Pharmacotherapy Principles and Practice, Second Edition (Chisholm-Burns, Pharmacotherapy), 2nd Ed.

36 Substance-Related Disorders

Sally K. Guthrie and Theadia L. Carey


LEARNING OBJECTIVES

Upon completion of the chapter, the reader will be able to:

1. Identify the extent of abuse of and dependence on commonly used drugs in different segments of the U.S. population.

2. Explain the commonalities of action of abused substances on the reward system in the brain.

3. Identify the typical signs and symptoms of intoxication associated with the use of alcohol, opioids, cocaine/amphetamines, and cannabis, and determine the appropriate treatment measures to produce a desired outcome following episodes of intoxication.

4. Determine when a patient meets criteria for substance dependence.

5. Describe the different approaches to treating drug withdrawal, and identify the circumstances in which each of these different approaches would be most appropriate.

6. Recognize when long-term maintenance therapy is indicated for an opioid addict, and describe how to choose and initiate a maintenance regimen.

7. Determine which nonpharmacologic therapies should be used, either alone or in combination with pharmacologic treatments, to foster a recovery from addiction.

8. Recommend a comprehensive treatment and monitoring program to establish lifestyle changes that help maintain sobriety and prevent relapse.


KEY CONCEPTS

image Virtually all abused substances appear to activate the same brain reward pathway.

image While activation of the reward pathways explains the pleasurable sensations associated with acute substance use, chronic use of abused substances, resulting in both addiction and withdrawal, may be related to neuroadaptive effects occurring within the brain.

image Individuals with a pattern of chronic use of commonly abused substances should be assessed to determine if they meet the Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR) criteria for substance dependence (addiction).

image The treatment goals for acute intoxication of ethanol, cocaine/amphetamines, and opioids include (a) management of psychological manifestations of intoxication, such as aggression, hostility, or psychosis and (b) management of medical manifestations of intoxication, such as respiratory depression, hyperthermia, hypertension, cardiac arrhythmias, or stroke.

image The treatment goals for withdrawal from ethanol, cocaine/amphetamines, and opioids include (a) a determination if pharmacologic treatment of withdrawal symptoms is necessary, (b) management of medical manifestations of withdrawal, such as hypertension, seizures, arthralgias, and nausea, and (c) referral to the appropriate program for substance abuse treatment.

image To facilitate recovery from addiction it is necessary to utilize a comprehensive biopsychosocial assessment that includes the motivation for change. Pharmacologic treatments are always adjunctive to psychosocial therapy.

image While pharmacologic agents may help prevent relapse, psychotherapy should be the core therapeutic intervention. Motivational enhancement therapy (MET), cognitive-behavioral therapy (CBT), 12-step facilitation (TSF), behavioral couples therapy (BCT), community reinforcement approaches, and contingency management are the best-studied forms of psychotherapy in this group of patients.

image Certain pharmacologic agents have been helpful in the treatment of withdrawal and drug maintenance programs.

image A major component of successful treatment of addiction is to continue monitoring the use of medications designed to decrease craving or to block the hedonic effects of abused substances, such as disulfiram, naltrexone, or acamprosate. Also, it is important to identify a mechanism for long-term support of sobriety that might be appropriate for a specific individual, such as Alcoholics Anonymous (AA), a spiritual group, or professional recovery programs for professionals, such as doctors, nurses, police officers, or other professionals.

Substance abuse and dependence are highly prevalent problems in the United States and in the world. In the United States, the use of all substances of abuse has undergone a series of periodic cycles of societal tolerance or condemnation. As an example, cocaine was first isolated from coca leaves in 1860 by a chemistry graduate student in Germany. Its use was advocated by many in the medical establishment until around the mid-1890s when it became evident that chronic use of cocaine might be addictive in some individuals and could be associated with deleterious physiologic effects. Its use decreased following restriction of prescribing and dispensing of cocaine in the early 20th century. Cocaine continued to be abused by a small segment of the population, but much of the medical community seemed to forget the earlier cocaine epidemic. By the late 1970s, at least one pharmacology textbook indicated that cocaine was not addicting. Unfortunately, in the 1980s, a smokeable formulation of cocaine (crack) became available, and cocaine use again became an epidemic. The cyclic nature of substance abuse is common to many drugs, including heroin and marijuana, in addition to cocaine.

The abused substances covered in this chapter include: nicotine, alcohol, cocaine, amphetamines, cannabis, and opioids. While many more substances can be and have been abused, these drugs are among the most popular.

EPIDEMIOLOGY

In the United States, the federal government annually conducts the National Survey on Drug Use and Health, using a sample of persons who are 12 years of age or older to determine the prevalence of licit and illicit drug use.1 In 2006, 8.3% of the American population (12 and older) had used an illicit drug within the previous month. Fifty percent of the population currently used alcohol, and 6.9% were heavy users. Tobacco use in Americans has stabilized, in recent years, to a rate of 29.6%. Unfortunately, use in the younger age groups remains high. In 2006, 35.6% of Americans in the 18-to 20-year-old range and 40.2% in the 21-to 25-year-old range reported using cigarettes within the previous month. The trends in prevalence of use for eighth, tenth, and twelfth graders are shown in Figure 36–1. The uses of any illicit drug and of marijuana have both decreased since 1999, but still remain higher than the minimum use recorded in 1992.2

While initiation of the use of substances is often in middle and high school, chronic use may be established in young adulthood. The National Alcohol Epidemiologic Survey reported that 9.2% of its 18-to 29-year-old sample met criteria for alcohol dependence.3

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FIGURE 36–1. Trends in illicit drug use in eighth, tenth, and twelfth graders from the Monitoring the Future survey showing the percent that used any illicit drug in lifetime. (From Ref. 2.)

The association of substance abuse with emergency department (ED) visits in the United States is reported by the Drug Abuse Warning Network (DAWN). This survey notes ED visits that are due to a condition induced by or related to drug use. Included in the data, are ED visits associated with alcohol, alone and in combination with other substances of abuse including cocaine, heroin, marijuana, and major stimulants. Figure 36–2 presents 2006 data depicting the number of ED visits per 100,000 people in the population that are associated with illicit drugs. Alcohol in combination with other substances ranged from 219 to 268 per 100,000 in each 4-year-age subpopulation from the ages of 18 to 44. The rate dropped to 173 per 100,000 for the 45-to 54-year-old group, and down to 51 for the 55 to 64 and further to 12 per 100,000 population for the 65 and over group.4

The results of these surveys indicate that substance abuse is wide ranging, begins early, and is associated with a considerable number of medical emergencies.

PATHOPHYSIOLOGY

Reward Pathway

Abused drugs generally produce pleasant effects that are desired by the user. However, while most individuals will experience pleasant effects, not everyone abuses these drugs, and not everyone who abuses them becomes dependent on them. Why some persons abuse drugs while most people do not is a complex area of research. It appears that genetic, environmental, and cultural factors may all interact to predispose some individuals to substance abuse and subsequent dependence. The initial hedonic experiences secondary to use of drugs appear to be primarily due to their ability to activate the primary reward circuits in the brain. These same reward circuits operate under normal circumstances to reinforce certain activities that promote survival, such as food, social affiliation, or sexual activity.

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FIGURE 36–2. Rates of emergency department visits involving selected illicit drugs: 2006. (From Ref. 4.)

image Virtually all abused substances appear to activate the same brain reward pathway. Key components of the reward pathway are the dopamine (DA) mesocorticolimbic system that projects from the ventral tegmental area(VTA) and the nucleus accumbens (NA) to the prefrontal cortex, the amygdala, and the olfactory tubercle (see Figs. 36–3 and 36–4).5 Animal studies indicate that ablation of DA neurons in the NA results in decreases in cocaine self-administration. Although many other neurotransmitters can be involved in activation of the reward system, DA appears to be a final common neurotransmitter of this pathway.6

Cocaine and stimulants, such as amphetamines, probably activate reward circuits by blocking the DA reuptake transporter. Additionally, amphetamines also cause the reverse transport of DA into the extracellular space.6 Although opioids eventually utilize the same circuitry as stimulants, initially they activate μ-opioid receptors, in the NA or VTA, which ultimately results in an increase DA release in the NA. However, reinforcement of opioid use may derive from two mechanisms because in animal studies, when the DA fibers are destroyed, the reinforcing effects of opioids remain.6 Ethanol probably produces its effects through multiple neurotransmitter pathways. Antagonists of γ-amino butyric acid (GABA) reverse some of the behavioral effects of ethanol, suggesting that there may be cross-reactivity between benzodiazepines and alcohol, and that alcohol may somehow modulate GABA receptors. Ethanol may activate the DA system indirectly by facilitating the activity of GABA neurons in the pars reticulata, ultimately disinhibiting the VTA DA neurons, resulting in an increase in DA in the NA.6 There also may be an interaction between serotonin (5-HT) and the reinforcing effects of ethanol, because both 5-HT reuptake inhibitors and 5-HT2C receptor antagonists decrease ethanol intake in animals. However, studies of these drugs in alcohol-dependent humans have not been very promising. Animal studies indicated that when opioid antagonists were administered to the central nucleus of the amygdala, oral ethanol self-administration decreased. Studies in humans showed a modest decrease in alcohol consumption in alcoholics who took a long-acting opioid antagonist (naltrexone) following detoxification. Finally, small doses of ethanol inhibit N-methyl-D-aspartate (NMDA) glutamate receptors, and animals will substitute glutamate receptor antagonists for ethanol, suggesting that they find the effects of the two drugs to be similar. Nicotine also affects the reward pathways by more than one mechanism. In animal studies, either DA antagonists or destruction of DA neurons in the NA decreased nicotine self-administration. Nicotine also interacts with the opioid pathway, because opioid antagonists can precipitate nicotine withdrawal in animals. Finally, marijuana’s main active component, tetrahydrocannabinol (THC), binds to cannabinoid-1 (CB)1 receptors resulting in activation of DA neurons in the mesocorticolimbic system. THC also increases the release of DA into the shell of the NA.6

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FIGURE 36–3. Location of the dopamine neural tracts associated with the reward system in the brain. (From Ref. 5.)

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FIGURE 36–4. Locations where different abused substances interact with the reward system in the brain. (From Ref. 5.)

Neuronal Adaptation

image While activation of the reward pathways explains the pleasurable sensations associated with acute substance use, chronic use of abused substances resulting in both addiction and withdrawal may be related to neuroadaptive effects occurring within the brain. Chronic use of drugs of abuse appears to cause a generalized decrease in DA neurotransmission, probably in response to the intermittent increases in DA induced by the frequent use of these drugs. Additionally, with chronic drug use, release of corticotropin releasing factor (CRF) is increased, indicating an activation of central stress pathways. In vivo microdialysis studies in rats withdrawing from ethanol, cocaine, or THC all showed an increase in extracellular CRF. Also, microinjections of a CRF antagonist into the amygdala reversed some of the anxiogenic behaviors seen during withdrawal.7

Two neuroadaptive models have been used to explain how changes in reward function are associated with the development of substance dependence: sensitization and counteradaptation.7 Sensitization refers to the increased response following repeated intermittent administration of a drug. This is in contrast to the tolerance to drug effects that occurs secondary to continuous exposure to the drug. Sensitization may be akin to the increase in “wanting” a drug after repeated intermittent use of the drug and would facilitate transition from occasional use to compulsive use. Counteradaptation postulates that the initial positive rewarding feelings are followed by the opposing development of tolerance. Because tolerance takes longer to dissipate than the positive rewarding effects, a cycle of escalating drug use ensues. Ultimately, chronic activation of the reward system may result in a depletion of neurotransmitter systems that are overactivated in an effort to maintain response to drugs of abuse. During withdrawal, microdialysis experiments have documented decreases in dopaminergic and serotonergic transmission in the NA. Also seen during alcohol withdrawal are an increase in opioid receptor sensitivity combined with decreased GABAergic and increased NMDA glutamatergic transmission in the accumbens–amygdala pathway. The increase in CRF and concomitant decrease in neuropeptide Y during withdrawal are associated with increases in anxiety, and an activation of norepinephrine (NE) pathways, which in turn also activates more CRF release, possibly resulting in an amplification of arousal and stress and maybe even neurotoxicity if these actions are long-lasting.7

With regard to relapse, multiple factors are associated with an increased risk including the availability of the abused drug, an increase in psychological stressors, and a triggering of conditioning factors (cues) such as seeing a white powder or going to a location where drugs were often previously used or obtained. These factors may be acting to trigger residual adaptive changes that occurred in the brain during the period of drug addiction.

OVERALL THEORY OF USE OF PHARMACOLOGIC AGENTS TO TREAT SUBSTANCE ABUSE

Unfortunately, unlike some medical diseases, substance dependence cannot be cured with medications alone. However, we can sometimes alleviate the effects of drug intoxication, attenuate the adverse effects of withdrawal, or use agents that may somewhat decrease craving for, and relapse to, abused substances.

The intoxicating effects of opioids appear to be due to their action as agonists on μ-receptors of the opioid neurotransmitter system. Competitive μ-opioid antagonists such as naloxone and naltrexone, acutely reverse many of the adverse effects of opioids. To date, we do not have specific antagonists for most other abused substances, so rapid pharmacologic reversal of intoxication is usually not possible.

Similarly, reversal of withdrawal syndromes caused by abused substances is not always possible. One pharmacologic solution for reversing a drug withdrawal syndrome, most commonly employed by dependent individuals, is to readminister the drug that caused the physiologic dependence. The more commonly used clinical method is to administer a medication that has some cross-dependence with the abused drug, but also has fewer of the reinforcing effects and a more predictable pharmacokinetic profile. A good example is the use of benzodiazepines for the withdrawal of ethanol. While benzodiazepines can cause dependence, they are rated as less desirable than ethanol by substance abusers, they cause fewer of the long-term adverse health effects of ethanol, and they are easier to manage medically.

In the case of heroin addiction, maintaining the addict on a regimen of medically managed, orally administered opioids may be preferred over rapidly detoxifying the patient who has a high likelihood of returning to heroin use when extensive strategies for rehabilitation have not been put in place. In order to allow time for psychosocial strategies to help the addicted individual change his or her overall lifestyle, a period of opioid agonist treatment may be indicated. This strategy has been used to maintain addicts on either orally administered μ opioid agonists such as methadone, or partial agonists such as buprenorphine.

No matter which method has been used to facilitate detoxification from the abused substance, addicts have a high risk for reusing substances and manifesting their dependence again. In the long term, the most effective mechanisms for maintaining sobriety are psychosocial strategies rather than pharmacologic ones.

CLINICAL PRESENTATION AND DIAGNOSIS

image Individuals with a pattern of chronic use of commonly abused substances should be assessed to determine if they meet the DSM-IV-TR criteria for substance dependence (addiction).8 Criteria are not defined for each separate abused substance, rather a pattern of behavior common to the abuse or dependence of all drugs of abuse is established.


Patient Encounter 1

BB, a 48-year-old man with a history of hypertension, presents to your clinic for follow-up evaluation of his hypertension. You notice that he admits to drinking between one-half to one pint of whiskey daily. He says he drinks more on the weekends, but he drinks every day. When you question him about his drinking, he says that he does not think that it is a problem but admits that his wife has told him he needs to “cut down.” He does not believe that he is alcohol dependent because on work days he never drinks before 5 PM. He admits to having had occasional blackouts.

What information would suggest that this patient might be alcohol dependent?

What additional information would you need to determine if he meets the criteria for alcohol dependence?


The criteria for abuse indicate an established pattern of using a substance that has resulted in undesirable family, job, or legal consequences, such as recurrent instances of neglecting school, work, or family responsibilities, or being arrested for driving under the influence. However, abuse becomes dependence when tolerance to the drug, withdrawal from the drug, or an inability to discontinue use of the drug is apparent or there is a loss of control over its use or the use has become compulsive. The criteria for substance dependence from the DSM-IV-TR are listed in Table 36–1.8

Intoxication Signs and Symptoms

Euphoria is the one symptom that most drugs of abuse (with the exception of tobacco) have in common. Other signs and symptoms are specific to the particular drug or class of drugs involved. Table 36–2lists the psychological/behavioral and physiologic effects of intoxication with ethanol, cocaine and amphetamines, opioids, and cannabis.9–11

Withdrawal Signs and Symptoms

Although most abused drugs can cause some degree of physiologic dependence, the severity of withdrawal varies considerably among these drugs. Table 36–3 lists the common withdrawal symptoms seen upon abstinence from drug use.9–12

TREATMENT OF INTOXICATION SYNDROMES

image The treatment goals for acute intoxication of ethanol, cocaine/amphetamines, and opioids include (a) management of psychological manifestations of intoxication, such as aggression, hostility, or psychosis and (b) management of medical manifestations of intoxication such as respiratory depression, hyperthermia, hypertension, cardiac arrhythmias, or stroke. In all cases of intoxication associated with a substance use disorder (abuse or dependence), referral to and participation in substance abuse treatment following acute treatment for intoxication is desirable.

Table 36–1 DSM-IV-TR Criteria for Diagnosis of Substance Dependence


A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period:

(1) Tolerance, as defined by either of the following:

(a) a need for markedly increased amounts of the substance to achieve intoxication or desired effect

(b) a markedly diminished effect with continued use of the same amount of the substance

(2) Withdrawal, as manifested by either of the following:

(a) the characteristic withdrawal syndrome for the substance

(b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms

(3) The substance is often taken in larger amounts or over a longer period than was intended

(4) There is a persistent desire or unsuccessful efforts to cut down or control substance use

(5) A great deal of time is spent in obtaining the substance (e.g., visiting multiple doctors or driving long distances), using the substance (e.g., chain-smoking), or recovering from its effects

(6) Important social, occupational, or recreational activities are given up or reduced because of substance use

(7) The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer was made worse by alcohol consumption)

Specify if:

• With physiologic dependence: Evidence of tolerance or withdrawal (i.e., either Item 1 or 2 is present)

• Without physiologic dependence: No evidence of tolerance or withdrawal (i.e., neither Item 1 nor 2 is present)


From Ref. 8.


Patient Encounter 2

KI, a 27-year-old woman, was admitted to the cardiology unit from the emergency department (ED) after she called 911 claiming that she had severe chest pain. Upon arrival in the ED it was noted that her blood pressure was slightly elevated at 143/92, and that she was diaphoretic. She was in otherwise good physical condition, with no previous cardiac history. After a urine toxicology screen was positive for cocaine she admitted that she had smoked several rocks of crack 1 hour prior to having the chest pain. She said she almost never uses crack, but she’s currently really depressed because she has lost her job.

What are the possible physical signs and symptoms of cocaine use?

What are the possible psychiatric symptoms associated with cocaine use?


Table 36–2 Signs and Symptoms of Drug Intoxication

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Alcohol Intoxication

Most cases of mild to moderate intoxication with alcohol, as well as cases in which blood alcohol levels (BALs) are at the lower limits of legal intoxication, do not require formal treatment. Such intoxications are characterized by mood lability, loud or inappropriate behavior, slurred speech, incoordination, or unsteady gait. Providing a safe environment and supportive reassurance until the effects of alcohol have worn off is sufficient in most cases. At more severe levels of intoxication, confusion, stupor, coma, and death may be observed. In nontolerant individuals, confusion, impaired consciousness, and vomiting are observed at BALs of 200 to 300 mg/dL (0.2–0.3% or 43.4–65.1 mmol/L); stupor and coma are seen with BALs exceeding 300 to 400 mg/dL (0.3–0.4% or 65.1–86.8 mmol/L). Death may occur at levels of 400 mg/dL (0.4% or 86.8 mmol/L) or higher from cardiac arrhythmias or respiratory depression. Thus, the most important physiologic goal of treating high levels of intoxication is maintaining cardiopulmonary functioning, including the prevention of aspiration. Accordingly, vital signs must be monitored regularly. Serial BALs at least hourly are strongly recommended, and patients should not be allowed to leave the treatment setting on their own while legally intoxicated (greater than or equal to 80 mg/dL [0.08% or 17.4 mmol/L]). Initially, BALs may continue to rise if GI absorption is still occurring. Otherwise, the BAL generally decreases at a rate of 15 to 20 mg/dL (0.015–0.02% or 3.3–4.3 mmol/L) per hour. Although more tolerant individuals may not show the same level of symptoms for a given BAL as nontolerant individuals, behavioral tolerance and tolerance for vital physiologic functions may differ. Thus, alcoholic patients who are awake and alert at a BAL greater than or equal to 400 mg/dL (0.4% or 86.8 mmol/L) may still be at risk for cardiopulmonary instability and collapse.

Table 36–3 Signs and Symptoms of Drug Withdrawal

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Other causes of confusion, stupor, or coma must be ruled out, because alcohol-intoxicated individuals commonly combine alcohol with other substances, sustain head and other injuries, and have vitamin deficiencies and electrolyte abnormalities. If consciousness is impaired, then thiamine should be given IV or intramuscularly (IM) at 100 mg daily for at least 3 days. Patients may also develop adverse interactions between alcohol and medications that have been prescribed including disulfiram. See Table 36–4 for a listing of drug–drug interactions.13–15 If hypoglycemia is suspected, then thiamine administration should precede administration of glucose-containing fluids to prevent precipitation of an acute Wernicke’s syndrome.

Behaviorally, patients may insist on driving, become physically aggressive and agitated, or otherwise become a danger to self or others. Indeed, most suicidal behaviors among alcohol-dependent individuals occur while intoxicated. In such cases, the desired outcomes are appropriate management of medical problems, prevention of harmful behaviors, and stabilization of mood. Antipsychotics may lower seizure threshold and are best avoided. However, in some instances, agitation may require treatment with haloperidol such as 5 to 10 mg by mouth every 2 to 4 hours, or 5 mg either IV or IM every 1 to 2 hours. Sedation with benzodiazepines has been used in some cases, but the risk of respiratory depression when mixed with the alcohol already in the patient’s system can be dangerous if not fatal.

There are no available medications that can fully reverse the effects of alcohol intoxication. Caffeine and other stimulants can induce arousal and alertness, but they are less effective at reversing poor judgment and motor incoordination, that are vital for complex tasks such as driving. Thus, stimulants are neither indicated nor considered a viable option to make driving safe. Flumazenil (Romazicon) reverses the effects of benzodiazepine agonists at GABA receptors, which mediate some of alcohol’s effects, but alcohol also acts on many other neurotransmitter systems making flumazenil generally ineffective in reversing alcohol intoxication.

Table 36–4 Drug Interactions With Abused Drugs or Drugs Used to Treat Drug Abuse

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Stimulant Intoxication (Cocaine and Amphetamines)

The desired outcomes of stimulant intoxication are appropriate management of medical and psychiatric problems. Medical problems include hyperthermia, hypertension, cardiac arrhythmias, stroke, and seizures. Some medical problems are related to route of administration such as nosebleeds with intranasal administration and infections with IV administration. Psychiatric effects include anxiety, irritability and aggression, and psychosis. Psychosis may take the form of tactile hallucinations (such as the sensation of bugs crawling under one’s skin, i.e., formication), visual hallucinations (usually simple geometric shapes), and most commonly, auditory hallucinations, as well as delusions of paranoia or grandeur. Cocaine is short acting, and a single dose of a benzodiazepine sedative-hypnotic may be sufficient treatment for anxiety reactions. Depending on the half-life of the benzodiazepine, one or more sequential doses may be required for amphetamine intoxication. Because stimulants are commonly used in combination with alcohol or opioids, benzodiazepines could increase sedation and respiratory depressant effects, so a comprehensive drug history and urine drug screen should be obtained. In a small percentage of patients, benzodiazepines can cause paradoxical activation and aggression. Thus, antipsychotics may be needed. Antipsychotics are definitely indicated when psychosis is present, and the psychosis usually responds quite rapidly in the absence of other co-occurring psychiatric disorders.

Opioid Intoxication

The word “opioid” is used to refer to the overall class including the semisynthetic and fully synthetic agents, but the word “opiate” only refers to the naturally occurring opioids, such as heroin, opium, and morphine.

Patients who are acutely intoxicated with an opioid usually present with miosis, euphoria, slow breathing and slow heart rate, low blood pressure, and constipation. Seizures may occur with certain agents, such as meperidine (Demerol). It is critically important to monitor patients carefully to avoid cardiac/respiratory depression and death from an excessive dose of opioids. One strategy is to reverse the intoxication by utilizing naloxone (Narcan) 0.4 to 2 mg IV every 2 to 3 minutes up to 10 mg. Alternatively, the IM or subcutaneous (SC) route may be used if an IV access is not available. Because naloxone is shorter acting than most abused opioids, it may need to be readministered at periodic intervals; otherwise the patients could lapse into cardiopulmonary arrest after a symptom-free interval of reversed intoxication. In addition, naloxone can induce withdrawal symptoms in opioid-dependent patients, so patients may awaken feeling quite distressed and agitated. The other critical issue is to secure the airway and breathing of a patient. In some cases, intubation and manual/mechanical ventilation might be required. This is a necessary measure to avoid oxygen desaturation leading to brain hypoxia or anoxia that may cause brain damage or death.

Overall, intoxication with any of the substances discussed above is evidence of substance abuse and is strongly suggestive of substance dependence. In all cases, it is important to strongly emphasize to the patient that this is an issue that needs to be addressed, and that entry into a treatment program could be very beneficial.

TREATMENT OF WITHDRAWAL SYNDROMES

image The treatment goals for withdrawal from ethanol, cocaine/amphetamines, and opioids include (a) a determination if pharmacologic treatment of withdrawal symptoms is necessary, (b) management of medical manifestations of withdrawal, such as hypertension, seizures, arthralgias, and nausea, and (c) referral to the appropriate program for substance abuse treatment. The desired outcomes in the treatment of withdrawal syndromes are to ensure patient safety, comfort, and successful transition from treatment of withdrawal to treatment of dependence. Referral to specialized treatment for substance dependence is strongly recommended following treatment for withdrawal syndromes, because treatment of withdrawal is not sufficient treatment to prevent relapse to problematic substance use. Achieving a drug-free state by detoxification and then rehabilitation with a focus on total abstinence is the ideal outcome.

Alcohol Withdrawal

There are four different alcohol withdrawal syndromes, which differ in terms of their pharmacologic treatment and need for hospitalization.

Uncomplicated Alcohol Withdrawal

This is the most commonly observed syndrome, and as the name denotes, is not complicated by seizures, delirium tremens (DTs), or hallucinosis. Symptoms are typically rated using a validated scale such as the Clinical Institute Withdrawal Assessment Scale for Alcohol—Revised (CIWA-Ar, Table 36–5).16 The recommended CIWA-Ar threshold score for treating uncomplicated alcohol withdrawal with medications on an outpatient basis is between 8 and 10. For patients who score greater than or equal to 15, inpatient treatment should be strongly considered. Patients who score 20 or higher on the CIWA-Ar should always be treated with medications. The risks of not treating high-scoring patients with medications are seizures and DTs, and those with a prior history of seizures or DTs have an increased risk for subsequent episodes. Therefore, when a history of seizures or DTs is positive, the lower threshold of eight is recommended, and hospitalization is safer than outpatient detoxification. There is some evidence for “kindling” during successive episodes of alcohol withdrawal, such that symptom severity and complications increase with additional withdrawal episodes. Thus, some authors recommend routinely using medications when the CIWA-Ar score is in the 8 to 10 range.

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly carbamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are lorazepam, oxazepam, diazepam, and chlordiazepoxide. They differ in three major ways: (a) their pharmacokinetic properties, (b) the available routes for their administration, and (c) the rapidity of their onset of action due to the rate of GI absorption and rate of crossing the blood–brain barrier.

Table 36–5 Clinical Institute Withdrawal Assessment for Alcohol—Revised (CIWA-Ar)

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Benzodiazepines can be administered using a symptom-triggered approach when withdrawal signs and symptoms are already present.18 In this approach, medication is administered every hour when the CIWA-Ar is greater than or equal to eight. For the shorter-acting agents, oxazepam (15–60 mg orally) or lorazepam (1–4 mg orally), the CIWA-Ar is repeated hourly after each administration during the first 24 hours until the patient is comfortably sedated. Because of their short half-life, dosing of lorazepam or oxazepam on subsequent days may be needed, and the risk of seizures may possibly (although not definitively proven) be higher. For the longer-acting agents, chlordiazepoxide and diazepam, the symptom-triggered approach is used in combination with another technique known as loading. With the loading technique, chlordiazepoxide at doses of 50 to 100 mg or diazepam (10–20 mg) is administered orally at 1-hour intervals during the first 24 hours until the patient is comfortably sedated and the CIWA-Ar score is lower than four. Then loading is stopped, and for the next 24 hours the benzodiazepine is used as needed only if the CIWA-Ar score is greater than or equal to eight, although the long half-lives of these drugs and their active metabolites usually provide a natural taper without further drug administration. The loading technique is especially useful in the hospital where patients can be medically monitored throughout the day. If vital signs are elevated in the absence of high CIWA-Ar scores, then antiadrenergic drugs like clonidine or propanolol may be used if there are no contraindications (see Chap. 5Hypertension).

In contrast to chlordiazepoxide and diazepam, lorazepam and oxazepam are not metabolized into active compounds in the liver. Instead, they are excreted by the kidneys following glucuronidation. This is important because many alcohol-dependent patients have compromised liver function. Therefore, when treatment is initiated before the results of blood tests for liver function are known, as is of ten the case in outpatient clinics, lorazepam and oxazepam may be preferred. Patients with liver disease may still be treated with diazepam or chlordiazepoxide, but at lower doses. This can be accommodated with the loading technique, although hourly dosing with 5 mg of diazepam or 25 mg of chlordiazepoxide may be sufficient.

Oxazepam is available in oral form only, so it is useful only for uncomplicated withdrawal. Other benzodiazepines are available in injectable form and will be further described below. Diazepam and lorazepam are more lipophilic than chlordiazepoxide and oxazepam, resulting in quicker GI absorption and passage across the blood–brain barrier, which makes them valuable in an inpatient setting, especially to treat or prevent seizures. However, their faster onset of action may be associated with feeling high, which can be a disadvantage of their use.

Alcohol Withdrawal Seizures

Alcohol withdrawal seizures (AWS) are a medical emergency and should be treated in an inpatient setting. Withdrawal seizures are usually few in number and generalized. The occurrence of focal seizures or status epilepticus may suggest another etiology. Management consists of keeping the airway open and preventing self-injury during convulsions. Benzodiazepines are the treatment of choice. IV diazepam 5 to 10 mg is preferred to terminate a seizure in progress if IV access is available. The dose may be repeated in 5 minutes if seizures persist. Alternatively, lorazepam 4 mg may be given IM, followed by insertion of an IV line when convulsive movements have subsided. In the event of a recurrent seizure, lorazepam 2 mg IV may be administered if the patient already received IM lorazepam. IM use of diazepam or chlordiazepoxide should be avoided because of erratic absorption that complicates the timing of subsequent doses and can result in delayed oversedation. IV benzodiazepines may depress respiration, so they should be administered only when and where advanced cardiopulmonary support is readily available. When the patient becomes conscious enough to take medication orally, then treatment may continue using the loading procedure for diazepam or the symptom-triggered technique for lorazepam as described above. Electrolyte imbalances can contribute to seizures and should be corrected if they exist. IV magnesium sulfate should be given in addition to benzodiazepine treatment. As with alcohol intoxication, thiamine should be given IV or IM at 100 mg daily for at least 3 days to prevent precipitation of an acute Wernicke’s encephalopathy, although some guidelines recommend higher doses (250 mg daily parenterally for 3–5 days) for patients with signs of malnutrition or a history of not eating properly.19 Still higher doses of thiamine (500 mg three times daily parenterally for at least 2 days followed by 250 mg IM or IV daily for 5 days) have been recommended to treat suspected or diagnosed cases of Wernicke’s encephalopathy and to prevent the development of Korsakoff s syndrome.19 In addition, thiamine administration should always precede administration of any dextrose-containing IV fluids.

Alcohol Withdrawal Delirium (Delirium Tremens)

DTs are another medical emergency that require hospitalization in order to prevent mortality. Parenterally administered benzodiazepines are the treatment of choice.20 DTs are characterized by hallucinations, delirium, severe agitation, fever, elevations of blood pressure and heart rate, and possible cardiac arrhythmias. A sample regimen consists of diazepam 5 mg IV (at 2.5 mg/min) every 5 to 10 minutes until “light somnolence” is achieved, referring to a tendency to fall asleep without stimulation or a light stage of sleep from which the patient is easily awakened. If the first two doses of diazepam are not effective, then 10 mg IV every 5 to 10 minutes can be administered for the third and fourth doses. If still not effective, then up to 20 mg IV may be used thereafter. Once a state of light somnolence is induced, then it should be maintained with diazepam 5 to 20 mg IV every 1 hour as needed. Similarly, lorazepam 1 to 4 mg IV every 5 to 10 minutes or lorazepam 1 to 4 mg IM every 30 to 60 minutes may be given to achieve light somnolence, which is then maintained by similar doses every hour as needed. The antipsychotic, haloperidol, is given only for severe agitation that is unresponsive to benzodiazepine therapy. The evidence does not support the use of an antipsychotic as a single agent.20 Haloperidol may be given as 0.5 to 5 mg IV or IM every 30 to 60 minutes as needed or 0.5 to 5 mg orally every 4 hours as needed. The newer generation antipsychotic agents have not been studied yet for the treatment of DTs. Thiamine should be given according to the same guidelines described above for AWS.

Alcohol Hallucinosis

Alcohol hallucinosis refers to auditory hallucinations that occur during a clear sensorium, which distinguishes it from DTs, during which hallucinations are associated with a reduced clarity of awareness of the environment. Alcohol hallucinosis is generally treated with oral antipsychotics at usual therapeutic dosages for psychosis.

Stimulant Withdrawal (Cocaine Withdrawal and Amphetamine Withdrawal)

Cocaine and amphetamine withdrawal are grouped together because their symptom profiles as described in DSM-IV-TR8 are identical, and the physiologic basis of their withdrawal syndromes involves the DA neurotransmitter system. Stimulants of this group also include methylphenidate, but not nicotine and caffeine, which have different neurophysiologic mechanisms of action. Although neurophysiologic alterations underlie the syndrome of stimulant withdrawal, its symptoms are manifested psychologically for the most part as a depressed or dysphoric mood. Consequently, the major adverse complication of stimulant withdrawal is profound depression with suicidal thoughts, and the major goal of treatment is to prevent suicide. Other symptoms that are commonly associated with the mood disturbance include fatigue, sleep disturbance, increased appetite, psychomotor retardation or agitation, and/or vivid dreaming—although these symptoms are neither life-threatening nor require pharmacologic treatment. Therefore, unless suicidality warrants hospitalization, stimulant withdrawal can be treated on an outpatient basis with psychological support and reassurance.

A number of medications have been studied to alleviate symptoms of stimulant withdrawal and the intense craving that may accompany it, but inconsistent results across controlled trials preclude any recommendations for their routine use. Patients with stimulant use disorders should be referred for substance abuse treatment because of the high risk for continued use either during or immediately following stimulant withdrawal.

Opioid Withdrawal

Almost no one dies from opioid withdrawal per se, however underlying medical complications (e.g., hypertension, recent myocardial infarction, etc.) increase the risk of complications and death. Therefore, it is important to manage and stabilize any medical issues (e.g., uncontrolled blood pressure, diabetes, among others), and then determine if hospitalization is appropriate. Patients with underlying medical problems should be evaluated for possible triage to an inpatient detoxification program, to be followed up with substance abuse treatment on either the inpatient or outpatient level. Rapid referral for substance abuse treatment will help “seize the moment” and introduce patients to the concept of recovery while they still vividly remember the negative consequences from using substances. Withdrawal from opioids is commonly described by patients as resembling “a bad case of the flu” and symptoms include: nausea, vomiting, diarrhea, anxiety, headaches, mydriasis, rhinorrhea, lacrimation, muscle/bone/joint pain, piloerection, yawning, fever, increased heart rate, and hypertension. The use of clinical withdrawal scales such as Clinical Opiate Withdrawal Scale (COWS),21 provides high inter-rater reliability and clinical utility since it is an objective measurement of withdrawal severity. See Table 36–6 for a copy of the COWS. The baseline score helps to make the decision to treat pharmacologically or to observe. A score of less than or equal to five is considered very mild, and these patients usually do not require pharmacologic intervention, although they benefit from a supportive environment and observation. A score of greater than 5 to 12 is considered mild and 13 to 24 is moderate. Patients with scores in these ranges should be managed with a “symptoms-based approach” (see Table 36–7) or initiation of buprenorphine induction/detoxification. A score of 25 to 36 is moderately severe, and a score greater than 36 is considered severe withdrawal. In severe withdrawal, either buprenorphine or a full μ-agonist is recommended for detoxification. Methadone is the most commonly used full μ-agonist but under current U.S. law, methadone detoxification requires referral to a federally approved methadone detoxification program. The two possible options for the treatment of opioid withdrawal in regular clinical settings are symptomatic treatment and μ opioid agonists.

Symptomatic treatment focuses on minimizing the withdrawal symptoms to help patients be as comfortable as possible (see Tables 36–7 through 36–9). This is combined with the use of methadone or buprenorphine (Suboxone or Subutex) to suppress the withdrawal symptoms by providing a μ-opioid full or partial agonist in a tapering dose schedule within a controlled environment.

Treatment with a μ-opioid agonist is accomplished with either buprenorphine or methadone. Buprenorphine is a partial agonist at the μ-opioid receptors that can be used sublingually. It is available in three formulations in the United States, two of which are indicated for the treatment of addiction. Buprenorphine plus naloxone (Suboxone) in ratio of 4:1 (2 mg:0.5 mg or 8 mg:2 mg) is the recommended formulation unless the patient is pregnant or hypersensitive to naloxone, in which case buprenorphine without naloxone (Subutex) is recommended. Naloxone was added to the Suboxone formulation to secure FDA approval in the United States. Because naloxone is poorly absorbed when used sublingually but blocks opioid receptors if injected, this combination is designed to minimize diversion of the drug to the street for IV use. Only 10% of buprenorphine is bioavai-lable if it is swallowed but 50% is bioavailable via the subli-ngual route. An IM/IV preparation of buprenorphine is available in the United States (Buprenex), and its bioavailability reaches 80% if used IM and 100% if used IV. The Buprenex formulation is indicated only for anesthesia and operative pain use, but not detoxification or maintenance of opioid dependence, due to the high risk for abuse and diversion.

Table 36–6 Clinical Opiate Withdrawal Scale

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To initiate a buprenorphine induction, a patient has to be suffering moderate or severe withdrawal, and the last opioid use should be at least 12 to 24 hours earlier, depending on the half-life of the particular opioid (the longer the half-life, the longer a clinician should wait before initiating buprenorphine induction). The score on the COWS should be greater than or equal to five, otherwise buprenorphine likely will induce withdrawal since it has high affinity for μ- receptors and it will displace any other μ-opioid agonist that is present. Also, buprenorphine should not be used in those taking greater than 60 to 80 mg/day of methadone because buprenorphine would have low efficacy; the methadone dose should be decreased below this amount prior to induction of buprenorphine detoxification. Once withdrawal is established, buprenorphine can be started at 2 to 4 mg every 2 hours with a maximum recommended dose of 8 mg the first day. See Table 36–10. The next day, if the patient is still in withdrawal, the first buprenorphine dose should be the total amount required in the previous 24-hour period. Then the dose can be increased gradually every 2 hours up to a maximum of 16 mg. By the third day, the dose can be increased up to 32 mg/day to achieve maximum relief of withdrawal symptoms (see Table 36–10 for a typical induction regimen). Then the dose is tapered down gradually to zero within 1 to 2 weeks (a 25% reduction per day is a general rule of thumb). Methadone, can also be used for opioid detoxification, however, in the United States, this can be done only at a federally approved methadone clinic. Because this drug cannot legally be used for opioid detoxification by the general clinician, methadone detoxification regimens will not be covered here, as they are available elsewhere.22

Table 36–7 A “Symptoms-Based” Treatment Approach for Opioid Withdrawal


This approach includes the use of any single or a combination of two or more of the following agents, depending on the symptoms reported:

(a) Clonidine (Catapres) 0.1–0.2 mg every 6–8 hours blocks the peripheral response and reduces anxiety (shaking, sweating, and piloerection). Patients may be given as-needed doses, maximum dosage not to exceed 1.2 mg in 24 hours. Blood pressure should be monitored prior to each clonidine dose in the clinic. Hold if systolic blood pressure is below 85 mm Hg or diastolic is below 55 mm Hg

Advantages and limitations: Clonidine is a non-narcotic agent that effectively reduces opioid withdrawal. However, lethargy, craving, insomnia, and muscle pains are not as well treated as other withdrawal symptoms, and supplemental medications are often necessary. Patients with low blood pressure may require inpatient treatment. Avoid in pregnant patients; they can be treated with buprenorphine (Subutex, NOT Suboxone) or methadone in a government-licensed program

(b) Dicyclomine (Bentyl) at 20 mg orally every 8–12 hours up to 80 mg/day as needed for abdominal cramps

(c) Loperamide (Imodium) 2-mg capsules; use two capsules by mouth initially, and then one capsule by mouth as needed for diarrhea (max dose 4 capsules/day)

(d) Trimethobenzamide (Tigan) suppository 200 mg; one per rectum daily as needed for nausea or vomiting to help with stomach contractions and cramping

(e) Nonsteroidal anti-inflammatory or analgesic medications (acetaminophen 500 mg–1 g by mouth every 6 hours or ibuprofen 600 mg by mouth every 8 hours or naproxen 600 mg by mouth every 12 hours) for general pain

(f) Benzodiazepines such as lorazepam (Ativan) by mouth 1 mg every 6–8 hours or oxazepam (Serax) 15–30 mg every 6–8 hours to help with anxiety and sleep


Developed by K. Brower and M. Karam-Hage.

Table 36–8 Sample Regimen of Clonidine for Withdrawal From All Opioids except Methadone and Fentanyl (Duragesic) Patches

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Table 36–9 Sample Regimen of Clonidine for Withdrawal From Methadone (Up to 20–30 mg/Day) or Equivalent Fentanyl (Duragesic) Patches

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Table 36–10 Sample Regimena for Buprenorphine Induction Treatment of Opioid Withdrawal

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General Patient Guidelines for Outpatient Opioid Detoxification

When treating opioid with drawal with pharmacologic agents, patient safety is the highest priority. The first step is to educate patients about the course of withdrawal. Symptoms peak at around 5 to 7 days and may last up to 2 weeks. Patients also should be advised regarding the side effects of the drugs used to detoxify. For instance, clonidine causes dizziness from low blood pressure, sedation (which may impair driving or operating heavy machinery), and dry mouth. There is also an overdose potential if clonidine is mixed with opioids or other CNS sedatives or antihypertensives. The risk of these adverse events needs to be balanced with potential benefits. The side effects of buprenorphine include constipation (most commonly), sedation, and headaches. It should also be noted that there is a potential for serious overdose when buprenorphine is mixed with benzodiazepines or other sedative-hypnotics. The risk of developing physiologic tolerance to buprenorphine is high if it is used for prolonged periods. In this case, buprenorphine should be slowly tapered to discontinuation. However, withdrawal from buprenorphine is easier and less severe than withdrawal from a pure agonist, such as methadone.

Successful transition from treatment of withdrawal to treatment of opioid dependence in a rehabilitation setting is the most important challenge for a clinician. Patients often think that all they need is detoxification, but this is not the case because a successful outcome is tied to successful rehabilitation and acquiring recovery skills after detoxification. This goal can be accomplished by either achieving detoxification on site during rehabilitation or by quick and seamless transition of the patient from detoxification to a rehabilitation program. The more time that elapses between the two, the greater the likelihood of failure and return to drug use. This transition is especially important for patients who have engaged in ultrarapid opioid detoxification using naltrexone or naloxone under conscious sedation. These opioid detoxification regimens are experimental and controversial and they are currently considered to be risky procedures due to several reported deaths mainly due to pulmonary edema.23

Nicotine Withdrawal

Smoking cessation counseling should be provided to all smokers, and those interested should be directed and assisted to achieve cessation (Surgeon General Report, July 2000). Furthermore, it is now a standard of practice for clinicians to screen for smoking and provide all smokers with brief advice and assistance with appropriate medications to quit or provide referral to specialized services when needed.24

Symptomatic detoxification from nicotine is achieved with any single or combination of the currently available nicotine replacement therapies (NRTs).25 Several CNS neurotransmitters, are affected by nicotine including: DA, NE, 5-HT, glutamate, GABA, and endogenous opioid peptides. In the brain, nicotine activates nicotinic acetylcholine (nACh) receptors, which are part of the neurotransmitter-gated ion channel family and have crucial neuromodulatory roles in the CNS.26 Nicotine dependence is assessed using the Fagerström test for nicotine dependence, and a score of greater than or equal to 4 is indicative of physical dependence on nicotine.27 Nicotine withdrawal can be measured using any of the available scales (e.g., the Wisconsin scale for nicotine withdrawal). In the United States, the FDA does not have the authority to regulate tobacco products; however, it does regulate all NRT formulations. Some of the NRTs are prescription-only (Rx), and some are available without prescription; others are available in both forms. The FDA has approved the following NRTs: polacrilex gum (nonprescription), patches (16- or 24-hour; Rx and nonprescription), nasal spray (Rx), buccal inhaler (puffer; Rx), flavored gum (nonprescription), and lozenges (nonprescription). Table 36–11 shows NRT and other smoking cessation products. Non-nicotine medications that are thought to be helpful for craving and maybe even with drawal from nicotine include sustained release bupropion (Zyban or Wellbutrin-SR), varenicline (Chantix or Champix), nortriptyline (Pamelor or Aventyl), and clonidine (Catapres) (see Table 36–11 for specific details and dosing). The sustained release form of the antidepressant bupropion was approved by the FDA with a new name (Zyban) for the treatment of tobacco dependence. It is started 1 to 2 weeks before the quit date. It is begun at 150 mg/day for 3 to 7 days and then increased to 300 mg/day (divided into two doses). Bupropion blocks reuptake of DA and NE. Additionally, it acts as a noncompetitive antagonist on a high-affinity nACh receptor. It reduces nicotine reinforcement, withdrawal, and craving.28 Doubling up the NRTs, i.e., double patch or adding NRTs to each other, is a more effective strategy for certain refractory smokers than either strategy used alone.29 Studies have also suggested that NRTs are safe in certain high-risk patients, such as those with cardiac diseases (i.e., postmyocardial infarction) and pregnant smokers, as long as the risk-to-benefit ratio is favorable. The FDA has approved varenicline, (Chantix), which is a α4β2 nACh partial agonist. Varenicline decreases withdrawal and craving and prevents reinforcing effects of nicotine if the patient relapses, and is at least as effective as bupropion in clinical trials.30 It is started 1 week before the quit date. It is begun at 0.5 mg daily for days 1 to 3, then 0.5 mg twice daily for days 4 to 7, then 1 mg twice daily.

Second-line pharmacotherapies include nortriptyline and clonidine. Clonidine exhibits modest efficacy in smoking cessation trials; two meta-analyses that included a total of 13 placebo-controlled clinical trials indicate that it is superior to placebo, with odds ratios of 2.4 (1.7–32.8) and 2.0 (1.3–3.0).31 Several tricyclic antidepressants (TCAs) that inhibit the reuptake of NE and 5-HT, such as nortriptyline, might facilitate smoking cessation, either alone or in combination with behavioral treatment. However, TCAs have significant disadvantages, including a significant anticholinergic burden, cardiac side effects, and possible lethality in overdose.32

Table 36–11 Pharmacotherapies for Smoking Cessation

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Nonpharmacologic Treatments for Tobacco Cessation

Behavioral treatment delivered by a variety of clinicians (e.g., physician, psychologist, nurse, pharmacist, and dentist) increases abstinence rates. The five As should be applied by all clinicians.24

• Ask if they smoke

• Advise to quit

• Assess motivation for change

• Assist if willing to change

• Arrange for follow-up

The Department of Health and Human Services, in concert with other public health and federal government agencies, has provided general guidelines for smoking cessation (Table 36–12).24

There are in excess of 100 studies validating the use of multimodal behavioral therapies for smoking cessation, either alone or in combination with pharmacologic therapies. Multimodal behavioral therapies without pharmacologic agents achieve double the quit rates compared with controls, and the 6-month efficacy ranges between 20% and 25%. Not every smoker requires the same amount of intervention.

One of the possible future directions in smoking cessation is the controversial notion of substituting smokeless tobacco for cigarettes. The idea is based on the premise that the exposure to most carcinogens in tobacco is a result of formation by pyrolysis during the combustion of tobacco. This approach has not been embraced widely by public health and antitobacco advocates because certain diseases are more prevalent in users of smokeless tobacco, such as gum disease (i.e., gingivitis) and oral (mouth and lip) cancers. Some types of smokeless tobacco products may be safer than others, such as the Swedish Snus (widely available in Sweden and available without prescription in some states in the United States). These contain air-dried and processed tobacco that eliminates most nitrosamines that are produced by bacterial fermentation of tobacco and constitute a major group of carcinogenic substances present in tobacco. Other potentially promising developments in different phases of testing25 include:

Table 36–12 General Guidelines on How to Assist if a Patient Wants to Quit Smoking


Start bupropion-SR (Zyban or Wellbutrin SR) 1–2 weeks before quit date

Help patient set a quit date (one of the most important strategies).

Remove all tobacco products the night before the quit date

Follow-up with patient on the quit date or next day to support self-efficacy

Provide nicotine replacement: patch, nasal spray or mouth inhaler, gum, or lozenge

Identify and help educate a support person (best if ex-smoker).

Educate about the high risk for relapse and how to cope with it: “don’t quit quitting”


From Ref. 24.

• CB1-blockers, rimonabant (under FDA review)

• Combination of nicotine antagonist mecamylamine and bupropion (Quitpack)

• Nicotine vaccine

GENERAL APPROACH TO THE TREATMENT OF SUBSTANCE DEPENDENCE

The overall goals in recovery from addiction are the same for all substances, and they consist of:

• Developing coping skills—establish a balanced lifestyle between stressors and positive healthy rewards

• Developing a sober social network—this can be through 12-step programs or other mutual self-help resources

• Relapse prevention skills and strategies—the recovering addict should develop a menu of options, a toolbox of coping skills

• Addressing and beginning to process prior histories of interpersonal problems/conflicts/abuse

• Searching for a spiritual meaning for one’s life

All of the above correlate with better long-term outcomes. image To facilitate recovery from addiction, it is necessary to utilize a comprehensive biopsychosocial assessment that includes the motivation for change. Pharmacologic treatments are always adjunctive to psychosocial therapy. It is important to remember that mere treatment of withdrawal is not sufficient treatment of DSM-IV-TR dependence (addiction), and that medications are always adjunctive to psychosocial therapy. Comorbid psychiatric conditions such as anxiety, depression, insomnia, pain, and continued smoking should be addressed. All of these conditions increase the risk of relapse to use of drugs. Special precautions are needed when treating dual diagnosis and chronic pain patients with controlled substances.

Nonpharmacologic Therapy

image While pharmacologic agents may help prevent relapse, psychotherapy should be the core therapeutic intervention. MET, CBT, TSF, and contingency management are the best-studied forms of psychotherapy in this group of patients.

Individual Therapy

Traditional psychodynamic therapy in the treatment of addiction often fails, however, the principles of psychodynamic therapy are still valuable and important for a clinician in order to understand patients and help them work through their mechanisms of defense, attachment difficulties, processing grief, and coping with internal and external drives.33 Among the validated and thoroughly studied approaches are the following:

• Enhancing motivation, known as motivational interviewing therapy or MET, is designed to engage patients with basic principles like expressing empathy, highlighting the discrepancy between patient’s ideals and their current behavior, working within the framework of a specific patient’s defenses.

• The development of coping skills is designed to help patients cope with life events, daily stressors, and managing painful affects.

• CBT has the specific goal of learning relapse prevention techniques, such a having a ready “toolbox” to deal with cravings and avoidance of triggers that have lead to relapses in the past.

• Contingency management consists of providing positive rewards for desirable behavior and setting limits and consequences for undesirable behavior.

• Improving interpersonal functioning and enhancing social supports can be accomplished through TSF, or any other mechanism for developing a sober social network.

• Finally, engaging the spouse or significant other, as well as the nuclear family, is a very important aspect in the initial stages, as well as in consolidating recovery. One such therapy is BCT.

Group Therapy

Group therapy for substance abuse/dependence includes more than three people (ideally eight to ten) who interact in the same room for 90 to 120 minutes. Group therapy provides patients with the opportunity to bond with others and the advantages of this can be mutual identification, dealing with shame and guilt, minimizing isolation and the provision of peer acceptance and role modeling, realistic feedback, and optimism and hope for future. The disadvantages are: a lack of focus on a particular person’s problem, the discussion is not always pertinent to every member, and scheduling times are inflexible. It is also not very successful in small communities where people might know each other prior to formation of the group, and or for people with certain personality disorders such as borderline, schizoid, avoidant, or paranoid.33

Pharmacologic Therapy

Maintenance Treatment

image Certain pharmacologic agents have been helpful in the treatment of withdrawal and in drug maintenance programs. Remaining sober following the treatment of withdrawal is extremely difficult. This is probably related to a complex interaction of biological factors (craving), social factors (lack of employment, lack of a sober social network), and psychological factors (lack of the ability to cope with negative emotions without resorting to drug use). Long-term use of medications to help achieve a reduction in drug craving or to maintain a steady state of legally supervised and predictable drug use may have a better long-term outcome than immediate abstinence. The ultimate goal is always abstinence, but these strategies may allow time to develop new behavioral strategies and a social network within which the patient will be more likely to achieve long-term sobriety.

Alcohol Dependence

Currently the three FDA-approved medications that are indicated to treat alcohol dependence are disulfiram, naltrexone, and acamprosate. Both disulfiram and acamprosate are indicated in patients who have already achieved initial abstinence. Only naltrexone may be initiated without regard to abstinence status.

Disulfiram

First marketed in the United States in the 1950s, disulfiram works by irreversibly blocking the enzyme aldehyde dehydrogenase, a step in the metabolism of alcohol, resulting in increased blood levels of the toxic metabolite acetaldehyde. As levels of acetaldehyde increase, the patient experiences decreased blood pressure, increased heart rate, chest pain, palpitations, dizziness, flushing, sweating, weakness, nausea and vomiting, headache, shortness of breath, blurred vision, and syncope. These effects are commonly referred to as the disulfiram-ethanol reaction. Their severity increases with the amount of alcohol that is consumed, and they may warrant emergency treatment. Disulfiram is contraindicated in patients who have cardiovascular or cerebrovascular disease or in combination with antihypertensive medications, because the hypotensive effects of the disulfiram-alcohol reaction could be fatal in such patients. Disulfiram is relatively contraindicated in patients with diabetes, hypothyroidism, epilepsy, liver disease, and kidney disease, as well as impulsively suicidal patients.

Psychologically, disulfiram works through negative reinforcement, and drinking is avoided to prevent the aversive disulfiram-ethanol reaction. The classic study by Fuller et al. demonstrated that the efficacy of disulfiram was compromised by noncompliance.34 Although that randomized controlled trial is widely cited as a negative study, because no difference between the three groups (disulfiram 250 mg daily, disulfiram 1 mg daily, and no disulfiram) was found for continuous abstinence rates over a 1-year follow-up period, the 250 mg group drank on significantly fewer days (49 days) during that 1-year period than the other groups (75.4 and 86.5 days for the 1-mg disulfiram and no disulfiram groups, respectively). Other controlled trials have demonstrated that disulfiram can be highly effective when procedures for enhancing compliance are employed, such as supervised administration.35 This may be particularly true when supervised administration is coupled with receiving incentives, such as described above for contingency management techniques, BCT, and the community reinforcement approach.

The usual starting dose of disulfiram is 250 mg/day orally, and the range is 125 to 500 mg daily. Compared to 250 mg daily, the larger dose is recommended in the absence of a disulfiram-ethanol reaction, and the smaller dose is given when intolerable side effects are experienced. Dosing begins only after the BAL is zero (usually 12–24 hours after the last drink) and after the patient understands the consequences of the disulfiram-ethanol reaction. The most common side effects are rash, drowsiness, metallic or garlic-like taste, and headache. If drowsiness occurs, the dose may be lowered or given at night. Other adverse effects include optic neuritis and peripheral neuropathy. Because of potential hepatotoxicity with disulfiram including rare cases of fulminant liver failure, estimated at 1 in 25,000 treated patients,35 baseline liver function tests (LFTs) and periodic monitoring are recommended. If serum levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are greater than three times normal values, then disulfiram should be withheld and the tests repeated every 1 to 2 weeks until they are normal. Once LFTs are within prescribing range, they may be repeated every 1 to 6 months. Although elevated LFTs may signal disulfiram-induced hepatotoxicity, the more likely cause in clinical practice is noncompliance and ethanol-induced hepatotoxicity. Alcohol-dependent patients are also at high risk for viral hepatitis. Another uncommon side effect of disulfiram is psychosis, which has been reported in doses exceeding 500 mg daily, especially in predisposed patients. Nevertheless, alcohol-dependent patients with schizophrenia and other cooccurring mental disorders have received disulfiram at usual therapeutic doses without difficulties.36

Drug Interactions. The disulfiram-ethanol interaction is described above. Depending on the dose of disulfiram, sensitivity to disulfiram, amount of alcohol consumed, and metabolism, patients may be at risk for an adverse interaction with alcohol for 2 to 14 days after stopping disulfiram (5 days on average) and should be warned accordingly. See Table 36–4 for additional drug-drug interactions with disulfiram.

Naltrexone

Naltrexone is a competitive opioid antagonist, especially at μ-opioid receptors, that decreases alcohol intake in both animals and humans. There is evidence that it works by decreasing both craving for alcohol and alcohol-induced euphoria. The large majority of over 15 double-blind randomized controlled trials of naltrexone versus placebo demonstrate its moderate efficacy for decreasing relapse to heavy drinking,37 but not for decreasing rates of total continuous abstinence. Both oral and sustained release injections of naltrexone are approved in the United States for the treatment of alcohol dependence. The usual therapeutic dose of oral naltrexone is 50 mg/day, with a range from 25 to 100 mg. The 25-mg dose is commonly given initially as a test dose to minimize side effects, especially nausea, and then increased to 50 mg daily as tolerated. An alternate dosing regimen is 100 mg on Mondays, 100 mg on Wednesdays, and 150 mg on Fridays, which is most conducive for patients taking naltrexone under conditions of supervised observation. Adherence to daily doses of naltrexone strongly affects both the days to relapse to heavy drinking and days of continuous abstinence. Because of this, a sustained release IM injection of naltrexone, designed to be given once monthly, has been marketed. A 380-mg monthly injection of naltrexone (Vivitrol) resulted in a significantly greater reduction in heavy drinking days compared to placebo injection.38 The major disadvantage of injectable naltrexone at this time is the high cost (approximately $700 per month).

Because naltrexone can precipitate withdrawal in patients dependent on opioids, the first dose should be withheld for 7 to 10 days following the last use of opioids and given only when the urine drug screen for opioids is negative. Also, naltrexone can be hepatotoxic, albeit typically not at oral doses less than 250 mg daily or at the recommended injectable dose of 380 mg per month. Nevertheless, the same guidelines for monitoring LFTs as with disulfiram (described above) are recommended. The most common side effects are nausea, headache, fatigue, and nervousness. Injectable naltrexone is also associated with injection site pain or reactions. It is important for patients to carry a pocket warning card or wear a warning bracelet because, in the event that emergency treatment is needed, they will be insensitive to opioid analgesia unless usually toxic doses are administered. Patients need to be warned of the potential for an opioid overdose under two different conditions. First, dosing with opioids to reverse opioid insensitivity (i.e., naltrexone’s competitive blockade of opioid receptors) requires very high doses of opioids that can cause respiratory depression and death. Second, chronic antagonist therapy with naltrexone may cause patients to become hypersensitive to opioid drugs after stopping naltrexone, thereby facilitating respiratory depression and death when opioids are used.

Reported predictors of naltrexone efficacy include, a family history of alcoholism, early age at onset of drinking problems, high levels of the active metabolite, β-naltrexol, and medication adherence.39Combining naltrexone with disulfiram had no advantage over either medication alone in one study of alcohol-dependent patients with comorbid psychiatric disorders.36 Combining naltrexone with acamprosate is discussed below in the section on acamprosate. Combining naltrexone with CBT possibly may have an advantage over combining naltrexone with other psychotherapies.40

Drug Interactions. Naltrexone can theoretically increase the risk of hepatotoxicity if combined with disulfiram, although in practice this was not demonstrated.36 As mentioned above, it can reverse the effects of opioid receptor agonists, rendering them therapeutically ineffective. Finally, somnolence and lethargy have been reported in combination with the antipsychotic, thioridazine. See Table 36–4 for drug-drug interactions.

Acamprosate

Acamprosate is an NMDA receptor antagonist that was approved by the FDA in 2004, but it has been available in Europe for nearly 20 years and is also available in Canada. Alcohol use acutely inhibits NMDA receptors and chronically causes upregulation of NMDA receptors. During alcohol withdrawal and postacute alcohol withdrawal, increased activity of the NMDA system is caused by upregulation of receptors and the absence of alcohol-related inhibition. Acamprosate is believed to modulate and normalize the NMDA receptor system, although it is ineffective in diminishing acute withdrawal symptoms. It may also have some GABA-enhancing activity.

The efficacy of acamprosate has been extensively reviewed.41 In contrast to both disulfiram and naltrexone, acamprosate increases continuous abstinence rates in alcohol-dependent patients for periods of 3 to 12 months.41 Project COMBINE used a large-scale, randomized, controlled trial to compare acamprosate and naltrexone to each other and to a combination of both drugs.42 Medical management alone was also compared to medical management in combination with a “combined behavior intervention” (consisting of elements from CBT, MET, and TSF). In this study naltrexone alone was more effective than placebo, and the addition of combined behavior intervention to naltrexone significantly increased efficacy. However, in this study, acamprosate alone or with combined behavior intervention was no more effective than placebo, nor did the addition of acamprosate to naltrexone increase time to first heavy drinking day. A recent meta-analysis concluded that acamprosate may be more effective at promoting complete abstinence, whereas naltrexone may more effectively prevent relapses to heavy drinking.43

The therapeutic dose of acamprosate is 666 mg orally three times daily, and it is supplied as a 333-mg tablet. It can be started at the full dose in most patients without titration. It is not metabolized by the liver and is excreted unchanged by the kidneys. Consequently, it is contraindicated in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min), and dose reduction is necessary when the creatinine clearance is between 30 and 50 mL/min. The most common side effects are GI and include nausea and diarrhea. Rates of suicidal thoughts were also increased in patients treated for 1 year with acamprosate (2.4%) versus placebo (0.8%). If necessary, the dose may be decreased by 333 to 999 mg/day to alleviate side effects.

Drug Interactions. Naltrexone can increase blood levels of acamprosate by increasing its absorption, but the clinical significance of this is not known.

Other Agents

Anticonvulsants, especially topiramate, and serotonergic drugs, especially ondansetron, showed promise in initial, well-designed, randomized, controlled trials.44 Further studies are needed. Buspirone is well-studied, but results are inconsistent. Finally, a recent metaanalysis of antidepressants to treat alcohol dependence with or without comorbid depression, concluded that any beneficial effects were modest at best.45

Stimulant Dependence

There are no proven pharmacotherapies for treatment of cocaine or amphetamine dependence. Disulfiram, however, shows some promise in randomized, controlled trials for treating cocaine dependence at doses of 250 mg daily, especially in combination with CBT.46 Its mechanism of action for treating cocaine dependence is not known, but may be due to its inhibition of the dopamine β-hydroxylase enzyme that converts DA to NE in the brain. The resulting increase in DA levels may counter the DA deficiency state that is believed to underlie cocaine withdrawal and craving.

Opioid Dependence

In certain patients who have failed one or more abstinence-based treatments for opioid dependence, maintenance treatment might be the best possible option.

After the conclusion of withdrawal, some patients still do not feel their usual selves for a long time and may relapse to using opioids again, just to “feel normal.” Long-term use of opioids results in changes in the brain, and the brain might not readily return to its prior homeostasis. Since the goal of treatment is to encourage stability, both in the body and in the patient’s life, if an individual is not successful in tapering off of opioids because of a reemergence of severe withdrawal or a return to opioid use then maintenance treatment should be considered.

Opioid Agonists

The time-honored opioid agonist treatment for opioid dependence is methadone maintenance, which is beyond the scope of this chapter. Methadone maintenance can be provided only in officially designated and approved methadone clinics. The Office-Based Opioid Treatment (OBOT) exclusively utilizes buprenorphine, a partial μ agonist.21 The effective maintenance dose of buprenorphine (Suboxone) is usually between 8 and 16 mg/day, with maximum reported efficacy at 64 mg/day. Patients receiving buprenorphine maintenance should sign a treatment contract requiring full compliance, financial responsibility for treatment, adherence to office policies, respectful behavior to staff, agreement to provide random urine samples for drug screens, and patients should bring their bottles for pill counts at every visit. In the event of failure of OBOT, the alternative to buprenorphine maintenance is a referral to an approved methadone clinic where methadone is used at minimal effective doses of 80 mg/day or higher. Under the provisions of the OBOT law, physicians may prescribe buprenorphine (Suboxone or Subutex) in their office if they meet requirements of expertise in the area of substance abuse or if they receive 8 hours of approved training.21 In either case a registration with the Drug Enforcement Administration (DEA) to obtain a specially designated DEA number is needed after receiving a “waiver.”

Opioid Antagonists

Naloxone, naltrexone, and nalmefene (not available yet in the United States for clinical use) can be used to reinforce abstinence. The long-acting naltrexone is especially ideal for health professionals or others who are highly motivated or face major consequences if they do not maintain their abstinence. It is important not to initiate an antagonist until the withdrawal period is over and after 7 to 12 days from the last use of opioid agonists. This is necessary to avoid precipitating more severe withdrawal due to hypersensitive or upregulated opioid receptors as a result of prior long-term or heavy use of opioid agonists. Naloxone can be used 0.2 to 0.4 mg SC (naloxone challenge) to test if an individual is indeed abstinent and to make sure it does not induce withdrawal before giving the longer-acting oral naltrexone, although this technique is rarely used in actual practice. Most opioid-dependent patients will be honest about how recently they have used when (a) they understand that severe withdrawal is a consequence of premature naltrexone administration, and (b) a urine drug test is obtained.


Patient Encounter 3

A 19-year-old man has undergone detoxification of his three-bags-per-day addiction to heroin. The detoxification regimen began when he had been heroin-free for 24 hours and was undergoing some mild withdrawal symptoms. He was begun on 8 mg daily of sublingual buprenorphine and the dose of buprenorphine was slowly tapered off during the next 4 weeks. He had begun snorting heroin at about 15 years of age and eventually had progressed to injecting his daily heroin. He dropped out of high school at 17 years of age, prior to graduation, and has never worked, except once in a fast-food restaurant for a 2-week period. Since achieving abstinence he has come to realize that he has no legal means of earning a living and he is reluctant to return home to his parents because they have recently divorced. He feels he is worthless and has wasted his life up to now.

What are the most immediate concerns regarding this young man’s newly achieved abstinence?

How can he be helped to maintain abstinence?


OUTCOME EVALUATION

To determine immediate treatment outcomes for patients with intoxication and withdrawal syndromes, evaluate parameters such as blood pressure, heart rate, respirations, and body temperature as well as mental state. Choose from a number of validated and standardized rating scales to monitor the responsiveness of withdrawal syndromes to medical treatment. To determine the overall effectiveness of your health system for the treatment of substance abuse and dependence, you could monitor outcomes using sentinel events such as the rates of cardiopulmonary arrest, seizures, discharges against medical advice, patient violence, and use of physical restraints. The ultimate goal should be to enable the transition of patients to formal substance abuse treatment when indicated because this is the optimal outcome of treatment for substance-induced intoxications and withdrawals.

image A major component of successful treatment of addiction is to continue monitoring the use of medications designed to decrease craving or to block the hedonic effects of abused substances, such as disulfiram, naltrexone, or acamprosate. Also, it is important to identify a mechanism for long-term support of sobriety that might be appropriate for a specific individual such as AA, a spiritual group, or professional recovery programs for professionals such as doctors, nurses, police officers, etc.

Important outcome indicators to evaluate postintoxication and/or postwithdrawal treatment can be divided into three major groups: decreased consumption of substances, decreased problems associated with substance use, and improved psychosocial functioning. Although it is less commonly employed, a quality of life scale can help determine how substance abuse/dependence treatment has affected your patients’ lives. If you are involved in the cost-justification of services, a cost-benefit analysis could also become important, although this is more often used at the administrative level, than the patient care level. In cases where complete abstinence has not been achieved, quantify the consumption of substances using: quantity-frequency measures, rates of abstinence, and time to first relapse as determined by interviews and self-report, and by biological markers such as urine and blood tests. One example of an instrument to measure alcohol-related problems is the drinker inventory of consequences.47 Another scale that you could use to determine the severity of alcohol-related problems is the addiction severity index, which measures problems associated with any type of substance dependence across a variety of dimensions, including legal, family, psychiatric, medical, and social.48 If you are concerned about the effects of substance abuse or dependence on cognitive abilities in an older adult, the mini-mental state examination is a commonly used scale. Scores of 26 and higher are generally considered to indicate acceptable cognitive ability with regard to every day functioning.49Quantify overall psychosocial functioning using the global assessment of functioning scale, which is readily accessible in DSM-IV-TR.8

Abbreviations Introduced in This Chapter

Image


Patient Care and Monitoring

1. By evaluating the patient’s history and symptoms, determine if substance intoxication, or withdrawal are likely.

2. If drug intoxication is the likely scenario:

• Conduct a physical exam, and obtain blood pressure, heart and respiratory rate, and body temperature.

• In most cases, management of intoxication is supportive. The most important goal is to maintain cardiopulmonary function. If consciousness is impaired, obtain blood chemistries and administer IV glucose and thiamine (100-250 mg).

• Cocaine or stimulant intoxication may require administration of a small dose of a short-acting benzodiazepine (e.g., lorazepam 1–2 mg) for agitation or severe anxiety. Antipsychotics (e.g., haloperidol 2–5 mg) should be used only if psychosis is present. If hyperthermia is present, initiate cooling measures.

• Observe the patient until the intoxication has resolved (if alcohol, the BAL should be less than 80 mg/dL [0.08% or 17.4 mmol/L]). Encourage the patient to consider treatment for substance abuse, especially if this is not the first episode of intoxication.

3. If substance withdrawal is the likely scenario:

• Determine from which substance or substances the patient is withdrawing.

• Conduct a physical exam to determine if medical problems are present.

• If withdrawal is from alcohol administer the CIWA-Ar to determine withdrawal severity. A score of 8 to 10 denotes relatively mind withdrawal, and the patient can be treated as an outpatient with supportive care only. A patient with score from 11 to 14 can be treated on either an outpatient or inpatient basis, with either supportive care or with benzodiazepines, depending on the presence of underlying medical problems and the prior history of the severity of withdrawal. A score greater than or equal to 15 merits strong consideration of inpatient treatment combined with medications. Those with a score of 20 or greater should always be treated in an inpatient setting with medications.

• Always treat AWS or DTs in the inpatient setting. The drug of choice for both is a benzodiazepine.

• Withdrawal from opioids is uncomfortable but unlikely to be fatal unless the patient has underlying medical problems. Administer the COWS to determine the severity of withdrawal. Those with a score of 5 or less require no pharmacologic intervention, while those with scores from 6 to 24 are likely to benefit from either a symptoms-based approach or the initiation of buprenorphine. Those with scores greater than 25 should receive either buprenorphine or an alternative full μ agonist.

4. Withdrawal from nicotine is treated in the outpatient setting. Symptomatic detoxification from nicotine is achieved with any single or combination of NRTs. Additional non-nicotine medications, such as bupropion, varenicline, nortriptyline, or clonidine may be helpful to reduce craving and various other withdrawal symptoms. Combining behavioral therapy with sobriety, utilizes both nonpharmacologic and pharmacologic means. pharmacologic treatment increases the abstinence rate.

5. The overall goals in recovery from addiction are the same for all substances and include improved coping skills and relapse prevention. To achieve long-term recovery:

• Consider initiation of buprenorphine or methadone maintenance treatment for opioid dependence. In the United States, buprenorphine is easier to arrange since physicians can be approved to prescribe buprenorphine following a short course of federally approved training.

• Disulfiram (250 mg/day) can be used to promote abstinence from alcohol. Acamprosate and naltrexone can be used to decrease craving for alcohol but are not likely to result in complete abstinence from alcohol use.


Image


image Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.


REFERENCES

1. Substance Abuse and Mental Health Services Administration. Results from the 2006 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-32, DHHS Publication No. SMA 07–4293). Rockville, MD, 2007.

2. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring the Future national study results on adolescent drug use: Overview of key findings, 2007. (NIH Publication No. 08–6418) Bethesda, MD: National Institute on Drug Abuse, 2008:11.

3. http//www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts/AlcoholDependence/abusdep2.htm

4. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-30, DHHS Publication No. (SMA) 08–4339. Rockville, MD, 2008.

5. The National Institute on Drug Abuse. The Neurobiology of Drug Addiction. http://www.drugabuse.gov/pubs/Teaching/

6. Kelly AE, Berridge KC. The neuroscience of natural rewards: Relevance to addictive drugs. J Neurosci 2002;22:3306–3311.

7. Koob GF, Ahmed SH, Boutrel B, et al. Neurobiological mechanisms in transition from drug use to drug dependence. Neurosci Behav Rev 2004;27:739–749.

8. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision. Arlington: American Psychiatric Publishing, 2000.

9. Rastegar DA, Fingerhood MI. Addiction Medicine: An Evidence-based Handbook. Chapter 5. Alcohol. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:36–75.

10. Knapp CM, Ciraulo DA, Jaffe J. Opiates: Clinical aspects. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds. Substance Abuse, A Comprehensive Textbook, 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:180–195.

11. Gold MS, Jacobs WS. Cocaine and crack: Clinical aspects. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds. Substance Abuse: A Comprehensive Textbook, 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:218–251.

12. Rustin TA. Management of nicotine withdrawal. In: Graham AW, Schultz TK, eds. Principles of Addiction Medicine, 2nd ed. Chevy Chase: American Society of Addiction Medicine 1998:487–495.

13. Hansten PD, Horn JR. Drug Interactions, Analysis and Management. St. Louis: Wolters Kluwer Health, 2008:1–1015.

14. Henderson L, Yue QY, Bergquist C, et al. St. John’s wort (hypericum perforatum): Drug interactions and clinical outcomes. Br J Clin Pharmacol 2002;54:349–356.

15. Michalets E. Update: Clinically significant cytochrome p-450 drug interactions. Pharmacotherapy 1998;18:84–112.

16. Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: The revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). Addiction 1989;84:1353–1357.

17. Chang G, Kosten TR. Detoxification. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, eds. Substance Abuse: A Comprehensive Textbook, 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:579–587.

18. Daeppen JB, Gache P, Landry U, et al. Symptom-triggered vs fixed-schedule doses of benzodiazepine for a lcohol withdrawal: A randomized treatment trial. Arch Intern Med 20 02;162:1117–1121.

19. Lingford-Hughes AR, Welch S, Nutt DJ. Evidence-based guidelines for the pharmacological management of substance misuse, addiction and comorbidity: Recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2004;18:293–335.

20. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004;164:1405–1412.

21. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication no. (SMA) 04–3939. Rockville MD: Substance Abuse and Mental Health Services Administration, 2004.

22. Dole VP, Nyswander ME. A medical treatment for diacetyl-morphine (heroin) addiction. JAMA 1965;193:646–650.

23. O’Connor PG, Fiellin DA. Pharmacologic treatment of heroin-dependent patients. Ann Int Med 2000;133:40–54.

24. The Tobacco Use and Dependence Clinical Practice Guidelines Panel, Staff, and Consortium Representatives. A clinical practice guideline for treating tobacco use and dependence. A US public health service report. JAMA 2000;283:3244–3254.

25. Nides, M. Update on pharmacologic options for smoking cessation treatment. Am J Med 2008;121:S20–S31.

26. Picciotto MR, Caldarone BJ, King SL, Zachariou V. Nicotinic receptors in the brain: Links between molecular biology and behavior. Neuropsychopharmacology 2000;22:451–465.

27. Heatherton TF, Kozlowski LT, Fecker RC, Fägerstrom KO. The Fägerstrom test for nicotine dependence: A revision of the Fägerstrom tolerance questionnaire. Br J Addict 1991;86:1119–1127.

28. Slemmer JE, Martin BR, Damaj MI. Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 2000;295:321–327.

29. Sweeney CT, Fant RV, Fägerstrom KO, et al. Combination nicotine replacement therapy for smoking cessation: Rationale, efficacy and tolerability. CNS Drugs 2001;15:453–467.

30. Hays, JT, Ebbert, JO, Sood, A. Efficacy and safety of varenicline for smoking cessation. Am J Med 2008;121:S32–S42.

31. Covey LS, Glassman AH. A meta-analysis of double-blind placebo-controlled trials of clonidine for smoking cessation. Br J Addict 1991;86:991–998.

32. Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML. Pharmacotherapy for nicotine dependence. CA Cancer J Clin 2005;55:281–299.

33. Galanter M, Kleber HD: Textbook of Substance Abuse Treatment, 4th ed. Washington, DC: American Psychiatric Publishing, 2008.

34. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism. A veterans administration cooperative study. JAMA 1986;256:1449–1455.

35. Fuller RK, Gordis E. Does disulfiram have a role in alcoholism treatment today? Addiction 2004;99:21–24.

36. Petrakis IL, Poling J, Levinson C, et al. Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders. Biol Psychiatry 2005;57:1128–1137.

37. Srisurapanont M, Jarusuraisin N. Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol 2005;8:267–280.

38. Garbutt JC, Kranzler HR, O’Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: A randomized controlled trial. JAMA 2005;293:1617–1625.

39. Rubio G, Ponce G, Rodriguez-Jimenez R, et al. Clinical predictors of response to naltrexone in alcoholic patients: Who benefits most from treatment with naltrexone? Alcohol Alcohol 2005;40:227–233.

40. Anton RF, Moak DH, Latham P, et al. Naltrexone combined with either cognitive behavioral or motivational enhancement therapy for alcohol dependence. J Clin Psychopharmacol 2005;25:349–357.

41. Mann K, Lehert P, Morgan MY. The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: Results of a meta-analysis. Alcohol Clin Exp Res 2004;28:51–63.

42. COMBINE Study Research Group. Combined pharmacotherapies and behavior interventions for alcohol dependence, the COMBINE study: A randomized controlled trial. JAMA 2006;295:2003–2017.

43. Rösner S, Leucht S, Ehert P, Soyka M. Acamprosate supports abstinence, naltrexone prevents excessive drinking: Evidence from a meta-analysis with unreported outcomes. J Psychopharmacol 2008;22:11–23.

44. Johnson BA. An overview of the development of medications including novel anticonvulsants for the treatment of alcohol dependence. Expert Opin Pharmacother 2004;5:1943–1955.

45. Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: A meta-analysis. JAMA 2004;291:1887–1896.

46. Carroll KM, Fenton LR, Ball SA, et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: A randomized placebo-controlled trial. Arch Gen Psychiatry 2004;61:264–272.

47. Miller WR, Tonigan JS, Longabaugh R. The drinker inventory of consequences (DrInc): An instrument for assessing adverse consequences of alcohol abuse. National Institute on Alcohol Abuse and Alcoholism Project MATCH Monograph Series, Vol. 4. Rockville, MD: National Institutes of Health (Publication No. 95–3911), 1995.

48. McLellan AT, Kushner H, Metzger D, et al. The fifth edition of the addiction severity index. J Subst Abuse Treat 1992;9:199–213.

49. Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA 1993;269:2386–2391.