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FIGURE 23-3 Differences in responses to heroin and methadone. Aperson who injects heroin (T) several times per day oscillates between being sick and being high. In contrast, the typical methadone patient remains in the "normal" range (indicated in gray) with little fluctuation after dosing once per day. The ordinate values represent the subject's mental and physical state, not plasma levels of the drug.

Time (hours)

FIGURE 23-3 Differences in responses to heroin and methadone. Aperson who injects heroin (T) several times per day oscillates between being sick and being high. In contrast, the typical methadone patient remains in the "normal" range (indicated in gray) with little fluctuation after dosing once per day. The ordinate values represent the subject's mental and physical state, not plasma levels of the drug.

problems. Mood also is affected. Heroin addicts are relatively docile and compliant after taking heroin, but during withdrawal, they become irritable and aggressive.

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. If a supply is available, the dose can be increased progressively 100 times. Even in highly tolerant individuals, the possibility of overdose remains if tolerance is exceeded. 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. There is a significant risk for opioid abuse and dependence among physicians and other health care workers who have access to potent opioids, thus tempting them toward unsupervised experimentation.

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 mortality rate for street heroin users is very high. Early death comes from involvement in crime to support the habit; from uncertainty about the dose, the purity, and even the identity of what is purchased on the street; and from serious infections associated with nonsterile drugs and sharing of injection paraphernalia. 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).

As with other addictions, the first stage of treatment addresses physical dependence and consists of detoxification. The opioid-withdrawal syndrome (Table 23-7) is very unpleasant but not life-threatening. It begins within 6-12 hours after the last dose of a short-acting opioid and as long as 72-84 hours after a very long-acting opioid medication. Heroin addicts go through early stages of this syndrome frequently when heroin is scarce or expensive. Some therapeutic communities as a matter of policy elect not to treat withdrawal so that the addict can experience the suffering while being given group support. 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. Protracted withdrawal also is likely to be longer with methadone.

Characteristics of Opioid Withdrawal

Symptoms

Signs

Regular withdrawal Craving for opioids Restlessness, irritability Increased sensitivity to pain Nausea, cramps Muscle aches Dysphoric mood Insomnia, anxiety

Protracted withdrawal Anxiety Insomnia Drug craving

Pupillary dilation Sweating

Piloerection ("gooseflesh")

Tachycardia

Vomiting, diarrhea

Increased blood pressure

Yawning

Fever

Cyclic changes in weight, pupil size, respiratory center sensitivity

Pharmacological Interventions Opioid withdrawal signs and symptoms can be treated by two different pharmacological approaches. The first and most commonly used approach consists of transfer to a prescription opioid medication and then gradual dose reduction. The same principles of detoxification apply as for other types of physical dependence. It is convenient to change the patient to a long-acting drug such as methadone. The initial dose of methadone is typically 20-30 mg. This is a test dose to determine the level needed to reduce observed withdrawal symptoms. 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 a2 adrenergic agonist that decreases adrenergic neurotransmission from the locus ceruleus. Many of the autonomic symptoms of opioid withdrawal such as nausea, vomiting, cramps, sweating, tachycardia, and hypertension 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 except generalized aches and opioid craving. When using clonidine to treat withdrawal, the dose must be titrated according to the stage and severity of withdrawal, beginning with 0.2 mg orally. Postural hypotension commonly occurs when clonidine treatment is used for withdrawal.

Cocaine and Other Psychostimulants

COCAINE Chronic cocaine users total 3.6 million in the U.S. The number of frequent users (at least weekly) has remained steady since 1991 at ~640,000. 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 the hydrochloride powder form suitable for nasal or intravenous use. Drug abuse in men occurs about twice as frequently as in women. However, smoked cocaine use is particularly common in young women of childbearing age, who may use cocaine in this manner as commonly as do men.

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 norepinephrine (NE) and serotonin (5-HT) reuptake, and chronic use of cocaine produces changes in these neurotransmitter systems.

The general pharmacology and legitimate use of cocaine are discussed in Chapter 14. 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 drugs. Involuntary motor activity, stereotyped behavior, and paranoia may occur after repeated doses. Irritability and increased risk of violence are found among heavy chronic users. The t1/2 of cocaine in plasma is ~50 minutes, but inhalant ("crack") users typically desire more cocaine after 10-30 minutes. Intranasal and intravenous uses also result in a high of shorter duration than would be predicted by plasma cocaine levels, suggesting that a declining plasma concentration is associated with termination of the high and resumption of cocaine seeking. The major route for cocaine metabolism involves hydrolysis of each of its two ester groups. Ben-zoylecgonine, 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, benzoylecgonine tests are useful for detecting cocaine use; heavy users have detectable amounts of the metabolite in their urine for up to 10 days following a binge. Cocaine frequently is used in combination with other drugs (see above). An important metabolic interaction occurs when cocaine and alcohol are taken concurrently. Some cocaine is transesterified to cocaethylene, which is equipotent to cocaine in blocking DA reuptake.

Since cocaine withdrawal is generally mild, treatment of withdrawal symptoms usually is not required (Table 23-8) 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.

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 primarily by stimulating presynaptic release rather than by blockade of reuptake. Intravenous or smoked methamphetamine produces an abuse/dependence syndrome similar to that of cocaine, although clinical deterioration may progress more rapidly and methamphetamine is thought to be neurotoxic in DA and 5-HT neurons. Methamphetamine can be produced in small, clandestine laboratories starting with ephedrine, and access to this previously widely available nonprescription stimulant has been restricted.

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. It mildly increases NE and DA release and enhances neural activity in numerous brain areas. Caffeine is absorbed from the digestive tract and is distributed rapidly throughout all tissues and easily crosses the placental barrier (see Chapter 27). Many of caffeine's effects are believed to occur by means of competitive antagonism at adenosine receptors. Adenosine is a neu-romodulator that influences a number of functions in the CNS (see Chapters 12 and 27). 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 abrupt cessation of as little as 1-2 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. Although a withdrawal syndrome can be demonstrated, few caffeine users report loss of control of caffeine intake or significant difficulty in reducing or stopping caffeine, if desired. Thus, caffeine is not listed in the category of addicting stimulants. It is a concern nonetheless that drinks marketed to the young and active are little more that flavored caffeine delivery systems (e.g., caffeinated water).

Cannabinoids (Marijuana)

The cannabis plant has been cultivated for centuries both for the production of hemp fiber and 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, A-9-tetrahydrocannabinol (A-9-THC), produces most of the characteristic pharmacological effects of smoked marijuana.

Surveys have shown that marijuana is the most commonly used illegal drug in the U.S. Cannabi-noid receptors CB-1 (mainly CNS) and CB-2 (peripheral) have been identified and cloned. An

Table 23-8

Cocaine Withdrawal Symptoms and Signs

Dysphoria, depression Sleepiness, fatigue Cocaine craving Bradycardia endogenous arachidonic acid derivative anandamide is a known agonist ligand. While the physiological function of these receptors and their endogenous ligands are incompletely understood, they are likely to have important functions because they are dispersed widely with high densities in the cerebral cortex, hippocampus, striatum, and cerebellum. Specific CB-1 antagonists have been developed and are in controlled clinical trials. One of these, rimonabant, has been reported to reduce relapse in cigarette smokers and to produce weight loss in obese patients.

The pharmacological effects of A-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 sought after by most users is the "high" and "mellowing out." This effect is described as different from the stimulant high and the opiate high. The effects vary with dose, but the typical marijuana smoker experiences a high that lasts ~2 hours. During this time, there is impairment of cognitive functions, perception, reaction time, learning, and memory. Impairments of coordination and tracking behavior have been reported to persist for several hours beyond the perception of the high. These impairments have obvious implications for the operation of a motor vehicle and performance in the workplace or at school.

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; several surveys indicate that 50-60% of marijuana users have reported at least one anxiety experience. These reactions are seen commonly with higher doses and with oral ingestion rather than smoked marijuana because smoking permits the regulation of dose according to the effects.

One of the most controversial of the reputed effects of marijuana is the production of an "amo-tivational syndrome"; however, there are no data that demonstrate a causal relationship between marijuana smoking and these behavioral characteristics. There is no evidence that marijuana use damages brain cells or produces any permanent functional changes.

Several medicinal benefits of marijuana have been described. These include antinausea effects that have been applied to the relief of side effects of anticancer chemotherapy, muscle-relaxing effects, anticonvulsant effects, and reduction of intraocular pressure for the treatment 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 and signs typically are not seen. In fact, relative to the number of marijuana smokers, few patients ever seek treatment for marijuana addiction. A withdrawal syndrome in human subjects has been described following close observation of marijuana users given regular oral doses of the agent on a research ward (Table 23-9). This syndrome, however, is only seen clinically in persons who use marijuana on a daily basis and stop abruptly. Compulsive or regular marijuana users do not appear to be motivated by fear of withdrawal symptoms, although this has not been studied systematically.

Psychedelic Agents

Perceptual distortions that include hallucinations, illusions, and disorders of thinking such as paranoia can be produced by toxic doses of many drugs. These phenomena also may be seen during toxic withdrawal from sedatives such as alcohol. There are, however, certain drugs that have as their primary effect the production of disturbances of perception, thought, or mood at low doses with minimal effects on memory and orientation. These are commonly called hallucinogenic drugs, but their use does not always result in frank hallucinations. In the late 1990s, the use of "club drugs" at

Table 23-9

Marijuana Withdrawal Syndrome

Restlessness Irritability Mild agitation Insomnia

Sleep EEG disturbance Nausea, cramping all-night dance parties became popular. Such drugs include methylenedioxymethamphetamine (MDMA, "ecstasy"), lysergic acid diethylamide (LSD), phencyclidine (PCP), and ketamine (ketalar). They often are used in association with illegal sedatives such as flunitrazepam (rohyp-nol) or g-hydroxybutyrate (GHB), drugs that have the reputation of being particularly effective in preventing memory storage and have been implicated in "date rape."

While psychedelic effects can be produced by a variety of different drugs, major psychedelic compounds come from two main categories. 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 5-HT2 receptors (see Chapter 11), but they differ in their affinity for other subtypes of 5-HT receptors. There is a good correlation between the relative affinity of these compounds for 5-HT2 receptors and their potency as hallucinogens in human beings.

LSD LSD is the most potent hallucinogenic drug and produces significant psychedelic effects with a total dose of as little as 25-50 pg. 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 pg 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 minutes, peaking at 2-4 hours, and gradually returning to baseline over 6-8 hours. At a dose of 100 pg, 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. 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.

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 3-4 daily doses, but no withdrawal syndrome has been observed.

Pharmacological Intervention Because of the unpredictability of psychedelic drug effects, any use carries some risk. Dependence and addiction do not occur, but users may require medical attention because of "bad trips." Severe agitation may require medication (e.g., diazepam, 20 mg orally), although "talking down" by reassurance has been shown to be effective and is the management of first choice. A particularly troubling after-effect of the use of LSD and similar drugs is the occurrence of episodic visual disturbances in a small proportion of former users. These originally were called "flashbacks" and resembled the experiences of prior LSD trips. There now is 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, neuroleptics, 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 one or two 100-mg tablets and lasts 3-6 hours, although dosage and potency of street samples are variable (~100 mg/tablet). There is possible neurotoxicity with the use of MDMA.

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 classed 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. The effects of PCP have been observed in normal volunteers under controlled conditions. As little as 50 pg/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 exhibit hostile or assaultive behavior. Anesthetic effects increase with dosage; stupor or coma may occur with muscular rigidity, rhab-domyolysis, 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 W-methyl-D-aspartate (NMDA)-type glutamate receptors (see Chapter 12). 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.

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 neuroleptic medication (see Chapter 18), although those with significant anticholinergic effects such as chlorpromazine should be avoided.

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at www.accessmedicine.com.

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SECTION IV AUTACOIDS: DRUG THERAPY OF INFLAMMATION

Do Not Panic

Do Not Panic

This guide Don't Panic has tips and additional information on what you should do when you are experiencing an anxiety or panic attack. With so much going on in the world today with taking care of your family, working full time, dealing with office politics and other things, you could experience a serious meltdown. All of these things could at one point cause you to stress out and snap.

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