Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II
Neuropharmacology

chapter 24
Drug Addiction

The terminology used in discussing drug dependence, abuse, and addiction has long been confusing. Confusion stems from the fact that repeated use of certain prescribed medications can produce neuroplastic changes resulting in 2 distinctly abnormal states. The first is dependence, or “physical” dependence, produced when there is progressive pharmacological adaptation to the drug resulting in tolerance. In the tolerant state, repeating the same dose of drug produces a smaller effect. If the drug is abruptly stopped, a withdrawal syndrome ensues in which the adaptive responses are now unopposed by the drug. The appearance of withdrawal symptoms is the cardinal sign of “physical” dependence. Addiction, the second abnormal state produced by repeated drug use, occurs in only a minority of those who initiate drug use; addiction leads progressively to compulsive, out-of-control drug use.

Addiction can be defined fundamentally as a form of maladaptive memory. It begins with the administration of substances (e.g., cocaine) or behaviors (e.g., the thrill of gambling) that directly and intensely activate brain reward circuits. Activation of these circuits motivates normal behavior and most humans simply enjoy the experience without being compelled to repeat it. For some (~16% of those who try cocaine) the experience produces strong conditioned associations to environmental cues that signal the availability of the drug or the behavior. The individual becomes drawn into compulsive repetition of the experience focusing on the immediate pleasure despite negative long-term consequences and neglect of important social responsibilities. The distinction between dependence and addiction is important because patients with pain sometimes are deprived of adequate opioid medication simply because they have shown evidence of tolerance or they exhibit withdrawal symptoms if the analgesic medication is stopped or reduced abruptly.

ORIGINS OF SUBSTANCE DEPENDENCE

Most of those who initiate drug use do not progress to become addicts. Many variables operate simultaneously to influence the likelihood that a beginning drug user will lose control and develop an addiction. These variables can be organized into 3 categories: agent (drug), host (user), and environment (Table 24–1).

Table 24–1

Multiple Simultaneous Variables Affecting Onset and Continuation of Drug Abuse and Addiction

images

AGENT (DRUG) VARIABLES. Reinforcement refers to the capacity of drugs to produce effects that make the user wish to take them again. The more strongly reinforcing a drug is, the greater is the likelihood that the drug will be abused. Reinforcing properties of drugs are associated with their capacity to increase neuronal activity in critical brain areas (see Chapter 14). Cocaine, amphetamine, ethanol, opiates, cannabinoids, and nicotine all reliably increase extracellular fluid dopamine (DA) levels in the ventral striatum, specifically the nucleus accumbens region. In contrast, drugs that block DA receptors generally produce bad feelings, i.e., dysphoric effects. Despite strong correlative findings, a causal relationship between DA and euphoria/dysphoria has not been established, and other findings emphasize additional roles of serotonin (5HT), glutamate, norepinephrine (NE), endogenous opioids, and γ-aminobutyric acid (GABA) in mediating the reinforcing effects of drugs.

The abuse liability of a drug is enhanced by rapidity of onset. When coca leaves are chewed, cocaine is absorbed slowly and this produces low cocaine levels in the blood and few, if any, behavior problems. Crack, sold illegally and at a low price ($1-3 per dose), is alkaloidal cocaine (free base) that can be readily vaporized by heating. Simply inhaling the vapors produces blood levels comparable to those resulting from intravenous cocaine owing to the large surface area for absorption into the pulmonary circulation following inhalation. Thus, inhalation of crack cocaine is much more addictive than chewing, drinking, or sniffing cocaine. The risk for developing addiction among those who try nicotine is about twice that for those who try cocaine (Table 24–2). This does not imply that the pharmacological addiction liability of nicotine is twice that of cocaine. Rather, there are other variables listed in the categories of host factors and environmental conditions that influence the development of addiction.

Table 24–2

Dependence among Users 1990–1992

images

HOST (USER) VARIABLES. Effects of drugs vary among individuals. Polymorphism of genes that encode enzymes involved in absorption, metabolism, and excretion and in receptor-mediated responses may contribute to the different degrees of reinforcement or euphoria observed among individuals (see Chapters 6 and 7). Innate tolerance to alcohol may represent a biological trait that contributes to the development of alcoholism (see Chapter 23). While innate tolerance increases vulnerability to alcoholism, impaired metabolism may protect against it (see Chapter 23). Similarly, individuals who inherit a gene associated with slow nicotine metabolism may experience unpleasant effects when beginning to smoke and reportedly have a lower probability of becoming nicotine dependent.

Psychiatric disorders constitute another category of host variables. People with anxiety, depression, insomnia, or even shyness may find that certain drugs give them relief. However, the apparent beneficial effects are transient, and repeated use of the drug may lead to tolerance and eventually compulsive, uncontrolled drug use. While psychiatric symptoms are seen commonly in drug abusers presenting for treatment, most of these symptoms begin after the person starts abusing drugs. Thus, drugs of abuse appear to produce more psychiatric symptoms than they relieve.

ENVIRONMENTAL VARIABLES. Initiating and continuing illegal drug use is influenced significantly by societal norms and peer pressure.

PHARMACOLOGICAL PHENOMENA

TOLERANCE. Tolerance, the most common response to repetitive use of the same drug, can be defined as the reduction in response to the drug after repeated administrations. Figure 24–1 shows an idealized dose-response curve for an administered drug. As the dose of the drug increases, the observed effect of the drug increases. With repeated use of the drug, however, the curve shifts to the right (tolerance). There are many forms of tolerance likely arising through multiple mechanisms.

images

Figure 24–1 Shifts in a dose-response curve with tolerance and sensitization. With tolerance, there is a shift of the curve to the right such that doses higher than initial doses are required to achieve the same effects. With sensitization, there is a leftward shift of the curve such that for a given dose, there is a greater effect than seen after the initial dose.

Tolerance to some drug effects develops much more rapidly than to other effects of the same drug. For example, tolerance develops rapidly to the euphoria produced by opioids such as heroin, and addicts tend to increase their dose in order to reexperience that elusive “high.” In contrast, tolerance to the GI effects of opioids develops more slowly. The discrepancy between tolerance to euphorigenic effects (rapid) and tolerance to effects on vital functions (slow), such as respiration and blood pressure, can lead to potentially fatal overdoses.

Innate tolerance refers to genetically determined lack of sensitivity to a drug that is observed the first time that the drug is administered. Acquired tolerance can be divided into 3 major types: pharmacokinetic, pharmacodynamic, and learned tolerance, and includes acute, reverse, and cross-tolerance. Pharmacokinetic or dispositional tolerance refers to changes in the distribution or metabolism of a drug after repeated administrations such that a given dose produces a lower blood concentration than the same dose did on initial exposure. The most common mechanism is an increase in the rate of metabolism of the drug. For example, barbiturates stimulate the production of higher levels of hepatic CYPs, causing more rapid removal and breakdown of barbiturates from the circulation.

Pharmacodynamic tolerance refers to adaptive changes that have taken place within systems affected by the drug so that response to a given concentration of the drug is reduced. Examples include drug-induced changes in receptor density or efficiency of receptor coupling to signal-transduction pathways (see Chapter 3). Learned tolerance refers to a reduction in the effects of a drug due to compensatory mechanisms that are acquired by past experiences. One type of learned tolerance is called behavioral tolerance. A common example is learning to walk a straight line despite the motor impairment produced by alcohol intoxication. At higher levels of intoxication, behavioral tolerance is overcome, and the deficits are obvious.

Conditioned tolerance (situation-specific tolerance) develops when environmental cues or situations consistently are paired with the administration of a drug. When a drug affects homeostatic balance by producing sedation and changes in blood pressure, pulse rate, gut activity, and so on, there is usually a reflexive counteraction or adaptation in the direction of maintaining the status quo. If a drug always is taken in the presence of specific environmental cues (e.g., smell of drug preparation and sight of syringe), these cues begin to predict the effects of the drug, and the adaptations begin to occur, which will prevent the full manifestation of the drug’s effects (i.e., cause tolerance). This mechanism follows classical (pavlovian) principles of learning and results in drug tolerance under circumstances where the drug is “expected.”

Acute tolerance refers to rapid tolerance developing with repeated use on a single occasion, such as in a “binge.” For example, repeated doses of cocaine over several hours produce a decrease in response to subsequent doses of cocaine during the binge. This is the opposite of sensitization, observed with an intermittent dosing schedule. Sensitization or reverse tolerance refers to an increase in response with repetition of the same dose of the drug. Sensitization results in a shift to the left of the dose-response curve (see Figure 24–1). Sensitization, in contrast to acute tolerance during a binge, requires a longer interval between doses, usually ~1 day. Sensitization can occur with stimulants such as cocaine or amphetamine. Cross-tolerance occurs when repeated use of a drug in a given category confers tolerance not only to that drug but also to other drugs in the same structural and mechanistic category. Understanding cross-tolerance is important in the medical management of persons dependent on any drug.

Detoxification is a form of treatment for drug dependence that involves giving gradually decreasing doses of the drug to prevent withdrawal symptoms, thereby weaning the patient from the drug of dependence. Detoxification can be accomplished with any medication in the same category as the initial drug of dependence. For example, users of heroin also are tolerant to other opioids. Thus, the detoxification of heroin-dependent patients can be accomplished with any medication that activates opioid receptors.

PHYSICAL DEPENDENCE. Physical dependence is a state that develops as a result of the adaptation (tolerance) produced by a resetting of homeostatic mechanisms in response to repeated drug use. A person in this adapted or physically dependent state requires continued administration of the drug to maintain normal function. If administration of the drug is stopped abruptly, there is another imbalance, and the affected systems must readjust to a new equilibrium without the drug.

WITHDRAWAL SYNDROME. The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence. Withdrawal signs and symptoms occur when drug administration in a physically dependent person is terminated abruptly. Withdrawal symptoms have at least 2 origins:

• Removal of the drug of dependence

• CNS hyperarousal owing to readaptation to the absence of the drug of dependence

Pharmacokinetic variables are of considerable importance in the amplitude and duration of the withdrawal syndrome. Withdrawal symptoms are characteristic for a given category of drugs and tend to be opposite to the original effects produced by the drug before tolerance developed. Tolerance, physical dependence, and withdrawal are all biological phenomena. They are the natural consequences of drug use and can be produced in experimental animals and in any human being who takes certain medications repeatedly. These symptoms in themselves do not imply that the individual is involved in misuse or addiction. Patients who take medicine for appropriate medical indications and in correct dosages still may show tolerance, physical dependence, and withdrawal symptoms if the drug is stopped abruptly rather than gradually.

CLINICAL ISSUES

Abuse of combinations of drugs is common. Alcohol is so widely available that it is combined with practically all other categories. Some combinations reportedly are taken because of their interactive effects. When confronted with a patient exhibiting signs of overdose or withdrawal, the physician must be aware of these possible combinations because each drug may require specific treatment.

CNS DEPRESSANTS

ETHANOL. More than 90% of American adults report experience with ethanol (commonly called “alcohol”). Ethanol is classified as a depressant because it produces sedation and sleep. However, the initial effects of alcohol, particularly at lower doses, often are perceived as stimulation owing to a suppression of inhibitory systems (see Chapter 23). Heavy use of ethanol causes development of tolerance and physical dependence sufficient to define an alcohol withdrawal syndrome (Table 24–3).

Table 24–3

Alcohol Withdrawal Syndrome

images

Tolerance, Physical Dependence, and Withdrawal. The symptoms of mild intoxication by alcohol vary among individuals. Some experience motor incoordination and sleepiness. Others initially become stimulated. As the blood level increases, the sedating effects increase, with eventual coma and death occurring at high alcohol levels. The innate tolerance to alcohol varies greatly among individuals and is related to family history of alcoholism. Experience with alcohol can produce greater tolerance (acquired tolerance) such that extremely high blood levels (300-400 mg/dL) can be found in alcoholics who do not appear grossly sedated. In these cases, the lethal dose does not increase proportionately to the sedating dose, and thus the margin of safety (therapeutic index) is decreased.

Heavy consumers of alcohol acquire tolerance and also develop a state of physical dependence. This often leads to drinking in the morning to restore blood alcohol levels diminished during the night. The alcohol-withdrawal syndrome generally depends on the size of the average daily dose and usually is “treated” by resumption of alcohol ingestion. Withdrawal symptoms are experienced frequently but usually are not severe or life-threatening until they occur in conjunction with other problems, such as infection, trauma, malnutrition, or electrolyte imbalance. In the setting of such complications, the syndrome of delirium tremens becomes likely.

Alcohol addiction produces cross-tolerance to other sedatives such as benzodiazepines. This tolerance is operative in abstinent alcoholics, but while the alcoholic is drinking, the sedating effects of alcohol add to those of other sedatives. This is particularly true for benzodiazepines, which are relatively safe in overdose when given alone but potentially are lethal in combination with alcohol. The chronic use of alcohol and other sedatives is associated with the development of depression and the risk of suicide. Cognitive deficits have been reported in alcoholics tested while sober. These deficits usually improve with abstinence. More severe recent memory impairment is associated with specific brain damage caused by nutritional deficiencies common in alcoholics (e.g., thiamine deficiency). Medical complications of alcohol abuse and dependence include liver disease, cardiovascular disease, endocrine and GI effects, and malnutrition, in addition to the CNS dysfunctions outlined earlier. Ethanol readily crosses the placental barrier, producing the fetal alcohol syndrome, a major cause of mental retardation (see Chapter 23).

Pharmacological Interventions

Detoxification. Although most mild cases of alcohol withdrawal never come to medical attention, severe cases require general evaluation; attention to hydration and electrolytes; vitamins, especially high-dose thiamine; and a sedating medication that has cross-tolerance with alcohol. To block or diminish the symptoms described in Table 24–3, a short-acting benzodiazepine such as oxazepam can be used at a dose of 15-30 mg every 6-8 h according to the stage and severity of withdrawal; some authorities recommend a long-acting benzodiazepine unless there is demonstrated liver impairment. Anticonvulsants such as carbamazepine have been shown to be effective in alcohol withdrawal, but not as well as benzodiazepines.

Pharmacotherapy. Detoxification is the first step of treatment. Complete abstinence is the objective of long-term treatment, and this is accomplished mainly by behavioral approaches. Disulfiram (ANTABUSE; see Chapter 23) has been useful in some programs that focus behavioral efforts on ingestion of the medication. Disulfiram blocks aldehyde dehydrogenase, resulting in the accumulation of acetaldehyde, which produces an unpleasant flushing reaction when alcohol is ingested. Knowledge of this unpleasant reaction helps the patient to resist taking a drink. However, disulfiram has not been found to be effective in controlled clinical trials because so many patients failed to take it.

Naltrexone (REVIA; see Chapter 23) is an opioid receptor antagonist that blocks the reinforcing properties of alcohol. Chronic administration of naltrexone was found to decrease the rate of relapse to alcohol drinking. It works best in combination with behavioral treatment programs that encourage adherence to medication and abstinence from alcohol. A depot preparation with a duration of 30 days (VIVITROL) is now available; it greatly improves medication adherence. Acamprosate (CAMPRAL) is a competitive inhibitor of the N-methyl-D-aspartate (NMDA)–type glutamate receptor (see Table 23–2). The drug appears to normalize the dysregulated neurotransmission associated with chronic ethanol intake and thereby to attenuate one of the mechanisms that lead to relapse (see Chapter 23).

BENZODIAZEPINES. Benzodiazepines are used mainly for the treatment of anxiety disorders and insomnia (see Chapters 15 and 17). Considering their widespread use, intentional abuse of prescription benzodiazepines is relatively uncommon. The proportion of patients who become tolerant increases after several months of use and reducing the dose or stopping the medication produces withdrawal symptoms (Table 24–4).

Table 24–4

Benzodiazepine Withdrawal Symptoms

images

It can be difficult to distinguish withdrawal symptoms from the reappearance of the anxiety symptoms for which the benzodiazepine was prescribed initially. Some patients may increase their dose over time because tolerance definitely develops to the sedative effects. Antianxiety benefits, however, seem to continue to occur long after tolerance to the sedating effects. Moreover, these patients continue to take the medication for years according to medical directions without increasing their dose and are able to function very effectively as long as they take the benzodiazepine. Patients with a history of alcohol- or other drug-abuse problems have an increased risk for the development of benzodiazepine abuse and should rarely, if ever, be treated with benzodiazepines on a chronic basis.

Pharmacological Interventions. If patients receiving long-term benzodiazepine treatment by prescription wish to stop their medication, the process may take months of gradual dose reduction. Withdrawal symptoms may occur during this outpatient detoxification, but in most cases the symptoms are mild. If anxiety symptoms return, a non-benzodiazepine such as buspirone may be prescribed. Some authorities recommend transferring the patient to a long t1/2 benzodiazepine during detoxification; others recommend the anticonvulsants carbamazepine and phenobarbital. Patients who have been on low doses of benzodiazepines for years usually have no adverse effects. The specific benzodiazepine receptor antagonist flumazenil is useful in the treatment of overdose and in reversing the effects of long-acting benzodiazepines used in anesthesia.

Abusers of high doses of benzodiazepines usually require inpatient detoxification. Frequently, benzodiazepine abuse is part of a combined dependence involving alcohol, opioids, and cocaine. Detoxification can be a complex clinical pharmacological problem requiring knowledge of the pharmacokinetics of each drug. One approach to complex detoxification is to focus on the CNS-depressant drug and temporarily hold the opioid component constant with a low dose of methadone. A long-acting benzodiazepine such as diazepam or clorazepate (TRANXENE, others) or a long-acting barbiturate such as phenobarbital can be used to block the sedative withdrawal symptoms. After detoxification, the prevention of relapse requires a long-term outpatient rehabilitation program similar to the treatment of alcoholism. No specific medications have been found to be useful in the rehabilitation of sedative abusers but specific psychiatric disorders such as depression or schizophrenia, if present, require appropriate medications.

BARBITURATES. Abuse problems with barbiturates resemble those seen with benzodiazepines in many ways.

Treatment of abuse and addiction to barbiturates should be handled similarly to interventions for the abuse of alcohol and benzodiazepines. Because drugs in this category frequently are prescribed as hypnotics for patients complaining of insomnia, physicians should be aware of the problems that can develop when the hypnotic agent is withdrawn and of possible causes for insomnia that are treatable by other means. Insomnia often is a symptom of an underlying chronic problem, such as depression or respiratory dysfunction. Prescription of sedative medications can change the physiology of sleep with subsequent tolerance to these medication effects. When the sedative is stopped, there is a rebound effect with worsened insomnia. This medication-induced insomnia requires detoxification by gradual dose reduction.

NICOTINE

Nicotine and agents for smoking cessation are discussed in Chapter 11. Because nicotine provides the reinforcement for cigarette smoking, the most common cause of preventable death and disease in the U.S., it is arguably the most dangerous dependence-producing drug. Although >80% of smokers express a desire to quit, only 35% try to stop each year, and fewer than 5% are successful in unaided attempts to quit.

Cigarette (nicotine) addiction is influenced by multiple variables. Nicotine itself produces reinforcement; users compare nicotine to stimulants such as cocaine or amphetamine, although its effects are of lower magnitude. While there are many casual users of alcohol and cocaine, few individuals who smoke cigarettes smoke a small enough quantity (≤5 cigarettes per day) to avoid dependence. Nicotine is absorbed readily through the skin, mucous membranes, and lungs. The pulmonary route produces discernible CNS effects in as little as 7 seconds. Thus, each puff produces some discrete reinforcement. With 10 puffs per cigarette, the 1-pack-per-day smoker reinforces the habit 200 times daily.

Negative reinforcement refers to the benefits obtained from the termination of an unpleasant state. In dependent smokers, the urge to smoke correlates with a low blood nicotine level, as though smoking were a means to achieve a certain nicotine level and thus avoid nicotine withdrawal symptoms (Table 24–5). Depressed mood (dysthymic disorder, affective disorder) is associated with nicotine dependence, but it is not known whether depression can predispose one to begin smoking or depression develops during the course of nicotine dependence.

Table 24–5

Nicotine Withdrawal Symptoms

images

PHARMACOLOGICAL INTERVENTIONS. The nicotine withdrawal syndrome can be alleviated by nicotine-replacement therapy, available with a prescription (e.g., NICOTROL inhaler and nasal spray) or without (e.g., NICORETTE gum and others; COMMIT lozenges and others; and NICODERM CQ transdermal patch and others). Different methods of nicotine delivery provide different blood nicotine levels over varying time courses (Figure 24–2). These methods suppress the symptoms of nicotine withdrawal. Although this results in more smokers achieving abstinence, most resume smoking over the ensuing weeks or months. A sustained-release preparation of the antidepressant bupropion (ZYBAN; see Chapter 15) improves abstinence rates among smokers and remains a useful option. The cannabinoid CB1receptor inverse agonist rimonabant improves abstinence rates and reduces the weight gain seen frequently in ex-smokers but is linked to depressive and neurologic symptoms. Varenicline, a partial agonist at the t4;2 subtype of the nicotinic acetylcholine receptor, improves abstinence rates but has also been linked to risk of developing suicidal ideation. See Chapter 11 for the pharmacology of varenicline.

images

Figure 24–2 Nicotine concentrations in blood resulting from 5 different nicotine delivery systems. Shaded areas (upper panel) indicate the periods of nicotine delivery. Arrows (lower panel) indicate when the nicotine patch was put on and taken off. (With permission from Benowitz NL, Porchet H, Sheiner L, Jacob P III. Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum. Clin Pharmacol Ther, 1988, 44:23–28 © Macmillan Publishers Ltd. and Srivastava ED, Russell MA, Feyerabend C, et al. Sensitivity and tolerance to nicotine in smokers and nonsmokers. Psychopharmacology, 1991, 105:63–68 © Springer Science and Business Media.)

OPIOIDS

Opioid drugs are used primarily for the treatment of pain (see Chapter 18). Some of the CNS mechanisms that reduce the perception of pain also produce a state of well-being or euphoria. Thus, opioid drugs also are taken outside medical channels for the purpose of obtaining the effects on mood.

Heroin is the most frequently abused opiate. There is no legal supply of heroin for clinical use in the U.S.; however, heroin is widely available on the illicit market. The purity of street heroin in the U.S. has increased from ~4 mg heroin per 100 mg bag (range: 0-8 mg; the rest was filler such as quinine) to reach 45-75% purity in many large cities, with some samples testing as high as 90%. This increase in purity has led to increased levels of physical dependence among heroin addicts. Users who interrupt regular dosing develop more severe withdrawal symptoms. The more potent supplies can be smoked or administered nasally (snorted), making the initiation of heroin use accessible to people who would not insert a needle into their veins.

TOLERANCE, DEPENDENCE, AND WITHDRAWAL. Injection of a heroin solution produces a variety of sensations described as warmth, taste, or high and intense pleasure (“rush”) often compared with sexual orgasm. There are some differences among the opioids in their acute effects, with morphine producing more of a histamine-releasing effect and meperidine producing more excitation or confusion. Even experienced opioid addicts, however, cannot distinguish between heroin and hydromorphone in double-blind tests. The popularity of heroin may be due to its availability on the illicit market and its rapid onset. After intravenous injection, the effects begin in less than a minute. Heroin has high lipid solubility, crosses the blood-brain barrier quickly, and is deacetylated to the active metabolites 6-monoacetyl morphine and morphine. After the intense euphoria, which lasts from 45 seconds to several minutes, there is a period of sedation and tranquility (“on the nod”) lasting up to an hour. The effects of heroin wear off in 3-5 h, depending on the dose. Experienced users may inject 2 to 4 times per day. Thus, the heroin addict is constantly oscillating between being “high” and feeling the sickness of early withdrawal (Figure 24–3). This produces many problems in the homeostatic systems regulated at least in part by endogenous opioids.

images

Figure 24–3 Comparative responses to heroin and methadone. A person who injects heroin (↑) several times per day oscillates (red line) between being sick and being high. In contrast, the a methadone patient (purple line) remains in the “normal” range (blue band) with little fluctuation after dosing once per day. Ordinate values represent the subject’s mental and physical state, not plasma levels of the drug.

Based on patient reports, tolerance develops early to the euphoria-producing effects of opioids. There also is tolerance to the respiratory depressant, analgesic, sedative, and emetic properties. Heroin users tend to increase their daily dose, depending on their financial resources and the availability of the drug. Overdose is likely to occur when potency of the street sample is unexpectedly high or when the heroin is mixed with a far more potent opioid, such as fentanyl (SUBLIMAZE, others).

Addiction to heroin or other short-acting opioids produces behavioral disruptions and usually becomes incompatible with a productive life. Apart from the behavioral changes and the risk of overdose, chronic use of opioids is relatively nontoxic in and of itself. Nonetheless, the mortality rate for street heroin users is very high. Heroin users commonly acquire bacterial infections producing skin abscesses; endocarditis; pulmonary infections, especially tuberculosis; and viral infections producing hepatitis C and acquired immune deficiency syndrome (AIDS).

Opioids frequently are used in combinations with other drugs. A common combination is heroin and cocaine (“speedball”). Users report an improved euphoria because of the combination, and there is evidence of an interaction, because cocaine reduces the signs of opiate withdrawal, and heroin may reduce the irritability seen in chronic cocaine users.

The first stage of treatment addresses physical dependence and consists of detoxification. The opioid-withdrawal syndrome (Table 24–6) is very unpleasant but not life-threatening. It begins within 6-12 h after the last dose of a short-acting opioid and as long as 72-84 h after a very long-acting opioid medication. The duration and intensity of the syndrome are related to the clearance of the individual drug. Heroin withdrawal is brief (5-10 days) and intense. Methadone withdrawal is slower in onset and lasts longer.

Table 24–6

Characteristics of Opioid Withdrawal

images

PHARMACOLOGICAL INTERVENTIONS. Opioid withdrawal signs and symptoms can be treated by 3 different approaches. The first and most commonly used approach consists of transfer to a prescription opioid medication and then gradual dose reduction. It is convenient to change the patient from a short-acting opioid such as heroin to a long-acting one such as methadone. The initial dose of methadone is typically 20-30 mg. The first day’s total dose then can be calculated depending on the response and then reduced by 20% per day during the course of detoxification.

A second approach to detoxification involves the use of oral clonidine (CATAPRES, others), an α2 adrenergic agonist that decreases adrenergic neurotransmission from the locus ceruleus. Many of the autonomic symptoms of opioid withdrawal result from the loss of opioid suppression of the locus ceruleus system during the abstinence syndrome. Clonidine can alleviate many of the symptoms of opioid withdrawal but not the generalized aches and opioid craving. When using clonidine to treat withdrawal, the dose must be titrated according to the stage and severity of withdrawal; postural hypotension is commonly a side effect. A third method of treating opioid withdrawal involves activation of the endogenous opioid system without medication. The techniques proposed include acupuncture and several methods of CNS activation using transcutaneous electrical stimulation. While attractive theoretically, this has not yet been found to be practical.

LONG-TERM MANAGEMENT. If patients are simply discharged from the hospital after withdrawal from opioids, there is a high probability of a quick return to compulsive opioid use. Numerous factors influence relapse. The withdrawal syndrome does not end in 5-7 days; a protracted withdrawal syndrome (see Table 24–6) persists for up to 6 months. Physiological measures tend to oscillate as though a new set point were being established; during this phase, outpatient drug-free treatment has a low probability of success, even when the patient has received intensive prior treatment while protected from relapse in a residential program.

The most successful treatment for heroin addiction consists of stabilization on methadone in accordance with state and federal regulations. Patients who relapse repeatedly during drug-free treatment can be transferred directly to methadone without requiring detoxification. The dose of methadone must be sufficient to prevent withdrawal symptoms for at least 24 h. The introduction of buprenorphine, a partial agonist at x-opioid receptors (see Chapter 18), represents a major change in the treatment of opiate addiction. This drug produces minimal withdrawal symptoms when discontinued and has a low potential for overdose, a long duration of action, and the ability to block heroin effects. Treatment can take place in a qualified physician’s private office rather than in a special center, as required for methadone. When taken sublingually, buprenorphine (SUBUTEX) is active, but it also has the potential to be dissolved and injected (abused). A buprenorphine-naloxone combination (SUBOXONE) is also available. When taken orally (sublingually), the naloxone moiety is not effective, but if the patient abuses the medication by injecting, the naloxone will block or diminish the subjective high that could be produced by buprenorphine alone.

ANTAGONIST TREATMENT. Naltrexone (REVIA, others; see Chapter 18) is an antagonist with a high affinity for the μ-opioid receptor; it will competitively block the effects of heroin or other μ-receptor agonists. Naltrexone will not satisfy craving or relieve protracted withdrawal symptoms, but it can be used after detoxification for patients with high motivation to remain opioid-free.

COCAINE AND OTHER PSYCHOSTIMULANTS

COCAINE. The number of frequent users (at least weekly) of cocaine in the U.S. has remained steady since 1991 at ~600,000. Not all users become addicts. A key factor is the widespread availability of relatively inexpensive cocaine in the alkaloidal form (free base, “crack”) suitable for smoking and in the hydrochloride powder form suitable for nasal or intravenous use. Drug abuse occurs about twice as frequently in men as in women.

The reinforcing effects of cocaine and cocaine analogs correlate best with their effectiveness in blocking the transporter that recovers DA from the synapse. This leads to increased DA concentrations at critical brain sites. However, cocaine also blocks both NE and 5HT reuptake, and chronic use of cocaine leads to changes in these neurotransmitter systems. The general pharmacology and medicinal use of cocaine as a local anesthetic are discussed in Chapter 20. Cocaine produces a dose-dependent increase in heart rate and blood pressure accompanied by increased arousal, improved performance on tasks of vigilance and alertness, and a sense of self-confidence and well-being. Higher doses produce euphoria, which has a brief duration and often is followed by a desire for more drug. Repeated doses may lead to involuntary motor activity, stereotyped behavior, and paranoia. Irritability and increased risk of violence are found among heavy chronic users. The t1/2 of cocaine in plasma is ~50 min, but inhalant (crack) users typically desire more cocaine after 10-30 min.

The major route for cocaine metabolism involves hydrolysis of each of its 2 ester groups. Benzoylecgonine, produced on loss of the methyl group, represents the major urinary metabolite and can be found in the urine for 2-5 days after a binge. As a result, the benzoylecgonine test is a valid method for detecting cocaine use; the metabolite remains detectable in the urine of heavy users for up to 10 days. Ethanol is frequently abused with cocaine, as it reduces the irritability induced by cocaine. Dual addiction to alcohol and cocaine is common. When cocaine and alcohol are taken concurrently, cocaine may be transesterified to cocaethylene, which is equipotent to cocaine in blocking DA reuptake.

Addiction is the most common complication of cocaine abuse. In general, stimulants tend to be abused much more irregularly than opioids, nicotine, and alcohol. Binge use is very common, and a binge may last hours to days, terminating only when supplies of the drug are exhausted.

Toxicity. Other risks of cocaine, beyond the potential for addiction, include cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasoconstriction, and seizures. Death from trauma also is associated with cocaine use. Cocaine may induce premature labor and abruptio placentae. Cocaine has been reported to produce a prolonged and intense orgasm if taken prior to intercourse, and users often indulge in compulsive and promiscuous sexual activity. However, chronic cocaine use reduces sexual drive. Chronic use is also associated with psychiatric disorders, including anxiety, depression, and psychosis.

Tolerance, Dependence, and Withdrawal. In intermittent users of cocaine, the euphoric effect typically is not subject to sensitization. On the contrary, most experienced users become desensitized and, over time, require more cocaine to obtain euphoria, i.e., tolerance develops. Because cocaine typically is used intermittently, even heavy users go through frequent periods of withdrawal or “crash.” The symptoms of withdrawal seen in users admitted to hospitals are listed in Table 24–7. Careful studies of cocaine users during withdrawal show gradual diminution of these symptoms over 1-3 weeks. Residual depression, often seen after cocaine withdrawal, should be treated with antidepressant agents if it persists (see Chapter 15).

Table 24–7

Cocaine Withdrawal Symptoms and Signs

images

Pharmacological Interventions. Because cocaine withdrawal is generally mild, treatment of withdrawal symptoms usually is not required. The major problem in treatment is not detoxification but helping the patient to resist the urge to resume compulsive cocaine use. Rehabilitation programs involving individual and group psychotherapy based on the principles of Alcoholics Anonymous, and behavioral treatments based on reinforcing cocaine-free urine tests, result in significant improvement in the majority of cocaine users. Nonetheless, there is great interest in finding a medication that can aid in the rehabilitation of cocaine addicts.

AMPHETAMINE AND RELATED AGENTS. Subjective effects similar to those of cocaine are produced by amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate, and diethylpropion.

Amphetamines increase synaptic DA, NE, and 5HT primarily by stimulating pre-synaptic release rather than by blockade of reuptake, as is the case with cocaine. Intravenous or smoked methamphetamine produces an abuse/dependence syndrome similar to that of cocaine, although clinical deterioration may progress more rapidly. Methamphetamine addiction has become a major public health problem in the U.S. Behavioral and medical treatments for methamphetamine addiction are similar to those used for cocaine.

CAFFEINE. Caffeine, a mild stimulant, is the most widely used psychoactive drug in the world. It is present in soft drinks, coffee, tea, cocoa, chocolate, and numerous prescription and over-the-counter drugs.

Caffeine mildly increases NE and DA release and enhances neural activity in numerous brain areas. Caffeine is absorbed from the digestive tract, is distributed rapidly throughout all tissues, and easily crosses the placental barrier. Many of caffeine’s effects are believed to occur by means of competitive antagonism at adenosine receptors. Adenosine is a neuromodulator (see Chapter 14) that resembles caffeine structurally. The mild sedating effects that occur when adenosine activates particular adenosine-receptor subtypes can be antagonized by caffeine. Tolerance occurs rapidly to the stimulating effects of caffeine. Thus, a mild withdrawal syndrome has been produced in controlled studies by abruptly discontinuing the intake of as little as 1 to 2 cups of coffee per day. Caffeine withdrawal consists of feelings of fatigue and sedation. With higher doses, headaches and nausea have been reported during withdrawal; vomiting is rare.

CANNABINOIDS (MARIJUANA)

The cannabis plant has been cultivated for centuries for its presumed medicinal and psychoactive properties. The smoke from burning cannabis contains many chemicals, including 61 different cannabinoids that have been identified. One of these, Δ-9-tetrahydrocannabinol (Δ-9-THC), produces most of the characteristic pharmacological effects of smoked marijuana. Marijuana is the most commonly used illegal drug in the U.S. The human cannabinoid endogenous ligand/receptor/signaling systems are described in Chapter 14.

The pharmacological effects of Δ-9-THC vary with the dose, route of administration, experience of the user, vulnerability to psychoactive effects, and setting of use. Intoxication with marijuana produces changes in mood, perception, and motivation, but the effect most frequently sought is the “high” and “mellowing out.” This effect is described as different from the high produced by a stimulant or opiate. Effects vary with dose, but typically last ~2 h. During the high, cognitive functions, perception, reaction time, learning, and memory are impaired. Coordination and tracking behavior may be impaired for several hours beyond the perception of the high. Marijuana also produces complex behavioral changes such as giddiness and increased hunger. Unpleasant reactions such as panic or hallucinations and even acute psychosis may occur. These reactions are seen commonly with higher doses and with oral ingestion rather than smoked marijuana. Numerous clinical reports suggest that marijuana use may precipitate a recurrence of psychosis in people with a history of schizophrenia. One of the most controversial of the reputed effects of marijuana is the production of an “amotivational syndrome.” This syndrome is not an official diagnosis, but it has been used to describe young people who drop out of social activities and show little interest in school, work, or other goal-directed activity. There is no evidence that marijuana damages brain cells or produces any permanent functional changes.

Marijuana has medicinal effects, including antiemetic properties that relieve side effects of anticancer chemotherapy. It also has muscle-relaxing effects, anticonvulsant properties, and the capacity to reduce the elevated intraocular pressure of glaucoma. These medical benefits come at the cost of the psychoactive effects that often impair normal activities. Thus, there is no clear advantage of marijuana over conventional treatments for any of these indications.

TOLERANCE, DEPENDENCE, AND WITHDRAWAL. Tolerance to most of the effects of marijuana can develop rapidly after only a few doses, but also disappears rapidly. Withdrawal symptoms are not seen in clinical populations. Human subjects develop a withdrawal syndrome when they receive regular oral doses of the agent (Table 24–8). This syndrome, however, is only seen clinically in persons who use marijuana on a daily basis and then suddenly stop. Marijuana abuse and addiction have no specific treatments. Heavy users may suffer from accompanying depression and thus may respond to antidepressant medication.

Table 24–8

Marijuana Withdrawal Syndrome

images

PSYCHEDELIC AGENTS

There are 2 main categories of psychedelic compounds, indoleamines and phenethylamines. The indoleamine hallucinogens include LSD, N, N-dimethyltryptamine (DMT), and psilocybin. The phenethylamines include mescaline, dimethoxymethylamphetamine (DOM), methylenedioxyamphetamine (MDA), and MDMA. Both groups have a relatively high affinity for 5HT2 receptors (see Chapter 13), but they differ in their affinity for other subtypes of 5HT receptors. There is a good correlation between the relative affinity of these compounds for 5HT2 receptors and their potency as hallucinogens in humans. However, LSD interacts with many receptor subtypes at nanomolar concentrations, and it is not possible to attribute the psychedelic effects to any single 5HT receptor subtype.

LSD. LSD is the most potent hallucinogenic drug and produces significant psychedelic effects with a total dose of as little as 25-50 dg. This drug is >3000 times more potent than mescaline. LSD is sold on the illicit market in a variety of forms. A popular contemporary system involves postage stamp-sized papers impregnated with varying doses of LSD (50-300 μg or more).

The effects of hallucinogenic drugs are variable, even in the same individual on different occasions. LSD is absorbed rapidly after oral administration, with effects beginning at 40-60 min, peaking at 2-4 h, and gradually returning to baseline over 6-8 h. At a dose of 100 μg, LSD produces perceptual distortions and sometimes hallucinations; mood changes, including elation, paranoia, or depression; intense arousal; and sometimes a feeling of panic. Signs of LSD ingestion include pupillary dilation, increased blood pressure and pulse, flushing, salivation, lacrimation, and hyperreflexia. Visual effects are prominent. Colors seem more intense, and shapes may appear altered. The subject may focus attention on unusual items such as the pattern of hairs on the back of the hand. A “bad trip” usually consists of severe anxiety, although at times it is marked by intense depression and suicidal thoughts. Visual disturbances usually are prominent. There are no documented toxic fatalities from LSD use, but fatal accidents and suicides have occurred during or shortly after intoxication. Prolonged psychotic reactions lasting 2 days or more may occur after the ingestion of a hallucinogen. Schizophrenic episodes may be precipitated in susceptible individuals, and there is some evidence that chronic use of these drugs is associated with the development of persistent psychotic disorders. Claims about the potential of psychedelic drugs for enhancing psychotherapy and for treating addictions and other mental disorders are not supported by controlled studies; there is no current indication for these drugs as medications.

Tolerance, Physical Dependence, and Withdrawal. Frequent, repeated use of psychedelic drugs is unusual, and thus tolerance is not commonly seen. Tolerance does develop to the behavioral effects of LSD after 3 or 4 daily doses, but no withdrawal syndrome has been observed.

Pharmacological Intervention. Because of the unpredictability of psychedelic drug effects, any use carries some risk. Users may require medical attention because of “bad trips.” Severe agitation may respond to diazepam (20 mg orally). “Talking down” by reassurance also is effective and is the management of first choice. Antipsychotic medications (see Chapter 16) may intensify the experience and thus are not indicated. A particularly troubling aftereffect of the use of LSD and similar drugs is the occasional occurrence of episodic visual disturbances. These originally were called “flashbacks” and resembled the experiences of prior LSD trips. Flashbacks belong to an official diagnostic category called the hallucinogen persisting perception disorder. The symptoms include false fleeting perceptions in the peripheral fields, flashes of color, geometric pseudohallucinations, and positive afterimages. The visual disorder appears stable in half the cases and represents an apparently permanent alteration of the visual system. Precipitants include stress, fatigue, emergence into a dark environment, marijuana, antipsychotic agents, and anxiety states.

MDMA (“ECSTASY”) AND MDA. MDMA and MDA are phenylethylamines that have stimulant as well as psychedelic effects.

Acute effects are dose-dependent and include feelings of energy, altered sense of time, and pleasant sensory experiences with enhanced perception. Negative effects include tachycardia, dry mouth, jaw clenching, and muscle aches. At higher doses, visual hallucinations, agitation, hyperthermia, and panic attacks have been reported. A typical oral dose is 1 or 2 100-mg tablets and lasts 3-6 h, although dosage and potency of street samples are variable (~100 mg per tablet).

PHENCYCLIDINE (PCP). PCP was developed originally as an anesthetic in the 1950s and later was abandoned because of a high frequency of postoperative delirium with hallucinations. It was classified as a dissociative anesthetic because, in the anesthetized state, the patient remains conscious with staring gaze, flat facies, and rigid muscles. PCP became a drug of abuse in the 1970s, first in an oral form and then in a smoked version enabling a better regulation of the dose.

As little as 50 μg/kg produces emotional withdrawal, concrete thinking, and bizarre responses to projective testing. Catatonic posturing also is produced and resembles that of schizophrenia. Abusers taking higher doses may appear to be reacting to hallucinations and may exhibit hostile or assaultive behavior. Anesthetic effects increase with dosage; stupor or coma may occur with muscular rigidity, rhabdomyolysis, and hyperthermia. Intoxicated patients in the emergency room may progress from aggressive behavior to coma, with elevated blood pressure and enlarged nonreactive pupils. PCP binds with high affinity to sites located in the cortex and limbic structures, resulting in blocking of NMDA–type glutamate receptors (see Chapter 14). LSD and other psychedelics do not bind to NMDA receptors. There is evidence that NMDA receptors are involved in ischemic neuronal death caused by high levels of excitatory amino acids; as a result, there is interest in PCP analogs that block NMDA receptors but with fewer psychoactive effects. Both PCP and ketamine (“Special K”), another “club drug,” produce similar effects by altering the distribution of the neurotransmitter glutamate.

Pharmacological Intervention. Overdose must be treated by life support because there is no antagonist of PCP effects and no proven way to enhance excretion, although acidification of the urine has been proposed. PCP coma may last 7-10 days. The agitated or psychotic state produced by PCP can be treated with diazepam. Prolonged psychotic behavior requires antipsychotic medication. Because of the anticholinergic activity of PCP, antipsychotic agents with significant anticholinergic effects such as chlorpromazine should be avoided.