Treatment for Stimulant Use Disorders
Treatment Improvement Protocol (TIP) Series 33

Route of Administration

The method by which stimulants are taken--the route of administration--determines the dosage and the rapidity and intensity of effects. Route of administration also affects the potential for adverse reactions and the likelihood of addiction. The principal routes used to administer cocaine and MA are oral ingestion, nasal insufflation (snorting), intravenous injection, and inhalation of smoke vapors (smoking/inhalation). These stimulants can also be taken vaginally, rectally, or sublingually.

In general, smoking and intravenous use rapidly evoke similarly intense responses, whereas oral ingestion and intranasal administration are slower delivery mechanisms, causing lower and more gradually rising blood levels and less intense subjective responses. Indeed, cocaine is seldom taken by mouth in this country because first-pass hepatic biotransformation metabolizes 70 to 80 percent of the dose and substantially diminishes the drug's effects (Gold and Miller, 1997). When crack cocaine is smoked, a highly concentrated dose is rapidly delivered to the brain. Several studies have reported a close correlation between subjects' plasma levels and the subjective effects from single doses given to relatively naive users who have not developed tolerance (Ellinwood and Lee, 1989; Gold and Miller, 1997; Volkow et al., 1997a). As the efficiency of the delivery system increases, so does the intensity of both the pleasurable and adverse effects. Figure 5-1 depicts these general variations in response times according to the different routes of administration for cocaine and MA.

To some extent, the dangerous consequences and addictive potential of stimulants also reflect the route of drug administration. Oral ingestion of MA is thought to protect the user from cardiotoxicity (Cook et al., 1993), and the lower and more sloped peak blood levels achieved by this route are also thought to be responsible for lower rates of addiction (Gold and Miller, 1997). Also, cocaine appears to be less addictive if doses remain small, peak plasma levels and the onset of drug effects are slow, and unpleasant withdrawal effects are absent or minimal. Oral ingestion and, to some extent, intranasal routes fulfill these criteria of slower, less hazardous consequences (Gold, 1997).

Intravenous use is more toxic than intranasal or oral routes, but inhalation is generally perceived as the quickest and, from the user's perspective, the most desirable delivery method because smoked crack cocaine and ice MA produce the highest peak blood levels and the most potent subjective impact without attendant hazards from syringe needle use (Cho, 1990; Cook, 1991; Gold, 1997). Other investigators report that smoked ice does not seem to produce the same intense "rush" as injection. There is some indication that in utero exposure alters cocaine reinforcement properties for adults or, at least, increases rates of cocaine self-administration in the laboratory (Gold and Miller, 1997).

Different routes of drug administration also produce different side effects. Intravenous users frequently develop illnesses associated with the preparation of drugs for use (i.e., mixing/making) and the use or sharing of unsterile needles, including HIV infection, hepatitis, tuberculosis, lung infections and pneumonia, bacterial or viral endocarditis, cellulitis, wound abscesses, sepsis, thrombosis, renal infarction, and thrombophlebitis (Sowder and Beschner, 1993; Gold, 1997).

Nasal insufflation is associated with sinusitis, loss of sense of smell, congestion, atrophy of nasal mucosa, nosebleeds, perforation or necrosis of the nasal septum, hoarseness, and problems with swallowing. Crack users complain of throat ailments and a productive cough with black sputum (Gold, 1997; Gold and Miller, 1997). Intravenous use of MA is associated with greater severity of medical and social problems compared with other routes of administration (Sowder and Beschner, 1993).

Figure 5-2 compares differences in use and consequent problems between intravenous and nonintravenous MA users. Apparently, MA users recognize these route-related effects and tend to vary the routes of administration because the drug causes irritation to nasal mucosa and lungs (Center for Substance Abuse Treatment [CSAT], 1997). Even prolonged use of amphetamine-containing diet pills has resulted in ischemic colitis and pulmonary edema (Sowder and Beschner, 1993).

Differences Between Cocaine and MA

The major differences between cocaine and MA pertain to the rapidity of responses and the duration of their effects. The sought-after effects of MA can persist for hours, whereas those from cocaine are over in minutes. This has important consequences for the choice of drug and the patterns of administration adopted by users. The plasma levels from smoked crack cocaine both peak and decline rapidly, whereas those from smoked MA also peak relatively rapidly but decline more slowly because metabolism takes longer. Regularly repeated use may be more common among cocaine users trying to sustain the drug's effects, whereas withdrawal is more protracted for MA users (Cook, 1991; Gold and Miller, 1997). Figure 5-3 shows some of the differences between cocaine and MA.

The plasma levels of cocaine/crack peak and decline rapidly, with a terminal half-life of about 56 to 60 minutes. MA plasma concentrations also peak rapidly but remain high for much longer (Cho, 1990; Cook, 1991). In normal subjects, the plasma half-life of cocaine ranges from 40 to 90 minutes (Rowbotham, 1993).

Because the biological half-life of cocaine is relatively short, repeated dosing is necessary to sustain an effect (Gold and Miller, 1997). By contrast, repeated dosing with MA, before metabolism and elimination are complete, can result in substantial accumulation of the drug in the body with increased likelihood for addiction (Cho, 1990; Cook, 1991).

Other factors in the growing preference for smokable forms of MA, as well as crack cocaine, include availability and price. Crack is generally less expensive and more available than powdered cocaine hydrochloride and produces, in the initial smoker, a very intense but brief rush described by some as a "full body orgasm" (Gold, 1997). Because ice costs less than other forms of MA per dose, and because the euphoria attained may persist for several hours, this form of MA delivers the most "bang for the buck." Because abuse liability increases as time before onset of action decreases, and the concentrations of the drug that reach the brain and receptor sites increase (Cornish and O'Brien, 1996), the current concern about increased use of stimulants pertains to both the smokable preparations (crack and ice) and to continuing intravenous use of both drugs.

Dose

The incidence and severity of MA- and cocaine-induced side effects and toxic reactions are also dose-related. As the dose increases, the profile of side effects progresses from mild excitement to more intense reactions, even psychosis (CSAT, 1997). Because tolerance develops rapidly to the desired euphoric effects, stimulant users nearly always escalate dose size and frequency of drug use in pursuit of the vanishing rush. If initial use was by oral or intranasal routes, users also tend to switch to intravenous administration or inhalation, methods that promise more rapid response rates and peak plasma levels (Ellinwood and Lee, 1989).

Chronic MA users may consume as much as 15 grams of the drug per day in doses exceeding 1 gram every 4 hours over a 24-hour period. Because the conventional dose is 10 mg, doses of 150 mg to 1 g would ordinarily be highly toxic to naive users (Cho, 1990). There is, however, considerable individual variation in toxicity and overdose from stimulants. Although general ranges have been established for lethal doses and blood levels, reactions are unpredictable (Gold and Miller, 1997).

The lethal dose of cocaine for 50 percent of novice users (LD50) is 1.5 grams. The LD50 for MA has not specifically been established, and there is significant individual variability to its toxicity. For example, doses of 30 mg can produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal. Reported tissue levels of MA in fatalities, nonetheless, have ranged from 1µg/mL to over 14 µg/mL. Reported blood levels have also ranged from 27 µg/mL to only 0.6 µg/mL (Mori et al., 1992).

Purity of the Drug

The purity of the stimulant used also influences the rate and completeness of its absorption and effects. The purer the drug, the greater the effects. "Street" drugs, however, are seldom entirely pure. The purity of confiscated cocaine hydrochloride intended for oral or intranasal consumption generally ranges between 20 and 80 percent; the purity of intravenous cocaine preparations can vary between 7 and 100 percent; and for freebase or crack intended for smoking, from 40 to 100 percent (Gold and Miller, 1997). Most seized batches of MA have 40 to 70 percent purity (Burton, 1991; CSAT, 1997).

Adulterants are added to cocaine to increase its weight by cutting or substituting less expensive but similar-tasting and acting products that will maximize profits for the dealer while still satisfying the customer. In general, the adulterants in cocaine do not pose serious health-related problems, although these cannot be completely discounted (Schrank, 1993). Cocaine is most often cut with mannitol, lactose, quinine, glucose, or other inert compounds for weight, and with caffeine, lidocaine, other stimulants, anesthetics, or hallucinogens for taste and effect (Schrank, 1993; Gold, 1997).

The manufacturing processes for illicit MA and ice are often crude and can involve many impurities and contaminants that do pose serious health consequences. Until recently, most of the MA sold on the street was manufactured from phenyl-2-propanone (P2P), a method of synthesis in which lead acetate is used as a chemical reagent. The large quantities of lead in the final product can result in symptoms of hepatitis, nephritis, and encephalopathy (Allcott et al., 1987). Two outbreaks of lead poisoning in Oregon in 1977 and 1988 involving a total of 14 cases among intravenous MA users were blamed on the lead acetate used in the P2P manufacturing process. Testing revealed the presence of 60 percent lead by weight in one case (Irvine and Chin, 1991).

The typical clandestine manufacturing process for MA has changed over the last 12 years--from the P2P method--to an ephedrine-based method and, more recently, to pseudoephedrine and phenylpropanolamine processing (CSAT, 1997). The difference between these two primary synthesis methods is primarily the precursor chemicals used.

The newer and more popular ephedrine method, which accounted for 89 percent of production in 1995, makes it simpler to synthesize MA, uses less strictly controlled ingredients, produces less odor than chemical reactions involving P2P, and yields a more potent and psychoactive form of MA (with a higher percentage of the more active dextro steroisomer, rather than equal proportions of dextro and levo stereoisomers produced by the P2P method) (Burton, 1991; Cho, 1990; CSAT, 1997; Drug Enforcement Agency [DEA], 1996). In addition, dextro-MA is three to four times more potent to the central nervous system than levo-MA (Sowder and Beschner, 1993). Therefore, the MA currently being manufactured has especially potent effects.

Illicit MA is also likely to contain potentially toxic contaminants from unintended reaction byproducts and reagent residuals as well as processing errors. Many clandestine laboratories are operated by uneducated and unskilled chemists who get recipes from unpublished, handwritten sources or through the Internet. As with cocaine, most of the contaminants are intentional fillers used to dilute or cut the product and may include lactose, lidocaine, procaine, caffeine, quinine, or sodium bicarbonate.

Other impurities in illicit MA can cause dangerous toxic reactions. Some identified contaminants have been shown to have great potency for producing seizures in mice. Poisoning from other reagents and organic byproducts, including mercury, has also been suspected but not documented (Burton, 1991).

Patterns of Use

The effects of stimulant use also reflect the temporal pattern of drug administration and the user's experience history or chronicity. Users describe various motivations for initial experimentation with cocaine or MA, including a desire for heightening a sense of well-being and euphoria, increasing alertness and energy, boosting self-esteem, enhancing sexual desire and responsiveness, dispelling fatigue, improving performance, losing weight, or consuming more alcohol without feeling intoxicated (Hando and Hall, 1997; Sowder and Beschner, 1993). Some users only administer stimulants periodically, although most discover that tolerance builds rapidly to many of the desired effects, particularly euphoria, so that increasing doses are needed to achieve similar effects.

Although serious medical, psychological, and social consequences have followed experimental low-dose use of stimulants, two other patterns of self-administration are of greater concern. The fourth edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Press, 1994) characterizes these as (1) episodic use, separated by at least 2 days of nonuse, with gradually escalating doses and more potent routes of administration that often culminate in binge use; and (2) daily, or almost daily, use with no wide fluctuations in dose, but a gradual escalation. Actually, compulsive users probably represent only 5 to 10 percent of the total number of MA users and an even smaller percentage of all users of amphetamines (Cho, 1990).

Because of their different pharmacological properties, MA users typically administer the drug on a daily basis, whereas crack cocaine users binge on large amounts for a shorter period, interspersed by periods of nonuse (CSAT, 1997; King and Ellinwood, 1997). Figure 5-4 illustrates rapidly escalating and sustained plasma levels attained by different time patterns of drug administration during cocaine and MA binges. An extremely compulsive pattern of rapidly repeated injections or inhalations is required to sustain high plasma levels of cocaine, in contrast to amphetamine/MA, which has a longer half-life (Ellinwood and Lee, 1989).

The greatest behavioral pathology and most serious medical consequences usually follow compulsive bingeing with high doses of either smoked or injected MA or cocaine (Ellinwood and Lee, 1989). The following paragraphs describe the sequence of phases that typically occur in the establishment of this hazardous, "high-transition" pattern and some of their accompanying side effects (as depicted in Ellinwood and Lee, 1989; King and Ellinwood, 1997). Knowledge of these phases can be useful for the medical practitioner in taking a substance use history and understanding what effects are likely to accompany a particular stage of acute intoxication, withdrawal, or more chronic use patterns.

Intoxication

Tolerance/Sensitization To Stimulant Effects

Chronic users of stimulants develop tolerance to many of the initial effects, often after only a few weeks of drug use. This means that a higher dose is required to achieve the same effects, or markedly diminished effects are attained if the same dose is continued (American Psychiatric Press, 1994). Most notably, tolerance develops rapidly to the euphorogenic effects of stimulants and is the ostensible cause for most dose escalation by stimulant users--although dose increases may also stem from a desire to experience more intense effects. Tolerance also develops to the anorectic effects of MA in humans because weight loss stops after several weeks. Tolerance also appears to develop to the cardiotoxic effects of large doses of MA that many users survive. In fact, many of the initial symptoms of stimulant intoxication disappear with chronic use: Blood pressure may be normal, and nausea and vomiting are seldom seen. This tolerance is not the result of increased MA metabolism because chronic users show metabolic patterns similar to naive users (Angrist, 1994).

Interestingly, chronic, high-dose stimulant users may also become sensitized to the drug, a unique phenomenon characteristic of psychomotor stimulants. Sensitization is essentially the reverse of tolerance and produces undesirable effects with lower doses of the drug than were required to yield these same reactions in an earlier phase of the addiction process. There appears to be some sensitization to the psychosis-inducing effects of stimulants in humans. After one psychotic episode is experienced following chronic, high-dose use, a lower minimal dose of cocaine or MA may induce another psychotic episode, with more rapid onset following drug intake and a longer duration than the initial psychosis. Many sensitized stimulant users experience an almost immediate return of paranoia, psychosis, and stereotyped thinking if drug use is resumed (Angrist, 1994; CSAT, 1997). The sensitization process in stimulant dependence is elaborated in the section on toxic psychosis in this chapter.

Distinctive Characteristics Of MA Intoxication

• There may be a peculiar odor of ammonia or stale urine, especially among users who smoke MA that has been crudely synthesized in illicit laboratories. Smoked ice is, however, essentially odorless.
• The MA user may present with tachycardia (rapid heart rate), although not usually accompanied by arrhythmia (irregular heartbeat). Compared with cocaine intoxication, MA intoxication causes fewer heart, pulmonary, and circulatory problems, especially for users of newer forms of ephedrine-based dextro-MA that stimulate the heart, lungs, and blood vessels to a lesser degree than older forms containing equal parts of levo- and dextro-MA (Inaba et al., 1993).
• MA users are more likely to appear in the ER as a result of trauma from fighting or motor vehicle accidents than for physical complaints.
• Because of its longer lasting effects, MA abuse may lead to more frequent psychiatric impairment, more potent central nervous system (CNS) effects, and more overdoses. Chronic abuse of MA (beyond 2 weeks) is more hazardous than chronic cocaine abuse because of MA's sustained effects. Moreover, drug-induced psychoses in MA users are likely to last longer than those of cocaine users and, in addition, may not respond as readily to available treatments.
• MA users are more likely than cocaine users to be single substance rather than polysubstance users (although many also use marijuana).
• Stereotyped activity--persistent, repetitive, and compulsive activity such as vacuuming the same part of the floor over and over again, popping knuckles repeatedly, picking at scabs, or taking apart and reassembling mechanical devices--may appear in MA users.

Distinctive Characteristics Of Cocaine Intoxication

• Cocaine users are more likely than MA users to present with serious and potentially lethal physical complications (e.g., cardiac arrhythmia, chest pains, cerebrovascular accident [e.g., strokes], toxic seizures, hypertension crises, hyperthermia).
• Cocaine users are also more likely than MA users to use multiple substances, especially alcohol, benzodiazepines, or opiates.

Management of Stimulant Intoxication

Acute MA intoxication, unless delirium or psychosis is present, seldom comes to medical attention. Most cocaine users who come to an ER with drug-related complaints have not used the drug for several hours, and peak plasma levels have already subsided, especially if the cocaine was injected or smoked (Rowbotham, 1993).

Uncomplicated intoxication requires only observation and monitoring in a subdued environment until symptoms subside over several hours. General measures include monitoring of vital signs for rising pulse rate, temperature, or blood pressure; providing a quiet and cool environment that helps to diminish agitation and overreaction to external stimuli; and close observation. Physical exertion and an overheated room can potentiate adverse effects because stimulants affect the body's heat-regulating mechanism at the same time that blood vessel constriction conserves heat. Although verbal reassurance is usually sufficient for quieting the patient, indications that agitation is escalating and moving toward paranoia and potential psychosis, with increasing risk for violence, may warrant pharmacological intervention. Fast-acting benzodiazepines such as lorazepam (Ativan) or diazepam (Valium) are useful for calming an anxious, agitated patient (Ellinwood, 1975; Weis, 1997).

Stimulant Overdose

Toxic, fatal, or subfatal syndromes are seldom seen in chronic, high-dose, intravenous stimulant users, probably because tolerance develops rapidly. Most stimulant overdose fatalities occur in neophytes or persons who accidentally ingest large amounts, such as "bodypackers" or children (Ellinwood, 1975). (Bodypackers are individuals who have swallowed waterproof packets filled with cocaine, usually in South America, in an attempt to clear U.S. customs undetected and then pass the packets through the gastrointestinal tract.) It should be noted, however, that the toxic dose for stimulants has enormous variability and appears to be idiosyncratic and unpredictable, without a known relationship to body weight. Hence, the amount of cocaine or MA used is not a reliable predictor of the reaction (Weis, 1997).

The symptoms of a sublethal stimulant overdose may include dizziness, tremor, irritability, confusion, hostility, hallucinations, panic, headache, skin flushing, chest pain, palpitations, cardiac arrhythmias, hypertension, vomiting, cramps, and excessive sweating. High doses of stimulants may cause high fever, cardiac arrhythmias and arrest, irregular breathing, seizures, and stroke. Agitated states characterized by increased aggressiveness or psychotic features may also occur with intoxication, particularly for MA (Weis, 1997). The development of hyperpyrexia (excessively high fever), severe hypertension, convulsions, and cardiovascular collapse signal a life-threatening situation (Ellinwood, 1975).

Lethal doses of stimulants--administered to laboratory dogs by injection or observed in bodypackers when ingested packets leak or break--produce a predictable sequence of events culminating in generalized convulsions and death. Heart rate, blood pressure, cardiac output, and body temperature rise rapidly, and a toxic delirium is observed before generalized and terminal seizures begin (Ellinwood, 1975; Rowbotham, 1993; Wetli, 1993).

Management of a Potentially Lethal Overdose

Stimulant users who present with life-threatening medical conditions and toxic drug levels should be treated with standard life-saving techniques that respond to the presenting symptoms (Weis, 1997). Acute neurological symptoms such as seizures or rapidly elevating vital signs require immediate intervention. Nondrug causes of any symptoms should be carefully ruled out, and the patient should also be evaluated for multiple substance use. Stimulant overdose patients should be hospitalized, especially if treatment is threatened by polysubstance use (Gold, 1997).

No specific antidotes or antagonists to stimulant overdose are available--unlike naloxone (Narcan) for opiates and the benzodiazepine antagonist flumazenil (Romazicon). However, the following procedures are suggested:

• Request specialist consultations as needed.
• Manage hyperthermia by sedating to slow down and stop agitated movements and rapidly cooling the patient with body ice packs, mist and fan techniques, or cooling blankets (Ellinwood, 1975; Gold, 1997). Simple measures such as preventing or correcting elevated body temperature can be remarkably effective in preventing death from cocaine toxicity (Rowbotham, 1993). Although dantrolene (Dantrium) can be administered for very serious and escalating, uncontrolled hyperthermia (Weis, 1997), such drugs do not always enhance the cooling process for patients with life-threatening hyperthermia (Goldfrank and Hoffman, 1993).
• If restraints are required to start an intravenous administration, use mesh-type blankets only transiently to avoid interfering further with heat loss.
• Provide adequate ventilation and oxygenation.
• Uncontrolled hypertension can be managed by intravenous administration of phentolamine (Regitine) or dopamine (Intropin). Although clinical experience supports the use of labetalol (Normodyne) for treating hypertension, no controlled experimental studies support the efficacy of this drug as an alpha-adrenergic blocker (its beta-adrenergic effects are more potent). Rapidly acting and easily controlled antihypertensive agents such as the vasodilator nitroprusside or the alpha-adrenergic blocker phentolamine are usually preferable (Goldfrank and Hoffman, 1993).
• Treat seizures like status epilepticus with intravenous diazepam or other benzodiazepine. Diazepam is most effective if administered before or shortly after cocaine ingestion but is less effective after seizures begin (Rowbotham, 1993). Phenobarbitol or phenytoin (Dilantin) may be used if diazepam is ineffective (Schrank, 1993). Alternatively, 25 to 50 mg of intravenous pentobarbitol can be administered to control cocaine-induced seizures (Gold, 1997).
• Complaints of chest pain warrant evaluation for possible myocardial ischemia and infarction. Nitrates are indicated for cocaine-induced myocardial ischemia to alleviate coronary vasoconstriction. Beta-adrenergic blockers such as propranolol (Inderal) should not be used because they may enhance vasospasm. Aspirin should be administered, unless contraindicated, to reduce cocaine-mediated platelet aggregation (Goldfrank and Hoffman, 1993).

Use standard treatments for arrhythmias, including phenytoin. Atrial arrhythmias that do not respond to cooling and sedation may require cautious use of calcium channel blockers or mixed alpha-/beta-adrenergic blockers such as verapamil (Calan), esmolol (Brevibloc), and labetalol (Goldfrank and Hoffman, 1993). Lidocaine may be contraindicated for ventricular arrhythmias that begin immediately after cocaine use as a response to catecholamine excess but is appropriate for ventricular arrhythmias that indicate an ischemic myocardium. Sodium bicarbonate has proven useful for cocaine-induced wide-complex arrhythmias (Goldfrank and Hoffman, 1993). Also note that management of acute psychiatric manifestations of cocaine intoxication by sedation appears to have a salutary effect on emerging cardiovascular complications.

In general, phenothiazines, especially chlorpromazine (Thorazine, Mellerial), are contraindicated because these drugs lower the seizure threshold (Gold, 1997). Haloperidol (Haldol) has not proven efficacious in preclinical studies in protecting against cocaine-induced seizures or fatalities, but it may have utility for MA-induced psychoses. The serious difficulties encountered in using haloperidol for sedative-hypnotic withdrawal in humans when agitation and hyperthermia are present may also apply to its use for acutely agitated or psychotic stimulant users who already have deficits in thermoregulatory control. Haloperidol may precipitate or exacerbate acute dystonic reactions associated with cocaine use (Goldfrank and Hoffman, 1993).

Manifestations of Stimulant Withdrawal/Abstinence

A characteristic withdrawal-type syndrome usually develops within hours to days after cessation of prolonged and heavy stimulant use. The symptoms can follow long-term use or much shorter binges. Although "cocaine blues" were described as early as the turn of the century (Gawin and Kleber, 1986), more recent investigators note that stimulant withdrawal is much less definitive than withdrawal from opiates or alcohol and has not been so well studied (Lago and Kosten, 1994; West and Gossop, 1994). (See Figure 5-5 for some common signs of stimulant withdrawal.)

Some clinicians distinguish between stimulant withdrawal symptoms following a several-day binge and complaints that characterize withdrawal after more chronic high-dose use. Stimulant users who have binged for 2 to 3 days are dysphoric, exhausted, and sleep for 24 to 48 hours. Cocaine users in this category commonly use alcohol, marijuana, benzodiazepines, or heroin with cocaine to reduce irritability. Following more chronic and regular stimulant use, withdrawal symptoms that subside over 2 to 4 days include dysphoria, irritability, difficulty sleeping, and intense dreaming (CSAT, 1995d).

Other clinicians emphasize differences in severity between withdrawal from cocaine and withdrawal from MA. A substantial number of persons with cocaine dependence have no clinically evident withdrawal symptoms. For the minority of cocaine users who do complain, symptoms begin within hours to days of the last dose, the crash lasts for 3 to 4 days, withdrawal persists from 1 to 10 weeks, with waxing and waning of the drug craving. The mood state of the cocaine user may return to normal after several days to a month.

Withdrawal symptoms seem to be most severe in the initial days following cessation of use (Cornish and O'Brien, 1996; Gold and Miller, 1997). Although there are no physical manifestations of a withdrawal syndrome when MA use is stopped, there are several symptoms that occur when a chronic user stops taking the drug (National Institute on Drug Abuse [NIDA], 1998a). Symptoms begin 12 to 24 hours after binge use is terminated and may persist for 1 to 2 weeks. The client initially feels depressed and anxious, with an intense craving for MA.

This phase is followed by fatigue and sleepiness, although this may be mixed with insomnia. Upon awakening after prolonged sleep, the client may be very hungry, and there may be persisting anhedonia and dysphoria. Other symptoms include paranoia and aggression. Depression appears to be more severe and prolonged following MA use and is correlated with duration of use and size of the doses (Gold and Miller, 1997; Gawin and Ellinwood, 1988).

Management of Stimulant Withdrawal

Stimulant withdrawal is not medically life threatening and, unlike alcohol or barbiturate withdrawal, does not require pharmaceutical intervention. Although no consistent physiological disruptions requiring gradual withdrawal have been observed, some medications may be used to attenuate symptoms and provide support.

The greatest risk from the distinctive stimulant abstinence syndrome is of doing harm to self or others. Because withdrawal-related dysphoria and depression can be particularly severe in stimulant users, risk of suicide is intensified, and sensitive management is essential. Cocaine-induced depression usually dissipates fairly rapidly--in a matter of hours. The depression is agitated and often related to actual situations resulting from drug use (e.g., the client is disturbed that all of his money has been "blown" on the cocaine binge or that interpersonal relationships are jeopardized by his continuing drug dependence).

However, withdrawal-associated depression following high-dose MA use is more prolonged. During the tweaking phase of withdrawal, the high-dose MA user begins a rocky, jittery reaction characterized by agitated paranoia, extreme frustration, and the return of intense drug cravings. Suicidal ideation may be high, and violence is easily provoked.

Tweaking effects after persistent bingeing on ice are particularly dangerous. Clients may misinterpret caretakers' gestures and turn against them. Restraints and sedation in a secure facility may be necessary. Although stress reduction techniques and other approaches to preventing harm should be used standardly, medical personnel can also use benzodiazepines (e.g., diazepam) to control agitation and tachycardia (see further discussion of violence as a special issue).

For clients with preexisting diagnosed or unrecognized clinical depression, cocaine worsens symptomatology. These individuals are most likely to experience deepening dysphoria and/or paranoia after cocaine use. Treatment with selective serotonin reuptake inhibitors (SSRIs) may be of use (Gold, 1997).

Continuing agitation and persistent inability to fall asleep during the tweaking stage may also be treated symptomatically by using the antidepressant trazodone (Desyrel), whose dopaminergic properties help to sedate the client. Benadryl is also used for its sedating properties and for its effects on the dermatologic problems that often accompany MA use (e.g., itching and hypersensitivity of the skin). However, caution should be exercised in using any medications with high abuse/dependence potential. In general, prescriptions should not be written for use outside the treatment facility because use or resale of these drugs is very tempting to this population.

After the tweaking stage, MA abstainers usually "crash" and sleep several days at a time, depending on the dose and duration of the binge. This hypersomnolence may interfere with assessment of mental status and potential for dangerous behavior. Hence, clients should be evaluated immediately after wakening from this prolonged sleep for persisting dysphoria and other psychiatric symptoms of anxiety and depression (Weis, 1997). During this hypersomnolent state, and until sleep deprivation is overcome, active participation in therapy or followup of a referral to a treatment program by stimulant users is not a realistic expectation.

Drug craving during stimulant withdrawal has been treated with a variety of medications (e.g., bromocriptine, amantadine) without demonstrated efficacy in alleviating symptoms, getting clients "clean," or preventing relapse.

"Cocaine dreams" may occur during this period or as late as 8 or 9 months after termination of stimulant use during a protracted abstinence phase. They usually entail vivid recall of actually using and experiencing the high. The client may actually sweat and experience other symptoms of intoxication while dreaming. These intense dreams, which may sometimes contain vignettes in which the drug user loses or drops a supply or refuses to smoke crack/ice, can be used therapeutically to convince clients that they are making progress in treatment by making a subconscious choice not to use. Otherwise, the dreams may enhance drug cravings and intensify a vulnerability for relapse. These dreams are primarily experienced by users of injected cocaine/MA and smoked crack or ice.

Because stimulant users frequently self-medicate withdrawal symptoms with alcohol, benzodiazepines, or opiates, there may be symptoms of withdrawal from these drugs if they have been used continuously or at high doses. These require specific management and titration of substitute doses or other means of alleviating symptoms.

Manifestations of Chronic Stimulant Use Disorders

Although fatalities from stimulant overdose or acute myocardial infarction following administration of cocaine by inexperienced users have been documented, and other medical and psychiatric complications have been observed at all dose levels and routes of administration among naive users, the majority of serious stimulant-induced medical and psychological complications follows chronic, high-dose use.

Because tolerance develops rapidly to the subjective and cardiovascular effects of stimulants, the specification of complications following chronic use is complex (Rowbotham, 1993). However, cocaine toxicity affects nearly every organ system, with the most dramatic changes found in the cardiovascular system, the brain, the liver, and the pulmonary system (Majewska, 1996). Although there are some minor differences between the sequelae of chronic MA and cocaine use, the incidence of such side effects as chest pain, seizures, paranoid reactions, and suicidal thoughts is about the same for both drugs. Chronic MA users appear to have more headaches, severe depression, and hallucinations than counterpart cocaine users, but the evidence from community samples is not definitive (CSAT, 1997).

Figure 5-6 summarizes some of the more common symptoms and potentially serious complaints presented by chronic stimulant users. The following section contains a detailed description of stimulant-induced medical and psychiatric complications with limited comments about management of these conditions. Schrank specifies more detailed ER procedures for responding to some of the more frequently seen complications (Schrank, 1993). Figure 5-7 shows the distinctive indicators of chronic MA use and chronic cocaine use.

Cardiovascular System Effects

Cardiotoxicity stemming from catecholamine excess is observed in both cocaine and MA users. Although the cardiac effects are more profound for MA users because this drug results in even greater elevation of catecholamines than cocaine, the incidence of fatalities following myocardial infarction has been less frequent until the recent increase in inhaling (smoking) or injecting MA (Cho, 1990; Cook et al., 1993; CSAT, 1997).

Stimulants, especially cocaine, have been linked to virtually every form of heart disease, including different forms of arrhythmias, coronary vasospasm, myocardial ischemia, myocardial infarction, and cardiomyopathy (Cornish and O'Brien, 1996; Gold, 1997). Case reports of fatalities from myocardial infarction and tachyarrhythmias document their occurrence at all dose levels and routes of administration in otherwise healthy young adults without the usual coronary risk factors, but preexisting coronary artery disease can exacerbate the response and increase the likelihood of sudden death, as can hyperthermia and agitation (Ellinwood and Lee, 1989; Gold, 1997; Schrank, 1993). Tachycardia, hypertension, ruptured blood vessels, arrhythmias, and arteriosclerotic lesions typically precede myocardial ischemia and infarction (Majewska, 1996). With prompt medical intervention, patients generally survive stimulant-induced cardiomyopathy with heart failure (CSAT, 1997). There is some controversy about optimal pharmacologic approaches to treating arrhythmias and other cardiac effects. Lidocaine was previously used but may be contraindicated for ventricular arrhythmias because it lowers the seizure threshold (Goldfrank and Hoffman, 1993). However, certain calcium channel blockers (e.g., Nifedipine, diltiazem, verapamil) seem promising (Gold, 1997; Schrank, 1993).

Respiratory/Pulmonary Effects

Cocaine crack smokers frequently seek medical attention for difficulties in breathing (dyspnea) or severe chest pain. This may result from cocaine-induced pulmonary hemorrhage, lung damage, pneumonia, pulmonary edema, asthma, pneumothorax, pneumomediastinum, or pneumopericardium (Cornish and O'Brien, 1996; Gold, 1997). Pulmonary barotrauma may result from spasmic coughing following smoke inhalation or odd mechanisms of drug delivery (mouth-to-mouth inhalation), with sudden increases in airway pressure that result in alveolar rupture and the induction of free air into the pleural cavity, mediastinum, or subcutaneous tissues. The amount of free air is usually small and resolves spontaneously under observation. The possibility of esophageal rupture should be considered in pneumomediastinum if vomiting is present (Schrank, 1993). Cocaine can also cause sudden death by respiratory failure from drug-induced inhibition of the medullary centers in the brain (Gold, 1997).

Tracheobronchitis with cough is a frequent accompaniment of crack smoking, as are lobar and nonlobar pneumonias. Bronchospasm is another complaint of these smokers, usually in clients with a history of asthma (Schrank, 1993). Crack lung is a new syndrome that manifests with symptoms of pneumonia--severe chest pains and breathing problems with high fever--but no substantiating lung X-ray evidence. The condition does not respond to standard treatment, although anti-inflammatory drugs may relieve symptoms. Clients with crack lung may suffer from oxygen starvation or loss of blood with potentially fatal results (Gold, 1997).

Pulmonary edema has been observed in both cocaine and MA fatalities and attributed variously to deep inhalation aggravation of preexisting conditions (Nestor et al., 1989) and granulomas formed in response to adulterants added to the drugs (CSAT, 1997). Chronic obstructive lung disease in MA users is thought to result from thrombosis of small pulmonary vessels with gradual reduction of pulmonary vascular bed, pulmonary fibrosis, and granuloma formation (CSAT, 1997).

Cerebrovascular Complications

An increasing amount of research has recently focused on neurological impairments apparently resulting from high-dose and chronic use of stimulants, particularly by more rapid routes of administration. Some of the more devastating cerebrovascular consequences of cocaine and MA use have been known for years--seizures, ischemic strokes, and subarachnoid and intracerebral hemorrhages. Other neurological complications include optic neuropathy, global brain ischemia, and edema following myocardial infarction. Newer brain-imaging techniques now demonstrate various degrees of previously undetected and unsuspected cerebral atrophy and brain lesions in many chronic cocaine users (Cornish and O'Brien, 1996; Schrank, 1993; Majewska, 1996).

Seizures are a well-known complication of cocaine use, occurring almost immediately after any of the more rapid delivery routes, but not always dose-related. Chronic use may sensitize (kindle) an individual's response, but this is not definitively proven (Daras, 1996; Gold, 1997). Most cocaine-induced seizures are of short duration and leave no residual effects, although prolonged seizures can be catastrophic (see earlier references under overdose management) (Schrank, 1993; Cornish and O'Brien, 1996).

Cerebral hemorrhage and ischemic strokes are relatively rare events for stimulant users but occur more frequently with users of crack and ice. At least half of those who suffer brain hemorrhages have such underlying abnormalities as arteriovenous malformations and cerebral aneurysms. Stimulant-induced hypertension probably leads to rupture of these abnormalities that will also require surgical intervention to correct. Cocaine-induced hypertension and vasospasm seem to be associated with other cases.

The toxic role of simultaneous alcohol and cocaine use that produces cocaethylene (see later discussion) is also under investigation (Schrank, 1993; Daras, 1996). Another unresolved issue is whether CNS vasculitis is a causal factor; MA-induced necrotizing vasculitis has been documented since 1970 (Miller et al., 1993). Cocaine-using clients who complain of headache while intoxicated should be evaluated for possible intracranial hemorrhage (Ellinwood and Lee, 1989; Daras, 1996).

The recently documented neurological deficiencies found in chronic cocaine users, particularly in the basal ganglia and frontal cortex, are similar to those found in a variety of neurological/psychiatric disorders, including bipolar disorder, schizophrenia, and frontal lobe degeneration from seizures, stroke, or injury that is accompanied by dementia, apathy, depression, and social disinhibition (Majewska, 1996). Animal studies have confirmed similar enduring, possibly permanent, CNS changes, associated with repeated high doses of MA. Neurotoxicity at an early age may predispose stimulant users to premature onset of movement disorders such as Parkinson's disease and other dystonic or choreoathetoid disorders involving undulating, involuntary, whole body movements that may appear at the end of a prolonged binge in chronic users and are not related to use of neuroleptic medications (CSAT, 1997; Gold and Miller, 1997).

An array of cognitive deficits is also observed in cocaine and other stimulant users that also characterizes brain aging and dementia and may indicate premature brain aging or possible cerebral atrophy in these drug-dependent individuals. These include problems in attention, concentration, problem-solving, abstraction, arithmetic performance, new learning, and short-term memory (Majewska, 1996; Cornish and O'Brien, 1996; Gold, 1997). Unfortunately, many of the studies documenting these deficits lack adequate data on respondents' premorbid performance (Daras, 1996).

Muscular and Renal Toxicity

Cocaine and MA may be direct muscle toxins because acute rhabdomyolysis--a condition that destroys skeletal muscle--has been diagnosed in users who did not have any of the previously associated risk factors (i.e., hyperthermia, agitation, seizures, hypotension, toxic delirium or coma, or acute renal failure). Muscle necrosis may occur after any route of drug administration, and the presence of rhabdomyolysis should be considered in stimulant-intoxicated clients, particularly those complaining of myalgia or muscle tenderness. One study found that one-fourth of clients presenting with cocaine-related complaints had evidence of mild, usually asymptomatic, rhabdomyolysis--defined as elevated creatine kinase levels that were five times higher than normal (Goldfrank and Hoffman, 1993; Schrank, 1993).

Although mild cases of rhabdomyolysis may not lead to renal complications, renal insult and failure is a distinct possibility for patients with concomitant hyperthermia, seizures, delirium, or coma (Schrank, 1993). Renal failure from rhabdomyolysis has been reported as an outcome of cocaine and MA use (Scandling and Spital, 1982). Accompanying hepatic damage is rare and probably an idiosyncratic response (CSAT, 1997).

Gastrointestinal Complaints

Abdominal pain, nausea, and vomiting are experienced by some stimulant users, probably indicating mild intestinal ischemia. Severe bowel infarction with elevated white blood cell counts, metabolic acidosis, and shock have also been observed. Occasionally, severe abdominal pain, bowel obstruction, or sudden onset of seizures are indicative of leakage or rupture of packets of cocaine ingested by "bodypackers" (Schrank, 1993). Another observed syndrome, "cocaine colitis," manifests as abdominal pain along with diarrhea and bloody stools, probably indicating diffuse gastrointestinal hemorrhage and tissue necrosis (Goldfrank and Hoffman, 1993).

Infections

As already noted, intravenous injection of cocaine or MA is associated with a variety of infectious diseases. Unsterile paraphernalia are particularly likely to result in blood-borne transmission of HIV/AIDS and hepatitis B, C, and D. Associated malnutrition in chronic users further lowers resistance to infection. Injection cocaine users are at greater risk of infectious endocarditis than other parenteral drug users (Daras, 1996).

Disinhibition and the initial aphrodisiac effects of stimulants are associated with participation in high-risk and unprotected sexual activity. Vigorous and prolonged sexual activity or anal intercourse is likely to damage tissues or protective condoms and thereby increase the likelihood of transmitting sexually contracted diseases (Cornish and O'Brien, 1996).

Effects on Reproductive Function And Fetus/Newborn

Use of stimulants by pregnant women has been related to poor obstetrical outcomes and adverse effects for the developing fetus, the newborn and the older child. An increased incidence of preecalmpsia, spontaneous abortions, and abruptio placentae has been observed among cocaine-using pregnant women. Toxic effects also result in fetal cerebral infarctions as well as low birth weight for gestational age and small head circumference. Recent studies in several separate locations have found similar rates of these complications in MA- and cocaine-using women and their prenatally exposed offspring (CSAT, 1997; Oro and Dixon, 1987).

Newborns exposed to stimulants in the womb may have poor feeding and sleep patterns, tremor, and hypertonia. Difficulties in consoling these "jittery" babies may inhibit close bonding with their mothers and contribute to developmental problems (Gold, 1997). Despite a sp