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InternalMed_Harrison. Herbal marijuana alternatives are also available. These are usually a combination of several herbs and synthetic cannabinoids. “Spice” and “K2” are among the best known, but many formulations exist, and marijuana is undetectable by the usual methods. These compounds are marketed on the Internet as containing no illegal ingredients. However a number of synthetic cannabinoids are now classified as Schedule I by the Drug Enforcement Administration due to reports of toxicity.


InternalMed_Harrison

InternalMed_Harrison. Marijuana is the most commonly used illegal drug in the United States. In 2012, an estimated 18.9 million people reported using marijuana within the past month. An estimated 7.2% of adolescents age 12 to 17 years reported current use of marijuana. Marijuana is relatively inexpensive and is often considered to be less hazardous than other controlled drugs and substances. Very potent forms of marijuana (sinsemilla) are widely available, and concurrent use of marijuana with other drugs such as cocaine is not uncommon. Due in part to the difficulty of detecting herbal marijuana alternatives, the prevalence of use is unknown.


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InternalMed_Harrison. Acute intoxication from marijuana and cannabis compounds is related to both the dose of THC and the route of administration. THC is absorbed more rapidly from marijuana smoking than from orally ingested cannabis compounds. Acute marijuana intoxication may produce a perception of relaxation and mild euphoria resembling mild to moderate alcohol intoxication. This condition is usually accompanied by some impairment in thinking, concentration, and perceptual and psychomotor function. Higher doses of cannabis may produce more pronounced impairment in concentration and perception, as well as greater sedation. Although the acute effects of marijuana intoxication are relatively benign in normal users, the drug can precipitate severe emotional disorders in individuals who have antecedent psychotic or neurotic problems. Like other psychoactive compounds, both the user’s expectations and the environmental context are important determinants of the type and severity of the effects of marijuana


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InternalMed_Harrison. or neurotic problems. Like other psychoactive compounds, both the user’s expectations and the environmental context are important determinants of the type and severity of the effects of marijuana intoxication.


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InternalMed_Harrison. As with abuse of cocaine, opioids, and alcohol, chronic marijuana abusers may lose interest in common socially desirable goals and devote progressively more time to drug acquisition and use. However, THC does not cause a specific and unique “amotivational syndrome.” The range of symptoms sometimes attributed to marijuana use is difficult to distinguish from mild to moderate depression and the maturational dysfunctions often associated with protracted adolescence. Chronic marijuana use has also been reported to increase the risk of psychotic symptoms in individuals with a past history of schizophrenia. Persons who begin marijuana smoking before the age of 17 may have more pronounced cognitive deficits and also may be at higher risk for polydrug and alcohol abuse problems in later life, but the role of marijuana in this sequence is uncertain.


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InternalMed_Harrison. The acute effects of herbal marijuana alternatives are based primarily on case reports and include anxiety, agitation, delusions, paranoia, and psychosis. The extent to which these symptoms reflect drug effects or exacerbation of an underlying psychiatric disorder is often difficult to determine. Conjunctival injection and tachycardia are the most frequent immediate physical concomitants of smoking marijuana. Tolerance for marijuana-induced tachycardia develops rapidly among regular users. However, marijuana smoking may precipitate angina in persons with a history of coronary insufficiency. Exercise-induced angina may increase after marijuana use to a greater extent than after tobacco cigarette smoking. Patients with cardiac disease should be strongly advised not to smoke marijuana or use cannabis compounds.


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InternalMed_Harrison. Significant decrements in pulmonary vital capacity have been found in regular daily marijuana smokers. Because marijuana smoking typically involves deep inhalation and prolonged retention of marijuana smoke, chronic bronchial irritation may develop. Impairment of single-breath carbon monoxide diffusion capacity (DlCO) is greater in persons who smoke both marijuana and tobacco than in tobacco smokers.


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InternalMed_Harrison. Although marijuana has also been associated with a number of other adverse effects, many of these studies await replication and confirmation. A reported correlation between chronic marijuana use and decreased testosterone levels in males has not been confirmed. Decreased sperm count and sperm motility and morphologic abnormalities of spermatozoa following marijuana use have been reported. Prospective studies found a correlation between impaired fetal growth and development and heavy marijuana use during pregnancy. Marijuana has also been implicated in derangements of the immune system; in chromosomal abnormalities; and in inhibition of DNA, RNA, and protein synthesis; however, these findings have not been confirmed or related to any specific physiologic effect in humans. Herbal marijuana alternatives produce many of the effects of marijuana including conjunctival injection and tachycardia.


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InternalMed_Harrison. Habitual marijuana users may develop tolerance to the psychoactive effects of marijuana, and then smoke more frequently and try to acquire more potent cannabis compounds. Tolerance for the physiologic effects of marijuana develops at different rates; e.g., tolerance develops rapidly for marijuana-induced tachycardia but more slowly for marijuana-induced conjunctival injection. Tolerance for both behavioral and physiologic effects of marijuana decreases rapidly upon cessation of marijuana use.


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InternalMed_Harrison. A distinct withdrawal syndrome has been documented in chronic cannabis users, and the severity of symptoms is related to dosage and duration of use. These symptoms typically reach their peak several days after cessation of chronic use and include irritability, anorexia, and sleep disturbances. Withdrawal signs and symptoms observed in chronic marijuana users are usually relatively mild in comparison to those observed in heavy opioid or alcohol users and rarely require medical or pharmacologic intervention. However, more severe and protracted abstinence syndromes may occur after sustained use of high-potency cannabis compounds. As yet there have been no systematic studies of tolerance and physical dependence to the herbal marijuana alternatives. The large number of synthetic cannabinoids available for combination with about 20 herbs presents a daunting challenge for analysis.


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InternalMed_Harrison. Marijuana, administered as cigarettes or as a synthetic oral cannabinoid (dronabinol), is thought to have a number of clinically useful medicinal properties. These include antiemetic effects in chemotherapy recipients, appetite-promoting effects in AIDS patients, reduction of intraocular pressure in glaucoma, and reduction of spasticity in multiple sclerosis and other neurologic disorders. With the possible exception of AIDS-related cachexia, none of these attributes of marijuana compounds is clearly superior to other readily available therapies.


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InternalMed_Harrison. Methamphetamine is also referred to as “meth,” “speed,” “crank,” “chalk,” “ice,” “glass,” or “crystal.” Methamphetamine is a mixed-action monoamine releaser with activity at dopamine, serotonin, and norepinephrine systems. Methamphetamine was considered second only to cocaine as a drug threat to society by the U.S. Department of Justice in 2009. Hospital admissions for methamphetamine treat-469e-3 ment more than doubled between 1998 and 2007, and young adults (age 18–25) have the highest use rates. In 2011, an estimated 439,000 people reported current use of methamphetamine in the United States, and emergency room admissions involving amphetamines/methamphetamine totaled 160,000. Persistent abuse of methamphetamine continues despite drug seizures, closures of clandestine laboratories that produce methamphetamine illegally, and an increase in methamphetamine abuse prevention programs.


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InternalMed_Harrison. Methamphetamine can be used by smoking, snorting, IV injection, or oral administration. Methamphetamine abusers report that drug use induces feelings of euphoria and decreased fatigue. Adverse consequences of methamphetamine use include headache, difficulty concentrating, diminished appetite, abdominal pain, vomiting or diarrhea, disordered sleep, paranoid or aggressive behavior, and psychosis. Chronic methamphetamine abuse can result in severe dental caries, described as blackened, rotting, crumbling teeth. Severe, life-threatening methamphetamine toxicity may include hypertension, cardiac arrhythmia or cardiac failure, subarachnoid hemorrhage, ischemic stroke, intracerebral hemorrhage, convulsions, or coma.


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InternalMed_Harrison. Methamphetamines increase the release of monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) from presynaptic neurons. It is thought that the euphoric and reinforcing effects of this class of drugs are mediated through dopamine and the mesolimbic system, whereas the cardiovascular effects are related to norepinephrine. MRS studies of the brain suggest that chronic abusers have neuronal damage in the frontal areas and basal ganglia. Treatment of acute methamphetamine overdose is largely symptomatic. Ammonium chloride may be useful to acidify the urine and enhance clearance of the drug. Hypertension may respond to sodium nitroprusside or α-adrenergic antagonists. Sedatives may reduce agitation and other signs of central nervous system hyperactivity. Treatment of chronic methamphetamine dependence may be accomplished in either an inpatient or outpatient setting using strategies similar to those described earlier for cocaine abuse.


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InternalMed_Harrison. MDMA is a derivative of methamphetamine also called Ecstasy or Molly. Reported use of MDMA in the United States has increased from 615,000 persons in 2005, to an estimated 869,000 people in 2012. Emergency ward admissions involving MDMA totaled more than 22,000 in 2011. Ecstasy is usually taken orally but may be injected or inhaled, and its effects last for 3–6 h. MDMA has amphetamine-like effects including vivid visual and auditory hallucinations and other perceptual distortions. Recent studies indicate that MDMA use is associated with cognitive and memory impairment. MDMA can induce hyperthermia and elevated blood pressure, seizures, comma, and death. Withdrawal symptoms after cessation of use may include teeth grinding, anxiety, loss of appetite, insomnia, and fever. The longterm consequences of recreational use of MDMA by young persons are poorly understood.


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InternalMed_Harrison. The rapid emergence of synthetic cathinone abuse during 2010 was accompanied by numerous reports of adverse medical and psychiatric effects, suicides, and deaths. Reports to poison centers and health agencies increased from about 300 in 2010 to over 6000 in 2011. In 2011, the Drug Enforcement Administration classified three commonly abused synthetic cathinones (mephedrone [4-methyl methcathinone], MDPV [3,4-methylenedioxy pyrovalerone], and methylone) as Schedule I compounds with no accepted medical use and a high potential for abuse. However, synthetic cathinones are readily available on the Internet as well as in convenience stores, gas stations, and head shops. These drugs are merchandised under a variety of names such as Vanilla Sky, Purple Wave, Blue Silk, White Lightening, and Snow Leopard. Regulatory constraints are evaded by labeling the products as plant food, insecticides, pond cleaner, and bath salts with the qualifier, “not for human consumption.”


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InternalMed_Harrison. Cathinone is the primary psychoactive ingredient in khat leaves. Chewing the leaves of the khat shrub (Catha edulis) produces mild stimulant and euphoric effects and remains a common practice in east Africa that has persisted for centuries. Cathinone is structurally similar to amphetamine, and mephedrone is structurally similar to methamphetamine. Cathinones, like amphetamines, inhibit dopamine, serotonin, and norepinephrine transporters to varying degrees, and this probably accounts for variations in the behavioral effects observed. The effects of cathinone derivatives are often described as similar to the effects of MDMA or Ecstasy. Synthetic cathinones can be inhaled, snorted, injected, or taken orally. These drugs may be taken repeatedly over several hours in episodes lasting for hours or days. The onset of effects after oral ingestion is relatively rapid for MDPV (15–30 min) and slightly slower for mephedrone and methylone (30–45 min). The duration of action varies from 2 to 5 or


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InternalMed_Harrison. or days. The onset of effects after oral ingestion is relatively rapid for MDPV (15–30 min) and slightly slower for mephedrone and methylone (30–45 min). The duration of action varies from 2 to 5 or 7 h. After mephedrone inhalation, effects occur within minutes and only last for 1 h or less, but mood changes may persist for several days. Evaluation of the neurotoxic effects of prolonged synthetic cathinone abuse is just beginning, and the long-term consequences are unknown.


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InternalMed_Harrison. The reported positive subjective effects of synthetic cathinones include euphoria, improved energy, alertness, sociability, and increased sensitivity to music and other sensory experiences. The reported negative subjective effects include agitation, visual and auditory hallucinations, anxiety and panic attacks, paranoid delusions, disorientation, depression, and suicidal ideation. Observers report irritability, aggression, violent behavior, tremors, and seizures. Medical evidence of adverse effects includes cardiovascular dysfunction and cardiac arrest, hypertension, hyperthermia, nausea and vomiting, and anorexia. There is no specific antagonist for synthetic cathinone intoxication. Patients with severe hyperthermia, seizures, and arrhythmia are medical emergencies and should be treated in a hospital. Sedation with benzodiazepines can be useful for managing agitation, seizures, aggression, and other related symptoms. Antipsychotic medications may be necessary for management of severe


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InternalMed_Harrison. a hospital. Sedation with benzodiazepines can be useful for managing agitation, seizures, aggression, and other related symptoms. Antipsychotic medications may be necessary for management of severe and persistent psychiatric symptoms.


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InternalMed_Harrison. Discovery of the psychedelic effects of LSD led to an epidemic of LSD abuse during the 1960s. Imposition of stringent constraints on the manufacture and distribution of LSD (classified as a Schedule I substance by the U.S. Food and Drug Administration [FDA]) and public recognition that psychedelic experiences induced by LSD were a health hazard have resulted in a reduction in LSD abuse. LSD still remains popular among adolescents and young adults, and there are indications that LSD use among young persons has been increasing in some areas in the United States. In 2011, an estimated 358,000 persons used LSD, whereas 200,000 and 271,000 persons reported LSD use in 2003 and 2007, respectively.


InternalMed_Harrison

InternalMed_Harrison. LSD is a very potent hallucinogen; oral doses as low as 20 μg may induce profound psychological and physiologic effects. Tachycardia, hypertension, pupillary dilation, tremor, and hyperpyrexia occur within minutes following oral administration of 0.5–2 μg/kg. A variety of bizarre and often conflicting perceptual and mood changes, including visual illusions, synesthesias, and extreme lability of mood, usually occur within 30 min after LSD intake. These effects of LSD may persist for 12–18 h, even though the half-life of the drug is only 3 h.


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InternalMed_Harrison. Emergency ward visits involving LSD totaled nearly 5000 in 2011. The most frequent acute medical emergency associated with LSD use is a panic episode (the “bad trip”), which may persist up to 24 h. Management of this problem is best accomplished by supportive reassurance (“talking down”) and, if necessary, administration of small doses of anxiolytic drugs. Adverse consequences of chronic LSD use include an enhanced risk for schizophreniform psychosis and derangements in memory function, problem solving, and abstract thinking. Treatment of these disorders is best carried out in specialized psychiatric facilities. Tolerance develops rapidly for LSD-induced changes in psychological function when the drug is used one or more times per day for >4 days. Abrupt abstinence following continued use does not produce withdrawal signs or symptoms. There have been no clinical reports of death caused by the direct effects of LSD.


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InternalMed_Harrison. PCP, a cyclohexylamine derivative, is widely used in veterinary medicine to briefly immobilize large animals and is sometimes described as a dissociative anesthetic. PCP binds to ionotropic N-methyl-daspartate (NMDA) receptors in the nervous system, blocking ion current through these channels. PCP is easily synthesized and is abused primarily by young people and polydrug users. It is used orally, by smoking, by snorting, or by IV injection. It is also used as an adulterant in THC, LSD, amphetamine, or cocaine. The most common street preparation, angel dust, is a white granular powder that contains 50–100% of the drug. Low doses (5 mg) produce agitation, excitement, impaired motor coordination, dysarthria, and analgesia. Physical signs of intoxication may include horizontal or vertical nystagmus, flushing, diaphoresis, and hyperacusis. Behavioral changes include distortions of body image, disorganization of thinking, and feelings of estrangement. Higher doses of PCP (5–10 mg) may


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InternalMed_Harrison. nystagmus, flushing, diaphoresis, and hyperacusis. Behavioral changes include distortions of body image, disorganization of thinking, and feelings of estrangement. Higher doses of PCP (5–10 mg) may produce profuse salivation, vomiting, myoclonus, fever, stupor, or coma. PCP doses of ≥10 mg cause convulsions, opisthotonus, and decerebrate posturing that may be followed by prolonged coma.


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InternalMed_Harrison. In 2011, more than 75,000 emergency ward admissions involved PCP. The diagnosis of PCP overdose is difficult because the patient’s initial symptoms (anxiety, paranoia, delusions, and hallucinations) may suggest an acute schizophrenic reaction. Confirmation of PCP use is possible by determination of PCP levels in serum or urine. PCP assays are available at most toxicologic centers. PCP remains in urine for 1–5 days following high-dose intake. PCP overdose requires emergency life-support measures that may involve treatment of coma, convulsions, and respiratory depression in an intensive care unit. There is no specific antidote or antagonist for PCP. PCP excretion from the body can be enhanced by gastric lavage and acidification of urine. Death from PCP overdose may occur as a consequence of some combination of pharyngeal hypersecretion, hyperthermia, respiratory depression, severe hypertension, seizures, hypertensive encephalopathy, and intracerebral hemorrhage.


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InternalMed_Harrison. Acute psychosis associated with PCP use is a psychiatric emergency because patients may be at high risk for suicide or extreme violence toward others. Phenothiazines should not be used for treatment because these drugs potentiate PCP’s anticholinergic effects. Haloperidol (5 mg IM) has been administered on an hourly basis to induce suppression of psychotic behavior. PCP, like LSD and mescaline, produces vasospasm of cerebral arteries at relatively low doses. Chronic PCP use has been shown to induce insomnia, anorexia, severe changes in behavior, and, in some cases, chronic schizophrenia.


InternalMed_Harrison

InternalMed_Harrison. This naturally occurring herb is a recent entry into the spectrum of hallucinogens. Like PCP and ecstasy, this drug can produce profound alterations in mood, hallucinations, and distorted perceptions. This drug is available on the Internet and is known by a variety of names including magic mint, mystic sage, Mariana Pastora, and purple sticky. The drug was first added to the annual National Surveys on Drug Use and Health in 2006, and its use is increasing. Between 2006 and 2011, the number of estimated users in the United States nearly tripled to more than 5000.


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InternalMed_Harrison. The active ingredient is salvinorin A, a selective kappa opioid receptor agonist that has a range of effects including hallucinations, sedation, analgesia, and depression. The hallucinatory symptoms may be associated with intense anxiety and severe agitation that can be managed with benzodiazepines. Importantly, this kappa opioid receptor agonist does not produce respiratory depression, and no significant change in blood pressure or heart rate was reported in a clinical study with healthy subjects.


InternalMed_Harrison

InternalMed_Harrison. Salvinorin A extract or crushed leaves of the Salvia divinorum plant can be chewed and absorbed through the buccal membrane or inhaled during smoking. The onset of the acute “high” is within 5–10 min after chewing and 30 s after inhalation. The duration of the effect is relatively brief, usually 15–20 min. However, if the drug is taken with alcohol or other hallucinogens, the duration and intensity of adverse effects may be increased. The effects of the drug are reported to be similar to those of ketamine, LSD, and marijuana.


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InternalMed_Harrison. A number of other pharmacologically diverse drugs of abuse are often referred to as “club drugs” because these are frequently used in bars, at concerts, and at rave parties. Commonly abused club drugs include flunitrazepam, GHB, and ketamine and are described below. Methamphetamine, MDMA, and LSD are also considered club drugs and were described earlier in this chapter. Abuse of club drugs at high doses, especially in combination with alcohol, can be lethal and should be treated as a medical emergency. GHB and ketamine can be identified in blood, and flunitrazepam can be identified in urine and hair samples. Flunitrazepam and GHB toxicity can be treated with antagonists at benzodiazepine and γ-aminobutyric acid B (GABAB) receptors, respectively.


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InternalMed_Harrison. Flunitrazepam (Rohypnol) is a benzodiazepine derivative primarily used to treat insomnia, but it has significant abuse potential because of its strong hypnotic, anxiolytic, and amnesia-producing effects. It is a club drug commonly referred to as a “date-rape drug” or “roofies.” The drug enhances GABAA receptor activity, and overdose can be treated with flumazenil, a benzodiazepine receptor antagonist. Flunitrazepam is typically used orally but can be snorted or injected. Concomitant use of alcohol or opioids is common, and this enhances the sedative and hypnotic effects of flunitrazepam and also the risk of motor vehicle accidents. Overdose can produce life-threatening respiratory depression and coma. Abrupt cessation after chronic use may result in a benzodiazepine withdrawal syndrome consisting of anxiety, insomnia, disordered thinking, and seizures.


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InternalMed_Harrison. GHB (Xyrem) is a sedative drug that is approved by the FDA for the treatment of narcolepsy. It is classified as a club drug, is sometimes used in combination with alcohol or other drugs of abuse, and has been implicated in cases of date rape. It is also used by body builders as a growth hormone stimulant. GHB is usually available as a liquid, is taken orally, and has no distinctive color or odor. Its stimulant properties are attributed to agonist activity at the GHB receptor, but it also has sedative effects at high doses that reflect its activity at GABAB receptors. GABAB antagonists can reverse GHB’s sedative effects, and opioid antagonists (naloxone, naltrexone) can attenuate GHB effects on dopamine release. Low doses of GHB may produce euphoria and disinhibition, whereas high doses result in nausea, agitation, convulsions, and sedation that can lead to unconsciousness and death from respiratory depression. In 2011, more than 2400 emergency ward admissions involved GHB.


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InternalMed_Harrison. Ketamine (Ketaset, Ketalar) is a dissociative anesthetic, similar to PCP. In veterinary medicine, it is used for brief immobilization. In clinical medicine, it is used for sedation, analgesia, and to supplement anesthesia. Ketamine increases heart rate and blood pressure, with less respiratory depression than other anesthetics. Ketamine’s popularity as a club drug appears to reflect its ability to induce a dissociative state and feelings of depersonalization, accompanied by intense hallucinations and subsequent amnesia. It can be administered orally, by smoking (usually in combination with tobacco and/or marijuana), or by IV or IM injection. Like PCP, it binds to NMDA receptors and acts as a noncompetitive NMDA antagonist. In 2011, ketamine accounted for 1550 emergency ward admissions. Ketamine has a complex profile of action and appears to be useful as an antidepressant in treatment-resistant patients and as an analgesic in patients with chronic pain.


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InternalMed_Harrison. The extent to which chronic recreational use leads to memory impair-469e-5 ment remains controversial.


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InternalMed_Harrison. Although some drug abusers may prefer a particular drug, the concurrent use of multiple drugs is common. Polydrug abuse often involves substances that may have different pharmacologic effects from the preferred drug. For example, concurrent use of such dissimilar compounds as stimulants and opioids or stimulants and alcohol is common. The diversity of reported drug use combinations suggests that achieving a change in subjective state, rather than any particular direction of change (stimulation or sedation), may be the primary reinforcer in polydrug abuse. There is also evidence that intoxication with alcohol, opiates, and cocaine is associated with increased tobacco smoking. Nicotine and cocaine enhance each other’s effects in clinical laboratory studies, and this drug combination maintains significantly higher levels of self-administration than either drug alone in preclinical models of addiction. There are relatively few controlled studies of multiple drug interactions. However, the


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InternalMed_Harrison. significantly higher levels of self-administration than either drug alone in preclinical models of addiction. There are relatively few controlled studies of multiple drug interactions. However, the combined use of cocaine, heroin, and alcohol increases the risk for toxic effects and adverse medical consequences. Similarly, some hallucinogens (MDMA, LSD) and club drugs (GHB, ketamine, flunitrazepam) are used in various combinations with an associated increase in toxic consequences.


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InternalMed_Harrison. One determinant of polydrug use patterns is the relative availability and cost of the drugs. For example, alcohol abuse, with its attendant medical complications, is one of the most serious problems encountered in former heroin addicts participating in methadone maintenance programs. Cocaine abuse often increases during methadone maintenance. The physician must recognize that perpetuation of polydrug abuse and drug dependence is not necessarily a symptom of an underlying emotional disorder. Neither alleviation of anxiety nor reduction of depression accounts for initiation and perpetuation of polydrug abuse. Severe depression and anxiety are the consequences of polydrug abuse as frequently as they are the antecedents. Interestingly, some adverse consequences of drug use may be reinforcing and contribute to the continuation of polydrug abuse.


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InternalMed_Harrison. Adequate treatment of polydrug abuse, as well as other forms of drug abuse, requires innovative intervention programs. The first step in successful treatment is detoxification, a process that may be difficult when several drugs with different pharmacologic actions (e.g., alcohol, opiates, and cocaine) have been abused. Because patients may not recall or may deny simultaneous multiple drug use, diagnostic evaluation should always include urinalysis for qualitative detection of psychoactive substances and their metabolites. Treatment of polydrug abuse often requires hospitalization or inpatient residential care during detoxification and the initial phase of drug abstinence. When possible, specialized facilities for the care and treatment of drug-dependent persons should be used. Outpatient detoxification of polydrug abuse patients is unlikely to be effective and may increase risk for dangerous medical consequences.


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InternalMed_Harrison. Drug abuse disorders often respond to effective treatment, but periods of relapse may occur unpredictably. The physician should continue to assist patients during episodes of relapse with compassion and understanding. The physician and the patient must recognize that occasional recurrent drug use is not unusual in this complex behavioral disorder. The aggregate of particulate matter, after subtracting nicotine and 2729 moisture, is referred to as tar.


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InternalMed_Harrison. The alkaline pH of smoke from blends of tobacco used for pipes and cigars allows sufficient absorption of nicotine across the oral mucosa to satisfy the smoker’s need for this drug. Therefore, smokers of pipes and cigars tend not to inhale the smoke into the lung, confining the toxic and carcinogenic exposure (and the increased rates of disease) largely to the upper airway for most users of these products. The acidic pH of smoke generated by the tobacco used in cigarettes dramatically reduces absorption of nicotine in the mouth, necessitating inhalation of the smoke into the larger surface of the lungs in order to absorb quantities of nicotine sufficient to satisfy the smoker’s addiction. The shift to using tobacco as cigarettes, with resultant increased deposition of smoke in the lung, has created the epidemic of heart disease, lung disease, and lung cancer that dominates the current disease manifestations of tobacco use.


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InternalMed_Harrison. Several genes have been associated with nicotine addiction. Some reduce the clearance of nicotine, and others have been associated with an increased likelihood of becoming dependent on tobacco and other drugs as well as a higher incidence of depression. Rates of smoking cessation have increased, and rates of nicotine addiction have decreased dramatically, since the mid-1950s, suggesting that factors other than genetics are important. It is likely that genetic susceptibility can influence the probability that adolescent experimentation with tobacco will lead to addiction as an adult.


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InternalMed_Harrison. Adult cigarette smoking prevalence has declined to about 19% in the United States, with 20–40% of those smokers not smoking every day. Male smoking prevalence is falling but remains high in most Asian countries, with increasing smoking prevalence among women in those countries. The highest rates of smoking and least cessation are observed in eastern European countries. Of particular concern is the rapidly rising smoking rate observed in the developing world. The World Health Organization Framework Convention on Tobacco Control is encouraging effective tobacco control approaches in these countries with the hope of preventing a future epidemic of tobacco-related illness. More than 400,000 individuals die prematurely each year in the United States from cigarette use; this represents almost one of every five deaths in the United States. Approximately 40% of cigarette smokers will die prematurely due to cigarette smoking unless they are able to quit.


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InternalMed_Harrison. The major diseases caused by cigarette smoking are listed in Table 470-1. The ratio of smoking-related disease rates in smokers compared to never smokers (relative risk) is greater at younger ages, particularly for coronary artery disease and stroke. At older ages, the background rate of disease in nonsmokers increases, diminishing the fractional contribution of smoking and the relative risk; however, absolute excess rates of disease mortality found in smokers compared to nonsmokers increase with increasing age. The organ damage caused by smoking and the number of smokers who die from smoking are both greater among the elderly, as one would expect from a process of cumulative injury.


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InternalMed_Harrison. Cigarette smokers are more likely than nonsmokers to develop both large-vessel atherosclerosis and small-vessel disease. Approximately 90% of peripheral vascular disease in the nondiabetic population can be attributed to cigarette smoking, as can ~50% of aortic aneurysms. In contrast, 20–30% of coronary artery disease and ~10% of ischemic and hemorrhagic strokes are caused by cigarette smoking. There is a multiplicative interaction between cigarette smoking and other cardiac risk factors such that the increment in risk produced by smoking among individuals with hypertension or elevated serum lipids is substantially greater than the increment in risk produced by smoking for individuals without these risk factors. In addition to its role in promoting atherosclerosis, cigarette smoking also increases the likelihood of myocardial infarction and sudden cardiac death by promoting platelet aggregation and vascular occlusion. Reversal of these effects on coagulation may explain the rapid


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InternalMed_Harrison. Nicotine addiction David M. Burns The use of tobacco leaf to create and satisfy nicotine addiction was introduced to Columbus by Native Americans and spread rapidly to Europe. Use of tobacco as cigarettes, however, only became popular in the twentieth century and so is a modern phenomenon, as is the 470 epidemic of disease caused by this form of tobacco use. Nicotine is the principal constituent of tobacco responsible for its addictive character, but other smoke constituents and behavioral associations contribute to the strength of the addiction. Addicted smokers regulate their nicotine intake by adjusting the frequency and intensity of their tobacco use both to obtain the desired psychoactive effects and avoid withdrawal.


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InternalMed_Harrison. Unburned cured tobacco used orally contains nicotine, carcinogens, and other toxicants capable of causing gum disease, oral and pancreatic cancers, and an increase in the risk of heart disease. When tobacco is burned, the resultant smoke contains, in addition to nicotine, more than 7000 other compounds that result from volatilization, pyrolysis, and pyrosynthesis of tobacco and various chemical additives used in making different tobacco products. The smoke is composed of a fine aerosol and a vapor phase; aerosolized particles are of a size range that results in deposition in the airways and alveolar surfaces of the lungs. Age 35–64 2.8 3.1 Age ≥65 1.5 1.6 Age 35–64 3.3 4 Age ≥65 1.6 1.5 Aortic aneurysm 6.2 7.1 Chronic airway obstruction 10.6 13.1 Lung 23.3 12.7 Larynx 14.6 13 Lip, oral cavity, pharynx 10.9 5.1 Esophagus 6.8 7.8 Bladder, other urinary organs 3.3 2.2 Kidney 2.7 1.3 Pancreas 2.3 2.3 Stomach 2 1.4 Liver 1.7 1.7


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InternalMed_Harrison. Lung 23.3 12.7 Larynx 14.6 13 Lip, oral cavity, pharynx 10.9 5.1 Esophagus 6.8 7.8 Bladder, other urinary organs 3.3 2.2 Kidney 2.7 1.3 Pancreas 2.3 2.3 Stomach 2 1.4 Liver 1.7 1.7 Colorectal 1.2 1.2 1.6 Acute myeloid leukemia 1.4 1.4 Sudden infant death syndrome 2.3 Infant respiratory distress syndrome 1.3 Low birth weight at delivery 1.8 benefit of smoking cessation for a new coronary event demonstrable among those who have survived a first myocardial infarction. This effect may also explain the substantially higher rates of graft occlusion among continuing smokers following vascular bypass surgery for cardiac or peripheral vascular disease.


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InternalMed_Harrison. Cessation of cigarette smoking reduces the risk of a second coronary event within 6–12 months; rates of first myocardial infarction and death from coronary heart disease also decline within the first few years following cessation among those with no prior cardiovascular history. After 15 years of abstinence, the risk of a new myocardial infarction or death from coronary heart disease in former smokers is similar to that for those who have never smoked.


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InternalMed_Harrison. Tobacco smoking causes cancer of the lung; oral cavity; naso-, oro-, and hypopharynx; nasal cavity and paranasal sinuses; larynx; esophagus; stomach; pancreas; liver (hepatocellular); colon and rectum; kidney (body and pelvis); ureter; urinary bladder; and uterine cervix, and also causes myeloid leukemia. There is evidence suggesting that cigarette smoking may play a role in increasing the risk of breast cancer. There does not appear to be a causal link between cigarette smoking and cancer of the endometrium, and there is a lower risk of uterine cancer among postmenopausal women who smoke. The risks of cancer increase with the increasing number of cigarettes smoked per day and with increasing duration of smoking. Additionally, there are synergistic interactions between cigarette smoking and alcohol use for cancer of the oral cavity and esophagus. Several occupational exposures synergistically increase lung cancer risk among cigarette smokers, most notably occupational asbestos and


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InternalMed_Harrison. and alcohol use for cancer of the oral cavity and esophagus. Several occupational exposures synergistically increase lung cancer risk among cigarette smokers, most notably occupational asbestos and radon exposure.


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InternalMed_Harrison. Cessation of cigarette smoking reduces the risk of developing cancer relative to continuing smoking, but even 20 years after cessation, there is a modest persistent increased risk of developing lung cancer.


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InternalMed_Harrison. Cigarette smoking is responsible for 90% of chronic obstructive pulmonary disease. Within 1–2 years of beginning to smoke regularly, many young smokers will develop inflammatory changes in their small airways, although lung function measures of these changes do not predict development of chronic airflow obstruction. After 20 years of smoking, pathophysiologic changes in the lungs develop and progress proportional to smoking intensity and duration. Chronic mucous hyperplasia of the larger airways results in a chronic productive cough in as many as 80% of smokers >60 years of age. Chronic inflammation and narrowing of the small airways and/or enzymatic digestion of alveolar walls resulting in pulmonary emphysema can result in reduced expiratory airflow sufficient to produce clinical symptoms of respiratory limitation in ~15–25% of smokers.


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InternalMed_Harrison. Changes in the small airways of young smokers will reverse after 1–2 years of cessation. There may also be a small increase in measures of expiratory airflow following cessation among individuals who have developed chronic airflow obstruction, but the major change following cessation is a slowing of the rate of decline in lung function with advancing age rather than a return of lung function toward normal.


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InternalMed_Harrison. Cigarette smoking is associated with several maternal complications of pregnancy: premature rupture of membranes, abruptio placentae, and placenta previa; there is also a small increase in the risk of spontaneous abortion among smokers. Infants of smoking mothers are more likely to experience preterm delivery, have a higher perinatal mortality rate, be small for their gestational age, and have higher rates of infant respiratory distress syndrome; they are more likely to die of sudden infant death syndrome and appear to have a developmental lag for at least the first several years of life. Smoking delays healing of peptic ulcers; increases the risk of developing diabetes, active tuberculosis, rheumatoid arthritis, osteoporosis, senile cataracts, and neovascular and atrophic forms of macular degeneration; and results in premature menopause, wrinkling of the skin, gallstones and cholecystitis in women, and male impotence.


InternalMed_Harrison

InternalMed_Harrison. Long-term exposure to environmental tobacco smoke increases the risk of lung cancer and coronary artery disease among nonsmokers. It also increases the incidence of respiratory infections, chronic otitis media, and asthma in children and causes exacerbation of asthma in children. Some evidence suggests that environmental tobacco smoke exposure may increase the risk of premenopausal breast cancer. Patients who continue to smoke during treatment for cancer with chemotherapy or radiation have poorer outcomes and reduced survival.


InternalMed_Harrison

InternalMed_Harrison. Cigarette smoking may interact with a variety of other drugs (Table 470-2). Cigarette smoking induces the cytochrome P450 system, which may alter the metabolic clearance of drugs such as theophylline. This may result in inadequate serum levels in smokers as outpatients when the dosage is established in the hospital under nonsmoking conditions. Correspondingly, serum levels may rise when smokers are hospitalized and not allowed to smoke. Smokers may also have higher first-pass clearance for drugs such as lidocaine, and the stimulant effects of nicotine may reduce the effect of benzodiazepines or beta blockers.


InternalMed_Harrison

InternalMed_Harrison. Other major forms of tobacco use are moist snuff deposited between the cheek and gum, chewing tobacco, pipes and cigars, and recently bidi (tobacco wrapped in tendu or temburni leaf; commonly used in India), clove cigarettes, and water pipes. Oral tobacco use leads to gum disease and can result in oral and pancreatic cancer as well as heart disease, with dramatic differences in the risks evident for products used in Africa and Asia as compared to those in the United States and Europe. aClinical implications uncertain.


InternalMed_Harrison

InternalMed_Harrison. aClinical implications uncertain. All forms of burned tobacco generate toxic and carcinogenic smoke similar to that of cigarette smoke. The differences in disease consequences of use relate to frequency of use and depth of inhalation. The risk of upper airway cancers is similar among cigarette, pipe, and cigar smokers, whereas those who have smoked only pipes and cigars have a much lower risk of lung cancer, heart disease, and chronic obstructive pulmonary disease. However, cigarette smokers who switch to pipes or cigars do tend to inhale the smoke, increasing their risk; and it is likely that comparable inhalation and frequency of exposure to tobacco smoke from any of these forms of tobacco use will lead to comparable disease outcomes.


InternalMed_Harrison

InternalMed_Harrison. A resurgence of cigar, bidi, and water pipe use among adolescents of both genders has raised concerns that these older forms of tobacco use are once again causing a public health problem. A variety of devices are currently sold that deliver nicotine by electronically heating materials containing nicotine, the so-called electronic cigarettes. Although these devices are marketed as substitutes for cigarettes and as cessation tools, the composition of the vapor and nicotine delivery varies widely from product to product, raising questions of both safety and efficacy in the absence of regulatory oversight.


InternalMed_Harrison

InternalMed_Harrison. Filtered cigarettes with lower machine-measured yields of tar and nicotine commonly use ventilation holes in the filters and other engineering designs to artificially lower the machine measurements. Smokers compensate for the lowered nicotine delivery by changing the manner in which they puff on the cigarette or the number of cigarettes smoked per day, and tar and nicotine deliveries are not reduced with use of these products. Cigarette design changes that reduce machine-measured tar and nicotine lead to deeper inhalation of the smoke and an increase in 2731 the carcinogenicity of the smoke inhaled by smokers. The presentation of more carcinogenic smoke to the alveolar portions of the lung has resulted in an increase in the risk of lung cancer, and possibly chronic obstructive pulmonary disease, among smokers over the past six decades. This change in cigarette product is also one cause of the dramatic rise in rates of adenocarcinoma of the lung observed over the past half century.


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InternalMed_Harrison. disease, among smokers over the past six decades. This change in cigarette product is also one cause of the dramatic rise in rates of adenocarcinoma of the lung observed over the past half century. There has been no increase in risk of lung cancer or adenocarcinoma of the lung in never smokers over time.


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InternalMed_Harrison. The process of stopping smoking is commonly a cyclical one, with the smoker sometimes making multiple attempts to quit and failing before finally being successful. Approximately 70–80% of smokers would like to quit smoking. More than one-half of current smokers attempted to quit in the last year, but only 6% quit for 6 months, and only 3% remain abstinent for 2 years. Clinician-based smoking interventions should repeatedly encourage smokers to try to quit and to use different forms of cessation assistance with each new cessation attempt rather than focusing exclusively on immediate cessation at the time of the first visit. Advice from a physician to quit smoking, particularly at the time of an acute illness, is a powerful trigger for cessation attempts, with up to half of patients who are advised to quit making a cessation effort. Other triggers include the cost of cigarettes, media campaigns, and changes in rules to restrict smoking in the workplace.


InternalMed_Harrison

InternalMed_Harrison. All patients should be asked whether they smoke, how much they smoke, how long they have smoked, their past experience with quitting, and whether they are currently interested in quitting. Intensity of smoking and smoking within 30 min of waking are useful measures of the intensity of nicotine addiction. Even those who are not interested in quitting should be encouraged and motivated to quit; provided a clear, strong, and personalized message by the clinician that smoking Ask: Systematically identify all tobacco users at every visit Advise: Strongly urge all smokers to quit Identify smokers willing to quit Assist the patient in quitting Arrange follow-up contact First-line therapies Nicotine gum (1.5) Nicotine patch (1.9) Nicotine nasal inhaler (2.7) Nicotine oral inhaler (2.5) Nicotine lozenge (2.0) Bupropion (2.1) Varenicline (2.7) Second-line therapies Clonidine (2.1) Nortriptyline (3.2) Physician or other medical personnel counseling (10 min) (1.3)


InternalMed_Harrison

InternalMed_Harrison. Second-line therapies Clonidine (2.1) Nortriptyline (3.2) Physician or other medical personnel counseling (10 min) (1.3) Intensive smoking cessation programs (at least 4–7 sessions of 20to 30-min duration lasting at least 2 and preferably 8 weeks) (2.3) Clinic-based smoking status identification system (3.1) Counseling by nonclinicians and social support by family and friends Telephone counseling (1.2) aNumerical value following the intervention is the multiple for cessation success compared to no intervention.


InternalMed_Harrison

InternalMed_Harrison. 22 is an important health concern; and offered assistance if they become interested in quitting in the future. Many of those not currently expressing an interest in quitting may nevertheless make an attempt to quit in the subsequent year. For those interested in quitting, a quit date should be negotiated, usually not the day of the visit but within the next few weeks, and a follow-up contact by office staff around the time of the quit date should be provided. There is a relationship between the amount of assistance a patient is willing to accept and the success of the cessation attempt. There are a variety of nicotine-replacement products, including over-the-counter nicotine patches, gum, and lozenges, as well as nicotine nasal and oral inhalers available by prescription. These products can be used for up to 3–6 months, and some products are formulated to allow a gradual step-down in dosage with increasing duration of abstinence. Antidepressants such as bupropion (300 mg in divided


InternalMed_Harrison

InternalMed_Harrison. can be used for up to 3–6 months, and some products are formulated to allow a gradual step-down in dosage with increasing duration of abstinence. Antidepressants such as bupropion (300 mg in divided doses for up to 6 months) have also been shown to be effective, as has varenicline, a partial agonist for the nicotinic acetylcholine receptor (initial dose 0.5 mg daily increasing to 1 mg twice daily at day 8; treatment duration up to 6 months). Severe psychiatric symptoms, including suicidal ideation, have been reported with varenicline, resulting in a U.S. Food and Drug Administration–mandated warning and a recommendation for closer therapeutic supervision, but evidence to establish the frequency of these responses and the specificity of their association with varenicline remains unclear. Some evidence supports the combined use of nicotine-replacement therapy (NRT) and antidepressants as well as the use of gum or lozenges for acute cravings in patients using patches. Pretreatment with


InternalMed_Harrison

InternalMed_Harrison. Some evidence supports the combined use of nicotine-replacement therapy (NRT) and antidepressants as well as the use of gum or lozenges for acute cravings in patients using patches. Pretreatment with antidepressants or varenicline is recommended for 1–2 weeks prior to the quit date, and pretreatment with nicotine-replacement products is also being explored, as is longer duration of nicotine replacement as a maintenance therapy for those who are unsuccessful in quitting with a shorter duration of use. NRT is provided in different dosages, with higher doses being recommended for more intense smokers. Clonidine or nortriptyline may be useful for patients who have failed on first-line pharmacologic treatment or who are unable to use other therapies. Antidepressants are more effective in those with a history of depression symptoms. Current recommendations are to offer pharmacologic treatment, usually with NRT or varenicline, to all who will accept it and to provide counseling and other


InternalMed_Harrison

InternalMed_Harrison. with a history of depression symptoms. Current recommendations are to offer pharmacologic treatment, usually with NRT or varenicline, to all who will accept it and to provide counseling and other support as a part of the cessation attempt. There are some data to suggest that longer term use of NRT may enable cessation in some smokers who are unable to quit with shorter duration use and that some individuals are able to achieve abstinence from tobacco through use of NRT chronically. Cessation advice alone by a physician or his or her staff is likely to increase success compared with no intervention; a more comprehensive approach with advice, pharmacologic assistance, and counseling can increase cessation success nearly threefold. Incorporation of cessation assistance into a practice requires a change of the care delivery infrastructure. Simple changes include (1) adding questions about smoking and interest in cessation on patient-intake questionnaires, (2) asking patients whether they


InternalMed_Harrison

InternalMed_Harrison. a change of the care delivery infrastructure. Simple changes include (1) adding questions about smoking and interest in cessation on patient-intake questionnaires, (2) asking patients whether they smoke as part of the initial vital sign measurements made by office staff, (3) listing smoking as a problem in the medical record, and (4) automating follow-up contact with the patient on the quit date. These changes are essential to institutionalizing smoking intervention within the practice setting; without this institutionalization, the best intentions of physicians to intervene with their patients who smoke are often lost in the time crush of a busy practice.


InternalMed_Harrison

InternalMed_Harrison. Approximately 85% of individuals who become cigarette smokers initiate the behavior during adolescence. Factors that promote adolescent initiation are parental or older-sibling cigarette smoking, tobacco advertising and promotional activities, the availability of cigarettes, and the social acceptability of smoking. The need for an enhanced self-image and to imitate adult behavior is greatest for those adolescents who have the least external validation of their self-worth, which may explain in part the enormous differences in adolescent smoking prevalence by socioeconomic and school performance strata.


InternalMed_Harrison

InternalMed_Harrison. Prevention of smoking initiation must begin early, preferably in the elementary school years. Physicians who treat adolescents should be sensitive to the prevalence of this problem even in the pre-teen population. Physicians should ask all adolescents whether they have experimented with tobacco or currently use tobacco, reinforce the fact that most adolescents and adults do not smoke, and explain that all forms of tobacco are both addictive and harmful.


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InternalMed_Harrison. Neuropsychiatric Illnesses in War Veterans Charles W. Hoge Neuropsychiatric sequelae are common in combat veterans. Advances in personal protective body armor, armored vehicles, battlefield resus-471e citation, and the speed of evacuation to tertiary care have considerably improved the survivability of battlefield injuries, resulting in a greater awareness of the “silent wounds” associated with service in a combat zone. Although psychiatric and neurologic problems have been well documented in veterans of prior wars, the conflicts in Iraq and Afghanistan that began after September 11, 2001, were unique in terms of the level of commitment by the U.S. Department of Defense (DoD) and Department of Veterans Affairs (VA), Veterans Health Administration (VHA) to support research as the wars unfolded and to use that knowledge to guide population-level screening, evaluation, and treatment initiatives.


InternalMed_Harrison

InternalMed_Harrison. The Iraq and Afghanistan conflicts produced over 2.5 million combat veterans, many of whom have received or will need care in government and civilian medical facilities in the future. Studies clearly showed that service in the Iraq and Afghanistan theaters was associated with significantly elevated rates of mental disorders. Two conditions in particular have been labeled the signature injuries related to these wars: posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI)—also known as concussion. Although particular emphasis will be given in this chapter to PTSD and concussion/mTBI, it is important to understand that the neuropsychiatric sequelae of war are much broader than these two conditions. Wartime service is associated with a number of health concerns that coexist and overlap, and a multidisciplinary patient-centered approach to care is necessary.


InternalMed_Harrison

InternalMed_Harrison. Service members involved in the Iraq and Afghanistan wars faced multiple deployments to two very different high-intensity combat theaters, and for many veterans, the cumulative strain negatively impacted health, marriages, parenting, educational goals, and civilian occupations. The stresses of service in these conflicts also led to a significant increase in rates of suicide in personnel from the two branches of service involved in the greatest level of ground combat (U.S. Army, Marines).


InternalMed_Harrison

InternalMed_Harrison. Service in a war zone can involve extreme physical stress in austere environments, prolonged sleep deprivation, physical injury, exposure to highly life-threatening events, and hazards such as explosive devices, sniper fire, ambushes, indirect fire from rockets and mortars, and chemical pollutants. Certain events, such as loss of a close friend in combat, leave indelible scars. All of these experiences have additive effects on health, likely mediated through physiologic mechanisms involving dysregulation of neuroendocrine and autonomic nervous system (ANS) functions.


InternalMed_Harrison

InternalMed_Harrison. Veterans of virtually all wars have reported elevated rates of generalized and multisystem physical, cognitive, and psychological health concerns that often become the focus of treatment months or years after returning home. These multisystem health concerns include sleep disturbance, memory and concentration problems, headaches, musculoskeletal pain, gastrointestinal symptoms (including gastroesophageal reflux), residual effects of wartime injuries, fatigue, anger, hyper-arousal symptoms, high blood pressure, rapid heart rate (sometimes associated with panic symptoms), sexual problems, and symptoms associated with PTSD and depression. In order to provide optimal care to veterans with these symptoms, it is important to understand how the symptoms interrelate and to consider the possibility that there may be underlying combat-related physiologic effects.


InternalMed_Harrison

InternalMed_Harrison. The overlapping and multisystem health concerns reported by warriors from every generation have been given different labels and have led to debates among medical professionals as to whether these are mediated primarily by physical or psychological causes. For example, World War I produced extensive debate about whether “shell shock,” diagnosed in more than 80,000 British soldiers, was neurologic (“commotional” from the brain being shaken in the skull by concussive blasts) or psychological (“emotional” or “neurasthenia”) in origin. World War II veterans were said to suffer from “battle fatigue,” Korean War veterans developed “combat stress reactions,” and Vietnam veterans developed the “post-Vietnam syndrome.” The role of environmental exposure (e.g., Agent Orange) and psychological causes (e.g., PTSD, depression, substance use disorders) continue to be debated.


InternalMed_Harrison

InternalMed_Harrison. Gulf War I (Operation Desert Storm), following the Iraqi invasion of Kuwait in 1990, led to extensive debates as to whether Gulf War syndrome, also known as multisystem illness, was best explained by environmental exposures (e.g., oil fires, depleted uranium, nerve gas, pesticides, multiple vaccinations) or the psychological stress of deployment to a war zone where there was anticipation of high casualty rates from chemical and biologic weapons, repeated stressful alerts, and training exercises involving the use of impermeable full-body protective uniforms (made from rubber, vinyl, charcoal-impregnated polyurethane, and other materials) in desert conditions under extreme temperatures. Although no clinical syndrome was ever definitively confirmed among the nearly 1 million service members who deployed in 1990–1991, studies consistently found that military personnel who served in the Gulf experienced elevations in generalized symptoms across all health domains (e.g., physical,


InternalMed_Harrison

InternalMed_Harrison. members who deployed in 1990–1991, studies consistently found that military personnel who served in the Gulf experienced elevations in generalized symptoms across all health domains (e.g., physical, cognitive, neurologic, psychological) compared with service members who deployed elsewhere or did not deploy. In addition, there is good evidence that deployment to the Persian Gulf region during this period was associated with subsequent development of PTSD; other psychiatric disorders including generalized anxiety disorder, depression, and substance use disorders (Chap. 467); functional gastrointestinal symptoms such as irritable bowel syndrome (Chap. 352); and chronic fatigue syndrome (Chap. 464e).


InternalMed_Harrison

InternalMed_Harrison. The conflicts in Iraq and Afghanistan led to similar debates as to whether postwar symptoms such as headaches, irritability, sleep disturbance, dizziness, and concentration problems are best attributed to concussion/mTBI or to PTSD. Numerous studies showed that either PTSD or depression explained the majority of the postdeployment “postconcussive” symptoms attributed to concussion/mTBI, a finding not well received by many experts in traumatic brain injury (TBI) but consistent with civilian studies on risk factors for developing persistent symptoms after concussion. As in past wars, the polarized nature of the debate largely focused on only the two conditions of PTSD and concussion/mTBI, which has interfered with full appreciation of how the large spectrum of deployment-related health concerns interrelate and of the clinical implications for designing effective evaluation and treatment strategies.


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InternalMed_Harrison. Veterans understandably may become angry at the suggestion that their postwar health concerns could be “stress-related” or psychological, and thus it is necessary for primary care professionals to be able to discuss the physical toll that war-zone service has on the body, the generalized nature of war-related health concerns, and the likely underlying physiologic neuroendocrine and ANS contributors. Mental health specialists also need to be able to reinforce this message and understand the important role they have in promoting physical health through addressing comorbid health concerns.


InternalMed_Harrison

InternalMed_Harrison. PTSD (Chap. 466) is the most common mental disorder documented following war-zone service. Studies from the conflicts in Iraq and Afghanistan found PTSD prevalence rates of 2–6% before deployment (comparable to civilian general population samples) and rates of 6–20% after deployment, depending primarily on the level of combat frequency and intensity. Many other veterans experience subclinical PTSD symptoms after war-zone service, sometimes termed posttraumatic stress (PTS) or combat stress. These subclinical symptoms can contribute to distress and affect health, even if overall functioning is not as impaired as in the full disorder.


InternalMed_Harrison

InternalMed_Harrison. The definition of PTSD was modified in the fifth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (2013), although most individuals who had PTSD diagnosed according to the previous criteria also meet the definition under the new criteria. PTSD is defined as persistent (>1 month) symptoms occurring after a traumatic event (involving exposure to actual or threatened death, serious injury, or sexual assault). The symptoms must be associated with significant distress or impairment in social or occupational functioning. Symptoms are grouped into four categories: (1) intrusion/reexperiencing symptoms in which the person has nightmares, flashbacks, or intrusive (often involuntary) memories connected with the traumatic event; (2) avoidance symptoms where the person avoids distressing memories or people, places, situations, or other stimuli that serve as reminders of the traumatic event (for example, a crowded mall that triggers heightened


InternalMed_Harrison

InternalMed_Harrison. where the person avoids distressing memories or people, places, situations, or other stimuli that serve as reminders of the traumatic event (for example, a crowded mall that triggers heightened alertness to threat); (3) negative alterations of cognitions or mood (for example, feeling detached or losing interest in things that previously brought enjoyment); and (4) hyperarousal symptoms in which the person is physiologically revved up, hyperalert, startles easily, and experiences sleep disturbance, anger, and/or concentration problems. Although PTSD is a clinical symptom-based case definition, it is best to think of PTSD not as an emotional or psychological/psychiatric condition, but rather as a physiologically-based response to life-threatening trauma that is associated with physical, cognitive, emotional, and psychological symptoms.


InternalMed_Harrison

InternalMed_Harrison. PTSD has strong biologic correlates, based in fear-conditioning responses to threat and responses to extreme stress involving neuroendocrine dysregulation and ANS reactivity. Numerous studies have shown that PTSD is highly correlated with generalized physical and cognitive symptoms—including hypertension, chronic pain, and cardiovascular disease—as well as cell-mediated immune dysfunction and shortened life expectancy. PTSD is frequently comorbid with other mental disorders such as major depressive disorder, generalized anxiety, substance use disorders, and risky behaviors (e.g., aggression, accidents); it has been estimated that up to 80% of patients with PTSD exhibit one or more comorbid conditions. Misuse of alcohol or substances is most prevalent, often reflecting self-medication. PTSD is also associated with tolerance and withdrawal symptoms related to prescription pain and sleep medications, as well as nicotine dependence (Chap. 470).


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InternalMed_Harrison. Clinicians should understand how to provide meaningful psychological education in a way that resonates with veterans who may have PTSD symptoms as a result of their military service. There is an important occupational context to consider, which is also applicable to trauma exposures that occur in other first responder professions, such as law enforcement officers and firefighters. Service members and other first responders are trained to respond to traumatic events and effectively learn to override automatic fight-or-flight reflexes in order to carry out their duties. Reactions that are labeled as symptoms of PTSD are based on adaptive survival responses that are beneficial in a combat environment. For example, physiologic hyperarousal, use of anger, and being able to shut down other emotions are very useful skills in combat and can be present even prior to traumatic events during tough realistic training. It is natural for these responses to persist after returning home, and the


InternalMed_Harrison

InternalMed_Harrison. emotions are very useful skills in combat and can be present even prior to traumatic events during tough realistic training. It is natural for these responses to persist after returning home, and the label of a “disorder” only gets applied when the responses that persist significantly impair functioning.


InternalMed_Harrison

InternalMed_Harrison. TBI (Chap. 457e) gained increased recognition during the conflicts in Iraq and Afghanistan because of the widespread exposure of troops to improvised explosive devices. Many veterans of Iraq and Afghanistan reported experiencing multiple concussions during deployments, and many also reported ignoring concussions and not seeking treatment at the time of injury in order to remain with their unit. However, these legitimate concerns were also counterbalanced and challenged by high prevalence estimates of deployment-related TBI that did not distinguish concussion/mTBI from moderate or severe TBI; data from animal models of blast exposure that did not necessarily extrapolate to human experiences on the battlefield; neuroimaging studies (e.g., diffusion tensor imaging) that attributed putative abnormalities to blast exposure but lacked adequate control comparisons; and fear-provoking speculation that repetitive blast exposure may lead to future dementia, based largely on case series of


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InternalMed_Harrison. abnormalities to blast exposure but lacked adequate control comparisons; and fear-provoking speculation that repetitive blast exposure may lead to future dementia, based largely on case series of professional athletes (e.g., boxers, football players) exposed to highly repetitive injuries linked to chronic traumatic encephalopathy (previously termed dementia pugilistica) (Chap. 444e).


InternalMed_Harrison

InternalMed_Harrison. TBI includes closed and penetrating head injuries; closed head injuries are categorized as mild (mTBI or concussion), moderate, or severe based on the duration of loss of consciousness, duration of posttraumatic amnesia, and the Glasgow coma score (GCS) (see Table 457e-2). Several studies have estimated that 10–20% of all military personnel deployed to Iraq or Afghanistan sustained one or more concussion/ mTBI events during deployment, most commonly from exposure to blasts; however, concussion injuries are also common in nondeployed environments from sports, training (e.g., hand-to-hand combatives), and accidents.


InternalMed_Harrison

InternalMed_Harrison. Although there is a neurophysiologic continuum of injury, there are stark clinical and epidemiologic distinctions between concussion/ mTBI and moderate or severe TBI (Table 471e-1). Concussion/mTBI is defined as a blow or jolt to the head that results in brief loss of consciousness (LOC) for <30 min (most commonly, only a few seconds to minutes), posttraumatic amnesia (PTA) of <24 h (most commonly <1 h), or transient alteration in consciousness (AOC) without LOC. The majority of concussions in Iraq or Afghanistan involved AOC without LOC or PTA (which soldiers may refer to as getting their “bell rung”). GCSs in concussion/mTBI are usually normal (15 out of 15). Concussion is treated with rest to allow the brain time to heal, and Loss of consciousness <30 min (usually a few ≥30 min to seconds to minutes) indefinite Altered consciousness <24 h (usually <30 min) ≥24 h to indefinite Posttraumatic amnesia <24 h (usually <30 min) ≥24 h to indefinite


InternalMed_Harrison

InternalMed_Harrison. Altered consciousness <24 h (usually <30 min) ≥24 h to indefinite Posttraumatic amnesia <24 h (usually <30 min) ≥24 h to indefinite Glasgow coma score 13–15 (usually 15) As low as 3 Clinical usefulness of neu-Usually inconclusive Essential and rocognitive testing after Neuronal cell damage Metabolic/ionic processes Direct injury effects associated with axonal plus metabolic/ionic swelling, which can lead effects to disconnection Sequelae, natural history, Full recovery expected Based directly on and recovery in majority of individuals; injury characteristics; no consensus on natural may be severely history; the percentage disabling who develop persistent symptoms is debated


InternalMed_Harrison

InternalMed_Harrison. Predictors of persistent Intensely debated; risk Not debated; prepostconcussive factors found to be most dictors are directly symptoms or disability predictive include psy-related to injury chiatric conditions (e.g., severity and clinical depression, PTSD) and progress with rehanegative expectations bilitation treatment Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PTSD, post-traumatic stress disorder. it almost never resulted in air evacuation from Iraq or Afghanistan unless there were other associated injuries.


InternalMed_Harrison

InternalMed_Harrison. it almost never resulted in air evacuation from Iraq or Afghanistan unless there were other associated injuries. In contrast, moderate, severe, or penetrating TBI, which is estimated to account for <1% of all battlefield head injuries in Iraq and Afghanistan, is characterized by LOC ≥30 min (up to permanent coma), PTA ≥24 h (also may be permanent), and GCSs as low as 3 (the minimum value). These virtually always result in air evacuation from the battlefield and carry a significant risk of severe long-term neurologic impairment and requirement for rehabilitative care.


InternalMed_Harrison

InternalMed_Harrison. Symptoms following concussion/mTBI can include headache; fatigue; concentration, memory, or attention problems; sleep disturbance; irritability; balance difficulties; and tinnitus, among other symptoms. Recovery is usually rapid, with symptoms usually resolving in a few hours to days, but in a small percentage of patients, symptoms may persist for a longer period or become chronic (referred to as persistent “postconcussive symptoms” [PCS]).


InternalMed_Harrison

InternalMed_Harrison. Establishing a clear causal connection between a deployment concussion injury and persistent PCS months or years after return from deployment has been difficult and often confounded by other postwar conditions that are associated with the same symptoms, including injuries not involving the head, other medical disorders, sleep disorders, PTSD, depression, grief, substance use disorders, chronic pain, and the generalized physiologic effects of wartime service. Contributing to the difficulty in establishing causation is the fact that the concussion/ mTBI case definition refers only to the acute injury event and lacks symptoms, time course, or impairment; case definitions for persistent postconcussion syndrome have failed tests of validation. Numerous studies found that PTSD and depression were much stronger predictors of PCS and objective neuropsychological impairment after combat deployment than concussions/mTBIs, and one study even found that bereavement (particularly related to the


InternalMed_Harrison

InternalMed_Harrison. were much stronger predictors of PCS and objective neuropsychological impairment after combat deployment than concussions/mTBIs, and one study even found that bereavement (particularly related to the death of a team member) was as strong a predictor of postdeployment symptoms and poor general health as were symptoms of depression or PTSD. These data do not minimize the importance of concussion/mTBI per se, but highlight the complex interrelationships of war-related health problems and the relatively lower importance of concussion/mTBI in overall postdeployment health than is generally thought.


InternalMed_Harrison

InternalMed_Harrison. Studies of veterans who sustained concussions in Iraq or Afghanistan have suggested that blast mechanisms produce similar clinical outcomes as nonblast mechanisms, in contrast to expectations based on some animal models. An explosion can produce serious injury from rapid atmospheric pressure changes (primary blast wave mechanism), as well as from munition fragments/flying debris (secondary blast mechanism) or being thrown into a hard object (tertiary blast mechanism). Secondary and tertiary mechanisms are similar to other mechanical mechanisms of concussions sustained during accidents. It is likely that blast physics explains differences between human clinical studies and experimental animal studies. Because the distribution of munition fragments usually extends well beyond the distribution of the primary blast wave in most explosions, the possibility of a unique head injury solely from the primary blast wave in otherwise uninjured service members appears to be very low.


InternalMed_Harrison

InternalMed_Harrison. Multisystem health problems that lack clear case definitions do not lend themselves well to uniform public health strategies such as screening. Nevertheless, mass population screening for concussion/ mTBI was mandated for all U.S. service members returning from Iraq or Afghanistan and all veterans presenting for care at VA health care facilities. These screening processes attempt to apply the acute concussion case definition (lacking symptoms, time course, or impairment) months or years after injury, and often involve questions that encourage patients and clinicians to make a direct link between current symptoms and past head injuries that likely have very little to do with the current symptoms. These screening approaches led to sharp criticism that they were encouraging clinicians to misattribute common postwar symptoms to concussion/mTBI. Nevertheless, the screening processes have persisted and are part of an extensive specialty structure of care erected in both the DoD and VA to


InternalMed_Harrison

InternalMed_Harrison. common postwar symptoms to concussion/mTBI. Nevertheless, the screening processes have persisted and are part of an extensive specialty structure of care erected in both the DoD and VA to address health concerns attributed to concussions/mTBIs.


InternalMed_Harrison

InternalMed_Harrison. Management of postwar physical and cognitive health concerns 471e-3 is largely symptom focused and ideally carried out within primary care–based structures of care. Studies suggest that optimal strategies for treatment of multisymptom health concerns include regularly scheduled primary care visits with brief physical exam at each visit, protecting patients from unnecessary diagnostic tests and nonevidence-based interventions, judicious use of consultations that protects patients from unnecessary specialty referrals, care/case management, and communication that enhances positive expectations for recovery. Concussion research has shown that negative expectations are one of the most important risk factors for persistent symptoms.


InternalMed_Harrison

InternalMed_Harrison. Although many questions remain regarding the long-term health effects of concussions (particularly multiple concussions) sustained during deployment, these are important battlefield injuries that require careful attention. However, they need to be addressed within the context of a much broader approach to other war-related health concerns.


InternalMed_Harrison

InternalMed_Harrison. Stigma and other barriers to care add to the complexity of treating veterans. Despite extensive education efforts among military leaders and service members, perceptions of stigma showed little change over the many years of war; warriors are often concerned that they will be perceived as weak by peers or leaders if they seek care. Studies have shown that less than one-half of service members and veterans with serious mental health problems receive needed care, and upwards of half of those who begin treatment drop out before receiving an adequate number of encounters. Many factors contribute to this, including the pervasive nature of stigma in society in general (particularly among men), the critical importance of group cohesiveness of military teams, the nature of avoidance symptoms in PTSD, perceptions of self-sufficiency (e.g., “I can handle problems on my own”), and sometimes negative perceptions of mental health care and skepticism that mental health professionals will be able to


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InternalMed_Harrison. perceptions of self-sufficiency (e.g., “I can handle problems on my own”), and sometimes negative perceptions of mental health care and skepticism that mental health professionals will be able to help.


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InternalMed_Harrison. APPROACH TO THE PATIENT: evaluation of Veterans with Neuropsychiatric health Concerns


InternalMed_Harrison

InternalMed_Harrison. Evaluation should begin with a careful occupational history as part of the routine medical evaluation; this includes the number of years served, military occupation, deployment locations and dates, illnesses or injuries resulting from service, and significant combat traumatic experiences that may be continuing to affect the individual (Table 471e-2). The clinician should evaluate the degree to which the patient’s current difficulties reflect the normal course of readjusting after the intense occupational experience of combat. It is helpful to reinforce the many strengths associated with being a professional in the military: courage, honor, service to country, resiliency in combat, leadership, ability to work in a cohesive workgroup with peers, and demonstrated skills in handling extreme stress, as well as the fact that reactions that interfere with functioning back home may have their roots in beneficial adaptive physiologic processes.


InternalMed_Harrison

InternalMed_Harrison. One of the challenges with current medical practice is that there may be multiple providers with different clinical perspectives. Care should be coordinated through the primary care clinician, with the assistance of a care manager if needed. It is particularly important to continually evaluate all medications prescribed by other practitioners and assess each for possible long-term side effects, dependency, or drug-drug interactions. Particular attention should be given to the level of chronic pain and sleep disturbance, self-medication with alcohol or substances, chronic use of nonsteroidal anti-inflammatory agents (which can contribute to rebound headaches or pain), chronic use of sedative-hypnotic agents, chronic use of narcotic pain medications, and the impact of war-related health concerns on social and occupational functioning.


InternalMed_Harrison

InternalMed_Harrison. Occupational Deployment locations and dates, combat experiences or context of health other deployment stressors, frequent moves, separations concerns from family, impact of deployment on civilian occupa Medical problems History of deployment-related injuries (including con-during deploy-cussions), environmental exposures, sleep pattern durment ing deployment, use of caffeine/energy drinks, use of Current medical Current symptoms, level of chronic pain, sleep problems, history evidence of persistent physiologic hyperarousal (hypertension, tachycardia, panic symptoms, concentration/ memory problems, irritability/anger, sleep disturbance), chronic use of caffeine or energy drinks, chronic use of nonsteroidal anti-inflammatory medications, chronic use of narcotic pain medications, chronic use of nonbenzodiazepine sedative-hypnotic medications, chronic use of benzodiazepines for sleep or anxiety


InternalMed_Harrison

InternalMed_Harrison. Mental health Screen for PTSD, major depressive disorder; ask about assessment suicidal or homicidal ideation, intent, or plans, as well as access to firearms Alcohol/substance Screen for alcohol and substance use disorders, quantity use and frequency of use, and evidence of tolerance; inquire about “self-medication” (e.g., use of alcohol to sleep, “calm down,” or “forget” war-zone experiences) Functional impair-Impact of current symptoms on social and occupational ment functioning; high-risk behaviors (e.g., drinking and driving, reckless driving, aggression) Social support, Level of social support; readjustment stress on spouse, impact of military children, or other family members service on marriage and family Abbreviation: PTSD, posttraumatic stress disorder.


InternalMed_Harrison

InternalMed_Harrison. Abbreviation: PTSD, posttraumatic stress disorder. Screening for PTSD, depression, and alcohol misuse should be performed routinely in all combat veterans. Three screening tools, which are in the public domain, have been validated for use in primary care, and have been used frequently in veterans: the four-question Primary Care PTSD Screen (PC-PTSD), the two-question Patient Health Questionnaire (PHQ-2), and the three-question Alcohol Use Disorders Identification Test-Consumption module (AUDIT-C) (Table 471e-3).


InternalMed_Harrison

InternalMed_Harrison. Because the clinical definition of an acute concussion/mTBI does not include symptoms, time course, or impairment, there is currently no clinically validated screening process for use months or years after injury. However, it is important to gather information about all injuries sustained during deployment, including any that resulted in loss or alteration of consciousness or loss of memory around the time of the event. If concussion injuries have occurred, the clinician should assess the number of such injuries, the duration of time unconscious, and injury mechanisms. This should be followed by an assessment of any PCS immediately following the injury event (e.g., headaches, dizziness, tinnitus, nausea, irritability, insomnia, and concentration or memory problems) and the severity and duration of such symptoms.


InternalMed_Harrison

InternalMed_Harrison. Given the interrelationship of postwar health concerns, care needs to be carefully coordinated. Specific techniques that have been found to be helpful include scheduling regular primary care visits instead of as-needed visits, establishing care management, using good risk-communication principles, establishing a consultative step care approach that draws on the expertise of specialists in a collaborative manner (instead of immediately referring the patient to a specialist and relying on the specialist to provide care), and having behavioral health support directly within primary care clinics (both for referrals and to provide education and support to primary care professionals prescribing treatment for depression or PTSD).


InternalMed_Harrison

InternalMed_Harrison. It is important not to implicitly or explicitly convey the message that physical or cognitive symptoms are psychological or due to “stress.” Even if depression or anxiety plays a large role in the etiology of physical health symptoms, the treatment approach should be designed within a patient-centered primary care structure, and referrals should be managed from within this framework. For example, it might help to explain that the primary goal of referral to a mental health professional is to improve sleep and reduce physiologic hyperarousal, which in turn will help with treatment of war-related chronic headaches, concentration problems, or chronic fatigue. If, however, the primary care professional conveys the message that the cause of headaches or concentration problems is anxiety or depression, and this conflicts with the patient’s own viewpoint, then this could damage therapeutic rapport and in turn exacerbate the symptoms.


InternalMed_Harrison

InternalMed_Harrison. Specific questions related to military service (Table 471e-2) combined with screening for depression, PTSD, and alcohol use disorders (Table 471e-3) should be a routine part of care for all veterans. A positive screen for depression or PTSD should prompt follow-up questions related to these disorders (or use of a longer screening tool such as the nine-question Patient Health Questionnaire or National Center for PTSD Checklist), as well as risk assessment for suicide or homicide. It is important to assess the impact of depression or PTSD symptoms on occupational functioning and interpersonal relationships.


InternalMed_Harrison

InternalMed_Harrison. A positive screen for alcohol misuse should prompt a brief motivational intervention that includes bringing attention to the elevated level of drinking, informing the veteran about the effects of alcohol on health, recommending limiting use or abstaining, exploring and setting goals related to drinking behavior, and follow-up and referral to specialty care if needed. This type of brief primary care intervention has been found to be effective and should be incorporated into routine practice. One way to facilitate dialogue about this topic with veterans is to point out how hyperarousal associated with combat service can lead to increased craving for alcohol as the body searches for ways to modulate this. Veterans may consciously or unconsciously drink more to help with sleep, reduce arousal, or avoid thinking about events that happened “downrange.” A key educational strategy is to help the veteran to learn that drinking to get to sleep actually damages sleep architecture and makes sleep


InternalMed_Harrison

InternalMed_Harrison. or avoid thinking about events that happened “downrange.” A key educational strategy is to help the veteran to learn that drinking to get to sleep actually damages sleep architecture and makes sleep worse (e.g., reduces rapid eye movement [REM] sleep initially followed by rebound REM activity and early morning wakening).


InternalMed_Harrison

InternalMed_Harrison. PTSD and depression are highly comorbid in combat veterans, and the evidence-based treatments are similar, involving antidepressant medications, cognitive behavioral therapy (CBT), or both. Psychoeducation that assists veterans to understand that their symptoms of PTSD have a basis in adaptive survival mechanisms and skills they exhibited in combat can facilitate therapeutic rapport. Remaining hypervigilant to threat, being able to shut down emotions, being able to function on less sleep, and using anger to help focus and control fear are all adaptive beneficial survival skills in a combat environment. Therefore, PTSD for warriors is both a medical disorder and a set of reactions that have their roots in the physiologic adaptation and skills they successfully applied in combat.


InternalMed_Harrison

InternalMed_Harrison. It is important to know that combat is not the only important trauma in a war-zone environment. Rape, assault, and accidents also occur. Rape or assault by a fellow service member, which affects a greater number of women veterans, but also occurs in men, can be particularly devastating because it destroys the vital feeling of safety that individuals derive from their own unit peers in a war environment. The treatments for PTSD considered by most consensus guideline committees to have an A level of evidence include CBTs and medications, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), with the strongest evidence from double-blind, placebo-controlled studies Never (0) Less than Monthly (1) Monthly (2) Two to three times per Four or more times a week (4) week (3)


InternalMed_Harrison

InternalMed_Harrison. Never (0) Less than Monthly (1) Monthly (2) Two to three times per Four or more times a week (4) week (3) Note: A positive AUDIT-C screen is defined as a total score for men ≥4; for women ≥3. A report of drinking 6 or more drinks on one occasion should prompt an in-depth assessment of drinking. Source: K Bush et al: The AUDIT Alcohol Consumption Questions (AUDIT-C): An effective brief screening test for problem drinking. Arch Intern Med 158:1789, 1998. for sertraline, paroxetine, fluoxetine, and venlafaxine (of which paroxetine and sertraline received U.S. Food and Drug Administration approval for PTSD). (See Table 466-3 for recommended dosages.) Prazosin has also gained very strong evidence recently through randomized placebo-controlled studies for its effectiveness in controlling nightmares as well as global PTSD symptoms, through modulation of the physiologic processes associated with PTSD.


InternalMed_Harrison

InternalMed_Harrison. CBT interventions include narrative therapy (often called “imaginal exposure”), in vivo exposure focused on retraining the body not to react to stimuli related to traumatic reminders (e.g., a crowded mall), and techniques to modulate physiologic hyperarousal (e.g., diaphragmatic breathing, progressive muscle relaxation). A number of complementary alternative medicine approaches including acupuncture, mindfulness meditation, yoga, and massage are also being used in PTSD. Although not evidence-based treatments per se, if they facilitate a relaxation response and alleviation of hyper-arousal or sleep symptoms, they can be considered useful adjunctive modalities.


InternalMed_Harrison

InternalMed_Harrison. There have been no head-to-head comparisons of medication compared with psychotherapy for treatment of PTSD. It is reasonable for primary care clinicians to consider initiating treatment for mild to moderate PTSD symptoms with an SSRI and to refer patients to a mental health professional if there are more severe symptoms, significant comorbidity, safety concerns, or limited response to initial treatment. All PTSD treatments are associated with a sizable proportion of individuals who fail to respond adequately, and it is often necessary to add modalities or switch treatment. SNRIs may be useful alternatives to SSRIs if there has been nonresponse or side effects with SSRIs or if there is comorbid pain (duloxetine, in particular, has indications for pain). Both SSRIs and SNRIs can increase anxiety initially; patients should be warned about this possibility, and treatment should be initiated with the lowest recommended dose (or even one-half of the lowest dose for a few days) and


InternalMed_Harrison

InternalMed_Harrison. anxiety initially; patients should be warned about this possibility, and treatment should be initiated with the lowest recommended dose (or even one-half of the lowest dose for a few days) and gradually increased thereafter. Antidepressants also are likely to be useful in comorbid depression, which is common in veterans with PTSD. All antidepressants have potential drug-drug interactions that must be considered.


InternalMed_Harrison

InternalMed_Harrison. Many other medications have been used in PTSD, including tricyclic antidepressants, benzodiazepines, atypical antipsychotics, and anticonvulsants. In general, these should be prescribed in conjunction with psychiatric consultation because of their greater side effects and risks. Benzodiazepines, in particular, should be avoided in the treatment of PTSD. Studies have shown that they do not reduce core PTSD symptoms, are likely to exacerbate substance use disorders that are common in veterans with PTSD, and may produce significant rebound anxiety and anger. Individuals with PTSD often report symptomatic relief upon initiation of a benzodiazepine, but this is generally short lived and associated with a high risk of tolerance and dependence that can worsen recovery. Atypical antipsychotics, which have gained widespread popularity as adjunctive treatment for depression, anxiety, or sleep problems, have significant long-term side effects, including metabolic effects (e.g., glucose


InternalMed_Harrison

InternalMed_Harrison. which have gained widespread popularity as adjunctive treatment for depression, anxiety, or sleep problems, have significant long-term side effects, including metabolic effects (e.g., glucose dysregulation), weight gain, and cardiovascular risks.


InternalMed_Harrison

InternalMed_Harrison. Sleep disturbance should be addressed initially with sleep hygiene education, followed by consideration of an antihistamine, trazodone, low-dose mirtazapine, or nonbenzodiazepine sedative-hypnotic such as zolpidem, eszopiclone, or zaleplon. However, the nonbenzodiazepine sedative-hypnotics should be used with caution in veterans because they can lead to tolerance and rebound sleep problems similar to those seen with benzodiazepine use. Concussion/mTBI is best treated at the time of injury with education and rest to allow time for the brain to heal and protect against a second impact syndrome (a rare but life-threatening event involving brain swelling that can occur when a second concussion occurs before the brain has adequately healed from an initial event). Randomized trials have shown that education regarding concussion that informs the patient of what to expect and promotes the expectation of recovery is the most effective treatment in preventing persistent symptoms.


InternalMed_Harrison

InternalMed_Harrison. Once service members return from deployment and seek care for postwar health problems, treatment is largely symptom focused, following the principles of patient-centered and collaborative care models. Cognitive rehabilitation, which is very useful in moderate and severe TBI to improve memory, attention, and concentration, has generally not been shown to be effective for mTBI in randomized clinical studies, although consensus groups have supported its use.


InternalMed_Harrison

InternalMed_Harrison. General recommendations for the clinical management of persistent, chronic PCS include treating physical and cognitive health problems based on symptom presentation, coexisting health problems, and individual preferences; and addressing coexisting depression, PTSD, substance use disorders, or other factors that may be contributing to symptom persistence. Headache is the most common symptom associated with concussion/mTBI, and the evaluation and treatment of headache parallels that for other causes of headache (Chaps. 21 and 447). Stimulant medications for alleviating neurocognitive effects attributed to concussion/mTBI are not recommended. Clinicians should be aware of the potential for cognitive or sedative side effects of certain medications that may be prescribed for depression, anxiety, sleep, or chronic pain.


InternalMed_Harrison

InternalMed_Harrison. Treatment of neuropsychiatric problems must be coordinated with care for other war-related health concerns, with the goal of treatment to reduce the severity of symptoms, improve social and occupational functioning, and prevent long-term disability. Understanding the occupational context of war-related health concerns is important in communicating with veterans and developing a comprehensive treatment strategy. The opinions or assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the Department of the Army or the Department of Defense. 472e-1 PART 18: Poisoning, Drug Overdose, and Envenomation that low-level arsenic may cause neurodevelopmental delays in chil-Heavy Metal Poisoning dren and possibly diabetes, but the evidence remains uneven. Serious cadmium poisoning from the contamination of food and water by mining effluents in Japan contributed to the 1946 outbreak


InternalMed_Harrison

InternalMed_Harrison. Metals pose a significant threat to health through low-level environmental as well as occupational exposures. One indication of their importance relative to other potential hazards is their ranking by the U.S. Agency for Toxic Substances and Disease Registry, which maintains an updated list of all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity. The first, second, third, and seventh hazards on the list are heavy metals: lead, mercury, arsenic, and cadmium, respectively (http://www.atsdr.cdc.gov/spl/). Specific information pertaining to each of these metals, including sources and metabolism, toxic effects produced, diagnosis, and the appropriate treatment for poisoning, is summarized in Table 472e-1.