Chapter 24. Evaluation of the Patient with Alcohol or Drug Addiction

1. Addiction is a very common medical illness. It is characterized by loss of control over an abusable substance, including an inability to voluntarily self-regulate drug use, compulsive preoccupation with obtaining or using a drug, and continued use despite adverse consequences.

2. Addiction may be managed successfully as a chronic disease, and many patients respond positively to treatment with long periods of abstinence.

3. Consultation with an addiction medicine specialist is encouraged when providing care for active or recovering alcohol or drug abusers during the perioperative period.

4. Preoperative assessment of all patients presenting for surgery should include a routine evaluation for alcohol or drug abuse.

5. Establishing a supportive, nonjudgmental but firm approach to the patient with active alcoholism or drug addiction is vital for successful care.

6. Preoperative history, physical examination, and laboratory testing should be guided by the known medical consequences of alcohol and drug addiction.

7. A blood alcohol concentration and a urine drug screen should be obtained in all active and most recovering alcohol or drug abusers.

8. Polysubstance abuse is common among alcohol or drug users.

9. Infectious diseases are epidemic in injection drug users.

10. Alcohol abuse has extensive medical consequences that impact every major organ system and is a major risk factor for perioperative morbidity and mortality.

11. Abuse of sedative–hypnotics, opioids, cocaine, amphetamines, hallucinogens, and inhalants is associated with a wide variety of drug specific medical complications.

12. Withdrawal is commonly encountered during the perioperative period in alcohol or drug abusers, and prophylaxis against withdrawal should be instituted before surgery.

13. Recovery involves abstinence in combination with a series of personal changes to maintain sobriety.

Addiction is a major public health problem. The lifetime prevalence of alcohol or drug addiction in the United States is estimated to be approximately 14% and 7%, respectively.1 The literature describing the evaluation and treatment of patients with addiction is exhaustive. This chapter focuses on what the anesthesiologist needs to know to effectively manage the perioperative care of the addicted patient.

Addiction is defined by loss of control over a drug or substance of abuse. The inability to voluntarily self-regulate drug use, compulsive preoccupation with obtaining or using a drug, and continued use despite adverse consequences are central features of this multifaceted disease.2 Initial drug use is usually voluntary, and most users do not develop drug dependence, but repetitive drug exposure in a susceptible individual appears to cause fundamental changes in central nervous system function that produce the disease. Evidence suggests that genetic predisposition to addiction may be related to alterations in neurocircuitry that enhance sensitivity to the reinforcing effects of drugs of abuse, thereby overwhelming cognitive control of behavior.3 Thus addiction is a chronic disease; once present, it is regarded as permanent. However, it may be managed successfully, and many patients respond positively to treatment with long periods of abstinence.4

The neurobiology of addiction has been well documented and is not discussed in detail here.3,5 Three major concepts pertain to the perioperative care of the patient with addiction: drug reward and reinforcement, cross-addiction, and disease permanence. The mesocorticolimbic dopamine system is central to the pathophysiology of addiction.5 This neurocircuitry involves the ventral tegmental area of the midbrain where dopaminergic neurons originate and the basal forebrain, the nucleus accumbens, and the amygdala to which these neurons project. All drugs of abuse interact with this system to produce reinforcement.3 Different drugs of abuse, including many of those routinely used by anesthesiologists, may activate sites in this reinforcement cascade, but all lead to reward stimulation.5 Thus exposure to one drug may mimic the reinforcing effects of another ("cross-addiction"). Alterations in reinforcement neurocircuitry may persist despite long-term abstinence. This observation supports the notion that addiction is a chronic disease4 and may be particularly important in the recovering addict because drugs commonly used during the perioperative period may inadvertently reactivate addiction independent of the relative duration of abstinence.

Medical and psychiatric diseases are very common in patients with addiction. Drugs of abuse produce direct toxic effects on a variety of organ systems or they may exacerbate preexisting medical conditions. Addictive behaviors (eg, sharing injection equipment, high-risk sexual activity) can markedly increase the risk of infectious diseases such as endocarditis, hepatitis, and acquired immunodeficiency virus (AIDS). Depressed socioeconomic conditions (eg, unemployment, reliance on housing in shelters, homelessness) also increase the risk of other infectious diseases such as community-acquired pneumonia and tuberculosis. Routine and preventive health care may be inadequate or nonexistent. Despite these, there is clear evidence that patients with addiction benefit from routine health care, particularly when it is linked to substance abuse treatment.6 Such an integration of services improves patient outcome and should be an important goal during the perioperative period.

Previously undiagnosed alcohol abuse occurs in many hospitalized patients,7 and physicians often fail to detect it8; thus the preoperative assessment of surgical patients should include an evaluation for alcohol or drug abuse. The CAGE and Michigan Alcohol Screening Test (MAST) questionnaires are brief but extensively validated screening instruments that are useful for the detection of a substance abuse disorder.9 The simple 4-question CAGE test is particularly helpful for the anesthesiologist because of its brevity and predictive value:

• C Have you ever felt you ought to Cut down on your drinking (drug use)?
• A Have people Annoyed you by criticizing your drinking (drug use)?
• G Have you ever felt bad or Guilty about your drinking (drug use)?
• E Have you ever had a drink (or used a drug) first thing in the morning ("Eye opener") to steady your nerves or get rid of a hangover?

Two or more positive responses to the CAGE questionnaire indicate that addiction is most likely present, whereas a single affirmative answer suggests that further assessment may be necessary. Corroborating history including evidence of alcohol- or drug-related amnesia ("blackouts"), multiple detoxifications or previous rehabilitation attempts, recurrent unemployment, and habitual criminal activity also suggest the diagnosis of a substance abuse disorder.10 A blood alcohol concentration and a urine drug screen should be obtained in the patient with a known history of addiction, a positive preoperative screening evaluation, or when indicated by other clinical conditions (eg, trauma, altered mental status, obtunded state). The results identify the class(es) of drugs abused by the patient, alert the anesthesiologist to the possibility of withdrawal or potential drug interactions, and provide the opportunity to challenge denial and initiate a discussion about treatment alternatives, including consultation with an addiction medicine specialist.

A nonjudgmental but firm approach to the patient with addiction is essential for successful care. Unfortunately, patients with addiction may encounter physicians whose attitudes about and treatment may be prejudicial.11 For example, general surgeons possessed the weakest educational background and the least desire to learn about resources for addiction management compared with psychiatrists and internists.12 Anesthesiologists displayed more negative attitudes about patients with addiction than primary care physicians13 (Fig. 24-1). A positive rapport also allows the anesthesiologist to strongly encourage the active alcohol or drug abuser to seek or reenter treatment.

Providing reassurance about prompt, effective management of pain to the patient with addiction deserves special emphasis during the preoperative evaluation. Chronic pain resulting from a variety of alcohol- or drug abuse-related medical illnesses was previously identified in many patients enrolled in methadone maintenance programs or residential treatment facilities14 (Fig. 24-2). Chronic opioid abusers frequently display hyperalgesia, in part as a result of drug tolerance.15 However, even well-intentioned, informed physicians may be hesitant to provide adequate doses of opioid analgesics to such patients because of fears about contributing to the disease process. Some physicians may intentionally withhold or restrict opioid analgesics because they are anxious about adverse consequences imposed by federal or state regulatory agencies,15 are concerned that patient requests for these drugs may represent manipulative "drug-seeking" behavior,16 or hold negative attitudes about addiction. These factors contribute to inadequate treatment of pain in patients with addiction,17 and as a result, these patients often harbor suspicions that they will be deliberately abused by physicians or nursing staff. Recognition that patients with addiction self-medicate or manipulate prescribed drugs to treat pain may further complicate this situation and thereby create "mutual mistrust."16 The potential for such a conflict should be honestly addressed during the preoperative evaluation. Guidelines for pain management in patients with addiction encourage early consultation with an addictionologist, meticulous observation of compliance with and clinical response to prescribed opioids, and continuous assessment of function.18

In addition to the chief complaint that led to the original surgical referral and other relevant past medical history, the known medical consequences of alcohol and drug abuse, the common occurrence of polysubstance abuse, and the presence of other coexisting diseases should guide the preoperative history and physical examination. A thorough review of systems is required if the interview or laboratory results (blood alcohol concentration, urine drug screen) suggest substance abuse. Importantly, the recognition that constitutional complaints or new presenting symptoms may or may not indicate drug use or withdrawal is a critical feature of the history and physical examination. For example, fever, myalgias, tachycardia, and gastrointestinal symptoms typically characterize alcohol or opioid withdrawal, but such generic complaints may also indicate the presence of an underlying infectious disease. Weight loss due to malnutrition is a very common finding in drug abusers, but infectious diseases including human immunodeficiency virus (HIV) and occult malignancy must also be considered in the differential diagnosis. Similarly, a seizure certainly suggests the presence of alcohol or opioid withdrawal in the patient with a recent history of heavy abuse, but other causes cannot be immediately excluded.

The physical examination of the patient with addiction is directed toward the medical ramifications of specific drugs of abuse, but routine investigation of other coexisting diseases and the potential for complications arising from polysubstance abuse should not be overlooked. Examination of the skin may reveal evidence of acute or chronic infection (eg, cellulitis, abscess), repetitive drug injection ("track" marks), or peripheral venous thrombosis and will help anticipate difficulty inserting intravenous or intra-arterial catheters. Skin examination may also reveal the stigmata of advanced liver disease. Diffuse lymphadenopathy strongly suggests the presence of systemic infection, tuberculosis, or HIV. Poor dentition, oral-pharyngeal carcinoma, or nasal septum damage may be detected during examination of the airway. Such findings may have potentially important implications for airway management. Wheezing, rhonchi, rales, or evidence of pulmonary consolidation detected during the lung examination suggests the presence of reactive airway disease, acute or chronic bronchitis, heart failure, or pneumonia that may be related to alcohol or drug abuse and merit further investigation. A cardiac murmur strongly suggests that active or healed endocarditis may be present. The abdominal examination should be directed specifically toward the liver because most drugs of abuse are associated with the development of hepatic disease. Last, the neurologic examination may reveal evidence of altered mental status, cerebrovascular accident, head trauma, central nervous system infection, or peripheral neuropathy.

Standard recommendations for obtaining preoperative laboratory and diagnostic tests in healthy subjects are often inadequate in patients with a history of alcohol or drug abuse. As in healthy patients, the preoperative laboratory and diagnostic evaluation of alcohol or drug abusers should be guided by the results of the history and physical examination, but a high index of suspicion is required about the possible existence of other subclinical medical complications of alcohol or drug abuse and their potential impact on perioperative management. For example, hepatic dysfunction resulting from drug toxicity or infection is very common in alcohol and injection drug abusers, and obtaining liver function tests, a coagulation panel, and viral hepatitis testing is warranted even if patients are supposedly asymptomatic. Similarly, a tuberculin skin test and a chest radiograph should be performed because subclinical tuberculosis may be present. Serum electrolyte, blood urea nitrogen, and creatinine concentrations and a urinalysis should also be obtained because renal insufficiency resulting from viral hepatitis or HIV infection commonly occurs. Routine screening for HIV should be performed, especially in alcohol or drug abusers who acknowledge high-risk behavior. A positive HIV screen facilitates further testing to confirm the infection, allows early initiation of medical treatment, and alerts the surgical team to the potential for viral transmission.

Infectious diseases are epidemic in injection drug users,19 and most hospital admissions of injection users are related to acute infection; the presence of chronic infectious diseases frequently complicates the perioperative management of these patients as well. This section focuses on infectious diseases that are of most immediate relevance to the anesthesiologist (Table 24-1).

Skin and Soft Tissue

Skin and soft tissue infections (eg, cellulitis, abscess, ulcer) are frequently responsible for hospital admission of injection drug users, and they may also be initially recognized during the preoperative evaluation. Skin and soft tissue infections with or without necrotizing fasciitis may be present in as many as a third of all active users.20 Staphylococcus aureus and β-hemolytic streptococci are the most frequently identified pathogens responsible for cutaneous and soft tissue infections,19 but geographic variations in organism identity are regularly reported.21 The route of administration and frequency of injection, the presence of HIV, and the combined use of heroin and cocaine (known as a "speedball") are known risk factors for abscess development. Ranked in descending order of occurrence, the arms, legs, buttocks, deltoids, and neck are the most common locations for abscess formation and correlate with typically used injection sites.22 Vasoactive drugs (eg, cocaine) may produce cutaneous or muscular ischemic necrosis at the injection site and contribute to ulcer formation. Infections of large skeletal muscles (pyomyositis) occur more commonly in injection drug users with HIV. Necrotizing fasciitis is associated with substantial morbidity and mortality; aggressive surgical intervention is required to manage this devastating complication.

Cardiovascular System

Endocarditis is one of the most common complications of injection drug abuse.23 The frequency of injection and the presence of HIV are major risk factors for the development of endocarditis. Mortality in injection drug users with endocarditis may exceed 35%24 and is undoubtedly higher in those who are immunocompromised. Endocarditis may affect any heart valve, but infection of right compared with left heart valves is more frequent and less likely to prove fatal.25,26 In contrast to other forms of endocarditis, injection drug use more commonly produces infection of structurally normal right heart valves (tricuspid more than pulmonic). Streptococcus viridans and Enterococcus are typically identified as responsible for endocarditis in patients without a history of substance abuse, but more virulent species, most notably S. aureus (with or without methicillin resistance), are most often implicated in injection drug abusers.

Persistent bacteremia is the major feature of active endocarditis. The diagnosis of the disease is established using standard criteria.27 The clinical presentation of endocarditis is typified by persistent fever, cardiac abnormalities (eg, new murmur, valvular insufficiency, congestive heart failure, intraventricular conduction defects), septic embolization with bacterial seeding of other structures (eg, meningitis, brain abscess, osteomyelitis), and immune complex–related complications (eg, glomerulonephritis, Roth spots, Osler nodes). Patients often present with cough, pleuritic chest pain, and bilateral pulmonary infiltrates because of septic embolization from the tricuspid valve. Hemoptysis, bronchopleural fistulae, pneumothorax, empyema, or infection of a major bronchial structure complicates necrotizing or cavitary pulmonary defects produced by septic thromboemboli. Echocardiography often provides direct visual evidence of vegetation (consisting of platelets, fibrin, and sequestered bacteria) located on the leaflet surface, but a normal echocardiogram alone does not definitively exclude the diagnosis. Primary treatment of endocarditis with organism-specific antibiotics or antifungal drugs often requires simultaneous surgical intervention to cardiovascular or neurologic sequelae.

Vascular infections also frequently occur in injection drug users. Contaminated injection equipment, hematoma surrounding a direct vascular injury, local ischemic damage from vasoactive drug injection, or thrombosis may cause thrombophlebitis, arteriovenous fistulas, or septic embolization. When septic emboli lodge in the vasa vasorum of an arterial wall, a mycotic aneurysm may result. Right or left heart valve endocarditis-induced septic embolization is the most common cause of pulmonary or brain mycotic aneurysm formation, respectively. Most of these arterial defects resolve with intravenous antibiotic treatment, but some patients with mycotic aneurysms may develop signs and symptoms despite appropriate antibiotic treatment. The clinical presentation of a mycotic aneurysm is typified by the presence of a painful pulsatile mass accompanied by a bruit, thrill, surrounding cellulitis or abscess formation, or frank rupture. Surgical excision is required for definitive treatment of the infection or to prevent rupture in a minority of cases.

Pulmonary System

Community-acquired pneumonia is a major cause of hospital admission in injection drug users. Aspiration risk resulting from drug-induced depression of airway-protective mechanisms, poor nutritional status, immunosuppression, and compromised mucociliary and phagocytic function associated with tobacco smoking contribute to increased susceptibility to pneumonia.28 Injection drug users with HIV are approximately 5 times more likely to develop community-acquired pneumonia than those without HIV.29 Streptococcus pneumoniae and Haemophilus influenzae are the most commonly identified pathogens responsible for pneumonia in injection drug users with or without HIV infection, but other bacteria may also be encountered. HIV-positive drug abusers are especially susceptible to opportunistic pulmonary infection with Pneumocystis jirovecii (formerly Pneumocystis carinii), Mycobacterium tuberculosis, Mycobacterium avium intracellulare, and cytomegalovirus.

Tuberculosis is also common in injection drug users, especially in those coinfected with HIV.30 Injection drug users have a prevalence of latent tuberculosis infection that is 3- to 5-fold greater than that observed in healthy subjects. Standard treatment of tuberculosis usually involves therapy with isoniazid, rifampin, ethambutol, and pyrazinamide.31 Rifampin stimulates methadone metabolism, and chronic opioid abusers in methadone maintenance programs often require dosing adjustments to avoid withdrawal.32 This drug interaction has potentially important ramifications perioperatively when using opioids for postoperative analgesia. Rifampin and pyrazinamide may also exacerbate preexisting hepatitis leading to severe liver dysfunction in users with tuberculosis.

Central and Peripheral Nervous System

Signs and symptoms of acute drug intoxication or withdrawal often complicate the diagnosis of neurologic infection. Meningitis, brain abscess resulting from septic embolization, cerebral infarction, or rupture of a mycotic aneurysm may occur in as many as 40% of injection drug users with endocarditis. Bacteremia-induced vertebral osteomyelitis with extension into the epidural space may accompany endocarditis, thereby potentially compromising spinal cord integrity. Bacterial invasion from ear, sinus, or mastoid infections, bacteremia resulting from another infectious source, or traumatic injury may also cause infection in the injection drug user. Immunosuppressed injection drug users with HIV are particularly vulnerable to central nervous system infections produced by unusual pathogens such as tuberculosis, Cryptococcus, Aspergillus, and Toxoplasma gondii. Viral hepatitis may also produce encephalopathy independent of liver dysfunction.

Injection drug users are also susceptible to neurotoxin-mediated infectious diseases. Subcutaneous or intramuscular injection sites infected with Clostridium botulinum releases botulinum toxin. The toxin produces blurred vision, dysphagia, descending bilateral flaccid paralysis, and respiratory failure as a result of irreversible inhibition of acetylcholine release. The anaerobic bacterium Clostridium tetani produces tetanus toxin (tetanolysin) that irreversibly blocks inhibitory neurotransmitter release in spinal motor neurons, thereby causing spastic paralysis characterized by trismus, dysphagia, hydrophobia, and profound, unrelenting muscle contraction in the upper and lower extremities. Neutralization of circulating tetanus toxin with hyperimmune globulin precedes surgical debridement to avoid additional tetanolysin release from the infected site.

Hepatitis

Injection drug abuse is strongly associated with all known forms of viral hepatitis. Collectively, these diseases have potentially devastating consequences and pose substantial risks of transmission to anesthesiologists and other health professionals who are responsible for their care. Hepatitis A virus (HAV) is the most common form of viral hepatitis in the United States, and drug abuse is a major risk factor for its transmission. Hepatitis A is often a self-limited disease characterized by fever, fatigue, gastrointestinal symptoms, jaundice, hepatosplenomegaly, and abnormal liver function tests concomitant with sequential appearance of immunoglobulin (Ig)E and IgG anti-HAV antibodies that confer immunity against subsequent infection. In contrast to hepatitis B virus (HBV) infection, a carrier state does not occur with HAV infection, extrahepatic manifestations of the disease are unusual, and most cases require only supportive care. However, acute HAV infection may cause fulminant hepatic failure and mortality in patients who are coinfected with hepatitis C virus (HCV) or those affected by chronic hepatic pathology.33

Transmission of HBV among drug abusers most often occurs as a result of sharing contaminated injection supplies or high-risk sexual activity. Drug abuse is responsible for a fifth of new HBV cases reported annually in the United States. Acute infection with HBV has a widely variable clinical course. Many patients infected with HBV remain completely asymptomatic, and fewer than half develop jaundice, hepatosplenomegaly, and elevated serum transaminases. Most patients require only supportive care, but a few (<0.1%) develop fulminant hepatic failure. The presence of antibodies directed against HBV surface and core antigens that occur with the resolution of acute infection confer protection against subsequent infection in most patients. Unlike HAV, a chronic HBV infection occurs in a small percentage of patients (5%–10%) characterized by the continued presence of HBV surface or e antigen, variable extent of hepatic inflammation and dysfunction, and persistent infectivity; cirrhosis or hepatocellular carcinoma may follow. Treatment with interferon-α and lamivudine (3-TC) may reduce the occurrence of these complications. Membranous nephropathy and renal insufficiency may also occur.

As many as 80% of injection drug users chronically infected with HBV are coinfected with the hepatitis D virus, which requires the presence of HBV for activity. Coinfection has a substantially greater incidence of fulminant hepatic failure compared with HBV alone.

Injection drug use is the primary route of transmission of HCV in the United States. The vast majority of injection drug users demonstrate evidence of HCV exposure. Most injection drug users develop the HCV shortly after beginning injection activity. The initial presentation of HCV infection is usually subclinical, but as many as 85% develop a long-term infection. Recent estimates suggest that more than 4 million Americans are chronically infected with HCV.34 Serum antibodies directed against the virus and the presence of HCV RNA establish the diagnosis of chronic infection. Ominously, as many as 20% of patients with chronic HCV develop cirrhosis, and hepatic failure resulting from this complication is currently the most common indication for liver transplantation in this country. Older patients with chronic HCV who abuse alcohol or those coinfected with HIV appear to be particularly vulnerable to more rapid progression of end-stage liver disease.35 The combination of peginterferon (interferon with a polyethylene side chain) and ribavirin is currently the most efficacious drug regimen for the treatment of chronic HCV infection and appears to reduce the incidence of cirrhosis and hepatic failure.36 Chronic HCV is also associated with membranoproliferative glomerulonephritis with or without cryoglobulinemia. Proteinuria, hematuria, hypertension, and renal insufficiency are prominent features of this mixed nephrotic-nephritic syndrome. A membranous glomerulonephropathy produced by the deposition of virus core protein has also been described in injection drug users with chronic HCV. Last, injection drug users with HCV- or HBV-induced cirrhosis are susceptible to bacterial hepatic infections and spontaneous bacterial peritonitis. Enteric gram-negative bacilli are the most common cause of these frequently fatal complications.

Human Immunodeficiency Virus

Injection drug use is a major risk factor for HIV transmission; the Centers for Disease Control and Prevention identified injection drug use as the presumed route of transmission in 31% of adults with newly diagnosed HIV infection.37 Injection drug use was also implicated as the primary cause of 39% of reported cases of maternal–fetal transmission of the virus. The use of highly active antiretroviral therapy (HAART) combined with intensive public health emphasis has transformed HIV infection from a "death sentence" diagnosis into a manageable chronic illness. HIV treatment is complex and not reviewed in detail here.

See Table 24-2.

Alcohol

Heavy alcohol use (defined as at least 5 drinks per day on >5 days of the week) has been documented in 7% of the US population and is even more common in patients presenting for surgery. Alcohol abuse is a major risk factor for perioperative morbidity and mortality,41 yet many clinicians often fail to recognize it. Achieving preoperative abstinence before elective surgery substantially reduces postoperative complications.42 Blood alcohol concentrations as low as 0.05 mg/dL produce acute hemodynamic effects that may have important consequences for patients with heart disease. Mildly intoxicating doses of alcohol reduce myocardial contractility in vitro and cause left ventricular dysfunction in vivo. Such actions cause further reductions in global cardiac performance in patients with preexisting cardiomyopathy. The mechanism responsible for alcohol-induced myocardial depression is unclear. The ingestion of alcohol increases cardiac output in healthy individuals because systemic vascular resistance declines. Conversely, alcohol and its metabolites also indirectly enhance sympathetic nervous system activity, thereby producing tachycardia, arterial vasoconstriction, and attenuation of baroreceptor reflex control of the circulation.43 These actions combine to increase myocardial oxygen consumption and may contribute to the development of myocardial ischemia or infarction in heavy drinkers with coronary artery disease. Myocardial ischemia or infarction may also occur during alcohol withdrawal in patients with coronary artery disease as a result of elevated sympathetic nervous system tone or coronary vasospasm.

A strong causal relationship between alcohol abuse and hypertension has been established.44 The combination of chronic alcohol use and withdrawal enhances centrally mediated sympathetic nervous system activity and produces hypertension by overwhelming the direct, but transient, vasodilatory effects of the drug and its metabolites.43 Heavy alcohol use is linked to the development of coronary atherosclerosis and is associated with increased morbidity and mortality resulting from coronary artery disease.45 Conversely, consumption of modest amounts of alcohol produces cardioprotection against ischemic injury.46 Several large-scale epidemiologic studies provided compelling evidence that chronic consumption of small amounts of alcohol reduces cardiovascular mortality, decreases the incidence of coronary artery disease, and improves survival during acute myocardial infarction. Despite these convincing data, substantial individual variability exists, and "rebound" phenomena that theoretically increase the risk of cardiovascular complications are also known to occur with abrupt cessation of alcohol intake. This latter caveat may be of particular importance because temporary abstinence from alcohol consumption is required during the perioperative period.

Chronic alcohol abuse produces a dilated cardiomyopathy characterized by myocardial hypertrophy, chamber dilatation, interstitial fibrosis, disruption of myocyte organelle structure, and severe contractile dysfunction (ie, alcoholic cardiomyopathy). These alterations cause irreversible congestive heart failure.47 Advanced cirrhosis produces changes in systemic hemodynamics that may obscure the presence of alcoholic cardiomyopathy. Increases in cardiac output occur in response to declines in systemic vascular resistance in patients with decompensated cirrhosis.48 There is correlation between the extent of hepatic dysfunction and the magnitude of reduction in systemic vascular resistance.48 Abnormal arterial-venous shunting that accompanies chronic hepatic dysfunction does not appear to be responsible for the decrease in afterload. Instead, enhanced production of nitric oxide is a major cause of cirrhosis-induced declines in peripheral resistance.49 Notably, the presence of ascites (and the consequent reduction in left ventricular preload) may stimulate compensatory sympathetic nervous system–mediated vasoconstriction that attenuates this vasodilation.

Atrial or ventricular arrhythmias are frequently observed in alcohol abusers, most often after a binge-drinking episode. This "holiday heart" effect usually develops in otherwise healthy subjects without heart disease or abnormal serum electrolytes. An increased risk of sudden cardiac death was also reported in alcohol abusers with or without coronary artery disease, presumably because of malignant ventricular arrhythmias.50

Alcohol abuse produces many pulmonary complications that are related to the acute and chronic effects of the drug.51 Alcohol is a potent depressant of respiratory drive, and intoxication may produce hypoxemia, hypercarbia, acidosis, atelectasis, and respiratory failure. These complications may be more pronounced in patients with preexisting pulmonary or airway pathology (eg, chronic obstructive or restrictive lung disease, obstructive sleep apnea, upper airway neoplasm). An altered level of consciousness and compromise of airway protective reflexes during acute intoxication predisposes to aspiration pneumonitis and adult respiratory distress syndrome. Alcohol ingestion exacerbates bronchospastic lung disease, especially in the presence of histamine-sensitive asthma. Acetaldehyde-induced mast cell degranulation with the release of histamine, leukotrienes, and other inflammatory mediators appears to be a major mechanism for alcohol-induced bronchospasm. Conversely, other patients with asthma report symptomatic improvement with alcohol ingestion. Thus the acute effects of alcohol on airway reactivity may be unpredictable and patient specific. Chronic alcohol abuse also causes several important pulmonary complications in patients with cirrhosis. Large quantities of ascitic fluid reduce vital and functional residual capacities, thereby producing atelectasis, tachypnea, dyspnea, and rapid arterial oxygen desaturation during anesthetic induction. Movement of ascitic fluid across the diaphragm to the pleural space may worsen this clinical picture. Abnormal pulmonary arterial-venous shunts produce hypoxemia in patients with alcoholic cirrhosis. This "hepatopulmonary syndrome" is observed in as many as 15% of patients with cirrhosis and occurs as a result of reduced pulmonary vascular resistance.52 Enhanced nitric oxide production and altered hepatic metabolism of estrogen and progesterone are possible etiologies of hepatopulmonary syndrome. Conversely, a small minority of patients with alcoholic cirrhosis develops pulmonary hypertension, most likely because the liver fails to metabolize circulating vasoactive substances. The diagnosis of this "portal" pulmonary hypertension may be overlooked because many of the signs and symptoms of right ventricular failure mimic those of chronic hepatic dysfunction. Depression of immunologic function, concomitant tobacco abuse, and malnutrition probably contribute to this increased incidence of pneumonia.

Seizures and cerebrovascular accidents are common in alcohol abusers. Anticonvulsant medications are usually unnecessary for the treatment of alcohol withdrawal seizures because these events are usually self-limited. Seizures occur less frequently during active alcohol consumption. Similar to previously reported reductions in cardiovascular risk associated with moderate alcohol consumption, several epidemiologic studies have suggested that daily ingestion of small quantities of alcohol may reduce the risk of cerebrovascular accidents (Fig. 24-3).53 In contrast, chronic alcohol abuse is strongly associated with stroke.

Sustained impairment of cognitive function or frank dementia frequently occurs in chronic alcohol abuse. Severe alterations in cognitive function may jeopardize the ability to obtain informed consent and may also undermine compliance with perioperative treatment. Thiamine deficiency accompanies alcohol-induced malnutrition and produces Wernicke encephalopathy. Confusion, memory and attention deficits, nystagmus, and ataxia characterize Wernicke encephalopathy, which is initially fully reversible with appropriate thiamine replacement. Irreversible memory deficits, amnesia, inability to recall new information, and confabulation are major features of Korsakoff syndrome. Peripheral compression nerve palsies ("Saturday night palsy"), rhabdomyolysis, and compartment syndromes commonly occur because alcohol abusers may lose consciousness and remain immobile for prolonged periods. Alcohol-induced myelopathy and polyneuropathy probably occur as a direct result of drug toxicity, but malnutrition most likely also plays an important contributing role.

Alcoholic liver disease is the most well-recognized complication of alcohol abuse. Hepatic failure resulting from alcohol abuse is responsible for over 25 000 deaths annually in the United States.54 Until it was recently surpassed by chronic HCV infection, alcohol-induced hepatic cirrhosis was the most common indication for liver transplantation in this country. Fatty liver may be observed in chronic alcohol abusers, but this change may also occur after several days of binge drinking in otherwise healthy subjects. Clinical signs and symptoms of alcohol-induced fatty liver include nausea, vomiting, anorexia, and right upper quadrant pain, whereas liver function tests remained preserved or only modestly elevated. The relative perioperative risk associated with alcoholic fatty liver has not been formally studied, but it may be prudent to delay elective surgery until abstinence is achieved and clinical symptoms resolve. Fever, jaundice, abnormal liver function tests, and right upper quadrant pain characterize the presentation of alcoholic hepatitis. Severe alcoholic hepatitis is associated with high mortality, is often accompanied by ascites, encephalopathy, and coagulopathy, and is a contraindication to elective surgery.55 Portal hypertension, ascites, esophageal varices, hepatic encephalopathy, spontaneous bacterial peritonitis, and coagulopathy resulting from decreased synthesis of coagulation factors and thrombocytopenia typify end-stage liver disease resulting from cirrhosis. A history of sustained alcohol abuse and characteristic abnormalities in liver function tests establishes the diagnosis of alcoholic liver disease, in addition to clinical signs and symptoms. Markedly increased blood γ-glutamyl transferase concentrations are accompanied by elevations in aspartate aminotransferase (AST) that usually exceed those of alanine aminotransferase (ALT), hyperbilirubinemia, hypoalbuminemia, and prolonged prothrombin time. The severity of alcoholic cirrhosis determines surgical risk; mortality rates for alcohol abusers with Child's classification A, B, and C hepatic disease undergoing abdominal surgery were identified as 10%, 31%, and 76%, respectively.56

Alcohol abuse is associated with gastrointestinal complications that are significant for anesthesia care. For example, alcohol abusers are predisposed to acid aspiration. Gastroesophageal reflux occurs frequently during alcohol ingestion because of reductions in lower esophageal sphincter tone. Chronic alcohol use also reduces maximal lower esophageal sphincter pressure. Upper gastrointestinal hemorrhage also increases aspiration risk during anesthetic induction and may occur as a result of esophageal, gastric, or duodenal mucosal injury, esophageal varices, or vomiting-induced tears of the gastroesophageal junction (Mallory-Weiss syndrome). Severe upper gastrointestinal bleeding may cause profound hypovolemia requiring aggressive volume replacement and often compels urgent endoscopic or surgical intervention. Active upper gastrointestinal hemorrhage with or without esophageal varices is a relative contraindication to transesophageal echocardiography. Alcohol abuse is also a major risk factor for acute and chronic pancreatitis.

Hepatorenal syndrome is the most devastating renal complication of chronic alcohol abuse: It is almost always fatal without liver transplantation. Profound hepatic dysfunction, splanchnic vasodilation, and intense renal arterial vasoconstriction are characteristic features of hepatorenal syndrome.57 Progressive oliguric renal failure and reduced glomerular filtration rate that are unresponsive to volume administration, a gradual increase in serum creatinine concentration, and a markedly reduced urine sodium concentration established the diagnosis of hepatorenal syndrome in the absence of other causes of nephrotoxicity. Hepatorenal syndrome may occur in conjunction with a major complication of alcohol-induced end-stage liver disease (eg, sepsis, upper gastrointestinal hemorrhage) but may also develop insidiously without any apparent underlying cause.

Alcohol abuse produces several acid–base and electrolyte abnormalities because of gastrointestinal losses and malnutrition. Perhaps the most frequent severe metabolic complication is alcoholic ketoacidosis, an anion gap acidosis that usually occurs in alcohol abusers after binge drinking. Hypokalemia is common in alcohol abusers; it occurs as a result of gastrointestinal tract losses combined with secondary hyperaldosteronism and may worsen preexisting hepatic encephalopathy or precipitate rhabdomyolysis. Other common electrolyte abnormalities are hypomagnesemia and hypophosphatemia. Gastrointestinal loss, malnutrition, and alcohol-induced renal tubular dysfunction combine to produce these deficiencies.

Alcohol causes direct bone marrow toxicity and pancytopenia. Iron and folate deficiency with or without acute or chronic blood loss and hemolysis resulting from red blood cell fragility contribute to anemia. Leukopenia and neutrophil dysfunction increase the risk for infection. Thrombocytopenia may be especially profound, and, when combined with reduced coagulation factor synthesis, it substantially increases the risk of bleeding from gastrointestinal causes, trauma, or surgery.

Sedative-Hypnotics

The clinical pharmacology of barbiturates and benzodiazepines is discussed in Chapter 42. Briefly, barbiturates, benzodiazepines (including the ultra–short-acting agent flunitrazepam, known as the "date rape" drug), and the gamma-aminobutyric acid (GABA) derivative γ-hydroxybutyrate (GHB, termed "liquid ecstasy") act through GABA receptors to exert anxiolytic, anticonvulsant, amnestic, and sedative effects.58 The major complications of barbiturate or benzodiazepine abuse are respiratory depression and overdose, especially in the presence of alcohol or opioids. Barbiturate or benzodiazepine abuse produces sedation, obtundation, or coma with eventual loss of airway protective reflexes. Progressive alveolar hypoventilation, hypoxemia, respiratory acidosis, and death subsequently occur. Mortality from barbiturate-induced respiratory depression was previously not uncommon, but the clinical use of these drugs for the treatment of anxiety disorders has been largely supplanted by benzodiazepines or specific serotonin reuptake inhibitors, which have a greater margin of safety. Nevertheless, death resulting from benzodiazepine overdose has been reported, most often in conjunction with the abuse of other drugs.

Opioids

Heroin is the most commonly abused opioid in the United States. The Office of National Drug Control Policy estimates that more than 900,000 individuals in this country suffer from heroin addiction.59 Heroin and other opioid abusers are at substantially increased risk for a wide variety of devastating medical complications. The clinical pharmacology of opioids is reviewed in detail in Chapter 42. This section focuses on the relevant pathology specifically associated with opioid abuse. Cardiovascular stability is a hallmark of administration of opioids, and even large quantities of opioids (such as those previously used during cardiac anesthesia) usually produce relatively small changes in systemic hemodynamics. Most naturally occurring and synthetic opioids dilate venous capacitance and splanchnic arteriolar vessels. These actions cause modest reductions in arterial pressure independent of histamine release (eg, heroin, morphine). Opioids also modestly reduce heart rate but do not affect left ventricular function or cardiac output under most conditions. Opioids exert cardioprotective effects against infarction60 and may also produce antiarrhythmic actions in ischemic myocardium. As a result, opioid abuse usually produces few, if any, direct cardiovascular consequences, in sharp contrast to stimulants such as cocaine or amphetamines. As mentioned previously, endocarditis is the most important cardiovascular complication of opioid abuse.

Pulmonary complications are more common; they are responsible for as many as 20% of hospital admissions for opioid abuse. Substances that contaminate the drug or those related to the route of administration cause acute or chronic respiratory consequences. For example, magnesium silicate (talc) is frequently used in oral pharmaceutical preparations or those mixed with an illicit opioid to dilute the drug. Injection or inhalation of magnesium silicate or other contaminants may cause pulmonary granulomatosis, a form of diffuse micronodular interstitial fibrosis characterized by cough, dyspnea on exertion, and diminished diffusion capacity. This "talc granulomatosis" is similar to the presentation of sarcoidosis and may be complicated by direct occlusion of pulmonary arterial branches by granulomas. In addition to this vascular occlusion, chronic hypoxemia and reactive pulmonary arterial vasoconstriction resulting from interstitial fibrosis also contribute to the development of pulmonary hypertension and right ventricular failure. Bullous emphysema is another complication of talc granulomatosis. Septic pulmonary embolization is a frequent complication of injection opioid abuse, as a result of thrombophlebitis or endocarditis. Mycotic aneurysms also occur because of pulmonary vascular seeding with septic emboli. Rupture of a pulmonary mycotic aneurysm may cause life-threatening hemoptysis. Attempted opioid injection into the internal jugular or subclavian vein ("pocket shooting") may cause pneumothorax, hemothorax, chylothorax, and empyema. Smoking or nasal inhalation of opioids produces particulate substances that are distributed throughout the bronchial tree and contribute to mucosal irritation, inflammation, fibrosis, or granulomatosis. Chemical compounds produced by ignition of drugs or solvents also produce mucosal damage. Thus patients who use inhaled opioids are susceptible to the development of bronchospasm, bronchitis, airway injury, or hemoptysis. Barotrauma may occur during inhaled opioid abuse as a result of intense inhalation and breath holding performed to maximize drug uptake. Smoke forcefully exhaled from one user into the lungs of another ("shotgunning") may also cause barotrauma. Finally, chronic abuse of inhaled opioids is associated with the development of emphysema.

The direct actions of opioids on control of respiration, airway reactivity, pulmonary arterial vascular tone, and immunologic response to infectious agents produce several other pulmonary consequences. Opioids bind to mu2 receptors in the pons and medulla, thereby attenuating respiratory automaticity, inhibiting airway protective reflexes, and reducing the influence of carbon dioxide on respiratory drive in a dose and route of administration-dependent manner. These actions produce respiratory depression, a major cause of mortality associated with opioid overdose.61 Loss of airway reflexes combined with a diminished level of consciousness further predisposes the opioid abuser to aspiration pneumonitis and its associated complications. Heroin-induced histamine release from mast cells may cause bronchospasm in drug abusers with asthma. This histamine release may occur because of direct activation of mu opioid receptors or through an IgE-mediated mechanism. Noncardiogenic pulmonary edema occurs in as many as half of patients presenting with intravenous or inhalational opioid overdose and is associated with substantial mortality. Opioids may directly increase pulmonary capillary permeability, thereby facilitating accumulation of protein and fluid in the alveoli by hydrostatic forces. A neurogenic mechanism may also cause pulmonary venoconstriction, thereby increasing pulmonary capillary permeability.62 Histamine release by some opioids also contributes to constriction of pulmonary veins and enhances permeability of pulmonary capillary membranes. Aspiration pneumonitis and pneumonia often complicate the management of patients with opioid-induced pulmonary edema. A hypersensitivity pneumonitis, characterized by cough, dyspnea, and bilateral pulmonary infiltrates, may present several days after nasal heroin inhalation. Opioid abuse attenuates neutrophil and macrophage phagocytosis, reduces T- cell and killer cell activity, decreases CD4 cell count, promotes leukocyte apoptosis (programmed cell death), depresses white blood cell chemotaxis, and inhibits delayed hypersensitivity reactions.63 These immunologic effects markedly increase the risk and severity of pulmonary infection in the chronic opioid abuser.

Opioid abuse is associated with neurologic consequences. Seizures are a rare side effect of heroin or morphine abuse or withdrawal, and the occurrence of seizures in patients who have abused these opioids should prompt investigation of other potential etiologies. In contrast to the findings with heroin or morphine, seizures may occur with meperidine abuse because of the epileptogenic properties of normeperidine, a major meperidine metabolite.64 Seizures have also been reported after intravenous abuse of the combination of the mixed opioid agonist-antagonist pentazocine and the antihistamine tripelennamine ("T's and Blues") may also cause seizures. Infectious disease-related complications or renal failure account for most of the hemorrhagic strokes in opioid abusers. A myelopathy distinguished by sensory deficits, paraparesis, and urinary retention has been described in heroin abusers that may be related to spinal cord infarction or vasculitis. Immunologically mediated Guillain-Barré syndrome and brachial or lumbar plexopathies have been reported in heroin abusers. Last, inhalation of heroin vapors produced by heating the drug on metal foil ("chasing the dragon") rarely causes a crippling, often fatal leukoencephalopathy.

Heroin use is associated with the development of focal and segmental glomerulosclerosis. This so-called heroin nephropathy is probably a manifestation of coincident HIV or HCV infection and is not an independent disease process.

Cocaine

More than 3.6 million Americans are chronic cocaine users.66 Most of the medical consequences of cocaine abuse are related to the pharmacologic properties of the drug67 or infectious disease implications of its use. In addition to its well-known local anesthetic effects, cocaine produces intense vasoconstriction in nearly all vascular beds. Cocaine inhibits presynaptic reuptake of norepinephrine, enhances actions of circulating endogenous catecholamines, and augments centrally mediated sympathetic nervous system activity. These actions produce tachycardia and hypertension, thereby increasing myocardial oxygen consumption. Cocaine also causes direct epicardial coronary artery vasoconstriction, coronary vasospasm, and prothrombotic effects (eg, increased platelet adhesion and aggregation). These combined actions may produce myocardial ischemia and infarction.68 Indeed, Mittelman et al reported that the risk of myocardial infarction was increased by greater than 20-fold during the first hour after cocaine use compared with other times.69 Cocaine use may be responsible for as many as 25% of acute myocardial infarctions in subjects between 18 and 45 years of age70 independent of route or frequency of administration, drug quantity, or plasma concentration. With the exception of smoking, risk factors for coronary artery disease are most often absent. Angiographically documented coronary stenoses are present in only 50% of these patients.68 Cocaine inhibits sarcolemmal Na+, voltage-dependent Ca2+, and K+ channel conductance attenuates Ca2+-induced Ca2+ release from the sarcoplasmic reticulum and reduces myofilament Ca2+ sensitivity.71 When combined with the sympathomimetic and vagolytic actions of the drug, these electrophysiological effects may produce ventricular arrhythmias and sudden cardiac death independent of ischemia or preexisting heart disease. Accelerated coronary atherosclerosis occurs in chronic cocaine abusers and contributes to the risk of myocardial ischemia and infarction.72 Release of inflammatory cytokines, repeated exposure to elevated circulating catecholamines, enhanced vascular endothelial permeability permitting intimal diffusion of atherogenic lipoproteins, and chronic vasospasm are postulated mechanisms for this accelerated atherosclerosis. Cocaine abuse causes focal myocarditis and necrosis. These pathologic findings are very similar to those observed in disease states in which serum catecholamine concentrations are chronically increased (eg, pheochromocytoma). Cocaine-induced hypertension contributes to the development of left ventricular hypertrophy, dilated cardiomyopathy, and congestive heart failure, especially in patients with preexisting essential or alcohol-induced hypertension. Cocaine abuse is a major risk factor for acute aortic or coronary dissection, peripheral vascular insufficiency, and limb ischemia. A greater risk of aortic or mitral valve endocarditis may occur in intravenous cocaine compared with heroin or amphetamine abusers.68

The pulmonary complications of cocaine abuse occur as a result of drug inhalation and are exacerbated by habitual tobacco or marijuana smoking. Like other inhaled drugs of abuse, inhalation of cocaine may cause bronchospasm, chronic bronchitis, barotrauma, hemoptysis, or pulmonary fibrosis.73 Inhaled cocaine produces intense pulmonary vasoconstriction and increases vascular permeability because of its sympathomimetic properties. These actions contribute to limited diffusion capacity similar to that observed in chronic tobacco smokers. More ominously, inhaled cocaine may cause diffuse alveolar hemorrhage or noncardiogenic pulmonary edema resulting from increased pulmonary capillary permeability.73 Cocaine-induced pulmonary edema may also occur because of high negative intrathoracic pressures during inhalation or increases in sympathetic nervous system activity in the pulmonary circulation.73 Despite the acute pulmonary vascular effects of cocaine use, pulmonary infarction has been rare. Irreversible pulmonary hypertension may occur in cocaine abusers resulting from pulmonary arterial medial hypertrophy and the frequent development of interstitial fibrosis mediated by the deposition of talc, silica, or other substances used to "cut" the drug.73 Inhaled cocaine suppresses B- and T-lymphocyte function and impairs the activity of alveolar macrophages, thereby predisposing the abuser to pulmonary infection. A delayed eosinophilic hypersensitivity pneumonitis that bears many similarities to Loeffler disease has also been described after cocaine inhalation. Pleuritic chest pain, hemoptysis, diffuse infiltrates, hypoxemia, fever, and eosinophilia are characteristic features of this "crack lung" syndrome that usually occurs within hours after binge abuse.74 Upper airway complications, including mucosal irritation and burns, are common among cocaine abusers. Vasoconstriction produced by nasal cocaine inhalation may cause septal perforation, acute or chronic sinusitis, epiglottis, airway obstruction, or an upper airway vasculitis that resembles Wegener granulomatosis.73 Severe upper airway burns may also occur as result of freebasing, a potentially explosive chemical process in which a flammable solvent is used to transform cocaine from a salt to a base, thereby increasing the drug's potency. Drugs users who smoke crack cocaine also have a higher incidence of tuberculosis compared with those who inhale other drugs of abuse.

Cerebrovascular accident and seizure are 2 primary acute neurologic complications associated with cocaine abuse. Ischemic strokes, including transient ischemic attacks and cerebral infarction, constitute approximately half of all cocaine-induced cerebrovascular accidents and may be attributed to the combination of cerebral vasoconstriction and a prothrombotic state. Indeed, direct cerebral vasoconstriction was observed using magnetic resonance angiography during administration of cocaine to healthy volunteers.75 Cocaine-induced hypertension is responsible for most hemorrhagic strokes. Chronic cocaine abusers may suffer from cognitive dysfunction as a result of multi-infarct dementia. Cocaine-induced seizures are usually single grand mal events that most often resolve without the need for therapeutic intervention. Notably, such seizure activity may be observed without signs or symptoms of systemic drug toxicity. Seizures occur more frequently with an inhalational or intravenous compared with an intranasal route of administration. Interestingly, seizures may also develop several hours after cocaine abuse, presumably because benzoylecgonine (a cocaine metabolite) has epileptogenic effects.

Cocaine abuse has several gastrointestinal and hepatic consequences. Mesenteric vasoconstriction and the direct toxic effects of cocaine on intestinal mucosa cause large or small intestinal ischemia, infarction, or perforation. Bowel obstruction or acute drug toxicity has been reported with the intentional ingestion of wrapped packages of cocaine ("stuffing" or "packing") that is performed to smuggle the drug or avoid imminent arrest when in its possession.76 These complications often require immediate surgical intervention. Cocaine hepatitis is a relatively rare disorder caused by hepatic vasoconstriction combined with toxic oxidative metabolites generated through cytochrome P450 3A1, a secondary route of cocaine metabolism. Cocaine hepatitis develops shortly after drug use and is most often associated with evidence of systemic toxicity. Simultaneous alcohol abuse induces P450 enzymatic activity and facilitates the development of cocaine hepatitis. Cocaine hepatotoxicity also occurs in patients with reduced plasma pseudocholinesterase activity (the major route of cocaine metabolism) because the P450 3A1 pathway assumes a greater role for drug metabolism. Centri- or panlobular hepatic necrosis and marked elevations in serum aminotransferase concentrations are characteristic findings in patients with cocaine hepatitis.

Other acute and chronic renal diseases are quite common in patients who abuse cocaine and are often related to infectious diseases, especially in intravenous users. A nephrotic syndrome characterizes HIV or hepatitis nephropathy, whereas glomerulonephritis results from bacterial endocarditis or sepsis. A mixed nephritic-nephrotic syndrome is most often observed with chronic HCV infection. Renal infarction, accelerated hypertension, rhabdomyolysis, or thrombotic microangiopathy contributes to cocaine-induced renal insufficiency.77 The pronounced sympathomimetic actions of cocaine and its prothrombotic effects cause direct renal arterial vasoconstriction and thrombosis. These actions produce acute renal ischemia and infarction. Cocaine-induced hypertension clearly worsens preexisting renal insufficiency. Cocaine abuse also causes rhabdomyolysis and acute tubular necrosis. A final cause of acute renal insufficiency in cocaine abusers is thrombotic microangiopathy, a syndrome that may occur and accompany hemolytic uremic syndrome or renal infarction.78

Amphetamines

Amphetamines, including d,l-amphetamine, methylphenidate, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), cause a wide variety of acute and chronic medical consequences. In recent years, abuse of MDMA and methamphetamine has increased dramatically, attracting the attention of federal regulatory agencies and the national media. Similar to the actions of cocaine, amphetamines produce sympathetic nervous system activation, inhibit the presynaptic reuptake of biogenic amines, and exert direct agonist actions on peripheral α- and β-adrenoreceptors to varying degrees depending on minor structural variations in their β-phenylethylamine chemistry. Amphetamines cause dose-related hypertension that may be sustained for several hours depending on each drug's pharmacokinetics. Tachycardia is also observed with methylphenidate and MDMA ingestion because these drugs produce relatively greater β1-adrenoceptor stimulation than other amphetamines. These hemodynamic effects increase myocardial oxygen consumption and may produce acute myocardial ischemia and infarction, malignant ventricular arrhythmias, and sudden cardiac death. Notably, the cardiovascular effects of amphetamines are potentiated by strenuous physical activity, and deaths attributed to MDMA at nightclubs or dance parties ("raves") may be related to this additive effect.79 Pathological examination of hearts from amphetamine abusers often demonstrates focal necrosis and myocarditis consistent with chronic catecholamine exposure. Amphetamines produce arterial vasospasm and promote thrombosis as a result of their sympathomimetic effects, and these actions further contribute to myocardial injury. Methamphetamine abuse also causes necrotizing angiitis, a vascular disease of the intima and media that is very similar to polyarteritis nodosa.

Similar to the findings with inhaled opioids and cocaine, inhalation of amphetamines may cause barotrauma, mucosal irritation and hemoptysis, and cardiogenic or noncardiogenic pulmonary edema.73 Amphetamine overdose may produce central nervous system depression or seizures. Aspiration is quite common under these conditions. In contrast to cocaine, amphetamines are sequestered within pulmonary parenchyma. When combined with pulmonary arterial vasoconstriction, this pulmonary sequestration contributes to the well-known relationship between chronic methamphetamine or methylphenidate abuse and pulmonary hypertension. Epidemiology studies indicated a strong link between the amphetamine derivative fenfluramine and pulmonary hypertension in many patients who had been prescribed the drug as an appetite suppressant.80 Amphetamines also reduce immune function and increase the risk of bacterial, viral, or fungal pneumonia. For example, inhaled amphetamine increases immunosuppressive cytokine expression and reduces CD4 cell number. These actions may predispose the HIV patient to pulmonary infection.

Cerebrovascular accidents in amphetamine abusers may be ischemic or hemorrhagic in origin. Similar to cocaine, amphetamine-induced ischemic strokes may occur because of cerebral vasoconstriction.81 Hypertension is the most common cause of amphetamine-induced hemorrhagic stroke. In contrast to seizures produced by cocaine, clinical signs and symptoms of drug toxicity often accompany seizures occurring as a result of amphetamine abuse. Psychological effects are also prevalent with amphetamine abuse. Exaggerated paranoia is a characteristic feature of active drug use, whereas withdrawal may cause prolonged clinical depression as a result of the absence of a stimulant effect.

Fulminant hepatic failure requiring urgent liver transplantation was reported in MDMA abusers.82 Such hepatic failure may occur acutely independent of drug dose or may develop days or even weeks after abuse. Delayed drug metabolism by cytochrome P450 2D6 in susceptible patients with reduced enzymatic activity or an immunologically mediated cause are proposed mechanisms by which this delayed hepatoxicity occurs. Jaundice, pruritus, severe hyperbilirubinemia, elevated transaminases (AST more than ALT), hypovolemia, hyperthermia, and rhabdomyolysis concomitant with drug abuse are prominent features of MDMA-induced hepatic failure. Methamphetamine use is also associated with the development of HAV. Amphetamine abuse alters kidney perfusion, and accelerated hypertension and acute renal failure are well-known complications of methamphetamine and MDMA abuse. Necrotizing vasculitis with microaneurysm formation and thrombosis may also occur, leading to renal ischemia and chronic renal insufficiency. Rhabdomyolysis and acute tubular necrosis often accompany MDMA abuse, especially during exercise-induced hyperthermia and hypovolemia. Interestingly, many MDMA abusers recognize the risk of developing acute hypernatremia under these conditions and attempt to prevent this complication by ingesting large quantities of water, thereby inadvertently causing neurologically significant hyponatremia.

Marijuana

Marijuana or hashish abuse increases heart rate and cardiac output and reduces systemic vascular resistance. As a result, arterial blood pressure is maintained. These hemodynamic effects mirror serum Δ-9-tetrahydrocannabinol (the psychoactive drug in marijuana and hashish) concentration, are more pronounced following inhalation compared with other routes of administration, and are often accompanied by ventricular ectopy. The cardiovascular actions of marijuana are usually well tolerated by healthy subjects but may have important consequences for patients with heart disease. Marijuana-induced tachycardia increases myocardial oxygen consumption. Elevated carboxyhemoglobin levels resulting from smoking the drug reduce myocardial oxygen supply. Thus patients with coronary artery disease who abuse marijuana are at risk of developing myocardial ischemia or infarction.83 The pulmonary complications of marijuana smoking are similar to those produced by tobacco smoking. Chronic bronchitis and emphysema occur in marijuana smokers, and the additional use of tobacco clearly exacerbates these diseases. Marijuana smoking causes more tar deposition and higher carboxyhemoglobin concentrations than tobacco smoking.84 These effects are related, at least in part, to sustained inhalation and breath holding, which are performed to maximize drug uptake. Like tobacco smoking, marijuana smoking weakens pulmonary defenses, including alveolar macrophage function, cytokine formation, and ability to combat oxidative stress against pathologic organisms. Chronic, heavy marijuana smoking may also contribute to the development of lung or oropharyngeal cancer. Marijuana is often contaminated with fungi or actinomycetes, inhalation of which may cause an infection or a hypersensitivity reaction. Immunosuppressed marijuana users, including those with HIV, are particularly vulnerable to pulmonary aspergillosis.

Hallucinogens

Similar to cocaine and amphetamines, phencyclidine and lysergic acid diethylamide (LSD) are potent sympathomimetics. Phencyclidine or LSD ingestion causes tachycardia and hypertension, increases myocardial oxygen consumption, produces coronary artery vasoconstriction or vasospasm, and creates a prothrombotic effect. These actions may combine to cause acute myocardial ischemia or infarction. Severe hypertension, left ventricular hypertrophy, and malignant ventricular arrhythmias also occur in chronic phencyclidine and LSD abusers. Notably, the mechanisms by which phencyclidine and LSD stimulate the sympathetic nervous system are somewhat different than cocaine or amphetamines. As a result, cardiovascular cross-tolerance between phencyclidine or LSD and other stimulants may not occur. In addition to cardiovascular consequences, phencyclidine and LSD abuse produce neurologic effects. Like ketamine, phencyclidine causes an acute dissociative state that bears a striking resemblance to schizophrenia. The phencyclidine abuser may be highly agitated and experience delusions, hallucination, and paranoia. Paradoxically, frank catatonia may be present. LSD also produces hallucinations that limit compliance with treatment. LSD users often report "flashbacks" (hallucination recurrence that is temporally remote from drug abuse itself). Abuse of large quantities of phencyclidine, LSD, or other hallucinogens (such as mescaline) may produce seizures, myoclonus, and coma. Phencyclidine or LSD abuse may cause ischemic or hemorrhagic stroke through direct cerebral vasoconstriction or hypertension, respectively. Hyperthermia and acute liver necrosis resembling malignant hyperthermia has been reported in phencyclidine abusers.85 Rhabdomyolysis and acute tubular necrosis may also occur with the abuse of hallucinogens.

Inhalants

Inhalants include volatile hydrocarbons (eg, hexane, xylene, toluene) contained in paints, solvents, and adhesives. Teenagers frequently abuse inhalants because they are inexpensive and readily available. These drugs may be directly sniffed or forcefully inhaled using an airtight container ("huffing") to produce rapid intoxication. Inhalant abuse causes many respiratory complications, including asphyxiation resulting from respiratory depression, bronchospasm in the presence or absence of preexisting asthma, airway mucosal irritation, hemoptysis, hypersensitivity pneumonitis, aspiration, and barotrauma.86 Methemoglobinemia and resultant cyanosis may occur with abuse of amyl nitrate or related compounds ("poppers"). Suffocation by a plastic bag used as an inhalant container has also been reported. Toluene inhalation may cause a white matter dementia in which extrapyramidal signs and symptoms, cerebellar ataxia, and oculomotor effects are present. Inhaled toluene also causes a nonanion gap metabolic acidosis and hypokalemia resulting from formation of the metabolite hippuric acid. Lead encephalopathy has been described in individuals who inhale gasoline. Inhalation of hexane-containing adhesives produces a progressive sensory-motor polyneuropathy ("glue sniffer's neuropathy").

Withdrawal commonly occurs during the perioperative period in alcohol or drug abusers, and prophylaxis against withdrawal should be initiated before surgery in patients with a history of recent heavy use. Alcohol withdrawal causes substantial increases in morbidity and mortality.87 Alcohol withdrawal usually begins within 24 hours after ingestion ceases. The severity of alcohol withdrawal does not appear to be correlated with the total quantity of alcohol ingested or the duration of consumption. Headache, anxiety, nausea, vomiting, diarrhea, and sleep disturbances characterize early alcohol withdrawal (Table 24-3). Fever, diaphoresis, tachycardia, hypertension, hyperreflexia, and tremor often accompany these symptoms. Visual, auditory, or tactile hallucinations may also be present, but the alcohol abuser initially recognizes that these hallucinations are not real. Alcohol withdrawal resolves spontaneously in most abusers without progressing to seizures or delirium tremens (DTs). An alcohol withdrawal seizure is usually a single grand mal event, correlates closely with maximal increases in electroencephalographic activity, and occurs in a minority (10%-33%) of alcohol abusers without benzodiazepine prophylaxis.88 Status epilepticus occurs in fewer than 3% of alcohol abusers who develop withdrawal seizures.89 Patients who have experienced multiple episodes of abuse and withdrawal are at greater risk of alcohol withdrawal seizures. DTs usually occur 3 to 4 days after alcohol consumption stops. Exaggerated signs and symptoms of withdrawal, vivid hallucinations that are indistinguishable from reality, profound confusion, disorientation, and marked agitation are common. This delirium usually resolves within 72 hours, is more frequent in older patients, and continues to carry a mortality rate of approximately 1% because of delayed or insufficient treatment and the presence of coexisting diseases.

Full discussion of the pathophysiology and treatment of alcohol withdrawal is beyond the scope of this chapter. Briefly, alcohol abuse is assumed to chronically stimulate inhibitory GABA-mediated neurotransmission and attenuate autonomic nervous system sensitivity. In response, an upregulation of GABAergic and central and peripheral adrenergic receptors occurs. Thus anxiety, tremor, hyperreflexia, and a reduction in seizure threshold are observed during alcohol withdrawal because GABA receptors are no longer stimulated and central nervous system excitatory neurotransmission is relatively unopposed. Sudden abstinence from alcohol consumption also causes a rebound activation of the sympathetic nervous system, thereby producing the characteristic findings of fever, diaphoresis, tachycardia, and hypertension during withdrawal. Benzodiazepines are used to treat alcohol withdrawal because these drugs activate GABA receptors and facilitate inhibitory neurotransmission. β1-or α2-adrenoceptor agonists may also blunt increases in sympathetic nervous system tone. Close monitoring for developing signs and symptoms of alcohol withdrawal using established guidelines (eg, Clinical Institute Withdrawal Assessment Scale for Alcohol) should be used to direct pharmacologic management and supportive care.

The clinical ramifications of benzodiazepine or barbiturate withdrawal are similar to alcohol withdrawal, largely because the primary site of action of the sedative-hypnotic drugs is also the GABA receptor. Fever, tachycardia, hypertension, gastrointestinal symptoms, and evidence of neurologic excitability occur after abrupt discontinuation of chronic benzodiazepine or barbiturate abuse. More severe withdrawal from these drugs causes hallucinations, seizures, delirium, and death. The elimination half-life of the abused drug determines the onset, whereas the type, dose, potency, and duration of sedative-hypnotic abuse are the major factors that establish the severity of withdrawal. In contrast to the findings during alcohol withdrawal, the duration of benzodiazepine or barbiturate withdrawal may be very prolonged, often extending from several weeks to months. Patients who abuse alcohol or other substances also frequently use benzodiazepines or barbiturates, and withdrawal from other drugs of abuse worsens the symptoms of simultaneous sedative-hypnotic withdrawal. Other factors that contribute to the severity of sedative-hypnotic withdrawal include coexisting psychiatric conditions (particularly anxiety disorders and depression), family history of alcohol abuse, age, and female gender. The addition of an acute surgical stress response may also increase the severity of benzodiazepine or barbiturate withdrawal. As a result, initiation of a cross-tolerant alterative sedative-hypnotic is recommended during the perioperative period to avoid withdrawal.

Prompt recognition and appropriate treatment of withdrawal are also essential in the opioid abuser during the perioperative period. Unlike alcohol or sedative-hypnotic withdrawal, mortality rarely occurs during opioid withdrawal unless significant coexisting diseases are present. Nevertheless, opioid withdrawal is so intensely uncomfortable that untreated abusers often leave the hospital against medical advice. Many opioid abusers report that continued drug use is motivated, in large part, by a desire to avoid withdrawal symptoms. Fever, anxiety, irritability, intense drug ideation, altered thermoregulation, rhinorrhea, piloerection, pupillary dilatation, and gastrointestinal symptoms are prominent features of acute opioid withdrawal. Hypertension and tachycardia also occur in response to sympathetic nervous system activation. The onset of acute opioid withdrawal depends on the elimination half-life of the abused drug. For example, opioid withdrawal usually occurs within 6 hours after heroin abuse, but the onset of withdrawal is delayed if methadone or a sustained-release opioid (eg, oxycodone, morphine) is the drug of abuse. The pharmacokinetics of the abused opioid are also responsible for the duration of the withdrawal symptoms. The duration of abuse, the dose of drug, and the route of administration (intravenous more than inhaled) are also determinants of the severity of opioid withdrawal.

The easiest strategy for managing opioid withdrawal during the perioperative period is methadone substitution therapy.90 A validated withdrawal evaluation tool to should be used to guide treatment. Using this method, an oral or intravenous loading dose of methadone is administered before the onset of withdrawal. Subsequent doses are titrated until symptoms are controlled and a stable daily dose is established. Methadone may be continued at this constant dose throughout the hospital course or the dose may be gradually reduced as opioid withdrawal symptoms improve. It is essential to recognize that methadone substitution therapy for opioid withdrawal should not be confused with acute or chronic pain management. Perioperative opioid withdrawal may also be treated independent of substitution therapy using a benzodiazepine and an α2-adrenoceptor agonist administered on a scheduled basis to control anxiety and sympathetic nervous system responses, respectively. Consultation with an addictionologist is recommended to guide perioperative therapy and arrange postoperative substance abuse treatment.

Drug ideation, depression, anhedonia, and hypersomnolence characterize cocaine or amphetamine withdrawal.91 These symptoms are usually self-limited but may initially be quite pronounced (known as a "crash"). Stimulant withdrawal is usually treated with supportive care alone and most often does not require pharmacologic intervention. Notably, the appearance of cocaine or amphetamine withdrawal symptoms (particularly hypersomnolence) during the perioperative period may be confused with a new neurologic event. Anxiety, irritability, insomnia, and gastrointestinal complaints may occur after abrupt cessation of marijuana use in a minority of patients. Treatment of these symptoms is primarily supportive, but antidepressants may benefit some patients. Specific phencyclidine or hallucinogen withdrawal syndromes have not been described, but some patients report constitutional complaints, including anxiety, fatigue, hypersomnolence, depression, and anhedonia. These acute symptoms and the delayed "flashbacks" of phencyclidine or hallucinogen abuse most often respond to supportive care, but some patients with severe manifestations may benefit from benzodiazepines or antidepressant medications.

A detailed description of the perioperative management each of the scenarios that might occur in active alcohol or drug abusers is beyond the scope of this chapter. However, the pharmacologic diversity of drugs of abuse combined with the wide range of complications that accompany substance abuse requires that the anesthesiologist has a clear understanding of the ramifications of substance abuse and applies this knowledge to the specifics of each patient. The perioperative approach to the patient with addiction varies depending on the type, location, and duration of the anticipated surgical procedure and the presence, severity, and relative stability of alcohol- or drug-related comorbidities. Several general principles should guide the perioperative care of the patient with an active substance abuse disorder (Table 24-4). Historical evidence of abstinence from alcohol and other drugs of abuse, confirmed by appropriate laboratory analysis, is strongly recommended before the patient undergoes elective surgery (Fig. 24-4) because of the well-recognized increase in the incidence and severity of perioperative complications and the potentially life-threatening consequences of withdrawal. Cessation of drug use before elective surgery also promotes stabilization of many abuse-related medical complications and may increase the probability that the patient will comply with postoperative instructions upon discharge (eg, follow-up appointments, wound care, physical therapy). In some patients, abstinence before elective surgery may be facilitated by frank discussions with the anesthesiologist and surgeon regarding the consequences of continued abuse. Other patients may require the assistance of an addiction medicine specialist to achieve abstinence before an elective procedure. Unfortunately, attaining preoperative abstinence is often an unrealistic goal for many alcohol or drug abusers undergoing urgent or emergent surgery. Under such circumstances, alcohol or drug withdrawal must be anticipated, and appropriate measures (eg, drug prophylaxis guided by history and laboratory tests, anticipated admission to an intensive care unit) should be instituted well before the expected onset of withdrawal signs and symptoms. Vigilance about the potential for drug withdrawal is essential for all patients with a history of recent substance abuse, and the benefits of proactive intervention cannot be overemphasized.

Physicians and nurses should take a straightforward, nonjudgmental approach to the patient. Such a strategy often encourages the alcohol or drug abuser to cooperate with the treatment plan. Patients should be assured repeatedly that withdrawal symptoms, anxiety, and pain will be appropriated addressed. A clear plan for postoperative pain management should be discussed before surgery. Use of continuous local anesthesia, nerve blocks, nonopioid analgesics, neuraxial techniques, or alternative pain modalities may be used for postoperative pain management, but opioids administered on a scheduled basis should be used as clinically indicated. It is critically important that pain be promptly and adequately treated to avoid the development of a "mutual mistrust" relationship between the patient and health care providers.16 Hyperalgesia is very common in patients with substance abuse disorders, and the anesthesiologist and other clinicians should be prepared to manage pain accordingly. A continuous evaluation of the efficacy of pain management, based on the behavioral and functional responses of the patient, should be conducted throughout the perioperative period.

Active participation of an addiction medicine specialist throughout the entire hospital course is advised. An addictionologist may contribute substantially to the evaluation and treatment of alcohol- or drug-related coexisting diseases, provide guidance about the management of perioperative alcohol or drug withdrawal, and serve as additional resource for pain management strategies. Perhaps most importantly, the addiction medicine specialist also facilitates the transition to substance abuse treatment during postoperative discharge planning. The anesthesiologist and surgeon should recognize that the perioperative experience provides a unique opportunity to intervene in cases of substance abuse.

Recovery is a complex process requiring intense, continuous effort that requires abstinence and a series of personal changes to maintain sobriety (Table 24-5). Acquisition of knowledge about substance abuse disorders, renewal of self-esteem and personal responsibility, development of sober living abilities and social interactions, identification with sources of inspiration, and a unified approach to guide these changes are essential components of recovery.92 The terms cured, former, recovered, and ex-alcoholic or addict are not appropriate to describe the recovering patient. The incidence of relapse may be inversely related to the duration of recovery, but return to use may occur despite many years of recovery. Abstinence alone is not recovery because effective skills for coping with stress independent of drug ideation or use may not be in place. Whether an abstinent individual has more difficulty coping with the perioperative experience than a patient in a well-established recovery program is unknown. Mutual-help organizations including Alcoholics Anonymous (AA) and other Twelve Step programs, individual psychotherapy, behavioral modification, and pharmacologic therapy may all be effective in the management of addiction. The US standard of care in addiction treatment is the Minnesota Model,93 a multidisciplinary approach that includes participation in a Twelve Step program, individual and group psychotherapy, patient and family education, vocational rehabilitation, and spiritual renewal. The experience of other recovering patients is the key element of the Minnesota Model. AA and related groups are fellowships of recovering patients who help each other maintain sobriety. The Twelve Steps are the central tenet of the AA program that serve as guidelines for recovery. Other components of recovery within AA include regular meeting attendance and sponsorship that increase the likelihood of maintaining sobriety.

Several medications used in sobriety maintenance therapy may have important implications for the anesthesiologist (Table 24-6). Alteration of a drug's metabolic consequences (eg, disulfiram in alcoholism), reduction in drug reward (eg, acamprosate in alcoholism), receptor antagonism (eg, naltrexone in opioid addiction), and drug substitution therapy (eg, methadone in refractory opioid addiction) are the major pharmacologic approaches. Several drugs have documented utility in alcohol or opioid addiction, but effective medications for treatment of addiction to other drugs of abuse have yet to be documented. A more frequent incidence of anxiety, psychotic, and affective disorders is also observed in recovering patients. Psychoactive drugs used to treat these disorders reduce the incidence of relapse by limiting self-medication of psychiatric symptoms.

Disulfiram is an alcohol-sensitizing drug that is still occasionally used in the treatment of chronic alcohol abuse. Disulfiram inhibits aldehyde dehydrogenase; acetaldehyde accumulates and a severe aversive reaction occurs when alcohol is ingested. Disulfiram also irreversibly inhibits other sulfhydryl-based enzymes responsible for drug metabolism. For example, disulfiram inhibits dopamine β-hydroxylase, thereby reducing presynaptic neuronal synthesis of norepinephrine. This action may attenuate the cardiovascular response to indirect-acting sympathomimetic amines. Disulfiram also reduces the clearance of benzodiazepines and interferes with the metabolism of barbiturates, tricyclic antidepressants, phenytoin, and warfarin through inhibition of hepatic microsomal enzymes. Calcium carbimide is another alcohol-sensitizing drug used clinically in Europe and Canada that reversibly inhibits alcohol dehydrogenase and may cause less pronounced drug interactions. Naltrexone and nalmefene are mu opioid receptor antagonists that reduce ideation and decrease the incidence of relapse in recovering alcohol abusers.94 Experience with naltrexone and nalmefene has been less successful in opioid addiction, but either of these drugs may be used as "insurance" in abstinence-based recovery because the threshold dose of opioid required to produce euphoria is increased. The recovering patient who continues to receive an opioid antagonist during the perioperative period will have an increased requirement for opioid analgesics. Conversely, the mu receptor is upregulated during chronic opioid antagonist treatment, and perioperative withdrawal of naltrexone or nalmefene is associated with increased sensitivity to opioid agonists.

Acamprosate is an amino acid derivative that substantially reduces ideation95 and improves treatment retention in recovering alcohol abusers. Acamprosate decreases neuronal hyperexcitability caused by chronic alcohol abuse by altering GABA- and glutamate-mediated neurotransmission. These actions reduce drug ideation, a major cause of relapse in recovering alcohol abusers. The anesthetic implications of acamprosate are unknown. Antiepileptics (eg, carbamazepine, valproate, gabapentin) also attenuate alcohol- or opioid-mediated drug ideation.96 Carbamazepine and other antiepileptics hasten recovery from nondepolarizing muscle relaxants by enhancing the drug clearance, increasing serum α1-acid glycoprotein concentration, and causing postsynaptic acetylcholine receptor proliferation. Selective serotonin reuptake inhibitors reduce alcohol use in chronic alcohol abusers with depression and may also prevent relapse in recovering patients with anxiety or affective disorders.97 Profound bradycardia and severe hypotension during anesthesia may rarely occur in patients receiving these drugs.

Methadone, the long-acting mu agonist levo-alpha acetyl methadyl (LAAM), and the partial agonist buprenorphine are used successfully as substitution pharmacotherapy in chronic opioid abusers. Methadone, LAAM, and buprenorphine decrease withdrawal symptoms, inhibit drug ideation, and attenuate the opioid-induced positive reward. Patients chronically treated with methadone, LAAM, or buprenorphine remain physically dependent on opioids despite attenuation of the behavioral aspects of addiction. Verification of the dose of methadone, LAAM, or buprenorphine with an addiction medicine specialist before surgery and unconditional administration of the drug throughout the perioperative period are required to prevent withdrawal. Patients receiving opioid substitution therapy may experience exaggerated pain responses to nociceptive stimuli because of drug tolerance.15 These patients often require inordinately large quantities of additional opioids for postoperative analgesia, and they may benefit from alterative pain control techniques. Substituting a new opioid for methadone, LAAM, or buprenorphine for maintenance therapy during the perioperative period is not recommended. Similarly, increasing the dose or frequency of methadone, LAAM, or buprenorphine administration to provide analgesia should be avoided because the boundaries between treatment of addiction and pain will be obscured.

Anesthesia and surgery may expose the recovering patient to several possible obstacles that increase the risk of relapse. Numerous anecdotal descriptions of drug ideation or relapse after brief perioperative exposure to sedatives or opioids have been reported in recovering patients with years of sobriety, but the precise incidence of such phenomena has not been formally studied. Anxiety about the perioperative experience may be heightened because of concerns about the possibility for relapse and the fear that pain will be inadequately treated. Anxiety and pain are important causes of relapse, and inadequate analgesia produces drug ideation.98 Recovering patients may also display abnormal behavioral responses to stress that increase the risk of relapse.99 Similar to the active alcohol or drug abuser, the recovering patient may encounter surgeons or anesthesiologists during the perioperative period who remain cynical about the sincerity or success of the recovery process. Conversely, other apparently well-intentioned physicians may withhold or restrict pain analgesics because they are afraid to contribute inadvertently to relapse. As a result, the recovering patient may be inadequately managed, a situation that may be further complicated if justified requests for additional analgesics are misinterpreted as "addictive behavior."

The preoperative evaluation allows the anesthesia provider to obtain a detailed history of addiction and recovery, and it also provides ample opportunity to allay anxiety. Many patients openly disclose their addiction and recovery, but others may be somewhat reticent to acknowledge this history because of the stigma that remains attached to the disease. Under these circumstances, the history of addiction and recovery may be elicited by tactfully asking direct questions in response to negative answers to routine inquiries about alcohol or drug use. The history of alcohol or drug abuse, type and quality of and compliance with a recovery program, and participation in mutual-help groups are important components of the past medical history. Involvement of an addictionologist, rehabilitation counselor, and sponsor in the patient's recovery should be noted, the duration and relative success of recovery explored, and the history of and apparent factors responsible for triggering relapse episodes identified. Encouraging the patient to intensify the practices of his or her recovery program is strongly recommended because the patient's support system is an essential defense against relapse during periods of stress.98

Much of the end-organ damage that occurs as a result of chronic substance abuse is reversible with long-term abstinence, but some permanent pathology may remain that requires further evaluation or stabilization before surgery. A urine drug screen is indicated to exclude drug use and identify the need for further referral. Most recovering patients are aware that drugs used for premedication have abuse potential and may refuse premedication on these grounds. Patients familiar with biofeedback, guided imagery, or meditation may want to use these relaxation techniques instead of drug therapy. Euphoria-associated premedication before surgery may theoretically stimulate drug ideation, but use of anxiolytics to control anxiety may be more important because apprehension and exaggerated stress responses are common in the recovering patient. Twelve Step meetings and increased sponsor contact may also be useful anxiolytics.

Clear strategies for the conduct of anesthesia and the management of postoperative pain should be established with the recovering patient before surgery. Reassurance that the history of addiction will not be an obstacle to anesthetic technique and adequate postoperative analgesia should be provided. The anesthesiologist's broad expertise in pain management also deserves strong emphasis. The anesthesiologist should also discuss evaluation of the recovering patient's possible behavioral responses to pain with the nursing staff before surgery because abnormal attitudes or conduct that may signify drug ideation or loss of control over pain medication need to be identified and promptly reported. Notably, unusual behavior specifically related to pain therapy may also indicate the "pseudoaddiction" (drug-seeking behavior related to inadequate analgesia). In contrast to addiction, extinction of aberrant behavior with adequate analgesia characterizes pseudoaddiction.

Analgesics without abuse potential may initially be proposed for the relief of postoperative pain. These drugs may be used with or without continuous regional anesthesia or selective nerve blocks in some recovering patients to provide adequate pain control and reduce or eliminate the use of opioids (see Chapter 72 for detailed approaches to acute postoperative pain management). Alternative pain techniques may also be considered. Importantly, the potential benefits of these methods must be weighed against the risk of inadequate analgesia, a crucial factor in precipitating relapse. Opioids remain the most efficacious analgesics for treatment of surgical pain, and their use should be guided by specific clinical indications. The selection of the type of opioid and the route of administration may be less important than the scheduling of administration. Mixed opioid agonist-antagonists may have less abuse potential than pure mu agonists, but these drugs are not completely devoid of risk and are often inferior to mu agonists for postoperative analgesia. Neuraxial opioids may be beneficial because of reduced euphoria and drug ideation, but this hypothesis has not been formally tested. Scheduled administration of opioids or patient-controlled analgesia (PCA; administered by intravenous or epidural routes) provides benefits over intermittent dosing by simplifying the pain management plan for nursing staff, reducing delays in drug administration that contribute to inadequate analgesia, and eliminating patient requests for opioids that may be misinterpreted as "addictive behavior." Nevertheless, the use of PCA in recovering patients is somewhat controversial because of the dynamics of self-administration. Prescription of opioids solely on a pro re nata basis is not recommended to avoid an association between pain symptoms and administration of the analgesic.

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