NEUROLOGY OF DRUG AND ALCOHOL ADDICTIONS

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CHAPTER 117 NEUROLOGY OF DRUG AND ALCOHOL ADDICTIONS

John C.M. Brust

DEFINITIONS

Substance dependence is of two types. Psychic dependence consists of craving and drug-seeking behavior. Physical dependence consists of somatic withdrawal symptoms and signs. Depending on the drug, psychic and physical dependence can occur together or alone. Tolerance is the need for increasing doses of a drug to produce desired effects or to avoid withdrawal symptoms.

ILLICIT DRUG DEPENDENCE

Intoxication and Withdrawal

Opioids

Opioid drugs include agonists (e.g., morphine, heroin, methadone, meperidine, fentanyl, hydromorphone, codeine, oxycodone), antagonists (e.g., naloxone, naltrexone), and partial agonists or mixed agonist/antagonists (e.g., buprenorphine, pentazocine, butorphanol). Intended doses of agonists produce drowsy euphoria, analgesia, miosis, cough suppression, and often nausea, vomiting, pruritus, sweating, postural hypotension, and constipation. Taken parenterally or smoked, heroin produces brief ecstatic “rush,” followed by euphoria and either relaxed “nodding” or hyperactivity. Overdose causes coma, respiratory depression, and pinpoint (but reactive) pupils. Adults with depressed respirations are treated with naloxone, 2 mg intravenously, repeated as needed up to 20 mg. Naloxone is short-acting, and so patients require admission and close observation.

Opioid withdrawal symptoms include irritability, lacrimation, rhinorrhea, sweating, mydriasis, myalgia, piloerection, nausea, vomiting, abdominal cramps, and fever. In adults, seizures and delirium are not part of the syndrome, which is hardly ever life-threatening and can usually be prevented or treated with methadone, 20 mg twice/day. In contrast, opioid withdrawal in newborns is protracted, severe, and often fatal. Treatment is with titrated doses of methadone or paregoric.

Psychostimulants

Psychostimulant drugs include dextroamphetamine, methamphetamine, methylphenidate, ephedrine, phenylpropanolamine, other anorectics and decongestants, and cocaine. 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) produces effects that appear to straddle those of amphetamine-like drugs and hallucinogens (see later discussion). Intended doses of amphetamine-like psychostimulants and cocaine produce alert euphoria with increased motor activity. Taken parenterally or smoked as alkaloidal cocaine (“crack”) or methamphetamine (“ice”), psychostimulants produce a “rush” psychically indistinguishable from heroin’s. Repeated use causes progressive movement disorders (stereotypy, bruxism, choreoathetosis, dystonia) and psychiatric symptoms (paranoia, hallucinatory psychosis). Overdose causes excitement, delirium, cardiac arrhythmia, hypertensive crisis, malignant hyperthermia, myoclonus, seizures, myoglobinuria, severe metabolic acidosis, shock, coma, and death. Treatment includes benzodiazepine sedation, oxygen, bicarbonate, anticonvulsants, cooling, blood pressure control (with an α-adrenergic blocker or a direct vasodilator), respiratory and blood pressure support, and cardiac monitoring.

Psychostimulant withdrawal consists of depression, fatigue, and craving but few objective signs.

Marijuana

Marijuana, from the hemp plant Cannabis sativa, contains many cannabinoid compounds, of which Δ9-tetrahydrocannabinol (Δ9-THC) is the psychoactive agent. Hashish is made from the plant resin, which contains high concentrations of Δ9-THC. Usually smoked, but sometimes taken orally, marijuana produces relaxed euphoria, often with disinhibition, subjective perception of time slowing, tachycardia, and postural hypotension. High doses cause auditory or visual hallucinations and psychosis, but fatal overdose has not been documented. Withdrawal symptoms other than jitteriness are rare, but craving is common.

Sedatives

Sedative drugs include barbiturates, benzodiazepines, and miscellaneous agents such as glutethimide, ethchlorvynol, and zolpidem. γ-Hydroxybutyrate (GHB) and its precursors γ-butyrolactone and 1,4-butaneidiol are “designer drugs” sold as street products.

The intended effects of sedatives resemble ethanol intoxication. Overdose causes stupor or coma and respiratory depression. The mainstay of treatment is ventilatory support. With γ-hydroxybutyrate, overdose can also cause hallucinations, myoclonus, and seizures. Sedative withdrawal produces tremor and seizures and can be prevented with titrated doses of a benzodiazepine or a barbiturate. Delirium tremens requires intensive care.

Phencyclidine

Phencyclidine (PCP, “angel dust”) is usually smoked. The related agents ketamine and dextromethorphan are more often used orally. Low doses of phencyclidine cause euphoria or dysphoria; increasing intoxication can lead to agitation, hallucinatory psychosis, rhabdomyolysis, tachycardia, hypertension, fever, myoclonus, seizures, coma, respiratory depression, and death. Supportive treatment includes benzodiazepine sedation, forced diuresis, cooling antihypertensives, anticonvulsants, and cardiorespiratory monitoring. Withdrawal signs—nervousness and tremor—are infrequent, but psychic dependence occurs.

Hallucinogens

Dozens of hallucinogenic plants are used recreationally around the world. In the United States, the most popular hallucinogenic agents are mescaline (from the peyote cactus), psilocybin and psilocin (from several mushroom species), and the synthetic ergot lysergic acid diethylamide (LSD)/β. Acute effects are perceptual (distortions or hallucinations, usually visual and often elaborate), psychological (altered mood), and somatic (dizziness, tremor). Paranoia or panic can occur, and overdose can produce hypertension and seizures, but fatalities are usually the result of accidents. Treatment consists of a calm environment or a benzodiazepine. There are no withdrawal symptoms.

Inhalants

Recreational inhalant use, popular among children and adolescents, involves a wide variety of commercially available products, including aerosols, glues, solvents, paints, and gasoline. Compounds include aliphatic, aromatic, and halogenated hydrocarbons, as well as nitrous oxide (from whipped cream dispensers) and butyl or amyl nitrite (from “room deodorizers”). The intended effect resembles those produced by ethanol; overdose can cause hallucinations, seizures, and death from cardiac arrhythmia or accidents. Treatment is supportive. The only predictable withdrawal symptom is craving.

Anticholinergics

The plant Datura stramonium contains anticholinergic compounds, and oral recreational use is popular among American adolescents. Also occasionally abused for its anticholinergic properties is the tricyclic antidepressant amitriptyline. Intoxication produces decreased sweating, fever, dilated unreactive pupils, and hallucinatory delirium, progressing to seizures, coma, and death. Treatment includes intravenous physostigmine, 0.5 to 3 mg as needed every 30 minutes to 2 hours, plus supportive care and, if necessary, anticonvulsants. Neuroleptic agents are contraindicated. There are no withdrawal symptoms.

Medical and Neurological Complications of Illicit Drug Use

Infection

Parenteral users of any drug are subject to an array of infections that often directly or indirectly affect the nervous system, including hepatitis, endocarditis, cellulitis, myositis, osteomyelitis, tetanus, and botulism. In the United States, nonhomosexual drug abusers currently account for 26% of reported cases of acquired immunodeficiency syndrome (AIDS), and male homosexual drug users account for another 6%. Neurological complications of AIDS are the same in parenteral drug users as in other susceptible groups, including patients with tuberculous meningitis and neurosyphilis.

Trauma

Trauma may be a consequence of drug intoxication but is more often related to the illegal activities necessary to distribute and procure illegal substances.

Seizures

Seizures are a toxic effect of psychostimulants. With amphetamine-like agents, they usually occur in the setting of obvious overdose. With cocaine, they more often occur in the absence of other symptoms. Cocaine-induced status epilepticus can be very difficult to control. In sedative users, seizures are a withdrawal phenomenon.

Opioids acutely lower seizure threshold, but seizures are so rarely a feature of heroin overdose that an alternative cause (e.g., concomitant cocaine use, ethanol withdrawal, meningitis, or head trauma) should be sought. Myoclonus and seizures occur in meperidine users as a result of its toxic metabolite normeperidine.

Stroke

Parenteral drug users are at risk for stroke through systemic complications such as hepatitis, endocarditis, and AIDS. Concomitant tobacco or ethanol abuse also increases stroke risk. In psychostimulant users, ischemic stroke can be cardioembolic as a result of myocardial infarction or arrhythmia. Amphetamine and methamphetamine users are prone to intracerebral hemorrhage in the setting of acute hypertension and high fever. They are also at risk for ischemic stroke secondary to cerebral vasculitis affecting either medium-sized arteries (resembling polyarteritis nodosa) or smaller arteries and veins (resembling hypersensitivity angiitis). In cocaine users, hemorrhagic stroke (including, frequently, rupture of an intracranial saccular aneurysm or a vascular malformation) is also usually secondary to acute surges of blood pressure. Ischemic stroke, however, is seldom secondary to vasculitis and is probably most often the result of acute cerebral vasospasm. Intracerebral and subarachnoid hemorrhage are described in “ecstasy” users in the United States, and both over-the-counter products containing phenylpropanolamine and dietary supplements containing ephedra have been banned by the U.S. Food and Drug Administration because of their association with stroke.

Heroin has infrequently been associated with ischemic stroke in young people without other risk factors. Phencyclidine and lysergic acid diethylamide are each vasoconstrictive, and both ischemic and hemorrhagic stroke are described in users.

Altered Mentation

Dementia in illicit drug users has many potential causes, including concomitant ethanol abuse, malnutrition, infection (especially AIDS), and head trauma. Whether the drugs themselves cause lasting cognitive or behavioral change is more difficult to establish, for pre–drug use psychometric testing is seldom available, and many drug users are probably self-medicating preexisting medical conditions.

Methamphetamine damages both dopaminergic and serotonergic nerve terminals, with lasting brain neurotransmitter disruption; whether such injury is associated with clinically significant cognitive impairment is uncertain. “Ecstasy” destroys serotonin nerve endings, and impaired cognition is described in abstinent users. Cocaine is not directly neurotoxic, but cognitive impairment is described, perhaps the result of widespread cerebral ischemia.

Sedatives reversibly impair cognitive function in elderly patients, and they are associated with delayed learning in small children. Persons who sniff products containing toluene develop a toxic leukoencephalopathy with dementia, and those who sniff gasoline have developed lead encephalopathy. Although the existence of a marijuana-induced “antimotivational syndrome” was overstated, more rigorous studies support the existence of lasting subtle cognitive impairment in heavy users.

The weight of evidence is against chronic mental abnormalities secondary to the use of opioids or hallucinogenic drugs.

Fetal Effects

The effects of illicit drugs on intrauterine development are similarly difficult to determine. Confounders include tobacco, ethanol, or other drug use; lack of prenatal care; malnutrition; and home environment. Studies of the in utero effects of cocaine have yielded conflicting results. Diffuse hypertonia is observed in cocaine-exposed neonates, with disappearance by 2 years of age. In animals, in utero cocaine exposure results in impaired learning; such effects in humans, if they occur at all, appear to be small.

Marijuana exposure has been associated with decreased birth weight and impaired executive function. Heroin exposure is also associated with low birth weight and later cognitive impairment. Organic solvents appear to be teratogenic in animals and humans.

Other Neurological Complications

Rhabdomyolysis and renal failure have followed use of heroin, amphetamine, cocaine, and phencyclidine. Guillain-Barré–type polyneuropathy and brachial or lumbosacral plexopathy (probably immunogenic) have affected heroin users. Severe sensorimotor polyneuropathy occurs in persons who sniff glue containing n-hexane. Myeloneuropathy indistinguishable from combined systems disease in cobalamin deficiency affects persons who sniff nitrous oxide; the cause is inactivation of the cobalamin-dependent enzyme methionine synthase. Acute myelopathy occurs in heroin users; it is unclear whether the mechanism is toxic, immunogenic, or vascular.

Spongiform leukoencephalopathy with dementia, ataxia, quadriparesis, and blindness is sometimes fatal and affects heroin users who inhale the vapor of the drug as it is burned on metal foil (“chasing the dragon”); the responsible toxin has not been identified. Severe parkinsonism occurred in parenteral users of a synthetic meperidine analog contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a metabolite of which is toxic to dopaminergic neurons of the substantial nigra. A parenteral heroin user became blind after repeatedly using a preparation containing quinine.

ETHANOL

Alcoholism

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