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Methamphetamine

1997; American Academy of Pediatrics; Volume: 18; Issue: 9 Linguagem: Inglês

10.1542/pir.18.9.305

1529-7233

Richard G. MacKenzie, Bruce Heischober,

Neurological and metabolic disorders

The roots of the current epidemic of methamphetamine abuse date back centuries. Use of ephedrine was documented in China more than 5,000 years ago, and cathinone was used in East Africa in the 14th century. These drugs were obtained from the plants Ephedra majaung and Catha edulis, respectively. Both were recognized for their stimulant, appetite suppressant, and bronchodilation properties.Amphetamine first was synthesized in 1887, but was not used clinically until the early 1930s. Predictably, abuse occurred almost immediately. Benzedrine® inhalers were available over the counter and contained 250 mg of amphetamine per inhaler. Developed as a topical decongestant, the amphetamine, contained in a cotton plug, often was ingested directly or the drug was extracted and injected. Worldwide epidemics of amphetamine abuse occurred over the next several decades, resulting in legislation in many countries in the 1950s and 1960s to control production and dispensing.In the United States in the 1960s, methamphetamine was well recognized for its potential to lead to tolerance and physiologic dependence. High-dose use resulted in a dysphoric,psychosis-like state. It was one of many drugs that defined the “drug culture” of that era, despite its often negative side effects. Some even credit methamphetamine with ending the “summer of love” in 1969; public service announcements began to appear that featured then popular musicians who promoted the warning, “Speed kills.”With the passage of the Controlled Substance Act of 1970, the availability of illicit amphetamines was restricted greatly, especially as “street”drugs. Laboratory analysis of black-market drugs in the mid-1970s found that fewer than 10% of the samples contained methamphetamine/amphetamine. However, in the late 1970s, “look-alike” speed began to appear. These drugs were a combination of the over-the-counter sympathomimetic amines caffeine, ephedrine, and phenylpropanolamine, which penetrate the blood-brain barrier less effectively than amphetamine/methamphetamine. Proportionately greater stimulation of the cardiovascular system thus occurs,often resulting in dangerous increases in blood pressure and pulse. Reports of emergency department visits for complications related to use of look-alikes, especially those containing phenylpropanolamine, escalated markedly in the late 1970s and early 1980s. “Biker speed,” a racemic methamphetamine, was produced in clandestine laboratories from precursors that included phenyl-2-propanone in an attempt to fill the need for a “safer” stimulant. The chemistry involved was fairly complex,and the product was much less potent than the pure d-methamphetamine of today. “Biker speed” did not enjoy widespread use.Makeshift chemical laboratories have appeared in crowded trailer parks, motor homes, underground, in residential backyards, and more commonly in rural areas. “Cookers” or amateur chemists, who often are abusers of the drugs they are producing, combine the often toxic, flammable,and explosive ingredients at these sites. Unfortunately, it is not unusual for these laboratories to be discovered only after a serious fire or explosion attracts the attention of authorities. Such was often the consequence when amateurs began using the ephedrine reduction method to produce methamphetamine. This simple process employs a strong H+ donor (eg,hydriatic acid) and a catalyst (eg, red phosphorous) to convert 1-ephedrine to essentially pure d-methamphetamine, but in a highly volatile reaction. Despite this risk, the ephedrine reduction method is used most commonly for production of methamphetamine in the United States. Thus, it is extremely unusual for a “street” sample of methamphetamine to contain less than 90% d-methamphetamine.At a National Conference on methamphetamines convened by the US Justice Department-Drug Enforcement Administration(February 1996), recommendations were made regarding education of police and the general public to assist in the recognition of an illicit drug laboratory site, safety training, and clean-up procedures. This education also emphasized reduction of demand by building partnerships among law enforcement, the community, and health-care workers. Physicians who are familiar with the characteristics of both drug users and the drug culture can play an important role in educating the community and local law enforcement officers.The 1994 High School Senior Survey does not report methamphetamine use separately from other substances being used. It does list “ice” and “stimulants” (the latter defined as a controlled prescription that is used outside of a medical regimen). These prescription-controlled stimulants include methylphenidate, commonly prescribed for attention deficit disorder. The “ice” category is less straightforward. The term “ice,” as used colloquially, refers to methamphetamine that is smoked, excluding other methods of use such as nasal insufflation (“snorting”) and intravenous injection (“slamming”). It is not clear, therefore, what is being reported in this category (or what is being responded to by the students). However, when both categories are combined, the prevalence has increased at alarming rates. This escalation was perceived originally to be a regional phenomenon in Hawaii and the western and southwestern states. New data, however, indicate that the use of methamphetamine and its congeners is spreading nationally(National Drug Control Strategy Report 1996).In California, amphetamine-related hospital admissions increased in 1994 to 10,167 or 49%over the previous year. San Diego substance abuse treatment providers reported more admissions for methamphetamine than for alcohol. In Iowa’s Polk County, which includes Des Moines, methamphetamine accounted for 65%of drug arrests, surpassing alcohol.Literature from other countries also indicates high levels of methamphetamine use. This increase is occurring primarily among adolescents and young adults, who use the drug for its stimulant properties and to enhance sexual pleasure. In England,methamphetamine is a public health concern not only because of the risk for addiction, but also for the risk of human immunodeficiency virus transmission from intravenous use and from the associated sexual disinhibition. Australia, Japan, and Sweden also report significant problems with methamphetamine. In Australia, it is the second most frequently abused illicit drug after marijuana.Known as “meth,” “speed,” “ice,” “crystal,” “crank,” “tweak,” and “go,” methamphetamine is sold in a variety of dosages. Price varies, but 1 g generally can be purchased for $60 to $80. Other dosages include 1 oz, an eight ball (⅛ oz = 3.5 g), and a “quarter” (0.25 g). One “line” is approximately 35 mg, and 1 g can provide up to 12 lines.There is much confusion about the term ice,which often is used mistakenly to describe any new form of amphetamine or other stimulant drug. Ice actually refers to extremely pure d-methamphetamine that has the appearance of a chunk of quartz crystal. The term ice is derived from the crystals formed from a supersaturated suspension of pure ephedrine-derived methamphetamine.Methamphetamine is the N-methyl homologue of amphetamine. It is a white, odorless, bitter, crystalline powder that is soluble in water and alcohol. The color varies, depending on the process used in its manufacture;it may be crystalline-white to brown. When copper is used in illicit laboratory manufacture, a brown or peanut butter appearance may result. Street nomenclature often refers to “pink,” “quartz,” or“peanut butter” speed.The N-methyl group that differentiates amphetamine from methamphetamine decreases the polarity of the molecule and allows better penetration of the blood-brain barrier. Methamphetamine has significantly higher central nervous system (CNS) stimulant (mood-altering)activity and less peripheral nervous system and cardiovascular stimulation compared with amphetamine.The amphetamines stimulate the CNS indirectly by provoking the release and inhibition of the breakdown and storage of catecholamines. They do not stimulate postsynaptic catecholamine receptors directly. Because the effect of the drug depends on endogenous catecholamine stores, continued use leads to depletion, and a clinical binge-crash cycle occurs. This action on endogenous catecholamines also explains the rapid development of tachyphylaxis. These effects are stereo-selective, with the d-form being approximately five times as active as the L-form. Evidence also suggests that permanent damage may occur to the synaptic “complexes” in chronic users of methamphetamine. Such damage has been documented in experimental animals given prolonged high doses of methamphetamine, possibly due to formation of free radicals or the interaction of an excitatory amino acid.Every drug used for recreation may be seen as having desirable (pleasant) and undesirable effects. For most illicit drugs, the effects desired by the user relate to the CNS. For methamphetamines, these effects are feelings of euphoria, increased alertness, concentration, and hypersexuality. On the other hand, undesirable (and unpleasant) effects result from methamphetamine stimulation of peripheral alpha and beta receptors (Table 1). Thus, the state of intoxication that the abuser seeks to achieve is maximal CNS and minimal peripheral nervous system stimulation (Table 2). In the toxic or overdose state, the peripheral effects become exaggerated, unpleasant, and often life-threatening.At doses resulting in the desired CNS effects, methamphetamine causes very few of the undesirable peripheral signs and symptoms. In fact, of all of the commonly abused stimulants, it has the lowest physical side effect profile. Derlet et al studied 127 consecutive emergency department admissions for methamphetamine toxicity (see Suggested Reading). Most of the patients presented with anxiety/paranoia or tachycardia/mild hypertension that did not require pharmacologic intervention or inpatient treatment. A similar series of emergency department visits for cocaine toxicity reflected a higher incidence of undesirable side effects, including seizures, stroke, myocardial infarction/arrhythmia, and hyperthermia.The imbalance between peripheral and central stimulation of so-called “look-alike” stimulants is weighted more toward the peripheral and undesirable effects. As described earlier, these drugs usually are some combination of caffeine, ephedrine,and propanolamine. The peripheral stimulation accounts for the limited popularity of these drugs and the frequent appearance of individuals who have had toxic reactions in emergency departments. “Herbal ecstasy,” derived from the Ephedra plant, quickly developed a reputation for these alpha and beta receptor effects and greatly curbed its popularity.Smoking usually permits a drug to reach the brain even more rapidly than injecting. The bioavailability of smoked methamphetamine is excellent. Unlike cocaine, the hydrochloride salt of methamphetamine does not have to be converted to a “free base” form to be smoked effectively. The rapid onset of action may cause some smokers to experience an acute psychotic episode characterized by violent behavior, severe paranoia, and hallucinations. Often the individual will have no memory of these episodes, which can last up to 48 hours. The term “whiteout”has been used to draw an analogy to the alcoholic “blackout”episode.The first principle is attention to the ABCs and to establishing intravenous (IV) access. Rather than trying to determine the amount of drug taken, management should be based on the results of physical examination, vital signs (rectal temperature), and clinical presentation. Normal saline is the preferred IV fluid if there is no contraindication such as congestive heart failure, pulmonary edema, or renal failure. The IV rate should be adequate to maintain a urine output of at least 1 to 2 mL/kg per hour. Appropriate laboratory evaluation includes blood gases, chemistry profile, clotting parameters, urine drug screen and urinalysis,electrocardiography, and complete blood count. In the case of suspected overdose, an immediate blood glucose level should be obtained and intravenous thiamine, glucose, and if indicated, naloxone administered. In the presence of altered mental status, a computed tomographic scan of the head and lumbar puncture may be indicated, depending on context and circumstance.For an overdose from oral ingestion, gastric decontamination with nasogastric suction should be considered. Methamphetamine is bound avidly by activated charcoal. Dosing should be repeated every 2 to 4 hours. Although theoretically appealing, acidification of the urine is contraindicated. With severe overdose, the risk of causing acute renal failure from precipitation of hemoglobin/myoglobin in the urine and of possibly exacerbating acidosis outweighs the benefits. Theoretically,hemodialysis or peritoneal dialysis also may enhance elimination of methamphetamine, yet clinical efficacy has not been shown except in the case of renal failure.Mild hypertension responds to moderate doses of benzodiazepines, as do anxiety and mild agitation. Severe hypertension is treated best with IV nitroprusside. Nitroprusside therapy should be initiated early, even before the arterial line is placed. Frequent manual measurements of blood pressure are adequate until the arterial line is placed. A combination of alpha blocker (phentolamine) and vasodilator(nifedipine) also may be useful. Use of beta blockers alone should be avoided because the resulting unopposed alpha stimulation may be fatal.Methamphetamine-induced seizure activity is controlled best with a benzodiazepine. Lorazepam is preferred because it can be given intravenously. In addition, only one metabolic step is necessary for activation. It is more effective than diazepam as an anticonvulsant.The agitated, delirious patient is a diagnostic and therapeutic challenge. Neuroleptics should be avoided if the patient’s vital signs are labile or frankly abnormal. In otherwise normal patients who are severely agitated, droperidol is the neuroleptic of choice. It is sedating, and its onset is more rapid than that of haloperidol. All neuroleptic agents may lower the seizure threshold and may exacerbate hyperthermia. Hyperthermia usually can be managed by calming the patient. If this is inadequate, external cooling measures should be instituted.Skin formications and cutaneous ulcers that are in various stages of healing are one of the hallmarks of the chronic methamphetamine abuser. Emergency departments in endemic areas often use these dermatologic complaints as an indication for urine drug screening. Although psychosis is the sine qua non of chronic abuse, it must be distinguished from schizophrenia. The hallucinations of schizophrenia usually are auditory, whereas those from chronic methamphetamine use are visual or tactile. Although paranoia and cutaneous symptoms are common in the methamphetamine toxic state, as they worsen in concert, the disturbed mental state often causes the suspicious patient to deny drug use even more aggressively. Because these patients frequently provide very convincing explanations of other etiologies for their skin lesions, the clinician must have a high index of suspicion and obtain a urine drug screen accordingly. Compulsive or repetitive behaviors also are manifestations of chronic use. Patients who have histories of any compulsive behaviors, including compulsive sexual behaviors, should be evaluated carefully.Methamphetamine traditionally has been thought of as a drug used initially in pill form. Addicted users usually become IV users. With adolescents, however, nasal insufflation (snorting) is the most common route of administration. The number of young people smoking methamphetamine also has increased recently. This is the predominate route used in Hawaii and parts of the western United States. IV use often is reported in drug studies to be the most common route of administration, but these studies usually do not report the route of administration by age groups.After a heavy binge cycle and before the “crash,” extreme paranoia, hallucinations (most commonly visual, tactile, or olfactory), and aggression/agitation occur. This clinical presentation is becoming increasingly common with the availability of potent, pure ephedrine-derived drug that has been smoked or injected. This stage has been coined “tweaking” or being “overamped.” Mistakenly, to many adolescents, a “tweaker” is anyone abusing speed. Whether the term is used uniformly, there are, no doubt, more severe cases of toxicity than in the past, with many of those experiencing severe “tweaking”at high risk for trauma or violence.The relationship between methamphetamine abuse and trauma frequently is overlooked. In one study of amphetamine-induced deaths, trauma accounted for two thirds of the victims and resulted from bizarre violent behavior that occurred acutely after a single large dose or as a consequence of chronic use. Homicide investigators in areas where abuse is endemic describe a “hyperviolence syndrome”in which the victim frequently is part of the perpetrator’s delusional belief system. A weapon is used most commonly, such as a knife or gun. There frequently are multiple (sometimes hundreds) wounds inflicted, many postmortem, and sometimes days after death.Methamphetamine exposure in pregnancy increases the incidence of placental hemorrhage. Intrauterine growth is retarded, and rates of prematurity are increased. Head circumference at birth is decreased. Infant behavior, including feeding and sleep patterns, is abnormal. Hypertonia and tremors are not uncommon. The incidence of birth defects and miscarriage is increased.In the homosexual community, methamphetamine is a preferred “sex drug.” Its use increases libido and is associated with high-risk sexual behavior in both homosexual and heterosexual youth.Marathon dance parties called “raves” that feature music having a repetitive, hypnotic beat (rather than melody), synchronized lights, and participants under the influence of lysergic acid diethylamide (LSD) or methylene-dioxymethamphetamine (MDMA) have been in existence for years. One theory for the popularity of methamphetamine use is that it promotes repetitive behaviors because of its effect on dopaminergic and norepinephrinergic systems. MDMA and LSD, on the other hand, are serotoninergic, giving rise to a more detached, blissful state. Methamphetamine users also like the music called “speed-metal”because of its rapid and repetitive nature.Dupont proposed that the use of certain drugs acted as a “gateway” into other drug use. Alcohol and tobacco are typical examples. Evidence for marijuana is inconclusive. Clearly, cocaine and methamphetamine fulfill the criteria for a gateway drug. It is not unusual to find young adolescents who do not drink or smoke using methamphetamine. Many young people admit to a continuum of use beginning with coffee, then over-the-counter energy or stay-awake pills,and finally methamphetamine. Competitive high school athletes who commonly abuse over-the-counter stimulants often switch to methamphetamine, acting on misinformation by teammates or even coaches that it is “just a little stronger.” Children who are prescribed methamphetamine for legitimate reasons often discover the abuse potential for themselves or others. In endemic areas it is not unusual to find 13- to 15-year-old girls using it as an appetite suppressant. In all of these circumstances, the individual likely will report a perception that methamphetamine is safer than cocaine because doctors prescribe it for weight control or learning disorders. With this potential for methamphetamine being used in this “gateway” or therapeutic context, erratic or unexplained behavior in any adolescent or young adult should raise suspicion.Specific treatment depends on a specific diagnosis, often a difficult task because of the protean clinical manifestations of methamphetamine use. In endemic areas,the clinician must have a high index of suspicion and a familiarity with the signs and symptoms of use.Management for medical and some psychiatric complications has been outlined, but two further issues need to be emphasized. The first involves the management of the postbinge phase—so-called “overamping” or “tweaking.” This phase is quite severe and accompanied by extreme paranoia and agitation/aggression. It is the most feared aspect of use to the abuser. Users often will prolong binges not so much to stay high, but to avoid the “crash” that may last for days. Although the “overamped” stage may be controlled initially with benzodiazepines or neuroleptics, it reappears rapidly as the initial dose of these drugs wears off. Breaking the cycle requires that the patient be medicated adequately for prolonged periods.A closely related issue involves treatment of the disease of addiction. Rarely can the dependent illicit drug user be treated solely within the medical setting or the confines of the pediatrician’s office. It is important to know and draw upon resources in the community for treatment and ongoing support of a sober lifestyle. The management program must be developmentally appropriate for the individual young person and be optimally integrated into schools and community-based organizations.