3560 PART 13 Neurologic Disorders

and 2013, the proportion of the U.S. population with a current (i.e.,

past 12 months) alcohol use disorder increased by 49% with increases

of almost 100% in women, African Americans, and individuals aged

≥45. Rates are similar in the United States, Canada, Germany, Australia,

and the United Kingdom; tend to be lower in most Mediterranean

countries, such as Italy, Greece, and Israel; and may be higher in

Ireland, France, Eastern Europe (e.g., Russia), and Scandinavia. An

even higher lifetime prevalence has been reported for most native

cultures, including Native Americans, Eskimos, Maori groups, and

aboriginal tribes of Australia. These differences in prevalence reflect

both cultural and genetic influences, as described below. In Western

countries, the typical person with an alcohol use disorder is more often

a blue- or white-collar worker or homemaker. The lifetime risk for this

disorder among physicians is similar to that of the general population.

■ GENETICS

Approximately 60% of the risk for alcohol use disorders is attributed to genes, as indicated by the fourfold higher risk in children

with an alcohol use disorder parent (even if adopted early in life

and raised by nonalcoholics) and a higher risk in identical twins compared to fraternal twins of affected individuals. Like most medical and

psychiatric conditions that are referred to as complex genetically influenced disorders, the risk for alcohol use disorders is related to hundreds of gene variations, each of which explains <1% of the vulnerability.

These genetic variations operate primarily through intermediate characteristics that subsequently combine with environmental influences to

alter the risk for heavy drinking and alcohol problems. These include

genes relating to a high risk for all substance use disorders that operate

through impulsivity, schizophrenia, and bipolar disorder. Another

characteristic, an intense skin flushing response when drinking,

decreases the risk for only alcohol use disorders through gene variations for several alcohol-metabolizing enzymes, especially ALDH (a

mutation only seen in Japanese, Chinese, and Korean individuals), and

to a lesser extent, variations in ADH.

An additional genetically influenced characteristic that increases

the risk for heavy drinking, a low level of response or low sensitivity

to alcohol, can be seen very early in the drinking career and before

acquired tolerance or alcohol used disorders develop. The low response

per drink operates, in part, through variations in genes relating to

calcium and potassium channels, GABA, nicotinic, dopamine, and

serotonin systems. Prospective studies have demonstrated that this

need for higher doses of alcohol to achieve effects predicts future heavy

drinking, alcohol problems, and alcohol use disorders, but not problems with drugs other than alcohol. The impact of a low response to

alcohol on adverse drinking outcomes is partially mediated by a range

of environmental and attitudinal influences, including the selection of

heavier-drinking friends, more positive expectations of the effects of

high doses of alcohol, and using alcohol to cope with stress. Several

studies of college freshmen demonstrated that helping students who

have a low sensitivity to alcohol modify these influences was associated

with lower drinking quantities and fewer alcohol-related problems over

the subsequent year.

■ NATURAL HISTORY

Although the average age of the first drink (~15 years) is similar in

individuals who do and do not go on to develop alcohol use disorders,

an earlier onset of regular drinking and drunkenness, especially in the

context of conduct problems, is associated with a higher risk for later

alcohol-related diagnoses. By the mid-twenties, most nonalcoholic men

and women begin to moderate their drinking (perhaps learning from

negative consequences), whereas those with alcohol use disorders are

likely to escalate their drinking despite difficulties. The first major life

problem from alcohol often appears in the late teens to early twenties,

and a pattern of multiple alcohol difficulties by the mid-twenties. Once

established, the course is likely to include exacerbations and remissions,

with little difficulty in temporarily stopping or controlling alcohol use

when problems develop, but without help, desistance usually gives way

to escalations in alcohol intake and subsequent problems. Following

treatment, between half and two-thirds of those with alcohol use disorders maintain abstinence for at least a year and often permanently. Even

without formal treatment or self-help groups, there is at least a 20%

chance of spontaneous remission with long-term abstinence. However,

should the individual continue to drink heavily, the life span is shortened by ~10 years on average, with the leading causes of early death

being enhanced rates of heart disease, cancer, accidents, and suicide.

■ TREATMENT

The approach to treating alcohol-related conditions is relatively

straightforward: (1) recognize that at least 20% of patients have

an alcohol use disorder; (2) learn how to identify and treat acute

alcohol-related conditions (e.g., severe intoxication); (3) know how to

help patients begin to address their alcohol problems; and (4) know

how to treat alcohol withdrawal symptoms and to appropriately refer

patients for additional help.

■ IDENTIFICATION OF PATIENTS WITH ALCOHOL

USE DISORDERS

Even in affluent locales, the ~20% of patients who have an alcohol use

disorder can be identified by asking questions about alcohol problems

and noting laboratory test results that can reflect regular consumption of six to eight or more drinks per day. The two blood tests with

≥60% sensitivity and specificity for heavy alcohol consumption are

γ-glutamyl transferase (GGT) (>35 U) and carbohydrate-deficient

transferrin (CDT) (>20 U/L or >2.6%); the combination of the two

tests is likely to be more accurate than either alone. The values for

these serologic markers are likely to return toward normal within

several weeks of abstinence. Other useful blood tests include high-normal

MCVs (≥91 μm3

) and serum uric acid (>416 mol/L, or 7 mg/dL).

The diagnosis of an alcohol use disorder ultimately rests on the documentation of a pattern of repeated difficulties associated with alcohol

(Table 453-2). Thus, in screening, it is important to probe for marital

or job problems, legal difficulties, histories of accidents, medical

problems, evidence of tolerance, and so on, and then attempt to relate

these issues to use of alcohol. Some standardized questionnaires can

be helpful, including the 10-item Alcohol Use Disorders Identification

Test (AUDIT) (Table 453-3), but these are only screening tools, and a

face-to-face interview is still required for a meaningful diagnosis.

TREATMENT

Alcohol-Related Conditions

ACUTE INTOXICATION

The first priority in treating severe intoxication is to assess vital

signs and manage respiratory depression, cardiac arrhythmias, and

blood pressure instability, if present. The possibility of intoxication

TABLE 453-2 Diagnostic and Statistical Manual of Mental Disorders, Fifth

Edition, Classification of Alcohol Use Disorder (AUD)

Criteria

Two or more of the following items occurring in the same 12-month period must

be endorsed for the diagnosis of an alcohol use disordera

:

Drinking resulting in recurrent failure to fulfill role obligations

Recurrent drinking in hazardous situations

Continued drinking despite alcohol-related social or interpersonal problems

Tolerance

Withdrawal, or substance use for relief/avoidance of withdrawal

Drinking in larger amounts or for longer than intended

Persistent desire/unsuccessful attempts to stop or reduce drinking

Great deal of time spent obtaining, using, or recovering from alcohol

Important activities given up/reduced because of drinking

 Continued drinking despite knowledge of physical or psychological problems

caused by alcohol

Alcohol craving

a

Mild AUD: 2–3 criteria required; moderate AUD: 4–5 items endorsed; severe AUD: 6

or more items endorsed.

3561Alcohol and Alcohol Use Disorders CHAPTER 453

with other drugs should be considered by obtaining, if needed,

toxicology screens for other central nervous system (CNS) depressants such as benzodiazepines and for opioids. Aggressive behavior

should be handled by offering reassurance but also by calling for

help from an intervention team. If the aggressive behavior continues, relatively low doses of a short-acting benzodiazepine such as

lorazepam (e.g., 1–2 mg PO or IV) may be used and can be repeated

as needed, but care must be taken not to destabilize vital signs or

worsen confusion. An alternative approach is to use an antipsychotic medication (e.g., olanzapine 2.5–10 mg IM repeated at 2 and

6 h, if needed).

INTERVENTION

There are two main elements to highlighting the need for compliance with treatment in a person with an alcohol use disorder:

motivational interviewing and brief interventions. During motivational interviewing, the clinician helps the patient to think through

the assets (e.g., comfort in social situations) and liabilities (e.g.,

health- and interpersonal-related problems) of the current pattern of drinking. The clinician should listen empathetically to the

responses, help the patient weigh options, and encourage the taking

of responsibility for needed changes. Patients should be reminded

that only they can decide to avoid the consequences that will occur

if heavy drinking continues. The process of brief intervention, a

similar approach, has been summarized by the acronym FRAMES:

Feedback to the patient; Responsibility to be taken by the patient;

Advice, rather than orders, on what needs to be done; Menus of

options that might be considered; Empathy for understanding the

patient’s thoughts and feelings; and Self-efficacy, i.e., offering support for the capacity of the patient to make changes.

Once the patient begins to consider change, the discussions can

focus more on the consequences of high alcohol consumption,

suggested approaches to stopping drinking, and help in recognizing and avoiding situations likely to lead to heavy drinking such

as going to night clubs or associating with heavy drinking friends.

Both motivational interviewing and brief interventions can be

carried out in 15-min sessions, but because patients often do not

change behavior immediately, multiple meetings are often required

to explore the problem and possible options, discuss optimal treatments, and explain the benefits of abstinence.

ALCOHOL WITHDRAWAL

If the patient agrees to stop drinking, sudden decreases in alcohol

intake can produce withdrawal symptoms, most of which are the

opposite of those produced by intoxication. Features include tremor

of the hands (shakes); agitation and anxiety; autonomic nervous

system overactivity including an increase in pulse, respiratory rate,

sweating, and body temperature; and insomnia. These symptoms

usually begin within 5–10 h of decreasing ethanol intake, peak on

day 2 or 3, and improve by day 4 or 5, although mild levels of these

problems may persist for 4–6 months as a protracted abstinence

syndrome.

About 2% of individuals with alcohol use disorders experience a

withdrawal seizure, with the risk increasing in the context of older

age, concomitant medical problems, misuse of additional drugs,

and higher alcohol quantities. The same risk factors also contribute

to the ~1% rate of withdrawal delirium, also known as delirium

tremens (DTs), where the withdrawal includes delirium (mental confusion, agitation, and fluctuating levels of consciousness)

associated with a tremor and autonomic overactivity (e.g., marked

increases in pulse, blood pressure, and respirations). The risks for

seizures and DTs can be diminished by identifying and treating

underlying medical conditions early in the course of withdrawal

and by instituting adequate doses of depressant medications such

as benzodiazepines.

Thus, the first step in dealing with possible withdrawal phenomena is a thorough physical examination in all heavy drinkers who

are considering abstinence. This includes evaluation of possible

liver impairment, gastrointestinal bleeding, cardiac arrhythmias,

infection, and glucose or electrolyte imbalances. It is also important

to offer adequate nutrition and oral multiple B vitamins, including

50–100 mg of oral thiamine daily for a week or more. Because

most patients with alcohol use disorders who enter withdrawal are

either normally hydrated or mildly overhydrated, IV fluids should

be avoided unless there is a relevant medical problem or significant

recent bleeding, vomiting, or diarrhea.

The next step is to recognize that because withdrawal symptoms

reflect the rapid removal of a CNS depressant, alcohol, the symptoms can be controlled by administering any depressant in doses

that decrease symptoms (e.g., a rapid pulse and tremor) and then

tapering the dose over 3–5 days. Although most depressants are

effective, benzodiazepines (Chap. 452) have the most supportive

data for use in this situation, combining a high level of safety and

low cost. Short-half-life benzodiazepines can be considered for

patients with serious liver impairment or evidence of significant

brain damage, but they must be given every 4 h to avoid abrupt

blood-level fluctuations that may increase the risk for seizures.

Therefore, most clinicians use drugs with longer half-lives (e.g.,

chlordiazepoxide), adjusting the dose if signs of withdrawal escalate and withholding the drug if the patient is sleeping or has

orthostatic hypotension. The average patient requires 25–50 mg

of chlordiazepoxide or 10 mg of diazepam given PO every 4–6 h

on the first day, with doses then decreased to zero over the next

5 days. Although alcohol withdrawal can be treated in a hospital,

patients in good physical condition who demonstrate mild signs of

withdrawal despite low blood alcohol concentrations and who have

no prior history of DTs or withdrawal seizures can be considered

for outpatient detoxification. For the next 4 or 5 days, these patients

should receive only 1 or 2 days of medications at a time and return

daily for evaluation of vital signs. They can be hospitalized if signs

and symptoms of withdrawal markedly escalate.

Treatment of patients with DTs can be challenging, and the condition is likely to run a course of 3–5 days regardless of the therapy

used. However, conditions that meet the criteria for DTs outlined

above represent medical emergencies that carry an estimated mortality as high as 5%, and treatment is best carried out in an intensive

care unit by well-trained clinicians who closely monitor vital signs.

TABLE 453-3 The Alcohol Use Disorders Identification Test (AUDIT)a

ITEM

5-POINT SCALE (LEAST TO

MOST)

1. How often do you have a drink containing

alcohol?

Never (0) to 4+ per week

(4)

2. How many drinks containing alcohol do you have

on a typical day?

1 or 2 (0) to 10+ (4)

3. How often do you have six or more drinks on one

occasion?

Never (0) to daily or almost

daily (4)

4. How often during the last year have you found

that you were not able to stop drinking once you

had started?

Never (0) to daily or almost

daily (4)

5. How often during the last year have you failed

to do what was normally expected from you

because of drinking?

Never (0) to daily or almost

daily (4)

6. How often during the last year have you needed

a first drink in the morning to get yourself going

after a heavy drinking session?

Never (0) to daily or almost

daily (4)

7. How often during the last year have you had a

feeling of guilt or remorse after drinking?

Never (0) to daily or almost

daily (4)

8. How often during the last year have you been

unable to remember what happened the night

before because you had been drinking?

Never (0) to daily or almost

daily (4)

9. Have you or someone else been injured as a

result of your drinking?

No (0) to yes, during the

last year (4)

10. Has a relative, friend, doctor, or other health

worker been concerned about your drinking or

suggested that you should cut down?

No (0) to yes, during the

last year (4)

a

The AUDIT is scored by simply summing the values associated with the endorsed

response. A score ≥8 may indicate harmful alcohol use.

3562 PART 13 Neurologic Disorders

Medications can include high-dose benzodiazepines (e.g., as much

as 800 mg/d of chlordiazepoxide has been reported) or, for those

who do not respond to that regimen, closely monitored doses of

propofol or dexmedetomidine. The focus of care is to identify and

correct medical problems and to control behavior and prevent

injuries. Antipsychotic medications are not recommended for treatment of alcohol withdrawal symptoms; although antipsychotics are

less likely than benzodiazepines to exacerbate confusion, they may

increase the risk of seizures.

Generalized withdrawal seizures rarely require more than the

administration of an adequate dose of benzodiazepines. There is

little evidence that anticonvulsants such as phenytoin or gabapentin

are more effective than benzodiazepines for alcohol-withdrawal seizures, and the risk of seizures has usually passed by the time effective drug levels are reached. The rare patient with status epilepticus

must be treated aggressively (Chap. 425).

HELPING INDIVIDUALS WITH ALCOHOL USE DISORDERS

TO STOP DRINKING: THE REHABILITATION PHASE

An Overview After completing alcoholic rehabilitation, ≥60% of

individuals with alcohol use disorders, especially highly functioning

patients, maintain abstinence for at least a year; many also achieve

long-term sobriety. The core components of the rehabilitation

phase of treatment include cognitive-behavioral approaches to help

patients recognize the need to change, while working with them to

alter their behaviors to enhance compliance. A key step is to optimize motivation toward abstinence through education of patients

and their significant others about alcohol use disorders and their

likely course over time. It is important to recognize that contrary

to what some physicians might think, the typical person with an

alcohol use disorder is likely to have a job and a family and not fit

the inaccurate “down and out” stereotype. However, after years of

heavy drinking, some patients require vocational or avocational

counseling to help to structure their days, and all patients should try

self-help groups such as Alcoholics Anonymous (AA) to assist them

in developing a sober peer group and to learn how to deal with life’s

stresses while remaining sober. Relapse prevention education helps

patients identify situations in which a return to drinking is likely

(e.g., stopping in a bar to meet friends but planning to only have a

nonalcoholic beverage), formulate ways to avoid the risky situation,

and if not possible, mitigate the risks to which they are exposed.

It is also important to develop coping strategies that increase the

chances of a quick return to abstinence after an episode of drinking.

Although many patients can be treated as outpatients, more

intense interventions are more effective, and some individuals

with alcohol use disorders do not respond to just AA or outpatient

groups. Whatever the setting, ongoing contact with outpatient

treatment staff should be maintained for at least 6 months and preferably for a year after abstinence. Counseling focuses on areas of

improved functioning in the absence of alcohol (i.e., why it is a good

idea to continue abstinence), helping patients to manage free time

without alcohol, encouraging them to develop a nondrinking peer

group, and discussions of ways to handle stress without drinking.

The physician serves an important role in identifying the alcohol

problem, diagnosing and treating associated medical and independent or substance-induced psychiatric syndromes, overseeing detoxification, referring the patient to outpatient or inpatient

rehabilitation programs, providing counseling, and, if appropriate,

selecting which (if any) medication might be needed. For insomnia, patients should be reassured that troubled sleep is temporary after alcohol withdrawal and will begin to improve over

subsequent weeks. They should be taught the elements of “sleep

hygiene” including maintaining consistent schedules for bedtime

and awakening, avoiding exercise or consumption of large meals

before bedtime, and keeping the bedroom cool, dark, and quiet at

night (Chap. 31). Depressant sleep medications are not the optimal approach for this type of insomnia that often continues for

several weeks or months. Patients are likely to develop rebound

insomnia when the depressant dose is decreased or stopped. The

rebound increases the chance they will increase the dose and

potentially develop problems controlling the prescribed depressant

drug. Sedating antidepressants (e.g., trazodone) should not be used

because they interfere with cognitive functioning the next morning

and disturb the normal sleep architecture, but occasional use of

over-the-counter sleeping medications (sedating antihistamines)

can be considered. An additional problem, anxiety symptoms, can

be addressed by increasing patients’ insights into the temporary

nature of the symptoms and helping them develop strategies to

achieve relaxation by using forms of cognitive therapy.

Medications for the Alcohol Rehabilitation Treatment Phase

Several medications have modest benefits when used in the first

6–12 months of recovery. The opioid antagonist naltrexone may

shorten subsequent relapses, whether used in the oral form

(50–150 mg/d) or as a once-per-month 380-mg injection. By

blocking opioid receptors, naltrexone decreases activity in the

dopamine-rich ventral tegmental reward system and decreases

the feeling of pleasure if alcohol is imbibed. A second medication,

acamprosate (Campral) (~2 g/d divided into three oral doses), has

similar modest effects. Acamprosate inhibits NMDA receptors,

decreasing mild symptoms of protracted withdrawal. Several trials

of combined naltrexone and acamprosate have reported that the

combination is well tolerated and the efficacy might be superior to

either drug alone, although not all studies agree.

It is more difficult to establish the asset-to-liability ratio of a

third drug, disulfiram, an ALDH inhibitor, used clinically at doses

of 250 mg/d, a dose usually selected to avoid the side effects of the

more effective 500 mg/d regimen. This drug produces vomiting and

autonomic nervous system instability in the presence of alcohol as

a result of rapidly rising blood levels of acetaldehyde. This reaction

can be dangerous, especially for patients with heart disease, stroke,

diabetes mellitus, or hypertension. The drug itself carries potential

risks of temporary depressive or psychotic symptoms, peripheral

neuropathy, and liver damage. Disulfiram is best given under supervision by someone (such as a spouse), especially during high-risk

drinking situations (such as the Christmas holidays).

A 16-week, placebo-controlled trial in patients with relatively

severe acute withdrawal reported better outcomes with use of a

depressant medication (gabapentin 1200 mg/d), but those results

have not yet been replicated. Additional drugs under investigation include another opioid antagonist, nalmefene; the nicotinic

receptor agonist varenicline; the serotonin antagonist ondansetron;

the α-adrenergic agonist prazosin; the GABAB receptor agonist

baclofen; the anticonvulsant topiramate; and cannabinol receptor

antagonists. At present, there are insufficient data to determine the

asset-to-liability ratio for these medications in treating alcohol use

disorders, and therefore, few data yet offer solid support for their

routine use in clinical settings.

■ GLOBAL CONSIDERATIONS

As described above, rates of alcohol use disorders differ across sex,

age, ethnicity, and country. There are also differences across countries

regarding the definition of a standard drink (e.g., 10–12 g of ethanol in

the United States and 8 g in the United Kingdom) and the definition of

being legally drunk. The preferred alcoholic beverage also varies across

groups, even within countries. That said, regardless of sex, ethnicity, or

country, the actual drug in the drink is still ethanol, and the risks for

problems, course of alcohol use disorders, and approaches to treatment

are similar across the world.

■ FURTHER READING

Anton RF et al: Efficacy of gabapentin for the treatment of alcohol use

disorder in patients with alcohol withdrawal symptoms: A randomized clinical trial. JAMA Intern Med 180:728, 2020.

Coutney KE et al: The effect of alcohol use on neuroimaging correlates of cognitive and emotional processing in human adolescents.

Neuropsychopharmacology 33:781, 2019.

3563 Nicotine Addiction CHAPTER 454

The use of tobacco leaf to create and satisfy nicotine addiction was

introduced to Columbus by Native Americans and spread rapidly to

Europe. Use of tobacco as cigarettes, however, only became popular

in the twentieth century and so is a modern phenomenon, as is the

epidemic of disease caused by this form of tobacco use.

Nicotine is the principal constituent of tobacco responsible for its

addictive character, but other smoke constituents and behavioral associations contribute to the strength of the addiction. Addicted smokers

regulate their nicotine intake by adjusting the frequency and intensity

of their tobacco use both to obtain the desired psychoactive effects and

avoid withdrawal.

Unburned cured tobacco used orally contains nicotine, carcinogens,

and other toxicants capable of causing gum disease, oral and pancreatic

cancers, and an increase in the risk of heart disease. When tobacco is

burned, the resultant smoke contains, in addition to nicotine, >7000

other compounds that result from volatilization, pyrolysis, and pyrosynthesis of tobacco leaf and various chemical additives used in making different tobacco products. Tobacco smoke is composed of a fine

aerosol and a vapor phase; the aerosol is of a size range that results in

deposition in the airways and alveolar surfaces of the lungs. The aggregate of particulate matter, after subtracting nicotine and moisture, is

referred to as tar.

The alkaline pH of smoke from blends of tobacco used for pipes and

cigars allows sufficient absorption of nicotine across the oral mucosa

to satisfy the smoker’s need for this drug. Therefore, those who smoke

pipes and cigars exclusively tend not to inhale the smoke into the lung,

confining the toxic and carcinogenic exposure (and the increased rates

of disease) largely to the upper airway. The acidic pH of smoke generated by the tobacco used in cigarettes dramatically reduces absorption

of nicotine in the mouth, necessitating inhalation of the smoke into

the larger surface of the lungs in order to absorb quantities of nicotine

sufficient to satisfy the smoker’s addiction. The shift to using tobacco as

cigarettes, with resultant increased deposition and absorption of smoke

in the lung, has created the epidemic of heart disease, lung disease,

and lung cancer that dominates the current disease manifestations of

tobacco use.

Several genes have been associated with nicotine addiction. Some

reduce the clearance of nicotine, and others have been associated

with an increased likelihood of becoming dependent on tobacco and

other drugs as well as a higher incidence of depression. It is likely that

454 Nicotine Addiction

David M. Burns

TABLE 454-1 Relative Risks for Current Smokers of Cigarettes

AGE 35–44 45–64 65–74 ≥75

Males

Lung cancer 14.33 19.03 28.29 22.51

Coronary heart disease 3.88 2.99 2.76 1.98

Cerebrovascular disease 2.17 1.48 1.23 1.12

Other vascular diseases 7.25 4.93

Chronic obstructive pulmonary

disease (COPD)

29.69 23.01

All causes 2.55 2.97 3.02 2.40

Females

Lung cancer 13.30 18.95 23.65 23.08

Other tobacco-related cancers 1.28 2.08 2.06 1.93

Coronary heart disease 4.98 3.25 3.29 2.25

Cerebrovascular disease 2.27 1.70 1.24 1.10

Other vascular diseases 6.81 5.77

COPD 38.89 20.96

All causes 1.79 2.63 2.87 2.47

Relative Risks for Selected Other Cancers

Other cancers Male Female

Larynx 14.6 13

Lip, oral cavity, pharynx 10.9 5.1

Esophagus 6.8 7.8

Bladder 3.3 2.2

Kidney 2.7 1.3

Pancreas 2.3 2.3

Stomach 2 1.4

Liver 1.7 1.7

Colorectal 1.2 1.2

Cervix 1.6

Acute myeloid leukemia 1.4 1.4

Grant BF et al: Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV alcohol use disorder in the United States, 2001-

2002 to 2012-2013: Results from the National Epidemiologic Survey

on Alcohol and Related Conditions. JAMA Psychiatry 74:911, 2017.

Schuckit MA: Recognition and management of withdrawal delirium

(delirium tremens). N Engl J Med 371:2109, 2014.

Schuckit MA: A critical review of methods and results in the search

for genetic contributors to alcohol sensitivity. Alcohol Clin Exp Res

42:822, 2018.

Schuckit MA et al: The low level of response to alcohol-based heavy

drinking prevention program: One-year follow-up. J Stud Alcohol

Drugs 77:25, 2016.

Sullivan FP, Geschwind DH: Defining the genetic, genomic, cellular,

and diagnostic architecture of psychiatric disorders. Cell 177:162,

2019.

Witkiewitz K et al: Advances in the science and treatment of alcohol

use disorder. Sci Adv 5:1, 2019.

genetic susceptibility can influence the probability that adolescent

experimentation with tobacco will lead to addiction as an adult. Rates

of smoking cessation have increased, and rates of nicotine addiction

have decreased dramatically, since the mid-1950s, suggesting that factors other than genetics are more important influences for tobacco use.

Adult cigarette smoking prevalence has declined to below 14% in

the United States, with only 75% of the cigarette smokers smoking

every day. The rapidly rising smoking rate observed in the developing

world is of concern, and the World Health Organization Framework

Convention on Tobacco Control is encouraging effective tobacco control approaches in these countries with the hope of preventing a future

epidemic of tobacco-related illness.

DISEASE MANIFESTATIONS OF CIGARETTE

SMOKING

More than 480,000 individuals die prematurely each year in the

United States from cigarette use; this represents almost one of every

five deaths in the United States. Approximately 40% of cigarette smokers

will die prematurely due to cigarette smoking unless they are able to quit.

The major diseases caused by cigarette smoking are listed in

Table 454-1. The ratio of smoking-related disease rates in smokers

compared to never smokers (relative risk) increases with advancing

age for most cancers and for chronic obstructive pulmonary disease

(COPD). However, relative risk declines with advancing age for cardiovascular diseases due to the increasing contribution of other risk

factors as age advances. Nevertheless, even for cardiovascular disease,

the absolute difference in mortality rate between smokers and never

smokers, called excess death rate, continues to increase with advancing

age, as one would expect from a process of cumulative injury.

3564 PART 13 Neurologic Disorders

following cessation is a slowing of the rate of decline in lung function with advancing age rather than a return of lung function toward

normal.

■ PREGNANCY

Cigarette smoking is associated with several maternal complications of

pregnancy: premature rupture of membranes, abruptio placentae, and

placenta previa; there is also a small increase in the risk of spontaneous

abortion among smokers. Infants of smoking mothers are more likely

to experience preterm delivery, have a higher perinatal mortality rate,

be small for their gestational age, and have higher rates of infant respiratory distress syndrome. They are more likely to die of sudden infant

death syndrome and appear to have a developmental lag for at least the

first several years of life.

■ OTHER CONDITIONS

Smoking delays healing of peptic ulcers; increases the risk of developing periodontal disease, diabetes, active tuberculosis, rheumatoid

arthritis, osteoporosis, senile cataracts, and neovascular and atrophic

forms of macular degeneration; and results in premature menopause,

wrinkling of the skin, gallstones, and cholecystitis in women, and

male impotence. Patients who continue to smoke during treatment

for cancer with chemotherapy or radiation have poorer outcomes and

reduced survival.

■ ENVIRONMENTAL TOBACCO SMOKE

Long-term exposure to environmental tobacco smoke increases the

risk of lung cancer and coronary artery disease among nonsmokers.

It also increases the incidence of respiratory infections, chronic otitis

media, and asthma in children and causes exacerbation of asthma in

children. Some evidence suggests that environmental tobacco smoke

exposure may increase the risk of premenopausal breast cancer.

PHARMACOLOGIC INTERACTIONS

Cigarette smoking may interact with a variety of other drugs

(Table 454-2). Cigarette smoking induces the cytochrome P450 system, which may alter the metabolic clearance of drugs such as warfarin.

This may result in inadequate serum levels in smokers as outpatients

when the dosage is established in the hospital under nonsmoking

conditions. Correspondingly, serum levels may rise when smokers are

hospitalized and not allowed to smoke. Smokers may also have higher

first-pass clearance for drugs such as lidocaine, and the stimulant effects

of nicotine may reduce the effect of benzodiazepines or beta blockers.

OTHER FORMS OF TOBACCO USE

Other major forms of tobacco use are moist snuff deposited between

the cheek and gum, chewing tobacco, pipes and cigars, and recently

bidi (tobacco wrapped in tendu or temburni leaf; commonly used in

India), clove cigarettes, and water pipes. Oral tobacco use leads to gum

disease and can result in oral and pancreatic cancer as well as heart

disease. There are dramatic differences in the risks evident for products

used in Africa or Asia as compared to those in the United States and

Europe.

The risk of upper airway cancers is similar among cigarette, pipe,

and cigar smokers, whereas those who have smoked only pipes and

cigars have a much lower risk of lung cancer, heart disease, and COPD.

Cigarette smokers who switch to pipes or cigars do tend to inhale the

smoke, increasing their risk. Use of combusted tobacco in forms resembling and smoking like a cigarette, but classified as a cigar, represents a

growing fraction of combusted tobacco use and likely has disease risks

similar to those of cigarette smoking.

A resurgence of cigar, bidi, and water pipe use among adolescents of

both genders has raised concerns that these older forms of tobacco use

are once again causing a public health problem.

ELECTRONIC CIGARETTES

Electronic cigarettes (e-cigarettes) are devices with a heating element

that produces an inhalable aerosol from a liquid usually containing

nicotine. Multiple different designs exist, but there are three general

categories. Disposable devices that look like cigarettes or ball point

■ CARDIOVASCULAR DISEASES

Cigarette smokers are more likely than nonsmokers to develop both

large-vessel atherosclerosis and small-vessel disease. Approximately

90% of peripheral vascular disease in the nondiabetic population can

be attributed to cigarette smoking, as can ~50% of aortic aneurysms.

In contrast, 24% of coronary artery disease and ~11% of ischemic and

hemorrhagic strokes are caused by cigarette smoking. There is a multiplicative interaction between cigarette smoking and other cardiac risk

factors such that the increment in risk produced by smoking among

individuals with hypertension or elevated serum lipids is substantially

greater than the increment in risk produced by smoking for individuals

without these risk factors.

In addition to its role in promoting atherosclerosis, cigarette smoking also increases the likelihood of myocardial infarction and sudden

cardiac death by promoting platelet aggregation and vascular occlusion. Reversal of these effects on coagulation may explain the rapid

benefit of smoking cessation for a new coronary event demonstrable

among those who have survived a first myocardial infarction. This

effect may also explain the substantially higher rates of graft occlusion

among continuing smokers following vascular bypass surgery for cardiac or peripheral vascular disease.

Cessation of cigarette smoking reduces the risk of a second coronary

event within 6–12 months. Rates of first myocardial infarction and

death from coronary heart disease decline within 2–4 years following

cessation among those with no prior cardiovascular history. After

15 years of abstinence, the risk of a new myocardial infarction or death

from coronary heart disease in former smokers is similar to that for

those who have never smoked.

■ CANCER

Tobacco smoking causes cancer of the lung; lip; oral cavity; naso-, oro-,

and hypopharynx; nasal cavity and paranasal sinuses; larynx; esophagus; stomach; pancreas; liver (hepatocellular); colon and rectum;

kidney (body and pelvis); ureter; urinary bladder; uterine cervix; and

acute myeloid leukemia. There is evidence suggesting that cigarette

smoking may play a role in increasing the risk of breast cancer, particularly for premenopausal women. There does not appear to be a causal

link between cigarette smoking and cancer of the endometrium, and

there is a lower risk of uterine cancer among postmenopausal women

who smoke. The risks of cancer increase with the increasing number

of cigarettes smoked per day and with increasing duration of smoking. Additionally, there are synergistic interactions between cigarette

smoking and alcohol use for cancer of the oral cavity and esophagus.

Several occupational exposures synergistically increase lung cancer

risk among cigarette smokers, most notably occupational asbestos and

radon exposure.

Cessation of cigarette smoking reduces the risk of developing cancer

relative to continuing smoking after about 4 years of abstinence, but

even 20 years after cessation, there is a persistent two- to threefold

increased risk of developing lung cancer.

■ RESPIRATORY DISEASE

Cigarette smoking is responsible for 80% of COPD. Within 1–2 years

of beginning to smoke regularly, many young smokers will develop

inflammatory changes in their small airways, although lung function

measures of these changes do not predict development of chronic

airflow obstruction. Pathophysiologic changes in the lungs manifest

and progress over longer durations of smoking proportional to smoking intensity and duration. Chronic mucous hyperplasia of the larger

airways results in a chronic productive cough in as many as 80% of

smokers >60 years of age. Chronic inflammation and narrowing of the

small airways and/or enzymatic digestion of alveolar walls resulting

in pulmonary emphysema can reduce expiratory airflow sufficiently

to produce clinical symptoms of respiratory limitation in ~15–25% of

smokers.

Changes in the small airways of young smokers will reverse after

1–2 years of cessation. There is also a small increase in measures of

expiratory airflow following cessation among many individuals who

have developed chronic airflow obstruction, but the major change

3565 Nicotine Addiction CHAPTER 454

pens are the oldest products, but they generally do not deliver levels of

nicotine comparable to a cigarette. Later vaping devices utilize a larger

power source and a bulky refillable tank to store the nicotine-containing

liquid. These devices deliver aerosolized nicotine at levels comparable

to cigarette smoking. Liquids to refill the tanks come in different concentrations of nicotine, but liquids with high concentrations of nicotine

create throat irritation, deterring their use. More recent designs include

smaller devices that resemble computer USB flash drives and deliver

nicotine as the salt of a mild acid. The nicotine salt aerosol leaving

the device is mildly acidic, markedly lowering the percentage of the

nicotine that is in the free base form. This reduces the irritation in the

upper airway. However, as the aerosol moves down the airway, its pH

rapidly converts to the lung tissue pH of ~7.4, releasing substantial

amounts of free base nicotine, which is readily absorbed across the

alveolar capillary wall. As the absorbed nicotine is carried away by

the pulmonary blood flow, the remaining nicotine salt converts to the

free base form, further enhancing the amount of nicotine that can be

delivered to the brain. Limited data suggest that the nicotine intake is

higher for users of devices delivering nicotine salts. It is likely that the

transition to use of nicotine salts substantially contributed to the rise in

use of e-cigarettes and addiction to nicotine among adolescents.

The role of e-cigarettes in smoking cessation remains conflicted.

There is convincing randomized controlled evidence that the use of

refillable-tank e-cigarettes is twice as effective as nicotine-replacement

medications in achieving sustained abstinence from conventional cigarettes. However, 80% of those who achieved abstinence were still using

e-cigarettes at 12 months, suggesting continued nicotine addiction.

Evidence on exposure to toxicants in smoke demonstrates markedly

lower exposures among those using e-cigarettes exclusively, but evidence on e-cigarette use in the United States shows that approximately

one-half of adult e-cigarette users continue to also smoke conventional

cigarettes, negating the benefits of reduced toxicant exposure. Rates of

relapse back to smoking among those with persistent nicotine addiction and the effectiveness of devices containing nicotine salts remain

to be demonstrated.

E-cigarette use among U.S. adolescents has risen dramatically over

recent years, becoming the most common form of nicotine delivery

among adolescents. Adolescents who ever use an inhaled nicotine

product are more likely to be a conventional cigarette smoker 1 year

later (three times more likely with ever e-cigarette use and four times as

likely with ever conventional cigarette use). These data show that adolescents who experiment with nicotine in any form are likely to become

continuing users; nevertheless, the steeply rising level of adolescent

e-cigarette prevalence has been accompanied by an independently

driven dramatic fall in adolescent conventional cigarette prevalence.

Concerns about e-cigarette use becoming a meaningful gateway to conventional cigarette use among adolescents and young adults are thus far

not borne out by prevalence data for both product types.

Refillable or reloadable e-cigarette devices can be used to aerosolize

a variety of liquids other than those provided by the manufacturer.

Disposable “pods” and liquids for these devices can be purchased

from the manufacturer but are also available from other sources that

may use poor-quality manufacturing practices and control of contaminants. They may also contain marijuana oils, other drugs, and

flavors not evaluated for potential lung injury with inhalation. Many

of these liquids are provided on the black market with little oversight

of the production process. Beginning in the spring of 2019, a rapidly

accelerating epidemic of severe hypoxic lung injury was associated

with e-cigarette use. The lung pathology includes diffuse alveolar

damage, acute fibrinous pneumonitis, and organizing pneumonia. The

closest associations were for cannabinoid products and vitamin E in

the aerosolized liquid, but ~15% of those affected reported using only

nicotine-containing liquids. Following widespread publicity of this

toxicity and its association with irregular product sources, there has

been a reduction in the incidence of this form of lung injury. Given the

capacity of e-cigarettes to produce small particles that readily penetrate

to the alveolar level, multiple toxicants may contribute to the epidemic.

Nevertheless, vitamin E has the strongest evidence to support its role

as a major contributor. Vitamin E is sometimes used as a thickening

agent in tetrahydrocannabinol (THC)-containing products. Given the

difficulty in controlling the illicit market for e-liquids, it is likely that

episodic exposure to pulmonary toxicants will continue to occur. Regulatory control may need to focus on the delivery devices.

LOWER TAR AND NICOTINE CIGARETTES

Filtered cigarettes with lower machine-measured yields of tar and

nicotine commonly use ventilation holes in the filters and other

engineering designs to artificially lower the machine measurements.

Smokers compensate for the lowered nicotine delivery resulting from

these design changes by changing the manner in which they puff on

the cigarette or the number of cigarettes smoked per day. Actual tar and

nicotine deliveries are not reduced with use of these products, negating

any reduction in disease risks with their use.

The amount of carcinogenic tobacco-specific nitrosamines in the

tobacco used in cigarettes has increased over time, and cigarette design

changes that reduce machine-measured tar and nicotine also led to

deeper inhalation of the smoke. Presentation of more carcinogenic

smoke to the alveolar portions of the lung increases the risk of adenocarcinoma of the lung. The increased adenocarcinoma risk produces

a substantively greater overall risk for lung cancer among current

smokers compared with smokers of cigarettes manufactured prior to

the 1960s. This increased risk may also be present for COPD. It is the

changes in cigarette design and composition of cigarettes over the past

TABLE 454-2 Interactions of Smoking and Prescription Drugs

DRUG INTERACTION

Cardiovascular and Pulmonary Drugs

β blockers Reduced lowering of heart rate and blood pressure

Flecainide Increased first-pass clearance

Heparin Faster clearance

Lidocaine Increased first-pass clearance

Mexiletine Increased first-pass clearance

Propranolol Increased first-pass clearance

Theophylline Faster metabolic clearance

Verapamil Increased clearance

Warfarin Increased metabolism lowers serum levels

Neuropsychiatric Drugs

Amitriptyline Increased clearance

Benzodiazepines Less sedation

Clomipramine, Imipramine Decreased serum concentrations

Chlorpromazine Decreased serum concentrations

Clozapine Decreased serum concentrations

Duloxetine Decreased serum concentrations

Fluphenazine Decreased serum concentrations

Fluvoxamine Decreased serum concentrations

Haloperidol Decreased serum concentrations

Naratriptan Increased clearance

Olanzapine Faster clearance

Trazodone Decreased serum concentrations

Anticancer Drugs

Erlotinib Increased clearance, higher response rate, and

improved survival in nonsmokers

Gefitinib Higher response rate and improved survival in

nonsmokers

Irinotecan Increased clearance

Other Drugs

Dextropropoxyphene Less analgesia

Estrogens (oral) Increased hepatic clearance

Fentanyl Increased clearance

Insulin Delayed absorption due to skin vasoconstriction

Rivastigmine Increased clearance

3566 PART 13 Neurologic Disorders

six decades that caused the dramatic rise in rates of adenocarcinoma

of the lung observed over the past half century. There has been no

increase in risk of lung cancer or adenocarcinoma of the lung over the

same period among never smokers.

CESSATION

The process of stopping smoking is commonly a cyclical one, with the

smoker sometimes making multiple attempts to quit and failing before

finally being successful. Approximately 70–80% of smokers would like

to quit smoking. More than one-half of current smokers attempted to

quit in the last year, but only 6% quit for 6 months, and only 3% remain

abstinent for 2 years. Clinician-based smoking interventions should

repeatedly encourage smokers to try to quit and to use different forms

of cessation assistance with each new cessation attempt, rather than

focusing exclusively on immediate cessation at the time of the first visit.

Advice from a physician to quit smoking, particularly at the time of

an acute illness, is a powerful trigger for cessation attempts, with up

to half of patients who are advised to quit making a cessation effort.

Other triggers that may be enhanced by timely physician advice to

quit include increases in the tax on cigarettes, media campaigns, and

changes in rules to restrict smoking in the workplace.

PHYSICIAN INTERVENTION (TABLE 454-3)

All patients should be asked whether they smoke, how much they

smoke, how long they have smoked, their past experience with quitting, and whether they are currently interested in quitting. The number

of cigarettes smoked per day and smoking within 30 min of waking are

useful measures of the intensity of nicotine addiction. Even those who

are not interested in quitting should be encouraged and motivated to

quit; provided a clear, strong, and personalized message by the clinician

that smoking is an important health concern; and offered assistance

if they become interested in quitting in the future. Many of those not

currently expressing an interest in quitting may nevertheless make an

attempt to quit in the subsequent year. For those interested in quitting, a quit date should be negotiated, usually not the day of the visit

but within the next few weeks, and a follow-up contact by office staff

around the time of the quit date should be provided. There is a relationship between the amount of assistance a patient is willing to accept

and the success of the cessation attempt.

There are a variety of nicotine-replacement products, including

over-the-counter nicotine patches, gum, and lozenges, as well as nicotine nasal and oral inhalers available by prescription. These products

can be used for up to 3–6 months, and some products are formulated

to allow a gradual step-down in dosage with increasing duration of

smoking abstinence. Antidepressants such as bupropion (300 mg in

divided doses for up to 6 months) have also been shown to be effective, as has varenicline, a partial agonist for the nicotinic acetylcholine

receptor (initial dose 0.5 mg daily increasing to 1 mg twice daily at

day 8; treatment duration up to 6 months). Combined use of nicotinereplacement therapy (NRT) and antidepressants as well as the use

of gum or lozenges for acute cravings in patients using patches can

increase cessation outcomes. Pretreatment with antidepressants or

varenicline is recommended for 1–2 weeks prior to the quit date.

Pretreatment with nicotine-replacement products is also useful prior

to a cessation date. Longer duration of nicotine replacement as a

maintenance therapy for those who are unsuccessful in quitting with a

shorter duration of use is a useful strategy. NRT is provided in different dosages, with higher doses being recommended for more intense

smokers. Clonidine or the tricyclic antidepressant nortriptyline should

be reserved for patients who have failed on first-line pharmacologic

treatment or who are unable to use other therapies. Antidepressants are

more effective among smokers with a history of depression symptoms.

Current recommendations are to offer pharmacologic treatment,

usually with nicotine patches or varenicline, to all who will accept it

and to provide counseling and other support as a part of the cessation attempt. Cessation advice alone by a physician or his or her staff

is likely to increase success compared with no intervention; a more

comprehensive approach with advice, pharmacologic assistance, and

counseling can increase cessation success nearly threefold.

For adult addicted smokers, switching to exclusive use of e-cigarettes,

but not dual use with combusted cigarettes, can promote combusted

cigarette cessation, particularly for those unlikely to try to quit with

other proven cessation modalities.

Incorporation of cessation assistance into a practice requires a

change of the care delivery infrastructure. Simple changes include

(1) adding questions about smoking and interest in cessation on

patient-intake questionnaires, (2) asking patients whether they smoke

as part of the initial vital sign measurements made by office staff, (3)

listing smoking as a problem in the medical record, and (4) automating

follow-up contact with the patient on the quit date. These changes are

essential to institutionalizing smoking intervention within the practice

setting; without this institutionalization, the best intentions of physicians to intervene with their patients who smoke are often lost in the

time crush of a busy practice.

PREVENTION

Approximately 85% of individuals who become cigarette smokers

initiate the behavior during adolescence. Factors that promote adolescent initiation are parental or older-sibling cigarette smoking, tobacco

advertising and promotional activities, the availability of cigarettes, and

the social acceptability of smoking. The need for an enhanced self-image

and to imitate adult behavior is greatest for those adolescents who have

the least external validation of their self-worth, which may explain in

part the enormous differences in adolescent smoking prevalence by

socioeconomic and school performance strata.

Prevention of smoking initiation must begin early, preferably in the

elementary school years. Physicians who treat adolescents should be

sensitive to the prevalence of this problem even in the preteen population. Physicians should ask all adolescents whether they have experimented with nicotine or currently use nicotine products, reinforce the

fact that most adolescents and adults do not smoke or use nicotine, and

explain that all forms of nicotine intake are both addictive and harmful.

TABLE 454-3 Clinical Practice Guidelines

Physician Actions

Ask: Systematically identify all tobacco users at every visit

Advise: Strongly urge all smokers to quit

Identify smokers willing to quit

Assist the patient in quitting

Arrange follow-up contact

Effective Pharmacologic Interventionsa

First-line therapies

Nicotine gum (1.5)

Nicotine patch (1.9)

Nicotine nasal inhaler (2.3)

Nicotine oral inhaler (2.1)

Nicotine lozenge (2 mg: 2.0, 4 mg: 2.8)

Bupropion (2.0)

Varenicline (3.1)

Second-line therapies

Clonidine (2.1)

Nortriptyline (1.8)

Other Effective Interventionsa

Physician or other medical personnel counseling (10 min) (1.84)

Intensive group smoking cessation programs (at least 4–7 sessions of 20- to

30-min duration lasting at least 2 and preferably 8 weeks) (1.3)

Intensive individual counseling (1.7)

Clinic-based smoking status identification system (3.1)

Telephone counseling (1.6)

Exclusive E-cigarette use (3.0)

a

Numerical value following the intervention is the multiple for cessation success

compared to no intervention.