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BenzodiazepineIntoxication and

Withdrawal: Assessment and Management

David W. Galarneau, MDa,*, Erich J. Conrad, MD

b

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Benzodiazepines are one of the most commonly prescribed classes of medi-

cation. In addition to their beneficial therapeutic effects, there are inherent

risks with their use, including abuse, dependence, intoxication, and

withdrawal.

2. Benzodiazepines act on gamma-aminobutyric acid (GABA) A receptors, exert-

ing a calming effect, as well as producing drowsiness and facilitating sleep.

They hold US Food and Drug Administration approved indications for gener-

alized anxiety disorder, panic disorder, insomnia, and seizure disorder.

3. Slurred speech, ataxia, and incoordination can occur with mild to moderate

intoxication. A paradoxic agitated confusion or delirium can occur on occa-

sion, in certain populations.

4. Development of stupor or coma can occur at more severe stages of intoxica-

tion. Benzodiazepines rarely lead to death when ingested alone.

5. Clinical interview and examination, collateral information, and urine toxicology

are the cornerstones of the evaluation of benzodiazepine intoxication.

6. The management of intoxication includes evacuation of the gastrointestinal

tract, as well as assessment and management of the airway if needed.

7. Chronic use of benzodiazepines routinely leads to tolerance, dependence,

withdrawal, and addiction.

8. Tolerance and withdrawal have been linked to neuroadaptive changes

involving GABAergic and glutamatergic receptors in the central nervous sys-

tem that are induced by chronic drug use.

CONTINUED

Disclosures: The authors have no conflicts of interest or funding sources to disclose.a Ochsner Health System, The University of Queensland, New Orleans, LA, USA; b LouisianaState University School of Medicine, New Orleans, LA, USA* Corresponding author.E-mail address: [email protected]

KEYWORDS

Benzodiazepine Intoxication Tolerance Withdrawal Dependence Addiction

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CONTINUED

9. Benzodiazepine discontinuation can lead to 4 distinct syndromes: recurrence

or relapse, rebound, pseudowithdrawal, and true withdrawal.

10. There is a great variability to withdrawal symptoms and syndromes: they differ

between and within people as well as agents.

11. Frequent symptoms of withdrawal include anxiety, insomnia, restlessness,

agitation, irritability, and muscle tension. Uncommon but serious symptoms

are psychosis, seizures, confusion, paranoid delusions, hallucinations, and

persistent tinnitus. Death can ensue if withdrawal is severe and not managed

properly.

12. Although a variety of factors exist, time course and severity of the withdrawal

syndrome are most commonly linked to the dose, duration of use, and dura-

tion of drug action.

13. In addition to pharmacokinetic and drug-specific factors, there are a variety of clinical factors that influence the withdrawal syndrome, including degree of

mental disorder, polysubstance abuse, chronic comorbid medical conditions,

age, gender, and educational level.

14. The evaluation and assessment of benzodiazepine withdrawal involves clinical

interview and history taking, physical and mental status examination, and

basic laboratory work (including urine toxicology and blood alcohol level).

15. The first step in the management of benzodiazepine withdrawal is the determi-

nation of the appropriate setting for detoxification.

16. There are 2 primary options for detoxification: tapering, or substitution and

tapering.17. Adjuvants to a benzodiazepine detoxification regimen include anticonvulsants

and cognitive behavior therapy.

18. The best prevention for benzodiazepine dependence and addiction is careful

prescribing.

OVERVIEW

Benzodiazepines have been one of the most commonly prescribed medications since

their introduction in the 1960s. They have long eclipsed the use of barbiturates, pri-

marily because of their improved safety profile. Continued controversy exists

regarding what role the benzodiazepines should have in the treatment of anxiety dis-

orders, and whether there is potential long-term risk with the development of demen-

tia.1–4 In addition to the beneficial therapeutic effects, there are inherent risks with use,

including abuse, dependence, intoxication, and withdrawal, which every clinician

needs to be able to recognize and manage.

PHARMACOLOGY

What is a benzodiazepine?

Benzodiazepines are a class of psychotropics that exert a variety of effects, including

hypnotic, anxiolytic, anticonvulsant, myorelaxant, and amnesic.5 Benzodiazepines are

agents that hold US Food and Drug Administration approved indications for general-

ized anxiety disorder, panic disorder, insomnia, and seizure disorder. They have

similar mechanisms of action, but have differing pharmacokinetic properties that

Galarneau & Conrad514



provide each agent with its own unique niche in a broader spectrum of general class

effects. Boxes 1 and 2 list the specific pharmacokinetic properties of the differing

agents.

Where do benzodiazepines exert their therapeutic effects?Benzodiazepines act on gamma-aminobutyric acid (GABA) A receptors.6 As depicted

in Fig. 1, the GABA A receptor is a pentamer spanning the plasma membrane and form-

ing a chloride channel. There are 19 different subunits that can compose the receptor

complex: a1 t o 6 , b1 t o 3 , g1 t o 3 , d, ε, q, r1 t o 3 .6 Classically, the pentamer is made up

of 2 b subunits, 2 a subunits, and 1 g subunit. There are 2 GABA recognition sites per

GABA A receptor complex, and an increase in the concentration of GABA results in an

increase in the mean channel open time.7 It seems that this complex is responsible for

the anxiolytic, sedative, and anticonvulsant effects of benzodiazepines. The GABA A receptor is modulated by several classes of drugs that bind allosteric sites on the re-

ceptor complex. The mechanism of action of benzodiazepine agonists is to enhance

GABAergic transmission by increasing the frequency of channel opening in response

to GABA.8 The benzodiazepine binding site is positioned between the a and g

subunits.7

INTOXICATION

What are the clinical signs and symptoms of intoxication?

Slurred speech, ataxia, and incoordination can occur with mild to moderate intoxica-

tion. A paradoxic agitated confusion or delirium can occur on occasion, particularly in

older adults or those with a history of traumatic brain injury.9,10 Box 3 provides more

details on benzodiazepine effect and intoxication.

Is intoxication dangerous?

Development of stupor or coma can occur at severe stages of intoxication. Benzodi-

azepines rarely lead to death when ingested alone; a lethal dose has not been estab-

lished for any of the benzodiazepines.10,11 The few deaths that have occurred involved

Box 1

Benzodiazepine dose comparisons (approximate)

Clonazepam (Klonopin): 0.25 mg

Triazolam (Halcion): 0.25 mg

Alprazolam (Xanax): 0.5 mg

Lorazepam (Ativan): 1 mg

Diazepam (Valium): 5 mg

Clorazepate (Tranxene): 10 mg

Temazepam (Restoril): 10 mg

Flurazepam (Dalmane): 15 mg

Oxazepam (Serax): 15 mg

Chlordiazepoxide (Librium): 25 mg

Benzodiazepine Intoxication and Withdrawal 515



short-acting, high-potency benzodiazepines such as alprazolam or triazolam, or

administration of benzodiazepines by an intravenous route.10

On rare occasions, patients have been simultaneously intoxicated and in with-drawal. This condition is most typically seen as a result of chronic daily use of very

Box 2

Half-life and potency of various benzodiazepines

Short half-life, high potency

Alprazolam (Xanax)

Lorazepam (Ativan)

Triazolam (Halcion)

Short half-life, low potency

Oxazepam (Serax)

Temazepam (Restoril)

Long half-life, high potency

Clonazepam (Klonopin)

Long half-life, low potency Chlordiazepoxide (Librium)

Clorazepate (Tranxene)

Diazepam (Valium)

Flurazepam (Dalmane)

Fig. 1. GABAA receptor. BZD, benzodiazepine.




high doses of benzodiazepines. Management of this condition is complex and best

accomplished in an inpatient setting.

Benzodiazepines seem to not cause damage to peripheral organ systems in either

long-term use or acute overdose.10 Benzodiazepines have a ceiling effect in terms of

respiratory depression, and for the most part escalating doses plateau in a nonlethal

state, which is in contrast with barbiturates, for which no ceiling effect exists. However,

in rare cases, respiratory depression is possible with the use of benzodiazepines, such

as in patients with severe chronic obstructive pulmonary disease.12 In addition, in pa-

tients with severely impaired liver function, benzodiazepines that rely on metabolism

through the liver can build up and be toxic. Despite their safety in single-agent overdose,

benzodiazepines can be fatal in mixed overdoses,11 especially if in combination with

neuronal inhibiting agents, such as alcohol, major tranquilizers, or opiates.

How is intoxication evaluated and assessed?

Clinical interview and examination, collateral information, and urine toxicology are the

cornerstones of the evaluation of benzodiazepine intoxication.

What is the management of intoxication?

In a benzodiazepine overdose, assessment and maintenance of the airway are essen-

tial. If necessary, intubation and ventilator support are initiated. Evacuation of the

Box 3

Benzodiazepine effect and intoxication

Beneficial effects

Decreases activity

Reduces excitement

Exerts a calming effect

Alleviates anxiety

Induces drowsiness

Facilitates sleep

Paradoxic effects (most often seen in the elderly)

Agitated confusion

DeliriumMild to moderate intoxication

Slurred speech

Ataxia

Incoordination

Severe intoxication

Respiratory depression

Stupor

Coma

Death (rare when ingested alone)




gastrointestinal tract with a large-bore orogastric tube may be necessary, because

some agents can slow gut motility or form concretions in the stomach.10 Activated

charcoal and a dose of cathartic should be given, and repeated doses of charcoal

may be needed for agents with extensive enterohepatic circulation in order to speed

elimination.10

Flumazenil is a competitive benzodiazepine receptor antagonist and can reverse the

effects of benzodiazepines. Flumazenil exceeding 1 mg has been associated with sei-

zures and cardiac arrhythmias; therefore, slow titration is recommended.10 Patients

physiologically dependent on benzodiazepines, or who have ingested benzodiaze-

pines in combination with other substances that lower the seizure threshold, are at

highest risk for seizures when given flumazenil.13

As intoxication wanes, it is important to be vigilant for the development of a with-

drawal syndrome.

WITHDRAWAL

What are tolerance and withdrawal?

When benzodiazepines are used routinely (ie daily or near daily) they can lead to the

development of tolerance and withdrawal. Box 4 provides brief definitions of these

terms, as well as other common addiction terms. Benzodiazepine and alcohol with-

drawal share many similarities, which are a function of the properties of the GABA

receptor.

What are the molecular underpinnings of tolerance and withdrawal?Tolerance and withdrawal have been linked to neuroadaptive changes in the central

nervous system that are induced by chronic drug use. In the case of benzodiazepines,

Box 4

Addiction terminology

Tolerance

The diminishing effect of a drug resulting from repeated administration at a given dose.

Withdrawal

A characteristic group of symptoms that occurs on the abrupt discontinuation or decrease inintake of a drug.

Dependence

An adaptive state associated with a withdrawal syndrome on cessation of repeated drugintake.

Physical dependence

Dependence that involves physical-somatic withdrawal symptoms (eg, fatigue).

Psychological dependenceDependence that involves emotional-motivational withdrawal symptoms (eg, dysphoria andanhedonia).

Addiction

A state characterized by compulsive engagement in rewarding behavior or compulsive druguse, despite adverse consequences.




chronic use leads to a diminution of GABAergic neuronal inhibition coupled with a

compensatory excitation of the glutamate system.7 These neuroadaptive changes

serve to counterbalance the uptick in benzodiazepine-induced GABA release. They

serve to dull or mollify the benzodiazepine response, thus leading to tolerance.

When the benzodiazepine agent is rapidly removed, an excitatory state ensues,

thus producing withdrawal. As withdrawal progresses and finally ceases, there is a re-

turn toward the original balance between GABAergic and glutamatergic tone, although

the initial set point is not necessarily reached.

Specific examples of neuroadaptation include the following:

Tolerance: GABA receptor downregulation (through decreased receptor number,

decreased GABA receptor function, and diminished protein synthesis for GABA

receptors)7

Withdrawal: GABA receptor upregulation and enhanced function (as shown by

greater affinity for GABA, increased affinity of the benzodiazepine receptor for

benzodiazepines, increased benzodiazepine receptor number)7

Thus it must be noted that although benzodiazepines act on the GABA receptor,

their use is intricately associated with the glutamatergic system as well. This associ-

ation is especially notable in the withdrawal syndrome, in which some of the symp-

toms are secondary to increased glutamatergic activity.

What are the possible clinical manifestations of benzodiazepine discontinuation?

Benzodiazepine discontinuation can lead to 4 distinct syndromes: recurrence or relapse,

rebound, pseudowithdrawal, and true withdrawal.10,14 Box 5 outlines these syndromes.

Although the 4 syndromes mentioned earlier are distinct entities, there exists

considerable overlap in the clinical setting. In addition, a subgroup of patients experi-

ence a protracted withdrawal syndrome, most commonly after the discontinuation of

long-term benzodiazepine use.10,15 The syndrome is characterized by an irregular and

unpredictable daily course, as well as qualitative and quantitative differences in symp-

toms from the initial symptoms that were present bef ore benzodiazepine initiation, as

well as those present in the acute withdrawal period.10,15

Box 5

Benzodiazepine discontinuation syndromes

Recurrence or relapse: a recurrence of symptoms (such as insomnia or anxiety) for which thebenzodiazepine was initially taken. Recurrence is not necessarily linked to physiologicdependence and is common. Recurrence can present rapidly or slowly, over days to months.

Rebound: symptoms that develop within hours to days of discontinuation and, althoughqualitatively similar to those for which the agent was prescribed, are significantly moreintense than what was experienced before initiation of drug treatment.

Pseudowithdrawal: an overinterpretation of symptoms, when an expectation of withdrawalleads to the experiencing of abstinence symptoms. Most notably, pseudowithdrawal has

been observed in patients who discontinued placebo medication or continuedbenzodiazepine use but thought it had been stopped, although it is not confined to thesepopulations.

True withdrawal: the emergence of somatic and psychological signs and symptoms of thewithdrawal syndrome after discontinuation of benzodiazepines in individuals who arephysically dependent on the drug. True withdrawal can be suppressed, either by restartingthe discontinued drug or by initiation of a cross-tolerant agent.




What are the clinical signs and symptoms of withdrawal?

The signs and symptoms of withdrawal are numerous; Box 6 provides a comprehen-

sive list.10,14 Considerable variation exists regarding which symptoms are experi-

enced by individual patients and in what sequence. Any combination can be

experienced throughout the withdrawal syndrome, and none are pathognomonic of

benzodiazepine withdrawal.

Frequent symptoms of the withdrawal syndrome include anxiety, insomnia, restless-

ness, agitation, irritability, and muscle tension. Less frequent symptoms include nausea,

diaphoresis, lethargy, myalgias, coryza, hyperacusis, blurred vision, nightmares, depres-

sion, hyperreflexia, and ataxia. Uncommon but serious symptoms are psychosis, sei-

zures, confusion, paranoid delusions, hallucinations, and persistent tinnitus. Clinicians

must exercise constant vigilance during a complicated withdrawal syndrome, because

it can end in death if it is not managed properly and in a timely fashion.

What affects the time course, duration, and severity of withdrawal?

There is a great variability to withdrawal syndromes: they differ between and within peo-

ple as well as agents. This variability is accounted for by a variety of factors, which are

Box 6

Benzodiazepine withdrawal signs and symptoms

Tachycardia

Hypertension

Fever

Diaphoresis

Anorexia

Diarrhea

Nausea

Agitation

Anxiety

IrritabilityRestlessness

Insomnia

Nightmares

Tremor

Hyperreflexia

Tinnitus

Sensory disturbances

Delirium

Hallucinations

Paranoid delusions

Seizures

Death




discussed later. These variables have commonly been divided into drug variables and

clinical variables.14 Three factors are of particular interest and are linked most

commonly to the time course, duration, and severity of withdrawal. These 3 factors,

which are classified as drug variables, are the dose, duration of use, and duration of

drug action.10 In terms of withdrawal severity, dose and duration of use are most impor-

tant. In relation to latency of onset of the syndrome, the elimination half-life is primary.10

Physiologic dependence can develop after just 2 weeks of daily use, but a clinically

significant withdrawal syndrome is most commonly seen after discontinuation of a

daily therapeutic dose lasting 4 to 6 months.10,14 This period can be shortened to 2

to 3 months if the daily dose used is supratherapeutic.10

What are the drug variables affecting withdrawal?

As noted earlier, there are a multitude of drug variables that affect the withdrawal syn-

drome. Perhaps one of the most important factors is the pharmacokinetics of the agent

in question. The onset, duration, and severity of the withdrawal syndrome are all linked

to the elimination half-life, which correlates with the decline in serum drug levels.10

Short-acting benzodiazepines

Onset of withdrawal: within 24 hours of cessation

Peak severity: within 1 to 5 days

Duration of withdrawal: 7 to 21 days on average

Long-acting benzodiazepines

Onset of withdrawal: within 5 days of cessation

Peak severity: within 1 to 9 days

Duration of withdrawal: 10 to 28 days on average

Withdrawal symptoms are usually more severe or intense for short-acting, high-po-

tency benzodiazepines.10,14,16 Severity of the withdrawal syndrome is also linked to

higher doses and longer use.10,14,16 Examples of the severities of characteristic with-

drawal syndromes are presented in Box 7; however, these serve only as examples

and, in practice, much variability exists.

Continuous use of benzodiazepines for greater than 1 year may also predispose pa-

tients to protracted withdrawal, independent of the severity of the withdrawal symp-

toms.15 Although most withdrawal syndromes tend to gradually resolve over a

period of 3 to 6 weeks, protracted withdrawal can persist for months or even years.

14

What are the clinical variables affecting withdrawal?

In addition to pharmacokinetic and other drug variables, there are a variety of clinical

factors that also influence the withdrawal syndrome.14 Degree of mental disorder is

Box 7

Severity of characteristic withdrawal syndromes

Daily benzodiazepine use for 10 days or less: transient insomnia Short-term (<2–3 months), low-dose therapeutic use: mild and easily managed withdrawal

symptoms

Short-term, high-dose use (>4 or 5 times the therapeutic range): a moderate to severewithdrawal syndrome

Long-term (>1 year), low-dose therapeutic use: a moderate to severe withdrawal syndrome.




correlated to the severity of withdrawal symptoms, as well as difficulty in discontinuing

benzodiazepine use.10,14 High initial anxiety or depression is associated with

increased withdrawal symptoms, and the reduction of anxiety symptoms is a predictor

of success in achieving and maintaining sobriety.10,14

Comorbidity is also linked to the severity of the withdrawal syndrome. This link holds

for the abuse of additional substances, as well as chronic medical conditions.10,14

The withdrawal syndrome is complicated by the use of concomitant sub-

stances.14,17 The specific effects seen are directly related to the properties of these

substances. Neuronal inhibitors, such as alcohol and opiates, produce additive or

overlapping effects that can lead to an exacerbation of symptoms.10 Moderate alcohol

use is a more significant predictor of benzodiazepine withdrawal severity than the

pharmacokinetics of the agent itself. Neuronal excitatory agents such as cocaine

and stimulants produce a variable clinical picture, often leading to a mixed syndrome

or a masking of symptoms.10 However, polysubstance abuse and multidrug detoxifi-

cation is more the rule than the exception, because benzodiazepines are most often

used in combination with other psychoactive drugs, rather than as initial or primary

agents of abuse.10,17

For the most part, patients with comorbid chronic medical illnesses experience a

more severe withdrawal syndrome than their healthy cohorts,10,18 particularly for con-

ditions involving the adrenergic system. This tendency must be taken into account

when deciding when to initiate a benzodiazepine detoxification program. As a general

rule, it should not be initiated until the patient is in a stable medical condition, espe-

cially if improvement in the comorbid medical condition is anticipated in the near future

with current medical management.

In general, older age is associated with a more severe withdrawal syndrome,9,10

inpart because of the decreased efficacy of the hepatic microsomal enzyme oxidase

system with age.9 A reduction in the efficacy of this system leads to longer elimination

half-lives and a more protracted and severe withdrawal syndrome.9,10 All benzodiaz-

epines use this system for degradation and excretion, with the exceptions of loraze-

pam, temazepam, and oxazepam, which are primarily excreted renally.

Female gender is associated with increased withdrawal severity in the tapered

cessation of a long-term therapeutic benzodiazepine, but gender is not implicated

in abrupt cessation of long-term use.10 The GABA A receptor contains a binding site

for the neurosteroid pregnenolone,7 which may play a role in gender differences con-

cerning the benzodiazepine receptor. Increased withdrawal symptoms have beenassociated with decreased educational level.10

Box 8 summarizes the factors discussed earlier that influence the withdrawal

syndrome.

How is withdrawal evaluated and assessed?

Box 9 outlines the steps routinely taken in the evaluation and assessment of benzodi-

azepine withdrawal.

What is the management of withdrawal?

Clinicians must consider carefully the findings of the evaluation and assessment in or-

der to decide what would be the best setting for the management of withdrawal. For

low-dose users, motivational interviewing may be used and the patient advised how to

quit or reduce the dose gradually. For patients dependent on sedative hypnotics, a

scheduled detoxification is likely to be necessary.14,16




There are 2 primary options for detoxification: tapering or substitution and

tapering.10 With the taper method, patients are slowly and gradually weaned from

the benzodiazepine on which they are dependent, using a fixed-dose taper schedule

with the dose being decreased on a weekly to every-other-week basis. The rate of

discontinuation for long-term users (>1 year) should not exceed 5 mg of diazepam

equivalents per week, or 10% of the current dose per week, whichever is smaller.10

Anticipating the needs of the patient, clinicians should be aware that the first half of

the taper is usually smoother, quicker, and less symptomatic than the last half. For the

final 25% to 30% of the taper, the rate or dose reduction schedule should be slowed to

half the previous dose reduction per week, and the reduction accomplished at twice

the original tapering interval.10 If symptoms of withdrawal occur, the dose should be

increased slightly until the symptoms resolve and the subsequent taper schedule

can be commenced at a slower rate.

If patients are unable to complete a simple taper program as outpatients, they may

require a substitution and taper program, or even a period of hospitalization.10

Substi-tution and taper methods use cross-tolerant long-acting benzodiazepines to

Box 8

Factors affecting the withdrawal syndrome

Drug variables

Elimination half-life

Potency

Dose

Duration of use

Clinical variables

Degree of mental disorder

Polysubstance abuse

Chronic medical conditions

AgeGender

Educational level

Box 9

Evaluation and assessment of benzodiazepine withdrawal

Take a sedative-hypnotic use history: dose, duration of use, substances used, clinicalresponse, attempts at abstinence, previous detoxifications, and complications ofwithdrawal experienced in the past.

Take a psychiatric history, including substance abuse.

Take a medical history, family history, and psychosocial history.

Perform a physical and mental status examination.

Collect a urine toxicology and blood alcohol level.

Procure basic laboratory work.

Determine the appropriate setting for detoxification.




substitute, at equipotent doses, for the sedative hypnotics on which the patient is

dependent. With longer acting benzodiazepines, there is negligible interdose serum

level variation. With tapering, a more gradual reduction in serum levels occurs,

reducing emergent withdrawal symptoms. However, there are reported cases in which

only the primary agent is capable of controlling withdrawal symptoms.19 This finding

tends to be true for high-potency agents such as alprazolam or clonazepam.

Phenobarbital has also been used in substitution and taper regimens and offers the

added advantage of rarely inducing behavioral disinhibition, in addition to possessing

broad clinical efficacy in the management of withdrawal from all classes of sedative-

hypnotic agents.10 If impaired hepatic function or increased liver tests are present,

then oxazepam or lorazepam are good substitutions.

Nonbenzodiazepine agents have been used as adjuvants to benzodiazepines in

detoxification protocols.20,21 Most notably, anticonvulsants such as valproic acid

and carbamazepine have shown efficacy in preventing withdrawal seizures. This strat-

egy is particularly appealing in patients with comorbid bipolar disorder, because val-

proic acid and carbamazepine are well-established mood stabilizers.

In addition to pharmacologic approaches, psychotherapy has been used to help

manage withdrawal symptoms. In particular, there are data that show the utility of

cognitive behavior therapy.14

Inpatient detoxifications are best for patients who have polysubstance dependence,

mixed alcohol and other sedative-hypnotic use, high-dose hypnotic sedative use,

erratic behavior, incompatible use histories, involvement with illicit sources, and

extensive mental health issues.10

After detoxification is complete, most patients benefit from a comprehensive recov-

ery program that includes both 12-step meetings and a formal rehabilitation program.In addition, note that the best prevention for benzodiazepine dependence is careful

prescribing.

PERFORMANCE IMPROVEMENT

There are no large-scale randomized controlled trials to compare different treatment

options in the management of benzodiazepine withdrawal. Future research could

help elucidate which management strategies are most beneficial, or whether there

is a difference in clinical outcome.

CLINICAL GUIDELINES

American Psychiatric Association clinical guidelines.

Substance Use Disorders (May 2006)

Practice Guideline

Guideline Watch

Quick Reference Guide

Available at: http://psychiatryonline.org/guidelines.

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