support groups.

PHENCYCLIDINE

Phencyclidine (PCP; also called angel dust) has been used on the streets since the mid-1960s and

remains relatively popular. The drug is usually smoked and is rapidly absorbed across the

blood-brain barrier. PCP appears to enhance dopaminergic transmission and also to modulate

N-methyl-D-aspartate (NMDA) and glutamate receptor activity. Acute PCP intoxication produces not

only behavior that mimics paranoid schizophrenia or manic states but also even more bizarre,

violent behavior than do amphetamines or LSD. There are sometimes muscle tension, tachycardia,

hypertension, drooling, and horizontal and vertical nystagmus. Other neurological signs include

analgesia, loss of proprioception, and ataxia.

Treatment of the PCP intoxication state may involve seclusion and restraints, because at least

one-third to two-thirds of PCP patients who come to ERs present in an agitated or violent state.

Trying to talk down such patients is usually unsuccessful and often dangerous; isolation in a quiet

area is better. These patients’ agitation and violent behavior may be managed with high-potency

antipsychotics alternated with benzodiazepines, as described in Chapter 10 (“Emergency Room

Treatment”). Low-potency antipsychotics may compound the already significant anticholinergic

effects of PCP and are sometimes associated with delirium. Acidifying the patient’s urine with

ammonium chloride (2.75 mEq/kg in 3 oz saline) may facilitate excretion, as may charcoal lavage.

PCP withdrawal appears very rare in humans but is occasionally reported in animals. No

detoxification is necessary other than to control the symptoms of intoxication. Unfortunately, no

prospective studies on pharmacological strategies for chronic PCP abuse or dependence have been

done.

Maintenance treatment interventions include drug counseling, support groups (including 12-step

programs like Narcotics Anonymous), and regular drug testing to monitor progress.

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