Drugs of Abuse

39 Drugs of Abuse Charles S. Bockman, Peter W. Abel, and Frank J. Dowd K E Y I N F O R M AT I O N • Drug abuse is the inappropriate use of a drug for a nonmedical purpose. • Drugs that are abused cause intense feelings of euphoria or alter perception. • Categories of abused drugs include opioid analgesics; general depressants of the central nervous system (CNS), e.g., sedativehypnotics, antianxiety drugs, and alcohol; cocaine, amphetamines, and related psychomotor stimulants; hallucinogens; marijuana; and inhalants. • Drug addiction refers to compulsive, relapsing drug use despite the negative consequences. • Drug dependence refers to the physical state produced in response to repeated drug exposure and is defined by a withdrawal syndrome.

• Withdrawal or abstinence syndrome is the drug class–specific group of symptoms that appear when drug administration is discontinued or reduced and is the cardinal sign of dependence. • Drug tolerance is the reduction in effect in response to repeated drug exposure. • Ethanol has both acute and chronic effects on several organs, including the brain, liver, heart, and GI tract. • Ethanol abuse is the most common example of substance abuse, with major impacts on individuals and society. • Damage to organs from ethanol is due to effects of ethanol, as well as acetaldehyde and nutritional deficiencies. • Metabolism of ethanol produces acetaldehyde and then acetic acid, displaying zero-order kinetics.

 

CASE STUDY Mr. C is a 27-year-old man, who on his first visit to a new dentist complains about recent changes in the appearance of his teeth. He reports losing weight lately, difficulty in sleeping and sometimes having “strange thoughts.” Mr. C presents with mild gingivitis and chewed tongue without other signs of soft tissue pathology. He exhibits worn teeth and extensive dental decay, including interproximal surfaces of anterior teeth and buccal surfaces of many maxillary and mandibular teeth. The effects of which drug of abuse are consistent with the signs and symptoms exhibited by Mr. C? Explain the connection between the effects of the abused drug and the oral health of Mr. C.

INTRODUCTION Drug abuse can be defined as an inappropriate use of a drug for a nonmedical purpose. Drug abuse is considered to cause harm to the individual abuser and to society as a whole. Many variables not directly related to a drug can influence whether a given individual becomes a drug abuser. Many experts argue that cocaine possesses the greatest potential for abuse based on its pharmacologic characteristics alone. For individuals who try nicotine, the risk of developing an addiction is approximately twice that for individuals who try cocaine, however. This statement is not meant to infer that the pharmacologic abuse potential of nicotine is twice that of cocaine; rather, some psychosocial factors are equally important in affecting onset and continuation of drug abuse and addiction. It is beyond the scope of this chapter to discuss these factors related to drug users and their environment; this chapter concentrates solely on the pharmacologic aspects of drugs of abuse. A wide variety of different types of drugs and other chemical substances are subject to abuse. Anabolic steroids are abused by bodybuilders

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and other athletes to add muscle mass and enhance athletic performance. The most commonly abused groups of drugs are those that act on the CNS to cause intense feelings of euphoria or alter perception. This chapter focuses on drugs that are abused because they have effects in the CNS that are perceived by some individuals as desirable.

HISTORIC PERSPECTIVE Natural products such as hemp flowers, opium, and coca leaves have been used for thousands of years for their ability to cause pleasurable sensations or other alterations in consciousness. Other than alcohol, the first major drugs of abuse in the United States were cocaine and opioids. Throughout the nineteenth century, unregulated opium use led to a plethora of patent medicines containing opium derivatives. As a result, many middle-class Americans became dependent on opium because of promiscuous use of such preparations. Nevertheless, social attitudes toward drug abuse remained relaxed until after the Civil War. The widespread use of morphine by injection for dysentery, malaria, and pain resulted in such large numbers of morphine-addicted veterans that morphine dependence became known as “soldier’s disease.” The chemical isolation of the alkaloid cocaine in 1859 was followed by a rapid increase in the use of that drug. It was enthusiastically promoted for various disorders, and by the turn of the 20th century, oral abuse of cocaine in the form of patent medicines and tonics was widespread. The manufacturers of Coca-Cola did not stop using cocaine-containing syrup in their soft drink until 1903, after 17 years in production. In the early 1900s, the mass media developed the myth of cocainecrazed renegades committing heinous crimes against society. Opioid dependence was still prevalent, and morphine was the major opioid of abuse. During this period, federal laws were enacted to control the

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CHAPTER 39  Drugs of Abuse widespread drug abuse problem. The introduction of the Pure Food and Drug Act in 1906, the Harrison Narcotic Act in 1914, and the Narcotic Drugs Import and Export Act in 1922, and the enforcement of these acts by law enforcement officials led to the virtual disappearance of cocaine abuse by the 1930s. The increased cost and reduced street availability of cocaine helped lead to the increase of amphetamine as a stimulant drug of abuse. Intravenous (IV) heroin use was also becoming popular, and by 1935, it was as widely abused as morphine. Between World Wars I and II, addiction began to be widely equated with criminality. In the case of marijuana, sensationalized accounts of murders perpetrated by individuals under the influence of the “killer weed” led to the passage of the Marihuana Tax Act of 1937, which effectively banned its production, distribution, and sale. In the 1960s, drug abuse began to make major inroads into middle-class society. The baby-boom generation began experimenting with lysergic acid diethylamide (LSD) and marijuana. Epidemic amphetamine abuse developed during the 1960s, peaking in 1967 with 32 million legal prescriptions written for amphetamines that suppress appetite and lead to weight loss. To combat the rising tide of drug abuse, the Comprehensive Drug Abuse Prevention and Control Act was enacted in 1970 and replaced previous laws in this area. This act classified drugs into five schedules according to their abuse liability and provided a graded set of penalties for violation of regulations relating to the manufacture, sale, prescription, and record keeping of drugs of abuse. A summary of the abuse potential and examples of drugs falling under this act are provided in Appendix 7. This act is the major regulatory legislation controlling drugs of abuse. In the early 1970s, cocaine was rediscovered as a recreational drug by the young, upwardly mobile, affluent generation. This second cocaine epidemic necessitated a redefinition of the picture of the typical drug abuser as an unemployed, minority male criminal. For example, the 1993 National Household Survey on Drug Abuse reported that 70% of illicit drug abusers are employed, 80% are white, and 75% live in areas outside of the city. In 1983, a glut in the world market for cocaine combined with the development of a smokable, inexpensive, and very addictive form of the drug called “crack” brought the third cocaine epidemic to the inner cities, where availability of powdered forms of the drug was limited because of its cost. In the 1990s, the preparation of a smokable form of methamphetamine led to the widespread abuse of this stimulant, called “ice” and “crank” on the street. More severe abuse patterns than had ever been seen before emerged with the appearance of these smokable, freebase forms of cocaine and methamphetamine. Smoking these drugs results in a more rapid onset of action and a more intense effect, conferring on them more abuse liability than other forms of these drugs that must be sniffed or taken orally. The abuse potential of these drugs increased so dramatically with this mode of administration that drug seeking became more paramount to this population of abusers than it previously had been. Equally insidious has been the emergence of clandestine laboratories that make “designer drugs,” synthetic substances that are inexpensive to produce and difficult to detect. Some examples include the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA) (i.e., “ecstasy”), synthetic cathinones (i.e., “bath salts”), and synthetic cannabinoids (i.e., “spice”). In addition, nonmedical use of prescription drugs such as clonazepam (Klonopin), methylphenidate (Ritalin), and oxycodone (OxyContin) has become common.

DRUG ABUSE CHARACTERISTICS AND TERMINOLOGY The term addiction refers to compulsive, relapsing drug use despite the negative consequences. Additional characteristics of addiction,

which may or may not be present, are dependence and tolerance. When the administration of a drug is discontinued or, in the case of certain drugs, significantly reduced, dependence leads to the appearance of a characteristic and specific group of symptoms, termed a withdrawal or abstinence syndrome. Tolerance exists when administration of the same dose of a drug has progressively less effect. This decreased response to the effects of a drug requires that increasingly larger doses of a drug be given to produce the same pharmacologic actions. The development of tolerance depends on the dose of the drug and the frequency of its administration. Tolerance is caused by compensatory responses that act to decrease the body’s response to a drug. The cellular basis for drug tolerance may be related to a decrease in receptors for the drug, a reduction in enzyme activity associated with signal transduction pathways, or other effects. Cross-­tolerance is the phenomenon whereby chronic use of a drug produces tolerance to that drug’s effects and to other drugs that produce the same effect. Cross-tolerance may be observed among drugs of similar or different chemical types. A related but different phenomenon is cross-­ dependence, which refers to an ability of one drug to substitute for another drug, usually in the same class, in a dependent individual without precipitating a withdrawal syndrome. On the basis of common pharmacologic actions and of cross-tolerance and cross-dependence, the major drugs of abuse can be divided into distinct categories: opioid analgesics; general depressants of the CNS, including sedative-hypnotics, antianxiety drugs, and alcohol; cocaine, amphetamines, and related psychomotor stimulants; hallucinogens; marijuana; and inhalants. Table 39-1 lists the major abuse characteristics of these six drug groups—the abuse potential and degree of dependence and tolerance development commonly associated with the abuse of each drug group. In the following discussion, each drug group is described in terms of three major factors: (1) the pharmacologic effects produced by the drug group; (2) the abuse characteristics of the drug group, including addiction, tolerance, dependence, withdrawal, and other characteristics; and (3) the toxicity caused by the drug group and how it is treated.

ABUSE OF OPIOID ANALGESICS Opioid analgesics most commonly abused include heroin, morphine, oxycodone, hydrocodone, and fentanyl. In addition to these agonists, various other synthetic and semisynthetic derivatives are subject to abuse. These agents differ from each other in their abuse characteristics, their onset and duration of action, the intensity of their effects, and, to some extent, the pattern of their abuse. Many of the mechanisms involved in the analgesic response to opioids also produce

TABLE 39-1  Abuse Characteristics of Drug

Groups

Abuse Potential Dependence Tolerance Opioid analgesics Sedative-hypnotics Amphetamines Cocaine Hallucinogens LSD PCP Marijuana Inhalants

++++ +++ +++ ++++

++++ ++++ ++ ++

++++ +++ ++++ ++

+ + ++ +

+ + + U

++ + ++ U

++++, Marked; +++, moderate; ++, some; +, slight; U, unknown.

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CHAPTER 39  Drugs of Abuse

euphoria or a perceived state of well-being, and much research has been generated in an attempt to develop efficacious analgesics that are not euphoric and have less abuse potential. Although this research has led to a greater understanding of the physiologic characteristics of pain, at present no opioids or other types of analgesics are superior to morphine. In the following discussion, morphine is considered the prototype for this group, unless another drug is specifically mentioned.

Pharmacologic Effects In the following discussion, the subjective effects of opioids are the effects observed in individuals who are opioid abusers. Although opioids produce similar pharmacologic effects in most individuals (see Chapter 16), not everyone reports the subjective effects of warmth, contentment, orgasm, and euphoria. In nonabusing individuals, the nausea and vomiting caused by opioids are construed as unpleasant and may obfuscate many of the reinforcing characteristics of these drugs. Many individuals view the mental clouding produced by opioids as an undesirable inability to concentrate, whereas addicts find this quality appealing. Most important, because opioids are the mainstay in the treatment of moderate–severe pain, it is relevant to know that in the therapeutic setting little substantive evidence suggests that effective and controlled pain management with opioids in individuals leads them to develop into opioid abusers. For individuals who abuse opioids, the IV administration of heroin causes an immediate overwhelming sense of warmth that permeates the abdominal area and that has been described as orgasmic. Nausea, vomiting, and histamine release occur soon after, causing a sense of itching, reddening of the eyes, and a decrease in blood pressure. Feelings of increased energy with talkativeness (“soapboxing”) alternate with periods of relaxation or tranquility (“coasting”). This intense euphoria may last several minutes. The depressant effects on the CNS then appear and include mental clouding, decreased visual acuity, and sedation accompanied by a feeling of heaviness in the extremities. The abuser has no motivation to participate in physical activity; the individual appears to be asleep, but only the head and facial muscles are relaxed (“nodding”). This period is followed by episodes of light sleeping accompanied by vivid dreaming. Feelings of anxiety and worry are absent, and a pervasive sense of contentment is present. Taken together, the early euphoric period followed by the sedation and sleeping may last 3 to 5 hours.

Abuse Characteristics The development of tolerance is a characteristic feature of all opioid agonists. Regardless of whether opioids are administered in a therapeutic setting or are self-administered, repetitive use leads to tolerance or a reduction in response, such that a greater dose of drug is required to achieve the same effect that was produced on initial administration of the drug. Tolerance develops most readily when opioids are given in large doses at short intervals or during constant infusion of the drug; the phenomenon can be observed within days after drug therapy has begun. Tolerance or desensitization to the effects of opioids develops at the cellular level and may be viewed as a homeostatic response by the cell to constant exposure to an agonist. Because the development of tolerance to the effects of opioids is a physiologic phenomenon, it inevitably occurs in patients after repeated drug administration. The development of tolerance is not a predictor of whether the patient will become an opioid abuser. Because most fatalities resulting from opioid overdose are caused by respiratory depression, the prescribing physician must understand that tolerance develops similarly to the respiratory depressant effect and to the analgesic and euphoric effects of opioids. This fact has important ramifications for the clinician, who may be wary about

administering 10 times the normal dose of morphine for adequate pain control in a patient who has developed tolerance to the analgesic effects. Out of concern for the respiratory depressant or addictive properties of morphine, the clinician may not provide adequate pain control even though the patient has developed a similar degree of tolerance to the respiratory depressant and euphoric effects of morphine. Because of this use-induced decrease in the ability of opioids to suppress respiration, considerable tolerance to the lethal effects of opioids may develop. Tolerance to the respiratory effect of opioids is rapidly lost during abstinence, however, and death may result if an addict returns to the previously maintained dosage after withdrawal has been completed. Similar to tolerance, dependence on opioids is also a result of repeated administration of an agonist and occurs for all opioids. Dependence results from cellular adaptation caused by uninterrupted agonist occupation of opioid receptors. Normal function of the individual now requires the presence of an opioid drug at its receptor. When the drug is removed from the receptor during drug withdrawal, an acute withdrawal syndrome ensues. The intensity of the withdrawal syndrome is related to the degree of dependence. As with tolerance, dependence develops most rapidly and to the greatest extent when the opioid receptors are constantly occupied. No outward signs of dependence are observed until the drug is withdrawn. The development of dependence to opioids is a physiologic response seen in all individuals; it does not predict whether they become abusers. In patients who become dependent, the dose of opioid can be decreased by 50% every other day and eventually stopped without overt signs of withdrawal. Withdrawal symptoms in an opioid-dependent individual include rhinorrhea, lacrimation, vomiting, sweating, yawning, diarrhea, irritability, restlessness, chills, piloerection (“cold turkey”), mydriasis, hyperventilation, tachycardia, hypertension, tremors, and involuntary muscle movements. In general, the appearance and severity of withdrawal signs depend on the duration of action of the opioid being taken. Signs of withdrawal in a heroin-dependent individual appear approximately 6 hours after the last dose, increase in intensity over the next 36 to 72 hours, and subside after about 1 week. In contrast, dependence on a long-acting opioid, such as methadone, results in a mild but protracted withdrawal syndrome with delayed onset. A withdrawal syndrome can also be precipitated in dependent individuals by displacing the opioid from the receptor with an antagonist (naloxone), an agonist-antagonist (pentazocine), or a partial agonist (buprenorphine). Death from opioid withdrawal is rare; however, when it does occur, it is because of cardiovascular collapse from dehydration and acid–base imbalance. Addiction to opioids is significant, as exemplified by the high relapse rate among addicts after withdrawal. The euphoria, tranquility, and abdominal effects, described as orgasmic, promote abuse of opioids. The rapidity with which opioids penetrate the CNS to cause their psychoactive effects correlates with their ability to cause addiction. Opioid addicts prefer the “rush” sensation produced by the rapid onset of psychoactive effects characteristic of IV administration over the slower onset of effects produced by other routes of administration. Heroin is preferred because its high lipid solubility confers rapid penetration into the brain and an intense effect. Conversely, orally administered methadone for control of chronic pain has much less potential for creating addiction. Addiction to opioids may occur independently from tolerance and physical dependence and is a result of an addict craving the feelings produced by opioids. This craving may even occur before, or in the absence of, the development of tolerance and dependence. The fact that discontinuance of opioids may precipitate a withdrawal syndrome may provide an incentive to continue their use, however. Because of

CHAPTER 39  Drugs of Abuse the short duration of action of heroin, a dependent addict oscillates between feelings of euphoria and sickness related to withdrawal and exhibits drug-seeking behavior. Drug-seeking behavior is manifested by pleas, complaints, demands, and other activities directed toward obtaining the drug to alleviate the discomfort caused by drug withdrawal. However, an individual may become addicted to opioids before developing fear of withdrawal. Patients in need of pain control should not be denied adequate opioid medication because they show evidence of tolerance or exhibit withdrawal symptoms if the medication is stopped, as these signs do not indicate addiction. In addition, a patient who is in pain and receiving opioids does not respond the same way a psychologically dependent addict responds to opioids. Patients who are able to selfadminister their opioid analgesic take the drug solely to reduce the pain, do not increase the dose greatly over time, and stop administration when the pain goes away.

Toxicity In acute opioid overdose, the classic triad of coma, respiratory depression, and pinpoint pupils is common to all opioid agonists (except meperidine, in which case the pupils may be dilated in tolerant individuals). Hypoventilation leads to marked hypoxemia and cyanosis, and acute pulmonary edema evidenced by pink, frothy sputum may occur, especially with heroin overdose. Nausea and vomiting may be prominent. Hypotension, as a result of cerebral ischemia, develops gradually and may eventually lead to circulatory shock. Convulsions do not occur with most opioids, although they have been reported in children with codeine overdose, in addicts in response to meperidine, and in cases of propoxyphene poisoning. The treatment of choice is rapid IV administration of 0.4 mg of naloxone, repeated if necessary at 2- to 3-minute intervals. Dramatic improvement occurs within minutes, with enhanced ventilation and dilation of the pinpoint pupils. The patient must be closely monitored because the antagonist’s effect lasts only 1 to 4 hours. Monitoring is especially important with methadone overdose because respiratory depression may last 48 hours. If vital signs return to normal, no attempt should be made to arouse the patient with additional naloxone because if the patient is opioid-dependent, large doses of the antagonist may precipitate an acute withdrawal syndrome. Formerly, naloxone was approved for use only in the health care setting. However, in recognition that deaths from opioid overdose, driven largely by prescription abuse, had steadily increased since 2000, naloxone administered by a handheld auto-injector was made available in 2014 by prescription for use by family members or caregivers of opioid drug abusers. The toxic effects of chronic abuse of opioids are minimal. Other than constipation, addicts with a stable supply of drug, individuals enrolled in a methadone maintenance program, or patients taking opioids long-term for pain control have few difficulties as long as they continue taking the drug. Many addicts share unsterile needles and equipment, however, which increases their risk of contracting acquired immunodeficiency syndrome (AIDS), hepatitis, skin abscesses, deep infections, and endocarditis. When the supply of an addict’s preferred drug is compromised, the addict may substitute substances of unknown content and potency or drugs thought to have a similar effect. Many addicts like the effects caused by IV injection of the agonist-antagonist pentazocine with the antihistamine tripelennamine. The talc contained in the crushed tripelennamine tablet has caused deaths as a result of lung emboli. Overdose leading to death may occur when an addict injects a purer sample than that to which he or she is accustomed or a sample containing a much more potent opioid, such as those seen

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with China white in the 1980s and fentanyl in the 1990s. Unexpected toxic effects also occurred in the late 1970s and early 1980s, when “bathtub chemists” trying to synthesize potent opioids produced a compound contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which caused Parkinson-like symptoms in many young abusers (see Chapter 13). Abuse of prescription opioid analgesics has also resulted in unexpected deaths. Beginning in the late 1990s and continuing into the 2000s, deaths from overdosage resulted when individuals crushed tablets of the controlled-release formulation of oxycodone to make the entire dose available for intranasal or IV administration. Opioid withdrawal or detoxification of heroin addicts or other opioid-dependent individuals can be managed with methadone because cross-dependence exists between it and other opioids. Because methadone and all other opioid analgesics act at opioid receptors, methadone can be substituted for the opioid being abused without precipitating a withdrawal syndrome. By substituting longer acting methadone for a short-acting opioid such as heroin, the addict is spared the undesirable effects of withdrawal because the opioid receptor remains occupied. Methadone, with its long duration of action, produces a protracted but tolerable withdrawal syndrome. The dose of methadone is gradually reduced over several weeks until the patient is opioid-free and no longer dependent. Detoxification is effective only if the patient wants to quit abusing opioids and breaks the cycle of relapse and detoxification. The α2–adrenergic receptor agonist, clonidine, can also be used alone or in combination with methadone to assist in the detoxification of an opioid-dependent individual. Many of the unpleasant effects experienced during opioid withdrawal, such as nausea, vomiting, sweating, tachycardia, cramps, and hypertension, are caused by hyperactivity of the autonomic nervous system. Clonidine, through its stimulation of α2–adrenergic receptors in the brain, suppresses the outflow of sympathetic nervous system activity, reducing the discomfort of opioid withdrawal. Although management of acute opioid withdrawal is relatively easy, the recidivism rate (i.e., the number of addicts who return to abusing opioids) is very high. Methadone can also be used in the long-term treatment of opioid abuse, that is, maintenance therapy, when detoxification fails. The pharmacologic basis of methadone maintenance therapy depends on its oral effectiveness in reducing opioid cravings, long duration of action, and the development of cross-tolerance between it and other opioids, particularly heroin. The first step in maintenance therapy is to provide an oral dose of methadone that is not sedating but prevents signs of withdrawal. Maintenance therapy is performed at a government-regulated clinic and is feasible because of the long duration of action of methadone. Patients function normally and do not have the “rush” associated with other routes of administration. If the patient relapses into opioid abuse, the development of cross-tolerance between methadone and heroin or other agents results in a blockade or diminution of the euphoric effect of the abused substance, removing the reinforcing properties of the abused agent. Although the patient is now dependent on a non-intoxicating dose of methadone, he/she can work and participate normally in society. In 2000, Congress passed the Drug Addiction Treatment Act (DATA), allowing certified physicians to prescribe narcotic medications for the treatment of opioid addiction. DATA produced an important paradigm shift that allowed for the treatment of addiction to opioids such as heroin to occur in physicians’ offices, rather than limiting it to highly stigmatized government-regulated methadone clinics. Buprenorphine, an agent now being used under this new legislation, is a long-acting partial agonist that acts on the same receptors as

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CHAPTER 39  Drugs of Abuse

heroin and morphine; it relieves opioid cravings in mildly to moderately addicted individuals and produces less respiratory depression and withdrawal symptoms than the full agonist methadone.

ABUSE OF SEDATIVE-HYPNOTICS Drugs in the sedative-hypnotic group are general CNS depressants and include sedative-hypnotic and antianxiety drugs (discussed in Chapter 11). Older sedative-hypnotic drugs, including barbiturates, glutethimide, and the widely abused but no longer approved drug methaqualone, have substantial abuse potential. Benzodiazepines and related drugs are now the most commonly used sedative-hypnotic and antianxiety drugs. Although these newer drugs have significant abuse potential, they are less frequently abused than the older sedative-hypnotic agents. Sedative-hypnotic drugs are readily available from illicit sources and by prescription abuse when large amounts of the drugs are accumulated by drug abusers visiting different prescribers.

Pharmacologic Effects The signs of intoxication with sedative-hypnotic and antianxiety drugs are similar to signs produced by alcohol: drowsiness, impairment of motor coordination, ataxia, and slurred speech. Sluggishness, difficulty in reasoning, mood swings, and irritability are also seen. Subjective effects include sensations of well-being, euphoria, and sometimes stimulation. The next day the abuser may experience nervousness, anxiety, tremor, headache, and insomnia. The exact constellation of effects depends on the dose of the drug, the route of drug administration, the frequency of administration, and the user’s expectations.

Abuse Characteristics The degree of addiction with sedative-hypnotic drugs depends on the dose of the drug, the frequency of administration, and the duration of drug use. Sedative-hypnotic drugs differ in onset and duration of action (short-acting and long-acting barbiturates and benzodiazepines are available). Addiction is most commonly associated with abuse of short-acting drugs, such as secobarbital, pentobarbital, oxazepam, and lorazepam. Dependence on longer acting agents, such as phenobarbital and chlordiazepoxide, is less common. Dependence occurs only rarely with intravenously administered ultrashort-acting sedative-hypnotics because they cannot be taken frequently enough to maintain adequate plasma concentrations. For benzodiazepines, drugs with a higher affinity for the BZ2 benzodiazepine receptor subtype (e.g., alprazolam) seem to have a greater potential for abuse than drugs with a higher affinity for the BZ1 benzodiazepine receptor. Initial exposure to sedative-hypnotics may occur when the drug is prescribed to relieve anxiety or insomnia. The dose is slowly increased, and the abuser may become preoccupied with obtaining and using the drug. So-called date rape drugs, such as γ-­ hydroxybutyrate, a metabolite of γ-aminobutyric acid, and the prescription benzodiazepine flunitrazepam (“roofies”) are also subject to misuse. Both drugs have similar effects as sedative-hypnotics; however, their rapid oral absorption, onset of action, and ability to cause anterograde amnesia have resulted in their surreptitious use as sedatives to facilitate rape of unwitting individuals. In contrast to opioids, sedative-hypnotics do not induce dependence unless increased doses of drugs are taken over a long period (≥1 month). The onset and severity of the abstinence syndrome also depend, in part, on the dose and the duration of drug use. For instance, some physical dependence is likely to occur with daily doses of secobarbital in excess of 400 mg for about 90 days or more. With chronic use of larger doses, progressively more severe

symptoms of withdrawal can be precipitated, even by abruptly reducing the accustomed dose by half. Withdrawal from daily doses of 600 to 800 mg of secobarbital for at least 35 days is sufficient to produce withdrawal seizures. Another important determinant of the onset, severity, and duration of the withdrawal syndrome is the half-life of the specific drug. Drugs with relatively short halflives (8 to 30 hours) tend to produce a severe withdrawal syndrome that develops quite rapidly. Drugs with longer half-lives (40 to 100 hours) produce a slower onset but less severe withdrawal syndrome of long duration. The withdrawal syndrome after cessation of sedative-hypnotics resembles that seen after alcohol withdrawal. After a usually symptomless period (8 to 18 hours after the last dose), the individual exhibits increasing symptoms of anxiety, insomnia, agitation, and confusion. Anorexia, nausea and vomiting, sweating, and muscle weakness are also seen. Coarse tremors in the face and hands; dilation of the pupils; and increases in respiratory rate, heart rate, and blood pressure may occur. Orthostatic hypotension and syncope may also occur. These symptoms become more severe during the first 24 to 30 hours of drug withdrawal. By the third or fourth day, major manifestations of abstinence may develop, which include delirium, hallucinations, agitation, hyperthermia, convulsions, and nonspecific symptoms of anxiety. Symptoms associated with benzodiazepine withdrawal also occur; these are persistent tinnitus (≤8 months), muscle twitching, paresthesias, visual disturbances, and confusion and depersonalization. Reports of xerostomia and pain in the jaws and teeth have particular dental significance. Muscle fasciculations and enhanced deep reflexes may progress to frank seizures. One or more grand mal convulsions lasting less than 3 minutes may occur, with consciousness being regained within 5 ­minutes. In some cases, status epilepticus may ensue. The prolonged postictal stupor typical of epileptic seizures is not seen, but confusion may persist for 1 or 2 hours. Delirium develops gradually over 2 to 4 days and is heralded by a period of insomnia. Delirium is characterized by confusion, disorientation of time and place, nightmares, and vivid auditory and visual hallucinations. Paranoid delusions with extreme fear and agitation may develop, especially at night (“night terrors”). The symptoms terminate spontaneously after a prolonged period of sleep. This withdrawal psychosis may be caused by rebound rapid eye movement sleep, which, having been suppressed during the period of intoxication, intrudes into the waking state. During the phase of delirium, body temperature is elevated. A continuous marked hyperthermia is a life-threatening problem that, if not immediately and vigorously treated, may (along with agitation) lead to fatal exhaustion and cardiovascular collapse. After the acute withdrawal syndrome, recovery is gradual but complete after approximately 8 days, although residual weakness may be noted for 6 to 12 weeks. Abrupt withdrawal from large doses of sedative-hypnotics can precipitate a severe, life-threatening withdrawal syndrome that has a significant mortality rate. The withdrawal syndrome from sedative-hypnotics may be more severe than withdrawal caused by opioids. Tolerance develops to sedative-hypnotic drugs, and partial cross-tolerance also occurs among the various drugs in this class. Tolerance is usually complete to doses of short-acting barbiturates of up to 500 mg/day, but doses of greater than 800 mg/day are associated with signs of intoxication. The onset of tolerance to benzodiazepines in humans develops slowly, beginning in 3 to 5 days, with maximal tolerance in 7 to 10 days. The mechanisms of tolerance to these drugs are unclear. Much of the tolerance to large doses of short-acting barbiturates is associated with hepatic enzyme induction that results in enhanced barbiturate elimination. This metabolic tolerance plays less

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CHAPTER 39  Drugs of Abuse of a role for benzodiazepines, for which cellular tolerance, a decreased responsiveness of neuronal pathways in the CNS, seems to play a more prominent role.

CH

Ingestion of large doses of sedative-hypnotic drugs may be life-threatening. Coma may develop with progressive deterioration of respiration and blood pressure. The victim exhibits hypoxia, cyanosis, shock, hypothermia, and anuria. Death is usually from cerebral anoxia caused by respiratory failure. Therapy is mainly supportive, consisting of oxygen administered by artificial respiration and fluids or pressor agents (or both) to maintain circulation. For barbiturates, osmotic diuretics with sodium bicarbonate are also used to alkalinize the urine and hasten elimination of the drug. The benzodiazepine receptor antagonist flumazenil has been used specifically to block toxic effects in the treatment of acute benzodiazepine overdose. Withdrawal from chronic therapeutic abuse of sedative-hypnotic drugs is associated with drug craving, nausea and abdominal cramps, tachycardia, palpitation, and generalized seizures. Panic attacks and disorientation may occur, progressing to paranoid psychosis with aggression, delusions, and visual hallucinations. Coma and respiratory depression cause a significant mortality rate. Treatment includes substitution with a long-acting sedative-hypnotic drug, such as phenobarbital, followed by a modest daily reduction in the maintenance dose. Seizures represent a medical emergency and are treated by immediate administration of diazepam, pentobarbital, or carbamazepine. Withdrawal from sedative-hypnotic drugs should be carried out in a hospital setting because life-threatening complications may develop.

ABUSE OF AMPHETAMINES, COCAINE, AND OTHER PSYCHOMOTOR STIMULANTS Psychomotor stimulants include analogues of phenylethylamine (d-­ amphetamine and methamphetamine), a group of amphetamine derivatives in which the terminal amine nitrogen is part of a heterocyclic group (methylphenidate, phendimetrazine) or a diethylated group (diethylpropion), and cocaine. The chemical structures of some of these drugs are shown in Figure 39-1. Amphetamines and methylphenidate are generally used for treatment of narcolepsy and attention-deficit/hyperactivity disorder; phendimetrazine and diethylpropion are anorectics. These drugs are available on the street and by prescription. Methamphetamine and cocaine are the most widely abused members of this class. The chemical structure of cocaine is shown in Figure 39-2. Generally, the effects of and abuse patterns associated with the individual drugs in this group are quite similar.

Amphetamine and Related Drugs Pharmacologic effects

Single oral doses of amphetamine and related drugs produce wakefulness, reduced fatigue and reaction times, and improved performance of psychomotor tasks, especially in sleep-deprived individuals. Feelings of enhanced well-being, moderate exhilaration, and euphoria are common. Judgment may be impaired, and irrational behavior may occur. These drugs can cause signs of increased peripheral adrenergic nerve activity, such as an increase in blood pressure, tachycardia, mydriasis, sweating, and constipation. These effects probably result from the release of norepinephrine from central and peripheral neurons or the blockade of neuronal uptake of norepinephrine at these sites. High oral doses of CNS stimulants induce feelings of cleverness, enhanced abilities, aggressiveness, and fearlessness and may cause a manic “high,” paranoid rage, violent diarrhea, and vomiting.

NH O

CH2CHNH2

Toxicity

COCH3

CH3 Amphetamine

Methylphenidate C2H5

O

CH3

N

C

CH

O

CH3

N C2H5

CH3 Phendimetrazine Diethylpropion FIG 39-1 Structural formulas of amphetamine and related stimulant drugs. O C NCH3

O

O CH3 O C

FIG 39-2  Structural formula of cocaine.

Abuse characteristics Patterns of oral use are usually intermittent and involve lower doses causing milder effects. Oral amphetamines have been abused by students who want to study through the night and by truck drivers who want to stay awake for long hauls. Amphetamine abusers also take these drugs intranasally, intravenously, and by smoking. IV administration of methamphetamine results in a markedly pleasurable rush described as an expanding, flashing, vibration feeling, or a total body orgasm. IV administration of amphetamines is more apt to promote repeated use than oral administration. Because the euphoric effect of IV methamphetamine is long, it can be injected every 3 hours to maintain its euphoric effect. The standard hydrochloride salt form of methamphetamine can be converted into its freebase, resulting in a form of the drug called “ice” or “crank” that can be administered by smoking cigarettes laced with the drug. Smoking methamphetamine in its freebase has become the most popular abused form of this drug in recent years. Because smoking the drug is a more acceptable route of administration, the easy availability of this form of the drug has been suggested to be responsible for the more recent increase in its abuse. The onset of effects and the intensity of the euphoria produced by smoking “ice” are reported to be at least as great as those seen when methamphetamine is injected intravenously. Both chemical forms of the drug are usually taken continuously for 2 to 5 days, during which time the abuser does not sleep or eat. This is called a “run” or “binge.” The next stage is the “crash,” during which the abuser sleeps for 24 to 48 hours. This stage is often followed by hunger, depression, dysphoria, and restlessness. The degree of addiction and abuse potential is high for all the drugs in this group. Individuals dependent on these drugs have a very strong compulsion to engage in drug-seeking behavior. Marked tolerance to the stimulant effects of amphetamine develops readily. Although the therapeutic dose of amphetamine is 10 to 15 mg, abusers may inject intravenously 2 g/day. The mechanism of tolerance is unknown but has been attributed to the depletion of central catecholamine stores with replacement by p-hydroxynorephedrine, a metabolite of amphetamine that may function as a false neurotransmitter in adrenergic nerves.

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CHAPTER 39  Drugs of Abuse

Dependence on amphetamine is not easily demonstrable because it may be difficult to differentiate true withdrawal symptoms from the body’s response to prolonged sleep and food deprivation and enhanced physical activity. Withdrawal from the drug after a “run” is followed, however, by a prolonged sleep and then by a ravenous appetite, fatigue, apathy, and depression. This complex of symptoms is interpreted as evidence of dependence. In humans, the depression associated with amphetamine withdrawal is correlated with a CNS reduction in 3-methoxy-4-hydroxyphenylglycol, a norepinephrine metabolite, which indicates that CNS catecholamines are depleted. This finding provides a neurochemical mechanism to explain the depression caused by drug withdrawal.

Toxicity Acute severe overdose, although uncommon, is characterized by CNS and cardiovascular stimulation. Coma and convulsions occur, which may develop into status epilepticus. These convulsions may be controlled with IV diazepam. Cardiac arrhythmias and hypertension, occasionally precipitating subarachnoid hemorrhage or intracerebral hematomas, may lead to cardiovascular collapse. Enhanced autonomic activity, including hyperthermia and dilated pupils, may also be seen. A chronic amphetamine abuser typically displays anxiety, akathisia, volatile mood, headaches, and cramps. In addition, the abuser frequently shows signs of mental and physical fatigue, poor personal hygiene, and facial twitching. Of particular interest to dentistry are the worn teeth and chewed tongue that result from continuous oral movements. Chronic stimulant abuse leads to stereotypy, psychosis, and overt violence. Stereotypic compulsive behavior is characterized by pleasurable curiosity and fascination with detail. Compulsive, repetitive activity develops, such as cleaning an immaculate home or disassembling and reconstructing mechanical objects. Chronic abuse can cause a drug-induced paranoid psychosis that resembles acute paranoid schizophrenia. Psychosis may develop within 1 to 5 days after beginning drug use and usually lasts 6 to 7 days. The most common symptoms are delusions of persecution; auditory, tactile, and especially visual hallucinations; and hyperactivity. Anxiety, agitation, aggressiveness, and depression are often observed. Paranoia, hallucinations, and terror reactions lead to hostility and difficulty in controlling rage. Amphetamine abusers display a high incidence of unpremeditated, unprovoked, and bizarre acts of violence and assaultive and even homicidal behavior. After amphetamine use is discontinued, confusion, delusions, and loss of memory may persist for several weeks or months. Treatment of toxicity is based on enhancing the elimination of the drug from the body. Acidification of the urine with ammonium chloride increases the rate of urinary excretion of amphetamine and causes rapid reduction of psychotic symptoms.

Cocaine The leaves of the coca plant, which contain up to 1.8% of the pure alkaloid, are the primary source of cocaine. The Andean Indians have chewed coca leaves, mixed with an alkaline substance to promote release of cocaine, for many years. Although peak blood concentrations of 95 ng/mL are achieved, little drug-induced euphoria is reported among Andean Indians who chew coca leaves. The leaves are used to make cocaine paste (30% to 90% cocaine), which is converted to pure cocaine hydrochloride, primarily in South America. Many samples of street cocaine apparently contain adulterants such as amphetamines, mannitol, or lidocaine. The local anesthetic procaine shares some characteristics with cocaine and can produce euphoria. Procaine

powder is frequently used to cut cocaine and, mixed with mannitol or lactose, is sold as cocaine.

Pharmacologic effects Cocaine is a local anesthetic that produces adrenergic effects by blocking neuronal uptake of norepinephrine. Pharmacologic responses to cocaine are mainly cardiovascular and are similar to those of amphetamine. Cocaine produces a dose-related tachycardia and increase in blood pressure, especially systolic. The onset of action is 2 to 5 minutes by the IV route and approximately 30 minutes by the intranasal route. In both cases the cardiovascular response dissipates over roughly 30 minutes. In IV doses of 32 mg, cocaine promotes a moderate mydriasis and hyperglycemia, but no effects on the electrocardiogram, respiratory rate, or body temperature. As a recreational drug, cocaine uniformly causes euphoria and signs of CNS stimulation. The subjective effects of cocaine include elation, arousal, and alertness. Garrulousness and enhanced friendliness facilitate social interaction in group settings. Hunger and fatigue are suppressed. The user has a subjective feeling of increased mental agility. As is true of amphetamine, performance may be enhanced in sleepdeprived, but not in rested, subjects. Cocaine can delay ejaculation, which together with heightened sensory awareness and elevated mood, enhances the sexual experience. The orgasmic rush produced by IV cocaine use may become a substitute for coitus. This essentially pleasant high is produced by doses of about 100, 25, and 10 mg of cocaine by the oral, intranasal, and IV routes, respectively. Negative subjective effects occur in 3% of intoxications in the early stages of abuse, but occur in 82% of compulsive cocaine abusers. The euphoric effects of the drug are followed by restlessness, irritability, and psychomotor agitation. Hyperexcitability and paranoia may occur. Chronic, high-dose cocaine abuse may result in aberrant sexual behavior, such as marathons of promiscuity. Men may have reduced libido, with an inability to maintain an erection or to ejaculate. Women may be unable to achieve orgasm.

Abuse characteristics Although ingested cocaine can have stimulant effects, it is rarely taken orally. The intranasal route (“snorting”) is more commonly used by cocaine abusers. Cocaine hydrochloride usually is inhaled as a “line” of powder containing 20 to 30 mg of the drug. It produces a maximum effect in 15 to 20 minutes and a duration of effect lasting 1 hour or more. Nasal mucosal vasoconstriction and paralysis of membrane cilia prevent complete absorption by this route, and measurable cocaine remains on the nasal mucosa for 3 hours after use. Snorting of cocaine in solution produces effects in 5 to 15 minutes that last 2 to 4 hours. The euphoric effect of cocaine is less intense when the intranasal route is used compared with IV injection or smoking the drug. When cocaine is injected, the IV route is preferred over the intramuscular or the subcutaneous route because local vasoconstriction delays the onset of action by the latter routes. IV injection produces an intense orgasmic rush in approximately 1 minute that lasts 30 to 40 minutes. Abusers average 16 mg of cocaine per injection in a recreational setting. Cocaine is also used intravenously with heroin. The mixture, referred to as a “speedball,” is used to attenuate the excessive stimulation caused by large doses of cocaine. The smoking of cocaine requires conversion of the hydrochloride salt of the drug to the freebase form. The salt form, when heated, decomposes before the vaporization temperature is reached. The freebase volatilizes at temperatures of approximately 90 °C and is not destroyed by heating. Smokers may manufacture their own freebase by dissolving the salt in an alkaline solution and extracting the alkaloid with a solvent such as ether. Since the mid-1980s, the freebase form

CHAPTER 39  Drugs of Abuse has become commonly available as “crack,” a form of freebase melted down into crystalline balls that can be smoked. Crack may be smoked in cigarettes or by heating with an alcohol flame in a pipe. Because the lung–brain circulation time is only 8 seconds, and the inhalation route bypasses the liver, the effects of smoking cocaine base are just as rapid and intense as IV cocaine and last approximately 20 minutes. Smokers average 100 mg of base with each smoke, increasing to 250 mg with rapid tolerance development. Smoking may be repeated every 5 minutes, with intake in compulsive abusers totaling 1.5 g/day. Smoking freebase cocaine has become the most popular method for administration of this drug, and similar to methamphetamine freebase, the freebase form of cocaine has contributed significantly to the increase in its abuse. Used intranasally as a low-dose recreational drug, cocaine produces moderate addiction. High-dose IV or inhalation use produces compulsive behavior characterized by loss of control over drug use and an inability to stop the drug despite repeated attempts. Cocaine shares with other addictive drugs a reinforcing property that results in rapid acquisition of self-administration behavior. This reinforcing property may result from activation of a CNS dopaminergic reward system with cell bodies located in the ventral tegmentum projecting to the nucleus accumbens. Cocaine enhances dopaminergic activity at the latter site by blocking dopamine uptake by nerve endings. This endogenous reward system is normally activated by responding to physiologic imperatives such as hunger, thirst, and sex drive. Cocaine directly stimulates this reward circuitry, dominating motivation for essential physiologic needs. Rats given free access to IV cocaine take the drug in preference to food and die of starvation in a few weeks. Significant tolerance does not develop with occasional cocaine use because of the short half-life of the drug. Frequent use resulting in constant cocaine concentrations in the body does cause tolerance, however. Acute tolerance to subjective and cardiovascular effects is observed within 1 hour after repeated IV doses. Dependence occurs primarily in compulsive, high-dose cocaine abusers. With chronic cocaine use, CNS dopamine depletion may occur, resulting in adverse symptoms during periods of abstinence. Withdrawal results in depression, dysphoria, social withdrawal, craving for the drug, appetite disturbances, tremor, and muscle pain. Such withdrawal phenomena may be severe enough to prevent some abusers from stopping the drug, even though toxic delirium may develop with continued drug use. Oral diazepam has been useful in treating withdrawal anxiety; psychotherapy or cautious use of tricyclic antidepressants is recommended for prolonged depression.

Toxicity Medical complications of cocaine abuse most often involve the CNS and the cardiovascular system. The CNS effects include a toxic psychosis, similar to that caused by amphetamine, which often develops in chronic, heavy abusers of cocaine. The syndrome is characterized by intense anxiety, inability to concentrate, stereotyped compulsive behavior, paranoid delusions, and violent loss of impulse control. Hallucinations may develop that are typically tactile, with sensations of insects burrowing under the skin or snakes crawling over the body. Such psychotic crises are reported in 10% of intoxications in compulsive abusers. Acute depression with suicidal ideation also may develop. Longer term personality changes include a tendency to paranoia with features of depression, reduced frustration threshold, difficulties in impulse regulation, and social maladjustment. Cardiovascular complications of cocaine include cardiac arrhythmias, with sinus and ventricular tachycardia, ventricular fibrillation, and fatal cardiac arrest. Acute myocardial infarction is a particular hazard among abusers with preexisting coronary artery disease because of

591

the increased systolic blood pressure, heart rate, and myocardial oxygen consumption engendered by cocaine. Abrupt increases in arterial blood pressure, occurring within minutes of intranasal use of cocaine, have resulted in subarachnoid hemorrhage, particularly in individuals with aneurysms of cerebral vessels. One case of fatal rupture of the ascending aorta was reported in an individual with preexisting chronic hypertension who had smoked freebase cocaine. Acute cardiac events may occur even with recreational intranasal use of cocaine in individuals without predisposing cardiac disease. Hepatotoxicity, with clinical findings of elevated titers of serum transaminases and jaundice, has been reported in chronic cocaine abusers. Such liver damage may occur in plasma cholinesterase–deficient individuals, in whom cocaine metabolism is shunted through hepatic oxidative pathways, resulting in the production of cytolytic superoxides. A significantly increased rate of spontaneous abortion has been noted in pregnant women. Because cocaine can cross the placental barrier, infants born to cocaine abusers may exhibit tremulousness. Frequent intranasal use leads to chronic rhinitis and rhinorrhea, atrophy of the nasal mucosa, loss of sense of smell, and necrosis and perforation of the nasal septum. These changes, occurring as a result of chronic ischemia, should alert the clinician to possible intranasal cocaine abuse. Bruxism and temporomandibular joint disorders are also more frequent in cocaine abusers. Death from cocaine overdose usually is attributable to generalized convulsions, respiratory failure, or cardiac arrhythmias. Deaths have occurred with each route of cocaine administration and may be so rapid that treatment comes too late. Because cocaine is metabolized by plasma esterases, individuals with low cholinesterase activity are at high risk of cocaine fatality. Treatment of cocaine overdose is symptomatic. CNS stimulation can be treated with IV diazepam, ventricular arrhythmias can be treated with IV lidocaine, and respiratory depression can be treated with oxygen and positive-pressure ventilation.

Other Psychostimulant Drugs Various other psychostimulant drugs collectively referred to as “bath salts” may be classified as synthetic cathinones because they are structurally related to the parent compound cathinone, which is a naturally occurring β-keto amphetamine. Synthetic cathinones include methylone, mephedrone, and 3,4-methylenedioxy-N-pryovalerone (MDPV); however, legislation banning the sale, possession, and use of these specific cathinones has promoted the clandestine development of many pharmacologically similar analogues. Synthetic cathinones interact with monoamine transporters on nerve cells analogously to other psychostimulant drugs and thus produce desirable subjective effects similar to those caused by amphetamine or cocaine. At high doses or prolonged use, synthetic cathinones can cause psychosis, tachycardia, hyperthermia, and death.

ABUSE OF HALLUCINOGENS Hallucinogens are defined as drugs that alter perception, mood, and thought without changes in consciousness or orientation. These drugs are also referred to as psychotomimetics because some of their effects mimic naturally occurring psychoses or as psychedelics because of their use by some people to induce mystical experiences. These drugs are claimed to provide the abuser with enhanced insight and self-knowledge, leading to new ways of looking at life and new insights into personal relationships.

Psychedelic Hallucinogens Psychedelic hallucinogens can be divided into different chemical classes. The chemical structures of some psychedelic hallucinogens are shown

592

CHAPTER 39  Drugs of Abuse O C

C2H5 N C2H5 N

OH

H3CO

CH3

CH2CH2N(CH3)2 N H

N H Lysergic acid diethylamide

H3CO

CH2CH2NH2

H3CO Psilocin

Mescaline

FIG 39-3  Structural formulas of representative hallucinogenic drugs.

in Figure 39-3. Lysergic acid diethylamide (LSD) is a semisynthetic chemical that does not occur in nature. LSD is a commonly used hallucinogen and has become the standard with which other hallucinogenic substances are compared. Drugs derived from tryptamine include the synthetic compound dimethyltryptamine and its derivative, psilocin, and the naturally occurring phosphorylated form of psilocin, psilocybin. The third class of hallucinogens includes amphetamine analogues such as MDMA and mescaline. Mescaline and psilocybin produce effects that are nearly the same as those produced by LSD. MDMA has stimulant effects similar to those of amphetamine and some psychedelic effects similar to those of LSD. Because MDMA possesses mild psychedelic and stimulant properties, it has become popular in club or dance settings, where it can enhance the light and sound experience and enable users to dance vigorously for extended periods. Under these conditions of prolonged physical exertion, MDMA can cause dangerous levels of dehydration and hyperthermia.

Pharmacologic effects Symptoms associated with the LSD experience occur sequentially, with somatic symptoms developing first, followed by perceptual and mood changes, and then by psychic or psychedelic phenomena. Within a half hour of ingestion of LSD, a feeling of inner tension develops, accompanied by somatic symptoms of mild sympathetic stimulation and motor alterations. The individual feels dizzy, weak, vaguely numb, and nauseated. Marked mydriasis is accompanied by an increase in blood pressure and pulse rate, tremor, hyperreflexia, and, at high doses, ataxia. These somatic effects are soon submerged by perceptual and psychic effects, which begin approximately 45 minutes after the drug is taken. Some individuals experience euphoria, elation, serenity, or ecstasy, whereas in others the initial tension may progress to anxiety and depression, evoking a panic reaction. A paranoid rage reaction occasionally occurs, although most subjects tend to be passive, quiet, and withdrawn.

Abuse characteristics The subjective effects of LSD are highly dependent on the psychological makeup of the individual, the environmental influences at the time of the drug experience, the expectations of the individual, and the size of the dose. Distortion of sense perception is the most specific symptom of the LSD experience, affecting all modalities but especially vision. Colors seem unusually bright and vivid, and objects appear distorted and seem to undulate and flow. Fixed objects appear to shift from near to far; fine surface details appear in deep relief; and colorful, dreamlike images occur as vivid streaming filmstrips even with the eyes closed. Frank visual hallucinations are rare, but visual illusions are common, as when a spot on the wall is mistaken for a face. There are distortions of body image, enhanced auditory perception, and, more

rarely, alteration of other sensory modalities. Time sense is distorted; it is often described as stopping or going backward. Synesthesias are common, so that music may be experienced visually, or colors may be “heard.” The changes in sensory perception are soon followed by the psychedelic “trip.” Subjects may experience depersonalization, and the separation between the self and the environment melts away. The user has a sense of profound insight, revelation, and expanded consciousness. This loss of self is interpreted as a “good trip” by psychedelic drug abusers, but occasionally loss of control and fear of self-disintegration foster panic and even attempts at self-destruction. The individual remains oriented and alert throughout the experience and often remembers all events during the “trip” even months later. In general, use of these drugs is not associated with marked dependence, and no clear withdrawal syndrome has been reported. If addiction develops at all, it is mild and infrequent. Tolerance to the effects of LSD is not common but has been reported, and cross-tolerance is seen among members of the psychedelic hallucinogens. With repeated use, tolerance to LSD develops within 1 week but lasts only a few days after discontinuance of the drug.

Toxicity The adult human lethal dose of LSD has been estimated to be 2 mg/ kg, although no deaths caused directly by LSD overdosage have been reported. Adverse psychological reactions to hallucinogens are common. Panic reactions or “bad trips” are relatively frequent and are related to an overdose of the drug. Often, companionship and reassurance, or “talking down,” is sufficient to control this reaction; if this is insufficient, other treatments include sedation with oral diazepam. Acute depression or psychotic reactions can also occur. Ingestion of 50 mg results in hyperactivity, psychosis, amnesia, upper gastrointestinal tract bleeding, and coma. Approximately 1 in 20 LSD abusers has “flashbacks,” in which episodic visual disturbances resembling previous LSD experiences occur during abstinence from the drug. This alteration is now called hallucinogen persisting perception disorder. This disorder may occur months after the previous trip and last a few minutes to a few hours. It is thought to be caused by a drug-induced permanent change in the visual system. This disorder is treated in the same way as panic reactions. In addition, prolonged psychotic states may be precipitated by LSD use, requiring long-term hospitalization and treatment with antipsychotic drugs.

Deliriant Hallucinogens The ketamine derivative phencyclidine, also called PCP or “angel dust,” is a synthetic drug that produces a unique state characterized by delirium, hallucinations, insomnia, and agitation. PCP produces what

CHAPTER 39  Drugs of Abuse (CH2)4CH3

HO N

593

H3C

O H3C

CH3

FIG 39-4  Structural formula of phencyclidine.

FIG 39-5  Structural formula of Δ-9-tetrahydrocannabinol.

is called a “dissociative state” because it is said to dissociate the mind from the body without loss of consciousness. The drug was investigated in 1958 as an anesthetic in humans, but was subsequently abandoned because of severe postanesthetic dysphoria and hallucinations. Derivatives of PCP, such as thienyl and N-ethyl analogs, are also available on the street. The chemical structure of PCP is shown in Figure 39-4.

Nystagmus is observed in approximately two-thirds of intoxications. Grimacing, localized dystonias, and tremor may progress to grand mal seizures or status epilepticus at doses greater than 70 mg, which also produce deep and prolonged coma with loss of protective reflexes that may last for 1 week or more. Death has been attributed to intracranial hemorrhage, status epilepticus, and respiratory failure. Life-threatening hyperthermia may also develop, sometimes in association with hepatic necrosis. Individuals under the influence of PCP act violently with some regularity, and accidents, including drownings, have been documented in many cases. Acute treatment centers on acidification of the urine to hasten renal excretion of PCP. IV diazepam is used to control seizures and the agitated or excited state caused by the drug. Prolonged psychotic episodes may require treatment with antipsychotic drugs.

Pharmacologic effects To produce its effects, PCP binds to receptors in the CNS that are associated with the N-methyl-d-aspartate acid (NMDA) type of glutamate receptor. NMDA receptors mediate some of the CNS effects of the excitatory amino acid glutamate. The PCP binding site resides within the NMDA-gated Ca2+ channel complex, where PCP acts as a noncompetitive antagonist at the NMDA receptor and inhibits some of the CNS effects of glutamate. Receptors that bind PCP have been identified in the CNS in the limbic system and frontal cortex, areas involved in memory, emotion, and behavior. PCP has also been reported to cause dopamine release and to inhibit the active reuptake of dopamine into dopaminergic nerves. This inhibition enhances and prolongs the effects of dopaminergic nerve stimulation. With lower doses, PCP abusers usually remain alert and oriented, while exhibiting euphoria, agitation, or bizarre behavior. Individuals may be irritable or mute and rigid, stare suspiciously, and exhibit impaired reasoning. They are easily provoked to anger and may exhibit violent behavior. The dissociative state, coupled with effects on limbic-mediated emotional control, may provoke feats of superhuman strength, causing harm to self and others. Inappropriate behavior, such as strolling down a street nude, may occur. Detachment, disorientation, stupor, and coma may also occur, but those are more common at higher doses.

Abuse characteristics Currently, the most common route of administration of PCP is by smoking, in which the drug is mixed with tobacco or marijuana. At the burning tip of a cigarette, PCP is converted to 1-phenyl-1-cyclohexene (PC), which is largely inactive. In smoking PCP cigarettes, approximately 40% of the dose is received by the smoker as PCP and approximately 30% as PC. Some abusers snort PCP powder or ingest it mixed with alcoholic beverages or in pill form. A small percentage of abusers inject the drug intravenously. Urine and serum concentrations of PCP do not correlate with the state of intoxication. PCP disappears from urine 2 to 4 hours after a single use (largely because of sequestration in fatty tissues), but it may be detected in the urine of chronic abusers for 30 days. Most PCP use is intermittent rather than chronic. Some PCP abusers develop addiction to the drug, although this is less common than with the drugs of abuse previously discussed. No clearly defined dependence on PCP has been identified, but withdrawal from chronic use has been reported to result in depression, irritability, confusion, and sleep disturbances along with a strong craving for the drug.

Toxicity Symptoms of acute intoxication appear 15 to 30 minutes after ingestion. Marked analgesia, shivering, salivation, bronchospasm, urinary retention, hypertension, tachycardia, and hyperpyrexia result.

ABUSE OF MARIJUANA Marijuana is ground-up leaves and flowers from the hemp plants, Cannabis sativa or Cannabis indica, and is one of the most frequently abused drugs in the United States. The cannabinoid Δ-9-­ tetrahydrocannabinol (THC) (Fig. 39-5) is thought to be the main psychoactive ingredient. Preparations of marijuana vary widely in their THC content, depending on the variety and part of the plant used and the environment in which the plant is raised. Stalk fibers from any variety of hemp contain no psychoactive agents, and the type of hemp plant from which stalk fibers are used commercially in the production of rope, twine, cord, and clothing is virtually drug-free because it is grown under conditions that favor high fiber and low THC content. Conversely, more potent samples of marijuana are made from the younger, topmost leaves of hemp varieties that can contain 5% or more THC by weight. Another component of the Cannabis plant that is commonly abused is an extract called hashish. In contrast to marijuana, which is ground-up plant material, hashish is an extract containing only the THC-rich resin that is secreted by the hemp plant. Hashish is more potent than marijuana, and it can contain 12% or more THC by weight. Synthetic cannabinoids are also abused. Their chemical structures range from tetrahydrocannabinols and bicyclic cannabinoids to aminoalkylindoles and anandamide analogues. These chemicals are typically sprayed onto plant material and then sold legally as herbal products with names like “K2” and “Spice.” Marijuana, hashish, and synthetic cannabinoids are usually smoked in the form of cigarettes or from a pipe.

Pharmacologic Effects THC, other phytocannabinoids found in marijuana, and synthetic cannabinoids produce their effects by activating the endocannabinoid system in the brain. The endocannabinoid system consists of CB1 and CB2 G protein–coupled receptors, two endogenous ligands (anandamide and 2-arachidonoyl-glycerol), and associated metabolic and synthetic enzymes. Although the physiologic significance of the cannabinoid receptors and their ligands remains a matter of much study, evidence suggests a role for the endocannabinoid system in appetite, pain, reward, mental illness, and neurodegenerative disease.

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CHAPTER 39  Drugs of Abuse

Intoxication with marijuana is unique, causing changes in mood, motivation, and perception that are similar to some of the effects caused by amphetamines, LSD, alcohol, sedative-hypnotics, and opioids. Within minutes of inhaling marijuana smoke, the typical abuser reports feelings of euphoria, uncontrollable laughter, depersonalization, alterations in judgment of time and space, and sharpened vision. Mild visual hallucinations may occur, particularly when the eyes are closed. Similar to LSD, the abuser knows that these visual disturbances are drug-induced. Later, the abuser experiences generalized feelings of well-being, relaxation, and tranquility that may last 2 to 3 hours. The abuser experiences a reduction in attention span, difficulty in thinking and concentrating, and impairment of short-term memory. All these effects are considered desirable by the abuser and are described as “mellowing out.” Many abusers report that the feelings of intoxication, dreaminess, and sedation can be more easily suppressed voluntarily than the equivalent effects produced by alcohol. The sedative-hypnotic property of marijuana facilitates the onset of sleep and resembles the effects caused by CNS depressants. This property of marijuana is in sharp contrast to the effects of LSD and other hallucinogens. Although it is generally agreed that a dose-related impairment in psychomotor performance occurs, many experienced abusers exhibit no such decrement in their performance; perhaps this is why no clear correlation has been shown between blood concentrations of THC and an individual’s ability to drive a car. Physiologic effects of smoking marijuana occur within a few minutes, peak in their action in approximately 20 minutes, and wane over 2 to 3 hours. Moderate marijuana use causes reddening of the eyes in association with a euphoric high that is followed by drowsiness. Autonomic effects of marijuana include xerostomia, tachycardia, reduced peripheral resistance, and, in large doses, orthostatic hypotension. These effects may be deleterious in individuals with ischemic heart disease or cardiac failure. Marijuana does not affect respiratory rate, blood glucose concentrations, or pupillary diameter; however, marijuana does reduce intraocular pressure. Studies of the potential therapeutic uses of dronabinol, the nonproprietary name of THC, show it to be effective in treating some conditions. Oral administration of dronabinol has been approved as an antiemetic in cancer patients undergoing chemotherapy and as an appetite stimulant in patients with weight loss resulting from AIDSrelated anorexia. Smoking marijuana may also have beneficial effects in the treatment of weight loss in patients with AIDS. Whether smoking marijuana has an advantage over orally administered dronabinol in the treatment of AIDS-related anorexia remains to be determined. Although THC is effective in reducing intraocular pressure in patients with glaucoma, its psychoactive properties make THC less desirable than other forms of drug therapy for this indication.

Abuse Characteristics In humans, the development of tolerance to marijuana is most apparent among heavy chronic abusers and is evidenced by increases in the amount of drug used over time. Although chronic use of marijuana has a long history, whether dependence on marijuana develops in humans remains controversial. Abrupt withdrawal of marijuana from chronic abusers has been reported to cause sleep disturbances, decreased appetite, nausea, and vomiting. Whether these alterations in normal function are alleviated by the readministration of marijuana has not been shown, and this is necessary to prove that constant exposure to marijuana causes the development of dependence. Although the magnitude of addiction to marijuana is difficult to quantify, marijuana clearly possesses some abuse potential because it is the most commonly used illegal drug in the United States. Perhaps the lack of understanding of the abuse potential of marijuana is related to the fact that few

individuals ever seek treatment for marijuana addiction, combined with the knowledge that the extensive and frequent use of this drug has led to few reports of severe toxicity.

Toxicity Although few reports exist of adverse effects caused by acute administration of marijuana, the most common adverse reaction usually seen in naïve abusers is an acute nonpsychotic panic reaction characterized by anxiety and fear of losing one’s mind. Many inexperienced elderly abusers interpret the THC-induced tachycardia combined with the psychological effects of THC as evidence that they are dying. Both of these conditions are best treated with authoritative reassurance or antianxiety agents of the benzodiazepine class. Very high doses of THC may result in self-limiting toxic delirium, acute paranoia, and psychotic episodes. When compared to marijuana, abuse of synthetic cannabinoids is associated with a higher incidence of severe effects such as hypertension, tachycardia, hallucinations, agitation, seizures, and panic attacks that often necessitate medical care. Chronic use of marijuana seems to cause no functional changes in the CNS; however, heavy smokers may be prone to chronic bronchitis, airway obstruction, poor dentition, and squamous cell metaplasia (similar to smokers of tobacco). Contamination of marijuana with Aspergillus or the herbicide paraquat can lead to severe pulmonary damage in abusers. Chronic, intensive use of 5 to 18 marijuana cigarettes weekly is reported to reduce testosterone concentration and cause oligospermia in men. Other studies of shorter exposures to marijuana have not confirmed these findings, although they do show that secondary sexual characteristics in very young abusers can be suppressed by marijuana. Teratogenic effects of THC are known to occur in animals; no such reports exist for humans smoking marijuana. Anecdotal reports suggest marijuana use produces an amotivational syndrome, which is described as an affliction of young abusers of marijuana who drop out of social activities and show little interest in school, work, or other goal-directed activities. Laboratory studies and cross-cultural analyses of marijuana smokers in countries where marijuana use is acceptable do not support the contention that THC use leads to psychosocial deterioration. Others have suggested that the lifestyle and goals of an abuser of any kind of illicit drug may more satisfactorily explain the amotivational syndrome.

ABUSE OF INHALANTS Modern awareness of the consciousness-altering effects of inhaled compounds began with the discovery of anesthetic agents such as ether, chloroform, and nitrous oxide in the early nineteenth century. Today this list also includes halothane and other halogenated compounds. The use of general anesthetics is discussed in Chapter 15. Although nitrous oxide, halothane, and other volatile anesthetics are usually available only to medical or health care personnel, nitrous oxide can also be found in restaurant supply stores as a propellant for making whipped cream and packaged in small metal canisters called whippets. Although ether and chloroform are no longer used as anesthetics, they are available through chemical supply houses. In addition to volatile anesthetics, three other main classes of inhalants are subject to abuse. The first are volatile solvents, which include glue, paint thinners, cleaning fluids, degreasers, and gasoline. The generalized depressant effects on the CNS caused by these solvents are mediated by ingredients such as trichloroethylene, benzene, toluene, naphthalene, hexane, heptaene, and acetone. This class of inhalants is widely abused because of ready availability. The second class of inhalants includes aerosol propellants such as methanol, ethanol, and isopropanol used in spray paint and

CHAPTER 39  Drugs of Abuse cooking sprays. Trichlorofluoromethane and other fluorocarbons used as refrigerants may also be abused. The alcohols are less rewarding than other volatile solvents, and ethanol is more prone to be abused by the oral route of administration. The third class includes organic nitrites, which include amyl, butyl, and isobutyl nitrite. Amyl nitrite is used as a vasodilator in the treatment of angina pectoris (discussed in Chapter 21) and is packaged in mesh-enclosed glass ampules designed to be crushed between the fingers, allowing for inhalation of the vapors for relief of the pain of angina. Amyl nitrite ampules are commonly referred to as “poppers” because of the popping sound resulting from their being broken. Amyl nitrite and isobutyl nitrite are perceived to be sexual enhancers, which increases their abuse potential. Although amyl nitrite is available only by prescription, isobutyl nitrite is used as a room deodorizer and can be purchased from shops that sell drug paraphernalia under the names “Locker Room,” “Doctor Bananas,” and “Rush.”

Pharmacologic Effects With the exception of the organic nitrites, all the abused inhalants have a generalized depressant effect on the CNS similar to that of volatile general anesthetics. Low doses of these agents first produce signs of stimulation followed by depression, unconsciousness, and, with larger doses, death. The desirable effects of these compounds—euphoria, perceptual distortions, ataxia, giddiness, and slurred speech—occur within seconds of inhalation and last 5 to 45 minutes. Undesirable effects may be experienced during use and for variable periods afterward and include coughing, vomiting, rhinitis, photophobia, irritation of the eyes, tinnitus, nausea, and sneezing. The vasodilatory action of the organic nitrites is immediate and produces a feeling of warmth and lightheadedness that is commonly referred to as a “head rush.” The “head rush” is brief and is considered desirable; however, it may result in loss of consciousness as a consequence of postural hypotension if the drug is inhaled while standing. Headaches commonly occur after use of organic nitrites and are caused by vasodilation of cerebral blood vessels.

Abuse Characteristics The euphoria, disinhibition, and general feelings of drunkenness are thought to be the reinforcing characteristics of inhaled CNS depressants; abusers take these agents repeatedly, suggesting addiction to them. Few controlled studies have been performed on the development of tolerance to solvents, aerosols, and nitrites. Because solvents, aerosols, ethanol, barbiturates, and benzodiazepines share many of the same pharmacologic effects, however, considerable interest remains in whether cross-tolerance exists among these agents. There is little evidence that signs of abstinence occur in individuals when inhalants are withdrawn, suggesting that dependence is not part of the experience of these abusers.

Toxicity Ascribing the toxic effects of an abused inhalant to an individual agent is difficult because the toxic effects of inhaled solvents and aerosols may be caused by more than one substance and because solvents typically contain several volatile compounds or may be tainted with heavy metals such as lead and cadmium. The major health risks associated with acute use of anesthetic gases and volatile liquids are sudden death from asphyxiation, respiratory depression, or arrhythmia-induced cardiopulmonary arrest. Halogenated hydrocarbons, such as trichloroethylene, are particularly likely to cause arrhythmias. Repeated abuse of inhalation agents may lead to toxic effects caused by chronic exposure. Industrial solvents are known to cause liver and kidney damage, sensory and motor neuropathies, bone marrow

595

suppression, and pulmonary disease. The toxic effects of chloroform on the liver and kidney are so well known that chloroform has not been used as an anesthetic for decades and has been eliminated from commercially available products. Continuous exposure to nitrous oxide can cause megaloblastic anemia, methemoglobinemia, and, rarely, peripheral neuropathy. In industrial settings where chronic exposure to organic nitrites occurs, cases of methemoglobinemia have been reported; however, this is rare in abusers of these compounds.

POLYDRUG ABUSE Drug abuse problems are often compounded by the practice of taking two or more drugs in combination or in sequence. Polydrug abusers may seek additive or potentiated effects (e.g., the simultaneous use of alcohol and another sedative) or the modulation or termination of effects (e.g., the sequential use of amphetamines and barbiturates). Approximately 20% of chronic alcoholics abuse other drugs, especially barbiturates, antianxiety drugs, and marijuana. Primary heavy abusers of marijuana frequently use amphetamines or psychedelic agents, whereas heroin addicts are particularly apt to abuse amphetamines, cocaine, hallucinogens, and barbiturates. Most patients in methadone maintenance programs apparently are polydrug abusers. When multiple drug dependencies develop, the withdrawal syndrome becomes difficult to treat and is associated with a significantly enhanced mortality rate.

IMPLICATIONS FOR DENTISTRY Certain signs may alert the dentist to the possible parenteral abuse of drugs. Telltale cutaneous lesions may result from chronic hypodermic administration of drugs of abuse. These lesions include acute septic complications, such as subcutaneous abscesses, cellulitis, and thrombophlebitis, and chronic cutaneous complications, including skin tracks and infected lesions, which occur most commonly in the thigh or antecubital or deltoid regions. Skin tracks result from frequent, multiple injections that produce chronic tissue inflammation. These are typically linear or bifurcated erythematous lesions that become indurated and hyperpigmented. Another sign that may alert the clinician to the problem of drug abuse is the presence of an ill-defined febrile illness. This finding often reflects a low-grade bacteremia resulting from the injection of drugs. In ascertaining whether a patient is abusing drugs, the dentist cannot depend on being able to identify a particular personality type, recognize cutaneous lesions (which may be concealed under clothing), or diagnose a mild febrile illness. Rather, the dentist must rely on careful and thorough questioning of the patient and on the skillful use of a well-designed medical history questionnaire. Drug abuse is a subject of considerable importance to dentists because they are occasionally the unwitting target or victim of drug abusers’ need to secure drugs. Also, drug abuse among health professionals has a long history, numerous medical and dental abnormalities are associated with drug abuse, and interactions may occur between drugs that dentists customarily prescribe and drugs the patient is abusing.

Dentists as a Target of Drug Abusers Inevitably, drug abusers, through pretense and subterfuge, attempt to obtain drugs from dentists. The dentist should be aware of any patient who complains of pain from pulpitis or an abscess and who refuses endodontic or surgical intervention. An opioid abuser may claim to be allergic to codeine or pentazocine in an effort to obtain more positively reinforcing drugs, such as oxycodone, morphine, or hydrocodone. As a general defense against drug abusers, the dentist should never let

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patients know where such drugs are kept, never leave prescription pads out where they may be taken, and avoid the use of prewritten prescription forms.

Drug Use Among Dentists Dentists are not immune to the hazards of drug abuse. Similar to physicians, they may be in greater danger of developing drug dependencies than the general population because of the ready accessibility of opioid analgesics and sedative-hypnotic drugs. Opioid addiction among medical personnel is much higher than that of the general population. One form of drug abuse common among dentists and other health professionals is the inhalation of nitrous oxide. Evidence suggests that the pleasurable effects of nitrous oxide inhalation can lead to a craving for the drug in some individuals. The abuse potential of nitrous oxide coupled with the ease of availability of the drug contributes to its relatively frequent abuse by dentists.

Medical and Dental Complications of Drug Abuse The most common and serious medical complications in drug-abusing patients are AIDS, endocarditis, and hepatitis. IV drug abusers are at risk of AIDS. Sharing needles for IV injections spreads the AIDS virus. IV drug abusers are responsible for a significant number of AIDS cases among heterosexuals. Bacterial endocarditis in drug abusers is most commonly caused by Staphylococcus aureus, which seems to derive from an increase in endogenous pathogens in the addict rather than from contaminated drugs or drug paraphernalia. In drug-abusing patients, the disease often affects the tricuspid valve, which is unusual in non­ abusers. Pseudomonas endocarditis, although less common, primarily involves the tricuspid valve and has an overall mortality rate of 50%. Candida albicans infects the left-sided valves and is almost invariably fatal. Candidiasis may be disseminated to skin, eyes, bones, or joints. Viral hepatitis is often seen among drug abusers and is probably transmitted by contaminated needles. The disease is usually mild, but individuals displaying early signs of elevated prothrombin time, fever, elevated leukocyte count, or encephalopathy have a poor prognosis. In 50% to 80% of cases, the acute infection results in chronic inflammatory hepatic disease. Opioid drugs have been reported to depress the immune system by interacting with opioid receptors on T lymphocytes and leukocytes. Other drugs of abuse have also been suggested either to suppress or to enhance the activity of the immune system. Whether the development of infectious diseases in drug abusers is caused by a direct effect of these drugs on the immune system is unknown. Specific dental complications of drug use include rampant caries and rapidly progressing periodontal disorders, probably resulting from nutritional deficiencies and neglect of personal hygiene. Xerostomia with an enhanced rate of dental caries has been reported in individuals who abuse opioids, amphetamines, sedative-hypnotic drugs, and marijuana. In other studies, opioid and marijuana use do not seem to reduce the rate of salivary secretion, however. Self-mutilation has occurred among drug abusers; teeth may be deliberately damaged in an effort to obtain drugs. Long-term cocaine and amphetamine abusers may develop facial tics and bruxism, which result in a traumatized tongue and worn teeth. These subjects may also chronically rub the tongue along the inside of the lower lip, producing ulcers on the abraded tissues.

Drug Interactions in Drug Abusers Drug interactions in drug abusers are not unique, but they depend on the drug of abuse. Barbiturates and other sedative-hypnotic drugs

induce hepatic cytochrome P450 enzyme activity. Abusers of such substances may be resistant to the therapeutic effects of corticosteroids, oral anticoagulants, and many CNS depressants because the metabolism of these drugs is enhanced by enzyme induction. Opioid abusers generally show tolerance to other opioid analgesics. The dentist should beware of giving pentazocine to such patients because this and other agonist-antagonists may precipitate an acute withdrawal syndrome in opioid-dependent patients. Marijuana may intensify CNS depression produced by barbiturates, general anesthetics, and other CNS depressant drugs. The sympathomimetic effects of cocaine, amphetamine, and marijuana may be enhanced by drugs used in dental practice. Administration of local anesthetics containing epinephrine or gingival retraction cords impregnated with epinephrine may enhance tachycardia and elevations in blood pressure caused by these drugs.

Pain Control and Drug Abusers Drug abusers may be more anxious and fearful of dental procedures and may have a lower pain tolerance than patients who do not abuse drugs. To counteract these fears, abusers may take their favorite drug of abuse before dental appointments. If the dentist knows that the drug abuser has taken such a drug, the dental procedure should be rescheduled, and the patient should be counseled to avoid drug use before the next visit. Complicating this picture is that tolerance to sedative drugs and local anesthetics has also been reported, particularly in parenteral drug abusers. These patients may need larger amounts of these drugs for pain-free dental treatment. Larger doses of sedatives and local anesthetics carry the risk of enhanced adverse effects caused by these drugs. Treatment of pain and anxiety in a recovering or reformed substance abuser presents a problem to the dentist. Whether the patient has abused alcohol or other drugs in the past, proper dental care demands a preoperative evaluation of the patient’s personal attitude toward drug treatment. Many of these individuals refuse mood-altering drugs, and such wishes must be respected. As a rule, it is best never to administer a drug, or another of its class, that has previously been abused by the patient. In cases in which anxiety is predominantly somatic (e.g., tachycardia, breathlessness, and tremulousness), oral propranolol may be valuable. Intraoperative pain control can be accomplished with local anesthetics, but systemic exposure to epinephrine should be minimized in patients being treated with neuronal uptake pump inhibitors such as desipramine for post-dependence depression. Postoperative pain can usually be adequately controlled with nonsteroidal antiinflammatory drugs or acetaminophen.

ETHYL ALCOHOL The principal medical use of ethyl alcohol (ethanol) is topical disinfection. Although ethanol has limited clinical application, as the most common intoxicant in Western civilization, it is of immense importance because of its potential for abuse and dependence and because it is a major contributing factor to individual and social ills in the United States and other nations. Ethanol can be obtained as anhydrous alcohol (100% ethanol), as neutral spirits (95% ethanol), and as denatured alcohol. Denatured alcohol, intended primarily for industrial use, is ethanol with a substance added to render it unfit for consumption, such as methanol, benzene, diethyl ether, or kerosene. The social costs of ethanol abuse are staggering. Ethanol abuse– related costs, including health care costs, criminal damage costs, and workplace costs, are estimated to be several hundreds of billions of U.S. dollars worldwide. Approximately 50% of all fatal

CHAPTER 39  Drugs of Abuse

597

TABLE 39-2  Effects of Ethanol on the CNS and Peripheral Nervous System Effect

Mechanism

Comments

Encephalopathy* (includes delirium, psychiatric symptoms, dementia)

Ammonia toxicity, thiamine, niacin, and other deficiencies

Hepatic toxicity from alcohol leads to excessive ammonia, and thiamine deficiency Hypoxia, ischemia, and damage to blood vessels

Increased reward mechanisms Excitement Sedation

Direct alcohol effect on glia, neurons, and blood vessels. Alcohol changes proteins, lipids, and DNA Stimulation of dopaminergic and opioid pathways Disinhibition of inhibitory pathways in the brain Increases the effect of GABA

Aggression Respiratory depression Peripheral neuropathy

Can deplete serotonin Depression of medullary respiratory center Thiamine deficiency

Pathways for addiction Euphoria, and social uninhibited behavior May also involve changes in the NMDA receptor pathway Acute toxicity can cause death Diminished tendon reflexes, sensory loss in feet or legs, muscle atrophy

*Includes Wernicke’s encephalopathy and Korsakoff syndrome. GABA, γ aminobutyric acid; NMDA, N-methyl-d-aspartate (a glutamate receptor).

traffic accidents are related to the use of ethanol. Drinking aggravates criminal behavior. Ethanol is involved in approximately one-third of suicides and rapes, half of assaults, and one-half to two-thirds of homicides.

Mechanism of Action It has long been believed that the effects of ethanol on the CNS are mediated by an increase in membrane fluidity, leading to disorder of the membrane lipids and resulting in abnormal activity of ion channels and other proteins. Although there is evidence to support this mechanism, the focus more recently has been on the effect of ethanol on excitatory and inhibitory amino acids in the brain. Ethanol potentiates the effect of γ-aminobutyric acid (GABA) at GABAA receptors. Its mechanism in this respect is similar to that of other sedatives, such as benzodiazepines, which also enhance the effect of GABA at GABAA receptors and increase Cl− conductance. In addition, ethanol exerts an inhibitory effect on the CNS by reducing glutamate activation of excitatory ion channels. More specifically, ethanol inhibits the response of the NMDA receptor to glutamate. Biochemical mechanisms involved in the CNS effects of ethanol also seem to involve, among others, dopaminergic, adrenergic, serotoninergic, and opioid pathways. Reward mechanisms are enhanced by dopaminergic stimulation and by opioid peptides. Naltrexone, an opioid receptor antagonist, inhibits the desire for alcohol intake, as do dopamine receptor antagonists.

Pharmacologic Effects Ethanol-induced damage in organs lacking significant ethanol oxidative capacity may result from enzyme-catalyzed esterification of fatty acids with ethanol. Transient accumulation of such fatty acid ethyl esters, or their fatty acid metabolites, seems to inhibit oxidative phosphorylation and may alter plasma membranes, leading to damage in organs such as the heart, pancreas, and brain. The inflammatory effects of alcohol on the gastrointestinal tract lead to esophagitis and chronic gastritis frequently associated with intense episodes of vomiting, which may lead to gastric laceration and hematemesis. There is a high correlation between heavy drinking and cancer of the mouth and throat. Peptic ulcers and pancreatitis are common among alcoholics. Effects of alcohol on skeletal muscle may produce acute alcoholic myopathy characterized by muscle cramps, weakness, and swelling, which resolve after a few weeks of alcohol abstinence. In severe cases, extensive muscle degeneration results in myoglobinemia,

hyperkalemia, and renal failure. A chronic form of alcoholic myopathy ultimately produces marked muscular atrophy, usually of the pelvic girdle and thighs. Chronic alcoholism is associated with numerous severe physical complications, including the central and peripheral nervous systems, liver, gastrointestinal tract, and skeletal and cardiac muscle.

Central nervous system There is a common but mistaken notion that ethanol is a CNS stimulant. To the contrary, ethanol is a sedative-hypnotic that depresses the CNS in a dose-dependent fashion. Much of the apparent stimulation resulting from ethanol use results from disinhibition of CNS function because of selective depression of inhibitory pathways at lower concentrations of ethanol. Although mental processes, memory, and concentration are reduced, the individual may feel euphoric, confident, and socially uninhibited. Higher doses (intoxication) lead to overall depression of the CNS. As with other CNS depressants, the major acute toxicity of ethanol is respiratory depression from inhibition of the medullary respiratory center. Effects of ethanol on the brain are shown in Table 39-2. The concentration of ethanol in alcoholic beverages is often listed as the “proof.” The actual concentration of ethanol, in percent by volume, is half the proof number: 80 proof equals 40% ethanol by volume. Because of the variability of absorption of different alcoholic beverages, the effects of ethanol are most commonly correlated with the blood alcohol concentration (BAC), as illustrated in Table 39-3. The effects of ethanol are dose-related and progress through the typical sequence of anxiolysis, sedation, hypnosis, anesthesia, and death. Ethanol is a soporific, increasing the time spent in sleep and decreasing the time it takes to get to sleep.

Liver A number of effects of ethanol on the liver have been documented (Table 39-4). Acute ingestion of intoxicating amounts of ethanol leads to a reduced liver-metabolizing activity. This effect is reversed when the ethanol is eliminated. In a long-term alcoholic, induction of liver microsomal enzymes is common; if the individual is not intoxicated, drug metabolism may be enhanced. If cirrhosis of the liver occurs, overall metabolism is reduced because of impaired hepatic blood flow and destruction of liver tissue. The use of ethanol has several implications for drug metabolism. Other effects of ethanol on the liver are listed in Table 39-4. The toxic effects on the liver of long-term ethanol abuse are summarized in Figure 39-6.

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TABLE 39-3  Correlates of Blood Alcohol

Concentration (BAC) BAC (mg/dL)

Clinical Effects

50

Altered vision, reduced fine motor functions, ataxia, disinhibition, drowsiness, slowed speech, impulsive actions, increased sexual motivation (Drivers younger than 21 are restricted to 20 mg/dL) Legally drunk, lower sexual performance, otherwise heightened effects than those seen at 50 mg/dL Nausea and vomiting, exaggerated action, memory deficits worsened, ataxia, amnesia, rage, nystagmus, analgesia, reduction in the length of rapid eye movement during sleep Dazed, loss of consciousness, hypothermia, hypotension, mydriasis, sweating “Dead drunk” severe medullary paralysis, cardiovascular depression Lethal effect due to medullary paralysis, severe cardiovascular depression

80 150

300 400 500

TABLE 39-4  Effects of Ethanol on the Liver Effect

Mechanism

Toxicity to hepatic cells, increased Inhibition of liver enzymes with acute response to some drugs high level alcohol intake Increased liver enzyme activity, Induction of liver microsomal enzymes reduced effect of some other with chronic alcohol intake during the drugs “sober” period Altered nutritional status Lowered levels of vitamins A and D, thiamine, niacin, pyridoxine, and others; acetaldehyde plays a major role Enhanced lipid peroxidation, Acetaldehyde plays a major role membrane damage Damage to liver cells, leading to Endotoxins from the altered flora of the GI fatty liver and cirrhosis tract stimulate Kupffer cells, leading to inflammatory mediators; recruitment of infiltrating macrophages (see Fig. 39-6) Inhibition of insulin-like growth factor

Cardiovascular system Acute alcohol administration results in an elevated catecholamine concentration in blood and urine. Adrenal gland activation results in increased blood concentrations of corticosteroids, epinephrine, and glucose. Adrenal monoamine release is accompanied by compensatory increases in the activity of medullary tyrosine hydroxylase, dopamine β-hydroxylase, and phenylethanolamine-N-methyltransferase. Vascular smooth muscle exhibits hyperreactivity to norepinephrine at low ethanol concentrations and hyporeactivity at high concentrations. The latter effect may be caused by ethanol-induced facilitation of neuronal monoamine uptake. The direct actions of ethanol on vasomotor tone, coupled with its complex adrenergic effects and centrally mediated influences, produce variable cardiovascular responses. In general, coronary blood flow is slightly enhanced, but there is no concomitant increase in myocardial oxygen uptake. Myocardial contractility is depressed by ethanol. Direct vasoconstriction has been observed in cerebral and renal vascular beds in vitro, but in vivo the effect of ethanol, occurring only at large doses, is an increase in blood flow to the brain and kidneys. Mesenteric blood flow also seems to be increased.

MAC

Ethanol, Acetaldehyde

Liver MAC HEP PGE2, Cytokines, Radicals KC

Stomach Endotoxin

FIG 39-6  Mechanism of liver damage from ethanol. Use of ethanol leads to an increase in certain intestinal gram-negative organisms, resulting in an increase in endotoxins. Damage to the GI tract contributes to the absorption of endotoxins. These stimulate Kupffer cells (KC) in the liver to produce mediators, including prostaglandin E2 (PGE2), cytokines, and free radicals, which damage hepatocytes (HEP). Effects on KC lead to the recruitment of infiltrating macrophages (MAC), which also release mediators that damage liver cells. Ethanol and acetaldehyde induce cytochrome P450 enzymes (CYP), especially CYP2E1, and damage mitochondria, resulting in production of reactive oxygen species that damage hepatic hepatocytes. Ethanol or acetaldehyde may also act directly on hepatocytes to alter lipid metabolism, damage cell macromolecules, or block the effect of insulin-like growth factor. (Modified from Thurman RG: Mechanisms of hepatic toxicity, II: alcoholic liver injury involves activation of Kupffer cells by endotoxin, Am J Physiol 275:G605-G611, 1998; and Wang et al., 2014, in General References.)

A consistent cardiovascular effect of alcohol ingestion is cutaneous vasodilation. The increased blood flow to the skin provides a feeling of warmth. In cold environments, heat loss may be greatly accentuated, and alcohol generally should be avoided in treating hypothermic individuals. At low ambient temperatures, individuals under the influence of ethanol have a high risk of hypothermia. The ethanol metabolite acetaldehyde causes catecholamine release and produces tachycardia, increased cardiac output, and increased arterial blood pressure, effects that are abolished by adrenoceptor blockade. The concentrations of acetaldehyde normally resulting from low amounts of ingested ethanol have little acute effect on the cardiovascular system, however. Long-term effects of ethanol differ from its short-term effects. When ingested in excess on a long-term basis, ethanol increases the risk of hypertension and adverse cardiac effects such as stroke. Long-term ethanol abuse can cause a cardiomyopathy characterized by a decreased ventricular ejection fraction and heart failure. Fibrosis of the myocardium may also occur, as well as atrial fibrillation. The “holiday heart syndrome” refers to severe atrial arrhythmias precipitated by bouts of periodic heavy drinking. Hypokalemia and hypomagnesemia are more likely with alcohol abuse.

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CHAPTER 39  Drugs of Abuse Kidney Ethanol has a diuretic effect resulting from inhibition of antidiuretic hormone secretion by the posterior pituitary. Urinary Na+, K+, and Cl− concentrations are reduced, whereas Mg++ and norepinephrine are increased.

Sexual function Ethanol interferes with sexual function in men and women. It can cause temporary impotence even though overall aggressiveness may be enhanced. Long-term alcoholism may lead to more lasting impotence and sterility. Testosterone production may be depressed, and testosterone metabolism may be enhanced, the latter as a result of induction of liver microsomal enzymes. Feminization in men is a possible outcome. The effects of ethanol on the peripheral vasculature, CNS, antidiuretic hormone secretion, and sexual function are summarized in the following exchange between Macduff and the porter in Shakespeare’s Macbeth: Macduff: What three things does drink especially provoke? Porter: Marry, Sir, nose-painting, sleep, and urine. Lechery, sir, it provokes and unprovokes: it provokes the desire but not the performance. Shakespeare W: Macbeth. In Wells S, Taylor G, editors: William Shakespeare, the complete works, Oxford, 1986, Clarendon Press.

Blood lipids A potential salutary effect of moderate consumption of ethanol relates to cholesterol status. Intake on the order of one to two drinks a day increases the ratio of high-density to low-density lipoproteins in the plasma, an effect inversely correlated with the incidence of coronary heart disease and myocardial infarction. Other effects of low to moderate ethanol use, such as reduced platelet aggregation, may also provide some cardioprotective effect. Alcohol consumption is associated with an increase in serum triglyceride levels. This association may pose a cardiovascular risk, and if the triglyceride levels are high enough, a risk of pancreatitis exists. The overriding issue for the individual and society as a whole is controlling ethanol intake to avoid its many adverse effects.

Gastrointestinal tract Small oral doses of ethanol temporarily enhance salivary and gastric acid secretion—the increased salivation probably by a conditioned reflex. Large doses of alcohol reduce salivation. Ethanol is a gastric irritant, producing inflammation of the stomach wall in concentrations greater than 15%. Ingestion of solutions of more than 20% ethanol results in increased gastric mucus secretion and in petechial hemorrhage and ulceration. Ethanol retards intestinal absorption of glucose, amino acids, folic acid, thiamine, and vitamin B12. Ethanol has also been shown to change the flora in the gastrointestinal tract, favoring the growth of certain gram-negative bacteria. This growth leads to the production of more bacterial endotoxins (lipopolysaccharides). Damage to the gastrointestinal tract leads to greater absorption of toxins. Endotoxins stimulate liver Kupffer cells, which produce inflammatory mediators and reactive oxygen species that cause apoptotic changes in hepatic parenchymal cells (see Fig. 39-6). Damage by this mechanism may account partly for short-term and long-term changes.

Absorption, Fate, and Excretion Ethanol is rapidly absorbed from the stomach and small intestine. After oral ingestion, the rate of absorption largely depends on the gastric emptying time because 75% of a dose is rapidly and completely taken up from the small intestine. Patients with gastrectomy often note enhanced effects of ethanol. The rate of gastric absorption is reduced by the presence of food. Concentrations of ethanol greater than 20% retard absorption by inducing gastric mucosal irritation and pylorospasm.

TABLE 39-5  Equivalents of Alcoholic

Beverages Form of Alcohol Regular beer (12 oz, 3.5% ethanol) Distilled spirits (1 oz, 40% ethanol)†

CLASSIFICATION OF DRINKER Sex

Age (yr)

Potential Resulting BAC (mg/dL)*

Male

17-34 57-86 20-31 60-82 17-34 57-86 20-31 60-82

22.7 25.5 27.7 30.7 17.1 19.3 21 23.2

Female Male Female

*Calculated on the basis of a lean body mass of 153.4 lb (70 kg). †American proof number is twice the percentage of ethanol by volume. BAC, Blood alcohol concentration.

Approximately 60% of inspired ethanol vapor is absorbed through the lungs, and intoxication can be achieved by this route. Percutaneous absorption can also occur and has led to death when infants were wrapped in ethanol-soaked cloth to treat hyperthermia. After oral intake, the arterial BAC exceeds the venous BAC because of rapid tissue uptake of alcohol from capillary blood. Maximum electroencephalogram changes occur approximately 25 minutes before the maximum venous BAC is achieved. The BAC after ingestion of a fixed amount of alcohol is a function of sex, age, and adiposity of the drinker; the nature of the beverage; and the time over which it is ingested. In Table 39-5, which shows the influence of alcoholic beverage, age, and sex on BAC, the BAC has been calculated on the basis of reported age-corrected and sex-corrected values for total body water and blood water content. The tissue alcohol concentration is proportional to lean body weight and tissue water content. Considering the BAC as unity, the relative concentration of ethanol at equilibrium is 1.35 in urine, 1.17 in brain, 1.16 in blood plasma, 1.12 in saliva, 0.05 in alveolar air, and 0.02 in fat. Under normal circumstances, more than 95% of ingested ethanol is metabolized. High doses of ethanol are associated with lower metabolism (approaching 90% metabolized). Metabolism occurs mostly by a three-phase hepatic oxidation (Fig. 39-7). Ethanol is initially converted to acetaldehyde by alcohol dehydrogenase, which requires nicotinamide adenine dinucleotide (NAD) as the hydrogen acceptor: CH3CH2OH + NAD+ ↔ CH3CHO + NADH + H+ The binding of substrate and coenzyme to alcohol dehydrogenase involves sites on the enzyme containing zinc and sulfhydryl groups. Human alcohol dehydrogenase also oxidizes methanol, isopropyl alcohol, and ethylene glycol. This dehydrogenase reaction is the rate-limiting step in the metabolism of alcohol except in individuals who have a deficiency in the subsequent enzyme. The second phase, conversion of acetaldehyde to acetate, occurs in liver and other tissues and is catalyzed by aldehyde dehydrogenase, which has a much greater affinity for acetaldehyde than does alcohol dehydrogenase: CH3CHO + NAD+ ↔ CH3COOH + NADH + H+ In the third step, acetate, as acetyl coenzyme A, is oxidized further through the Krebs cycle to carbon dioxide and water. The reductive environment resulting from ethanol oxidation upsets hepatic chemistry and results in reduced gluconeogenesis and enhanced

600

CHAPTER 39  Drugs of Abuse Disulfiram

CH3CH2OH

Alcohol dehydrogenase

CH3CHO

MEOS

Aldehyde dehydrogenase

CH3COOH Krebs cycle

CO2 + H2O

FIG 39-7  Metabolism of ethanol and its blockade by disulfiram. Disulfiram inhibits the mitochondrial and cytoplasmic forms of aldehyde dehydrogenase. MEOS, Microsomal enzyme oxidizing system.

triglyceride and lactate formation. Heavy bouts of drinking can cause hypoglycemia, lactic acidosis, and hyperuricemia (because acetate and lactate stimulate the synthesis of uric acid and inhibit its renal excretion), which can precipitate gout, hyperlipidemia, and fatty liver. An alternate oxidative pathway for alcohol involving the microsomal enzyme oxidation system (MEOS) becomes an important factor in alcohol elimination at high BACs, during which it may account for 10% to 20% of ethanol metabolism. This pathway also yields acetaldehyde. The MEOS pathway is inducible and may account for the higher metabolic inactivation of ethanol seen in individuals who abuse ethanol over the long-term. Ethanol elimination follows zero-order kinetics even at moderate doses. Thus, metabolism is readily saturated. A 70-kg adult can metabolize approximately 1.0 oz of 80 proof distilled spirits per hour. Approximately 2% to 10% of absorbed alcohol is excreted unchanged, largely through the lungs and kidneys. Minor amounts are detectable in saliva, tears, sweat, and feces. Because ethanol is metabolized to acetate, it can provide calories (a maximum of approximately 1200 kcal/ day). It provides no other essential nutrients, however, such as vitamins, amino acids, or fatty acids.

Drug Interactions Ethanol produces additive effects with all CNS depressants and increases the hypotensive effects of most vasodilators. Long-acting drugs such as diazepam may cause increased depression with ingested alcohol for 24 hours after the drug was given. The benzodiazepine– ethanol combination seems to pose a particular risk. At high BACs, ethanol may inhibit the metabolism of, and potentiate the effects of, benzodiazepines and some other CNS depressants. Short-term alcohol ingestion may also result in exaggerated clinical responses to oral anticoagulants and hypoglycemic agents. The use of ethanol influences the in vivo absorption of certain drugs. Short-term ethanol ingestion increases, although long-term alcoholism reduces, the oral absorption rate of diazepam. Ethanol also inhibits the absorption and enhances the breakdown of penicillins in the stomach for 3 hours after ethanol intake. Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) promote gastric bleeding when combined with ethanol and can cause gastric hemorrhage in alcoholics who have alcoholic gastritis. In a long-term alcoholic without liver damage, induction of MEOS activity occurs. Increased enzyme activity appears after approximately 3 weeks of heavy drinking and lasts 4 to 9 weeks after the cessation of drinking. A significant reduction in plasma half-life of, and clinical response to, many drugs occurs (e.g., intravenous anesthetics, barbiturates, antianxiety drugs). In long-term alcoholics, the development of hepatic damage offsets the effects of enzyme induction, and drug sensitivity may return to normal. Eventually, cirrhosis leads to significantly

reduced drug metabolism. The induction of liver microsomal enzymes with long-term ethanol ingestion is the basis for the enhanced toxicity of acetaminophen in long-term alcohol abusers. Induction of the cytochrome enzymes, CYP2E1 and CYP3A4, favors the production of reactive and hepatotoxic metabolites of acetaminophen (see Chapter 17). Drugs that inhibit aldehyde dehydrogenase can lead to unpleasant and potentially life-threatening symptoms after ethanol ingestion. These inhibitors include disulfiram (Antabuse), which is given to prevent the use of ethanol by abusers; metronidazole; certain cephalosporins; and oral hypoglycemics. Acutely, acetaldehyde can cause flushing, headache, nausea and vomiting, hypotension, blurred vision, and mental confusion. Because acetaldehyde concentrations vary directly with ethanol intake, high doses of ethanol alone may lead to these symptoms. If aldehyde dehydrogenase is inhibited by drugs such as disulfiram, even low and moderate amounts of ethanol can lead to adverse reactions because of acetaldehyde accumulation. Individuals with a genetic deficiency in aldehyde dehydrogenase, which is common in certain races, also experience the accumulation of acetaldehyde and have alcohol intolerance.

General Therapeutic Uses Topically applied 70% ethanol is used as a rubefacient, anhidrotic, and antiseptic and as a means to cool the skin in cases of fever. Ethanol is a solvent for the irritating principle of poison ivy, and early ethanol use on affected skin can markedly reduce resulting dermatitis. Absolute ethanol has been injected to destroy nerves or ganglia in treating intractable pain arising from conditions such as trigeminal neuralgia and inoperable cancer. Other treatment modalities are usually more desirable, however. Ethanol is also used to treat poisoning by methanol, isopropyl alcohol, and ethylene glycol, because ethanol has the highest affinity for alcohol dehydrogenase.

Therapeutic Uses and Implications for Dentistry Uses of ethanol in dentistry as an antiseptic and disinfectant are discussed in Appendix 3. The dentist can expect to encounter alcoholic patients in everyday practice. Alcoholics usually exhibit signs of deficient oral hygiene, such as coated tongue and heavy plaque and calculus deposits. They have twice the rate of tooth loss of the general population, commonly lack mandibular and maxillary first molars, and frequently have severe chronic periodontitis. Chronic asymptomatic enlargement of the parotid, and sometimes submandibular, glands may be observed. The dentist should be aware of the increased incidence of oral leukoplakia in alcoholics and be familiar with its appearance, particularly the erosive form, because 6% of such individuals develop carcinoma, especially of the tongue, within 9 years of diagnosis of the lesion. Postoperative healing time is prolonged in alcoholics; this may be related to a marked increase in collagenase activity, which has been observed in the

CHAPTER 39  Drugs of Abuse liver of alcoholics. The potential interactions of ethanol with acetaminophen and NSAIDs should be kept in mind. Large therapeutic doses of acetaminophen should be avoided in moderate to heavy drinkers. Concurrent intake of NSAIDs and ethanol should be avoided.

Alcohol Dependence Abuse characteristics

Alcoholism is similar to dependence on CNS depressants except that ethanol produces unique direct neurologic, hepatic, and muscular toxicity. Ethanol dependence is characterized by marked psychic and physical dependence, moderate tolerance, and a wide range of pathologic sequelae as well as personal and social problems. Tolerance develops to ethanol after long-term abuse, but the degree of tolerance, as with other sedative-hypnotics, is much less than that which occurs with opioids. Tolerance to ethanol is partly a result of behavioral adaptation to the effects of ethanol. Adaptive changes by receptor mechanisms and membrane fluidity may also play a role. Induction of MEOS increases the rate of ethanol metabolism. The acute lethal dose of ethanol is not greatly increased, however, over that for nonalcoholics. Cross-tolerance with other sedative-hypnotics also occurs.

Alcohol abstinence syndrome The severity of acute alcohol abstinence syndrome correlates with the amount and duration of pre-abstinent ethanol intake. The mildest form is the tremulousness and nausea experienced “the morning after,” which is readily reversed by “taking a hair of the dog” (i.e., a small amount of ethanol). The most severe abstinence syndrome is delirium tremens. Severe withdrawal symptoms appear 6 to 8 hours after drinking ceases, peak at 48 to 96 hours, and generally resolve in approximately 2 weeks. Moderate abstinence results in anorexia, nausea, epigastric upset, tremulousness, sweating, apprehension, and insomnia. In more severe abstinence, additional symptoms of diarrhea, vomiting, nightmares, and agitation occur, together with autonomic signs of tachycardia, hyperpnea, and fever. Delirium tremens, if it occurs, is manifested by all the preceding symptoms together with possible psychosis, seizures, and hyperthermia. Psychotic manifestations include muttering; delirium; paranoia; delusions; and auditory, visual, and tactile hallucinations of a threatening nature. The individual usually displays agitation, confusion, disorientation, and panic. Neuromuscular hyperexcitability is manifested by gross tremors and grand mal convulsions (with a marked sensitivity to stroboscopically induced seizures), both of which correlate with a rapid urinary excretion of Mg++ and a resultant hypomagnesemia during withdrawal. Abstinence may also lead to hyperthermia and circulatory collapse.

Fetal alcohol syndrome Fetal alcohol syndrome is a cluster of physical and mental defects occurring in children of women who consume ethanol during pregnancy. In more than 90% of cases of fetal alcohol syndrome, there is growth deficiency, microcephaly, and short palpebral fissures. Also common are midfacial hypoplasia, mental retardation, and deficiencies in coordination and fine motor skills. The mental and motor deficiencies may be causally related to the developmental abnormalities of cortical neurons, as observed in rats prenatally exposed to ethanol. The degree of dysmorphogenesis correlates with mental deficiency, with IQs ranging from 55 to 82. Neither the dysmorphic nor the intellectual aspects of fetal alcohol syndrome improve with age. Pregnant patients should be advised to avoid alcoholic beverages and to be aware of the alcoholic content of food and drugs.

Treatment of alcoholism The treatment of alcoholism involves the detoxification of an acutely inebriated individual, medication to prevent severe symptoms of

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abstinence, and long-term rehabilitation. The rate of detoxification is determined largely by the rate at which the liver disposes of the ethanol, but the nature of the withdrawal period also depends on the degree of dependence, the environment, and the nutritional status of the patient. The symptoms associated with abstinence are usually treated with a benzodiazepine (e.g., diazepam, if liver function is adequate; oxazepam or lorazepam if liver function is compromised). Supplemental dietary thiamine is given. In addition, three other drugs are approved for treating alcohol dependence: naltrexone, disulfiram, and acamprosate. All modalities of drug treatment for alcoholics are more clinically effective when accompanied by behavioral therapy. Naltrexone is a long-acting opioid receptor antagonist. Naltrexone reduces the rewarding effects of alcohol by interfering with the activation of dopaminergic reward pathways in the brain. The pharmacology of naltrexone is discussed further in Chapter 16. Disulfiram is used in avoidance therapy for alcoholics because alcohol intake with disulfiram leads to very unpleasant reactions in patients. Disulfiram is rapidly converted to metabolites such as diethyldithiocarbamate and diethylthiomethylcarbamate. These and possibly other metabolites probably account for the action of the drug (see Fig. 39-7). Disulfiram inhibits aldehyde dehydrogenase through the formation of a covalent disulfide bond between an enzymic thiol group and an active drug metabolite. The enzyme is inhibited irreversibly. Disulfiram also inhibits other enzymes, notably dopamine β-hydroxylase and oxidases of MEOS. If ethanol is ingested during disulfiram treatment, symptoms of acetaldehyde poisoning develop. Drinking 1.2 oz of 80 proof liquor causes flushing, tachycardia, palpitation, and tachypnea, all lasting approximately 30 minutes. Ingestion of more than 1.6 oz of 80 proof liquor produces intense palpitation, dyspnea, nausea, vomiting, and headache lasting up to 90 minutes. Unconsciousness, hypotensive shock, and sudden myocardial infarction may occur. For this reason, disulfiram must be used only under strict medical supervision. Acamprosate (calcium acetylhomotaurine) is a GABA analogue that is used to reduce relapse in alcoholics. The drug can reduce nerve excitotoxicity caused by alcohol; this is likely due to its ability to block group 5 metabotropic glutamate receptors (mGluR5) as well as the resulting effects on dopaminergic and other pathways. This action likely promotes abstinence and reduces alcohol withdrawal symptoms.



 RUGS USED FOR DETOXIFICATION D FROM ALCOHOL AND FOR TREATMENT OF ALCOHOL DEPENDENCE Nonproprietary (Generic) Name

Proprietary (Trade) Name

Benzodiazepines Diazepam Oxazepam Lorazepam

Valium Serax Ativan

Opioid Antagonist Naltrexone

Vivitrol

Alcohol Dehydrogenase Inhibitor Disulfiram

Antabuse

Glutamate (mGluR5) Receptor Antagonist Acamprosate Campral Nutritional Supplement Thiamine

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CHAPTER 39  Drugs of Abuse

CASE DISCUSSION Mr. C is abusing methamphetamine, and chronic exposure to it is causing important problems in the oral and overall health of Mr. C. Methamphetamine reduces appetite and salivary flow, and abusers typically have poor nutrition and consume cariogenic carbonated beverages. Together these factors predispose abusers to dental decay. In addition, methamphetamine causes bruxism and continuous oral movements that result in worn teeth and damage to the tongue, respectively. The overall poor condition of the oral cavity and the characteristics of the caries in Mr. C are consistent with chronic methamphetamine abuse. The oral health effects of chronic methamphetamine abuse are sometimes collectively referred to as “Meth Mouth”; however, other stimulants such as amphetamine, cocaine, and MDMA (i.e., “ecstasy”) may also produce oral health effects similar to those caused by methamphetamine. The altered sleep pattern and mental changes are also consistent with amphetamine abuse. Dental treatment for Mr. C should include calculus and plaque removal and polishing of teeth with application of topical fluoride. Mr. C should be encouraged to floss regularly and brush with prescription-strength fluoride toothpaste. Directions should be given to Mr. C on how to improve his diet. For xerostomia, a saliva substitute or cholinergic agonist (pilocarpine or cevimeline) should be considered to stimulate salivary flow. (See Chapter 6.) Mr. C should also be counseled to seek help in treating his substance abuse disorder. Future visits should concentrate on motivating Mr. C to avoid substance abuse, reinforcing preventive practices, and restoring the teeth.

GENERAL REFERENCES 1. Acute reactions to drugs of abuse, Med Lett Drug Ther 44:21–24, 2002. 2. Aston R: Drug abuse: its relationship to dental practice, Dent Clin North Am 28:595–610, 1984. 3. Baumann MH, Solis E, Watterson LR, Marusich JA, Fantegrossi WE, Wiley JL: Bath salts, spice, and related designer drugs: the science behind the headlines, J Neurosci 34:15150–15158, 2014. 4. Cami J, Farre M: Drug addiction, N Engl J Med 349:975–986, 2003. 5. De la Monte S, Kril JJ: Human alcohol-related neuropathology, Acta Neuropathol 127:71–90, 2014. 6. Karch SB: Karch’s pathology of drug abuse, ed 3, Boca Raton, FL, 2002, CRC Press. 7. May PA, Baete A, Russo J, Elliot AJ, et al.: Prevalence and characteristics of fetal alcohol spectrum disorders, Pediatrics 134:855–866, 2014. 8. O’Brien CP: Drug addiction. In Brunton LL, Chabner B, Knollman B, editors: Goodman & Gilman’s the pharmacological basis of therapeutics, ed 12, New York, 2011, McGraw-Hill. 9. Rees TD: Oral effects of drug abuse, Crit Rev Oral Biol Med 3:163–184, 1992. 10. Stewart A, Maity B, Anderegg SP, Allamargot C, et al.: regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol, Proc Natl Acad Sci E786–E795, 2015 (online). 11. Wang M, You Q, Lor K, Chen F, et al.: Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice, J Leukocyte Biol 96:657–665, 2014. 12. Winger G, Woods JH, Hofmann FG: A handbook on drug and alcohol abuse: the biomedical aspects, ed 3, New York, 2004, Oxford University Press.