Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

49. Substance-Related Disorders II: Alcohol, Nicotine, and Caffeine

Paul L. Doering and Robin Moorman Li


 Images Tobacco is the number one preventable cause of death in the United States.

 Images Nearly 17 million Americans report current heavy alcohol use or alcohol abuse.

 Images Pharmacogenomic studies have identified genotypic and functional phenotypic variants that either serve to protect patients or predispose them toward alcohol dependence.

 Images Alcohol is a CNS depressant that shares many pharmacologic properties with the nonbenzodiazepine sedative–hypnotics.

 Images The metabolism of alcohol is considered to follow zero-order pharmacokinetics, and this has important implications for the time course in which alcohol can exert its effects.

 Images Benzodiazepines are the treatment of choice for alcohol withdrawal.

 Images Disulfiram, naltrexone, and acamprosate are FDA-approved drug therapies for the treatment of alcohol dependence. The clinical utility of these agents to improve sustained abstinence remains controversial. Relapse is common.

 Images More than three quarters of smokers are nicotine dependent. Tobacco dependence is a chronic condition that requires repeated interventions.

 Images Use of nicotine replacement therapy along with behavioral counseling doubles cessation rates.

 Images Bupropion and varenicline are efficacious alone and in combination with nicotine replacement therapy for smoking cessation.

Images Alcohol, nicotine, and caffeine are considered by most to be socially acceptable drugs, yet they impose an enormous social and economic cost on our society. Approximately 443,000 deaths each year are attributable to tobacco use, making tobacco the number one preventable cause of death and disease in this country.1,2 The three leading causes of death attributable to smoking include lung cancer, chronic obstructive pulmonary disease, and ischemic heart disease.3

Images In 2011, heavy drinking was reported by 6.2% of the population aged 12 or older, or 15.9 million people,4 a decrease from the previous year’s data in which 16.9 million people were heavy drinkers. Approximately one quarter (22.6%) of persons aged 12 or older participated in binge drinking at least once in the 30 days prior to the National Survey on Drug Use and Health (NSDUH) in 2011.4

The World Health Organization estimates that there are approximately 2 billion people worldwide who consume alcoholic beverages, and 76.3 million with diagnosable alcohol-use disorders.5 Long-term alcohol abuse often leads to chronic disease. A causal relationship between alcohol abuse and at least 60 types of chronic disease or injury has been established (e.g., esophageal cancer, liver cancer, and cirrhosis of the liver, epileptic seizures, homicide, and motor vehicle accidents) worldwide.5 Nationally, according to the Drug Abuse Warning Network 2010 survey,6 687,574 emergency department visits involved either alcohol in combination with other drugs (for patients of all ages) or alcohol only for patients aged 20 or younger.

Images Worldwide, alcohol abuse leads to 1.8 million deaths annually.5 Nationally, according to the Alcohol-Attributable Deaths Report, 80,374 U.S. citizens with medium and high average daily alcohol consumption die each year because of alcohol-related causes, including traffic collisions and cirrhosis of the liver.7 Direct and indirect health and social costs of alcoholism to the nation are estimated to be $223.5 billion annually,8 and governments pay more than 60% of their healthcare costs.

Caffeine is currently the most widely used psychoactive substance in the world. In the United States, 80% to 90% of adults regularly consume behaviorally active doses of caffeine.


Epidemiology of Alcohol Use

Approximately half of Americans aged 12 or older reported being current drinkers of alcohol according to the NSDUH 2011 (51.8%). This translates to an estimated 133.4 million people, which is similar to the 2010 estimate of 131.3 million people (51.8%).4 In 2011 heavy drinking was reported by 6.2% of the population aged 12 or older, meaning that they drank five or more drinks on the same occasion on at least 5 different days in the past month.4

The Disease Model of Addiction as Applied to Alcoholism

The disease concept of addiction, using alcoholism as a model, states that addiction is a disease, and that individuals who suffer from the disease do not choose to contract the disease any more than someone who suffers from heart disease or diabetes mellitus chooses to contract that illness. A disease is defined as “any deviation from or interruption of the normal structure or function of any part, organ, or system (or combination thereof) of the body that is manifested by a characteristic set of symptoms and signs and whose etiology, pathology, and prognosis may be known or unknown.”9 Diagnostic criteria for alcoholism do not specify frequency of drinking or amount of alcohol consumed. The key determinant is whether drinking is compulsive, out of control, and consequential when one drinks.10

Images It has long been recognized that alcoholism is heritable, as 50% to 60% of first-degree relatives of alcoholics become alcohol dependent themselves.11 Research has identified several traits (or phenotypes) that attenuate one’s risk of alcohol dependence. Initially based on data from preclinical studies, pharmacogenomic studies have identified genotypic and functional phenotypic variants that either serve to protect patients or predispose them toward alcohol dependence.12 Large-scale pharmacoepidemiologic studies have further elucidated the environmental risk factors that are associated with either protective effects or predisposition toward alcoholism.13 The known susceptibility genes, phenotypic characteristics, and environmental risk factors are summarized in Table 49-1.1115

TABLE 49-1 Genotypic, Phenotypic, and Environmental Factors that Increase Alcohol-Dependence Risk


Pharmacology and Pharmacokinetics of Alcohol

Alcohol as a Drug

Images Alcohol is a CNS depressant that affects the CNS in a dose-dependent fashion, producing sedation that progresses to sleep, unconsciousness, coma, surgical anesthesia, and finally fatal respiratory depression and cardiovascular collapse. Alcohol affects endogenous opiates and several neurotransmitter systems in the brain, including γ-aminobutyric acid (GABA), glutamine, and dopamine. Alcohol is available in a variety of concentrations in various alcoholic beverages. There is approximately 14 g of alcohol in a 12-oz (355 mL) can of beer (approximately 5%), 4 oz (118 mL) of nonfortified wine (approximately 10% to 14%), or one shot (1.5 oz [44 mL]) of 80-proof whiskey (40%). Full consumption of this amount will cause an increase in blood alcohol level of approximately 20 to 25 mg/dL (4.3 to 5.4 mmol/L) in a healthy 70-kg (154 lb) male, although this varies with the time frame over which the alcohol is consumed, the type of alcoholic beverage, whether food is consumed along with it, and many patient variables. The lethal dose of alcohol in humans is variable, but deaths generally occur when blood alcohol levels are greater than 400 to 500 mg/dL (87 to 109 mmol/L).16


Absorption of alcohol begins in the stomach within 5 to 10 minutes of oral ingestion. The onset of clinical effects follows fairly rapidly. Peak serum concentrations of alcohol usually are achieved 30 to 90 minutes after finishing the last drink, although it is variable depending on the type of alcoholic beverage consumed, what and when the person last ate, and other factors.17

More than 90% of alcohol in the plasma is metabolized in the liver by three enzyme systems that operate within the hepatocyte. The remainder is excreted by the lungs and in urine and sweat. Alcohol is metabolized to acetaldehyde by alcohol dehydrogenase in the cell. In turn, acetaldehyde is metabolized to carbon dioxide and water by the enzyme aldehyde dehydrogenase. A second pathway for oxidation of alcohol uses catalase, an enzyme located in the peroxisomes and microsomes. The third enzyme system, the microsomal alcohol oxidase system, has a role in the oxidation of alcohol to acetaldehyde. These last two mechanisms are of lesser importance than the alcohol dehydrogenase–aldehyde dehydrogenase system.17

Images The metabolism of alcohol generally is said to follow zero-order pharmacokinetics.17 This can, in fact, be an oversimplification because at very high or very low concentrations of alcohol the metabolism can follow first-order pharmacokinetics.18 On average, the blood alcohol concentration (BAC) is lowered from 15 to 22.2 mg/dL (3.3 to 4.8 mmol/L) per hour in the nontolerant individual, assuming that the individual is in the postabsorptive state (Table 49-2). Alcohol has a volume of distribution of 0.6 to 0.8 L/kg, representing the total body water.17

TABLE 49-2 Specific Effects of Alcohol Related to BAC


Clinical Indicators of Chronic Alcohol Abuse

The CAGE questionnaire is a tool for detecting individuals more likely to be abusing alcohol and therefore at greater risk for alcohol withdrawal. CAGE is a mnemonic for four questions: (a) Do you ever feel the need to cut down on your alcohol use? (b) Have you ever been annoyed by others telling you that you drink too much? (c) Have you ever felt guilty about your drinking or something you did while drinking? (d) Do you ever have an “eye opener”? A positive response to two or more of these four questions suggests an increased likelihood of alcohol abuse with an average sensitivity of 0.71 (71%) and an average specificity of 0.90 (90%).19

Acute Effects of Alcohol

At lower serum concentrations, euphoria and disinhibition may be noted. Slurred speech, altered perception of the environment, impaired judgment, ataxia, incoordination, nystagmus, and hyperreflexia may occur. As plasma levels increase, combative and destructive behavior may occur. With higher levels still, somnolence and respiratory depression may ensue. The typical effects of various BACs are shown in Table 49-2, although effects vary from individual to individual.

Alcohol Poisoning

Acute alcohol poisoning usually occurs with rapid consumption of large quantities of alcoholic beverages. With sustained drinking of moderate amounts of alcohol, the user passes out before a toxic dose of alcohol can be ingested, and/or the person vomits to rid the stomach of its toxic reservoir. With rapid drinking, the person may fall asleep or pass out without vomiting, allowing continued alcohol absorption from the GI tract until fatal BACs are achieved.

Laboratory Studies

In the emergency room, a BAC should be ordered in any patient in whom alcohol ingestion is suspected, regardless of the presenting complaint. For clinical purposes, most laboratories report BAC in units of mg/dL or mmol/L. In legal cases, results are reported in percentage (grams of ethyl alcohol per 100 mL of whole blood). If the diagnosis is unclear, if the intoxication seems atypical, or when there is suspicion of multiple drug ingestions, a complete toxicologic screen to rule out the presence of other substances may be useful.


Alcohol-Related Disorders

Desired Outcomes

Goals for alcohol-dependent persons trying to decrease or discontinue alcohol intake include: (a) the prevention and treatment of withdrawal symptoms (including seizures and delirium tremens) and medical or psychiatric complications, (b) long-term abstinence after detoxification, and (c) entry into ongoing medical and alcohol-dependence treatment.

Alcohol Withdrawal

Pharmacologic Therapy

Images Symptom-triggered treatment with a benzodiazepine is the current standard of care in alcohol detoxification to manage and minimize symptoms and avoid progression to the more severe stages of withdrawal. A meta-analysis was performed to provide evidence-based recommendations on the pharmacologic management of alcohol withdrawal.20 A similar study was done to develop treatment strategies for alcohol withdrawal delirium.21 Trials comparing different benzodiazepines demonstrated that all appear similarly efficacious in reducing signs and symptoms of withdrawal.20,21

Clinical Controversy

Some clinicians believe that chlordiazepoxide is the “drug of choice” for alcohol withdrawal because some of the earliest literature reported successful use of this drug. Symptom-triggered treatment with a benzodiazepine is the current standard of care in alcohol detoxification to manage and minimize symptoms and avoid progression to the more severe stages of withdrawal. However, substantial evidence exists that no specific drug in this class is better than the others. Despite this, many practitioners still believe that chlordiazepoxide is superior to other benzodiazepines.

A Cochrane review22 of the effectiveness and safety of benzodiazepines in the treatment of alcohol withdrawal symptoms was published in 2010. According to this report “the available data show that benzodiazepines are effective against alcohol withdrawal seizures when compared to placebo, but data on safety outcomes are sparse and fragmented. There is a need for larger, well-designed studies in this field.”

CLINICAL PRESENTATION Alcohol Intoxication and Withdrawal


    • Acute alcohol detoxification and withdrawal after chronic alcohol abuse is a serious condition that can require hospitalization and adjunctive pharmacotherapy. If the BAC gets high enough, death is possible.


    • The intoxicated patient can present with slurred speech and ataxia. The patient can be sedated or unconscious. As BACs decrease rapidly, nausea, vomiting, and hallucinations can ensue. Delirium and seizures are the most severe symptoms.


    • The intoxicated patient can present with nystagmus.

    • In withdrawal, the patient can present with tachycardia, diaphoresis, or hyperthermia.

Laboratory Tests

    • In the emergency department, a BAC should be ordered when alcohol ingestion is suspected. Most laboratories report BAC in units of milligrams per deciliter. A whole blood alcohol level of 150 mg/dL (33 mmol/L) reported in the hospital corresponds to 0.15% BAC obtained by law enforcement.

    • A complete toxicologic screen to rule out the presence of other substances can be useful.

Other Diagnostic Tests

    • Differentiate acute alcohol intoxication from other medical illnesses (e.g., head trauma).

    • Use computed tomography (CT) on any patient with focal neurologic findings, failure to improve, new-onset seizures, or mental status out of proportion to degree of intoxication.

Treatment Regimens

Symptom-Triggered Therapy With symptom-triggered therapy, medication is given only when the patient has symptoms. This approach results in treatment that is shorter, potentially avoiding oversedation and allowing the clinician to focus on specific therapy for alcohol dependence.20,21 A typical regimen would include lorazepam 2 mg administered every hour as needed when a structured assessment scale—for example, the Clinical Institute Withdrawal Assessment–Alcohol, Revised (CIWA-AR)—indicates that symptoms are moderate to severe (Table 49-3).23

TABLE 49-3 Dosing and Monitoring of Pharmacologic Agents Used in the Treatment of Alcohol Withdrawal


Fixed-Schedule Therapy Over the years, benzodiazepines given regularly at a fixed dosing interval have been used for alcohol withdrawal. The major problem with this approach is underdosing of the benzodiazepine because of cross-tolerance (see Table 49-3). Current guidelines take exception with this rigid approach, urging clinicians to allow for some degree of individualization within fixed-schedule therapy.20,21

Treatment of Alcohol Withdrawal Seizures Alcohol withdrawal seizures do not require treatment with an anticonvulsant drug unless they progress to status epilepticus because seizures usually end before diazepam or another drug can be administered.21 Phenytoin, which is not cross-tolerant to alcohol, does not prevent or treat withdrawal seizures, and without an IV loading dose, therapeutic blood levels of phenytoin are not reached until acute withdrawal is complete. Patients experiencing seizures should be treated supportively. An increase in the dosage and slowing of the tapering schedule of the benzodiazepine used in detoxification or a single injection of a benzodiazepine can be necessary to prevent further seizure activity. Patients with a history of withdrawal seizures can be predicted to experience an especially severe withdrawal syndrome. In such patients, a higher initial dosage of a benzodiazepine and a slower tapering period of 7 to 10 days are advisable.

Treatment of Nutritional Deficits and Electrolyte Abnormalities Fluid status should be carefully assessed, and fluid, electrolyte, and vitamin abnormalities should be corrected. Hydration can be necessary in patients with vomiting, diarrhea, increased body temperature, or severe agitation. Alcoholics often have electrolyte imbalances because of inadequate nutrition and fluid volume related to antidiuretic hormone inhibition. Hypokalemia can be corrected with oral potassium supplementation as long as renal function is adequate. Thiamine (vitamin B1) is often depleted in alcoholics, and supplementation is standard because it can prevent the development of the Wernicke-Korsakoff syndrome (e.g., mental confusion, eye movement disorders, and ataxia [poor motor coordination]). An initial dose of 100 mg IV or IM is commonly used. In practice, thiamine is usually given 100 mg once daily orally, IV, or intramuscularly for 3 to 5 days (see Table 49-3).

Alcohol hypoglycemia usually occurs in the absence of overt liver disease, and it is more likely if the patient is fasting or exercising or is sensitive to alcohol; it is less likely if the patient is obese. The alcohol directly interferes with hepatic gluconeogenesis but not glycogenolysis. The energy required for metabolism of alcohol is diverted away from the energy needed to take up lactate and pyruvate—substrates for gluconeogenesis. So, patients who drink alcohol can become hypoglycemic once glycogen stores are depleted. Neurologic symptoms of hypoglycemia can be confused with alcohol intoxication, and in the inpatient setting, blood glucose should be monitored regularly.

Treatment Settings Alcohol withdrawal treatment can take place in hospitals, inpatient detoxification units, or outpatient settings. Only patients with mild to moderate symptoms should be considered for outpatient treatment, and it is a good idea to have a responsible, sober person available to help the patient monitor symptoms and administer medications. Patients with a strong craving for alcohol, those concurrently using other drugs, and those with a history of seizures or delirium tremens are not good candidates for outpatient treatment. Pharmacologic agents used in the treatment of alcohol withdrawal are summarized in Table 49-3.

Pharmacologic Management of Alcohol Dependence

Images In the United States, disulfiram, naltrexone, once-monthly injectable extended-release naltrexone, and acamprosate are the only four drugs that are FDA-approved for the treatment of alcohol dependence. Disulfiram acts as a deterrent to the resumption of drinking, and naltrexone is a competitive opioid antagonist that has been shown to reduce cravings for alcohol. Acamprosate is a GAB-Aergic agonist that modulates alcohol cravings (Table 49-4). Other drugs, including nalmefene, bupropion, various serotonergic agents (including selective serotonin reuptake inhibitors and vascular serotonin-3 [5-HT3] receptor antagonists), topiramate, and lithium, also have been used either abroad or in the United States off-label for alcohol dependence.

TABLE 49-4 Dosing and Monitoring of Pharmacologic Agents Used in the Treatment of Alcohol Dependence



Disulfiram deters a patient from drinking by producing an aversive reaction if the patient drinks. In the absence of alcohol, disulfiram has minimal effects. Disulfiram inhibits aldehyde dehydrogenase in the biochemical pathway for alcohol metabolism, allowing acetaldehyde to accumulate. The resulting increase in acetaldehyde causes severe facial flushing, throbbing headache, nausea and vomiting, chest pain, palpitations, tachycardia, weakness, dizziness, blurred vision, confusion, and hypotension. Severe reactions including myocardial infarction, congestive heart failure, cardiac arrhythmia, respiratory depression, convulsions, and death can occur, particularly in vulnerable individuals.24


Naltrexone, an opiate antagonist available in the United States since 1984 for the treatment of opioid dependence, blocks the effects of exogenous opioids. In 1994, the FDA approved its use in the treatment of alcohol dependence. Naltrexone is thought to attenuate the reinforcing effects of alcohol, and those who consume alcohol while taking naltrexone report feeling less intoxicated and having less craving for alcohol.25 Evidence suggests that genetics plays a role in the clinical response to naltrexone. Carriers of the Asp40 polymorphism in the μ-opioid receptor gene show increased response to naltrexone with lower rates of relapse to heavy drinking.

Naltrexone should not be given to patients currently dependent on opiates because it can precipitate a severe withdrawal syndrome. Naltrexone is associated with dose-related hepatotoxicity, but this generally occurs at doses higher than those recommended for treatment of alcohol dependence. Nevertheless, it is considered contraindicated in patients with hepatitis or liver failure, and liver function tests should be monitored monthly for the first 3 months and every 3 months thereafter.

Nausea is the most common side effect of naltrexone, occurring in approximately 10% of patients. Other side effects are headache, dizziness, nervousness, fatigue, insomnia, vomiting, anxiety, and somnolence. If dosed daily, naltrexone 50 mg is sufficient to effectively block μ-opioid receptors.

In April 2006, the FDA approved Vivitrol, a once-monthly intramuscular naltrexone formulation. The usual effective dose is 380 mg IM each month.26,27 Extended-release formulations reduce the likelihood of forgetting or choosing not to take medication, assuring that once the patient receives an injection, he or she will be “adherent” for the next month.26

Criticism has been leveled at the extended-release dosage form, suggesting that naltrexone’s benefit may be limited to less severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence. Pettinati et al.27 report the results of a study in alcohol-dependent patients who had higher baseline severity, as measured by: (a) the Alcohol Dependence Scale (ADS) or (b) having been medically detoxified in the week before randomization. Higher severity alcohol-dependent patients, when receiving 380 mg (n = 50) of the extended-release compound compared with placebo (n = 47), had significantly fewer heavy-drinking days during the study (hazard ratio = 0.583; P = 0.0049) and showed an average reduction of 37.3% in heavy-drinking days compared with 27.4% for placebo-treated patients (P = 0.039). The authors contend that their data support the efficacy of extended-release naltrexone 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence.


Acamprosate is a glutamate modulator at the N-methyl-D-aspartate (NMDA) receptor that reduces alcohol craving. Acamprosate, approved in the United States in 2004, had been available in Europe for many years. Patients treated with acamprosate are more successful in maintaining abstinence from alcohol versus placebo. Acamprosate is well tolerated, with GI adverse effects most common.

A Cochrane review of 24 randomized controlled trials (RCTs) with 6,915 participants28 found that, compared with placebo, acamprosate significantly reduced the risk of any drinking (RR 0.86 [95% CI 0.81 to 0.91]; NNT 9.09 [95% CI 6.66 to 14.28]) and significantly increased the cumulative abstinence duration (mean difference 10.94 [95% CI 5.08 to 16.81]), while secondary outcomes did not reach statistical significance. Diarrhea was the only side effect that was more frequently reported with acamprosate than placebo (risk difference 0.11 [95% 0.09 to 0.13]; NNTB 9.09 [95% CI 7.69 to 11.11]). See Table 49-4for dosing information for this and the other options used in treating alcohol dependence.


Clinical guidelines for tobacco use and dependence were released in 2000 and updated in 2008.29 Telephone quitlines are available in every state, and more patient are now referred to smoking cessations counseling services. There also is a growing number of Internet and mobile phone text messaging programs that have been developed to reach the teenage and young adult population to promote smoking cessation.30,31 The number of adults who smoke has decreased from 42.4% in 1965 to 19.3% in 2010, and now there are more former smokers than current smokers.

Despite this encouraging news, cigarette smoking continues to be the leading cause of preventable morbidity and mortality in the United States. Data from the 2010 National Health Interview Survey (NHIS)32found that the overall percent of current smokers from the years 2005 to 2010 in adults ≥18 years old decreased from 20.9 to 19.3. It was determined this represents 3 million fewer smokers in 2010 compared with those in 2005, but this decline has not been uniform across all subsets of the population. The Healthy People 2020 target is currently set for the prevalence of smoking to be less than or equal to 12%, and based on the current rate of decline, this target will not be met. Healthy People 2020 also calls for greater utilization of tobacco use counseling within ambulatory settings to improve smoking cessation rates.33

Epidemiology of Tobacco Use

The NSDUH reported in 2011 that an estimated 26.5% (68.2 million) of the U.S. population 12 years of age and older used a tobacco product at least once in the month prior to being interviewed. In addition, 56.8 million Americans were current cigarette smokers, 12.9 million smoked cigars, 8.2 million used smokeless tobacco, and 2.1 million smoked pipes.4 Comparing age groups, adults between the ages of 18 and 25 years have the highest rate of cigarette use (39.5%), but it is encouraging to see the rates continue to decrease each year since 2002 when 40.8% of young adults were using cigarettes. Within youth aged 12 to 17, use of cigarettes also continued to decline from 15.2% in 2002 to 10% in 2011.4

Data trends from the 2011 NSDUH continue to show smoking prevalence varies based on the level of education. The highest percentage of adults who admitted to smoking were adults who had not completed high school (33.7%). The lowest rate of smoking was seen in adults who graduated from college (11.7%). Results from the NSDUH also showed cigarette smoking was higher in unemployed adults (40.7%) in comparison to adults who were employed full time (23.3%).4

Economic Impact of Smoking

The direct healthcare expenditures associated with smoking total approximately $298 billion a year, which includes factors such as lost productivity, premature death, and direct medical expenditures.34Medicaid patients’ smoking rates are substantially higher in comparison to the general population. Smoking-attributable medical expenditures are estimated at 11% of Medicaid program expenditures.35


Cigarette smoking substantially increases the risk of (a) cardiovascular diseases such as stroke, sudden death, and heart attack; (b) nonmalignant respiratory diseases including emphysema, asthma, chronic bronchitis, and chronic obstructive pulmonary disease; (c) lung cancer; and (d) other cancers.33

Exposure to environmental tobacco smoke (passive exposure) has been cited as the cause of 3,400 lung cancer deaths and 46,000 heart disease–related deaths in the United States every year.36 Children who are exposed to environmental smoke have a higher risk of respiratory infection, asthma, and middle ear infections than those who are not exposed. Sudden infant death syndrome occurs more often in infants whose mothers smoked during pregnancy than in offspring of nonsmoking mothers.36 The harmful effects of smoking on reproduction and pregnancy include reduced fertility and fetal growth, as well as increased risk of ectopic pregnancy and spontaneous abortion.36


Nicotine is a ganglionic cholinergic agonist with pharmacologic effects that are highly dependent on dose. These effects include central and peripheral nervous system stimulation and depression, respiratory stimulation, skeletal muscle relaxation, catecholamine release by the adrenal medulla, peripheral vasoconstriction, and increased blood pressure, heart rate, cardiac output, and oxygen consumption. Cigarette smoking or low doses of nicotine produce an increased alertness and increased cognitive functioning by stimulating the cerebral cortex. At higher doses, nicotine stimulates the “reward” center in the limbic system of the brain.37

When nicotine is ingested, a feeling of pleasure and relaxation can occur. Repetitive exposure to nicotine leads to neuroadaptation, which builds tolerance to the initial effects. An accumulation of nicotine in the body leads to a more substantial withdrawal reaction if cessation is attempted.38 Common symptoms experienced during withdrawal can include anxiety, difficulties concentrating, irritability, and strong cravings for tobacco. Onset of these withdrawal symptoms usually occurs within 24 hours and can last for days, weeks, or longer.38 This powerful force of nicotine addiction is one reason smokers who attempt to achieve smoking cessation have a high rate of relapse, and only 3% remain abstinent 6 months following the quit date.39


Desired Outcomes

Ideally, we would hope that more and more people stop smoking altogether and that young people never take up the habit. This is unlikely to happen. The Healthy People 2020 target setting the prevalence of smoking to be less than or equal to 12% discussed above is a realistic and achievable goal.

Nicotine Dependence

Agency for Healthcare Research and Quality Clinical Practice Guideline: Treating Tobacco Use and Dependence

The Agency for Healthcare Research and Quality (AHRQ) periodically convenes expert panels to develop clinical guidelines for healthcare practitioners. Because of the widespread prevalence of smoking-related illnesses, its related morbidity and mortality, and the economic burden imposed, the agency convened a panel of experts in 1994 to develop guidelines on the treatment of tobacco addiction. The resultant guideline for smoking cessation was updated in 2008,29 and no further updates have been released at the time of this writing.



    • The patient may experience anxiety but may not be in acute distress. Symptoms can wax and wane over time.


    • The patient may complain of cravings, difficulty concentrating, frustration, irritability, and impatience. Hostility, insomnia, and restlessness can also occur.


    • Increased skin temperature can be present.

The revised guideline suggests strategies for providing appropriate treatments for every patient. Because effective treatments for tobacco dependence now exist, every patient should receive at least minimal treatment every time he or she visits a clinician (Figs. 49-1 and 49-2).


FIGURE 49-1 Model for treatment of tobacco use and dependence.


FIGURE 49-2 Algorithm for treating tobacco use.

The guideline identified a number of key findings that clinicians should use:

   1. Images Tobacco dependence is a chronic condition that often requires repeated intervention. However, effective treatments exist that can produce long-term or permanent abstinence.

   2. Because effective tobacco-dependence treatments are available, every patient who uses tobacco should be offered at least one of these treatments.

   3. It is essential that clinicians and healthcare delivery systems (including administrators, insurers, and purchasers) institutionalize the consistent identification, documentation, and treatment of every tobacco user who is seen in a healthcare setting.

   4. Brief tobacco-dependence treatment is effective, and every patient who uses tobacco should be offered at least brief treatment.

   5. There is a strong dose–response relationship between the intensity of tobacco-dependence counseling and its effectiveness. Treatments involving person-to-person contact (via individual, group, or proactive telephone counseling) are consistently effective, and their effectiveness increases with treatment intensity (e.g., minutes of contact).

   6. Three types of counseling and behavioral therapies were found to be especially effective and should be used with all patients who are attempting tobacco cessation:

    • Provision of practical counseling (problem-solving/skills training)

    • Provision of social support as part of treatment (intratreatment social support)

    • Help in securing social support outside treatment (extratreatment social support)

Numerous effective pharmacotherapy options for smoking cessation now exist (Table 49-5). Seven first-line pharmacotherapy options reliably increase long-term smoking abstinence rates: sustained-release (SR) bupropion, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, nicotine patch, and vareni-cline. Combinations of these should be considered if a single agent has failed.

TABLE 49-5 Dosing and Monitoring of Pharmacologic Agents Used for Smoking Cessation


Two second-line pharmacotherapy options are considered efficacious and can be considered by clinicians if first-line options are not effective: clonidine and nortriptyline.

Tobacco-dependence treatments are both clinically effective and cost-effective relative to other medical and disease prevention interventions. As such, insurers and purchasers should ensure all insurance plans include as a reimbursed benefit the counseling and pharmacotherapeutic treatments that are identified as effective in this guideline, as well as clinician reimbursement for providing tobacco-dependence treatment just as they are reimbursed for treating other chronic conditions.

Other Factors Important to the Success of a Smoking-Cessation Strategy

The AHRQ expert panel emphasized the importance of the type and intensity of the contact with the counselor to the success of the intervention. When interventions last for more than 10 minutes, the increase in cessation rates is much better than when interventions do not involve contact with a professional. Group and individual counseling is more effective than no intervention in increasing abstinence rates. Self-help materials (e.g., handouts, pamphlets, and brochures) without any direct physical contact are not effective.40 Interventions are more successful when they include social support and training in general problem-solving skills, stress management, and relapse prevention. The number of treatment sessions offered is also important. Providing at least four or more sessions, longer than 10 minutes in length, and if possible providing treatments from multiple types of clinicians have proven higher success rates compared with less intensive interventions.29 Although comprehensive behavioral interventions have been shown to be more effective in helping people quit smoking and remain abstinent, less intensive treatments are beneficial as well. Even minimal contacts lasting less than 3 minutes and simple advice to quit are more successful in increasing cessation rates than intervention involving no contact.29 A recent study also showed physicians offering assistance to all smoking patients to achieve smoking cessation is much more effective than only offering assistance to patients who are interested in smoking cessation.41

Motivational interviewing is a form of counseling to help patients identify barriers for making a behavior change. A meta-analysis42 of 14 studies published between 1997 and 2008, including over 10,000 smokers who underwent motivational interviewing as part of the smoking cessation program, found that motivational interviewing with standard care or brief cessation advice did improve quit rates modestly. Subgroup analysis found that motivational interviewing was most effective when completed in longer sessions by primary care physicians and counselors.

Counseling alone can be effective, but counseling efficacy is further augmented by the addition of pharmacotherapy. In a meta-analysis that included 111 trials with more than 43,000 participants using one or more of the five forms of nicotine replacement therapy (NRT) including nicotine gum, nasal spray, patches, lozenges, or inhaler, it was found that the use of NRT significantly increased the rate of cessation compared with placebo.43

Pharmacologic Therapy for Smoking Cessation

All patients attempting to quit should be encouraged to use effective pharmacotherapy agents for smoking cessation except in the presence of special circumstances. As with other chronic diseases, the most effective treatment of tobacco dependence encompasses multiple modalities. Pharmacotherapy is a vital element of a multicomponent smoking cessation program that should always include nonpharmacologic components. The role of pharmacotherapy in smoking cessation is summarized in Table 49-5.

Nicotine Replacement Therapy

Images In 2009, a systematic review43 was performed to determine the effectiveness of the different forms of NRT (e.g., chewing gum, transdermal patches, nasal spray, inhalers, and tablets) in achieving abstinence or a sustained reduction in the amount smoked. The review showed that all of the commercially available forms of NRT were effective for smoking cessation. Use of NRT doubled the odds of quitting.

A head-to-head placebo-controlled trial44 comparing 5 smoking cessation pharmacotherapies was done in 1,504 smokers who had smoked at least 10 cigarettes per day for 6 months. Patients were randomized to receive SR bupropion, nicotine patch, nicotine lozenge, nicotine patch plus nicotine lozenge, bupropion plus nicotine lozenge, or placebo. At 6 months it was found the quit rates were 40.1% for the nicotine patch plus nicotine lozenge, 34.4% for the nicotine patch, 33.5% for the nicotine lozenge, 33.2% for bupropion plus nicotine lozenge, 31.8% for bupropion alone, and 22.2% for placebo.

Nicotine Gum Clinicians should offer 4-mg rather than 2-mg nicotine gum to highly dependent smokers.29 The 2-mg gum is recommended for patients smoking fewer than 25 cigarettes per day, whereas the 4-mg gum is recommended for patients smoking 25 or more cigarettes per day. Generally, the gum should be used for up to 12 weeks, no more than 24 pieces chewed per day.

Gum should be chewed slowly until a peppery or minty taste emerges and then “parked” between cheek and gums to facilitate nicotine absorption through the oral mucosa. Acidic beverages (e.g., coffee, juices, or soft drinks) interfere with the buccal absorption of nicotine, so eating and drinking anything except water should be avoided for 15 minutes before and during chewing. Instructions to chew the gum on a fixed schedule (at least one piece every 1 to 2 hours) for at least 1 to 3 months can be more beneficial than ad libitum use.29

Nicotine Patch The nicotine patch is available both as a nonprescription medication and as a prescription drug, and it approximately doubles long-term abstinence rates over those produced by placebo interventions.43 Treatment of 8 weeks or less has been shown to be as efficacious as longer treatment periods. The 16- and 24-hour patches are of comparable efficacy. Clinicians should consider starting treatment on a lower patch dose in patients smoking 10 or fewer cigarettes per day.29

A patch should be applied as soon as the patient wakes on the quit day and at the start of each day thereafter. The patient should place a new patch on a relatively hairless location, typically between the neck and waist. There are no restrictions on activity while using the patch. Patients who experience sleep disruption should remove the 24-hour patch prior to bedtime or use the 16-hour patch.

Nicotine Nasal Spray Nicotine nasal spray more than doubles long-term abstinence rates when compared with a placebo spray. It is available exclusively as a prescription medication. A dose of nicotine nasal spray consists of one 0.5-mg delivery to each nostril (1 mg total). Initial dosing should be one to two doses per hour, increasing as needed for symptom relief. The minimum recommended treatment is 8 doses per day, with a maximum limit of 40 doses per day (5 doses per hour). Recommended duration of therapy is 3 to 6 months. Patients should not sniff, swallow, or inhale through the nose while administering doses because this increases irritating effects.29

Nicotine Lozenge The nicotine lozenge is available as a 2-mg and a 4-mg dose. The 2-mg lozenge is recommended for patients who normally smoke their first cigarette later than 30 minutes after awakening, and the 4-mg lozenge is recommended for smokers who smoke within 30 minutes of waking. The duration of treatment is 12 weeks. It is recommended no more than 20 lozenges should be used in 1 day.29The most common side effect of the lozenge is nausea. As with the nicotine gum, acidic beverages (e.g., coffee, juices, or soft drinks) interfere with the buccal absorption of nicotine, so eating and drinking anything except water should be avoided for 15 minutes before and during use of the lozenge.29

Instructing Patients in the Use of NRT Compliance with NRT improves when the patient is presented a clear rationale for its use and a realistic expectation about the response. It should be explained to the patient that nicotine is responsible for addiction and that discontinuation of the nicotine causes craving for cigarettes, tension, irritability, sadness, problems with sleep, and difficulty concentrating. The patient should be told that using the patch results in less desire to smoke and provides an opportunity for a new nonsmoker to practice all the new nonsmoking skills without being burdened by craving. The patient should understand that with smoking, there are naturally peaks and valleys in the amount of nicotine in the bloodstream. With the patch there is a steady gradual rise in the blood nicotine concentration that levels off and remains constant for much of the day and then gradually decreases while the person is asleep.29

Side Effects Nicotine replacement products have relatively few side effects. Nausea and light-headedness are possible symptoms of nicotine overdose that warrant a reduction of the nicotine dose.

The most frequent side effect with the nicotine patch is skin irritation related to the adhesive or the medium containing nicotine and not to the nicotine itself. Approximately 50% of patients report skin irritation during the course of treatment with the patch. The patch site can be rotated to diminish this problem. Switching to a different brand of patch can alleviate the problem because different products use different adhesives or media. The gum can be used instead of the patch when the skin irritation is severe. Less than 5% of patients were forced to discontinue therapy because of skin reactions.29

Duration Those who commit to quitting smoking using NRT should be told that treatment for up to 3 months is common.45 However, some patients will experience severe withdrawal even beyond this time period; thus, long-term use of NRT might be indicated. Long-term use of NRT has not been linked to any safety concerns and is supported by the 2008 updated U.S. Public Health Service Guidelines.29

Non-Nicotine Options

Bupropion Images Bupropion inhibits neuronal reuptake and potentiates the effects of norepinephrine and dopamine. Although its precise mechanism in smoking cessation is not well understood, dopamine has been associated with the rewarding effects of addictive substances. The AHRQ panel concluded that SR bupropion is an efficacious smoking cessation treatment that patients should be encouraged to use.29

Contraindications for bupropion use include current or past seizure disorders, a history of monoamine oxidase inhibitor use over the last 14 days, and a history of anorexia nervosa or bulimia. Along with multiple other precautions listed in the product labeling, current alcohol use, use of medications that lower seizure threshold (e.g., antidepressants, antipsychotics), and depression are possible concerns when using this medication.28 In 2009, the FDA required manufacturers of Zyban (bupropion) and generic manufacturers to add new boxed warnings and to develop a medication guide highlighting the risk of serious neuropsychiatric symptoms in patients using this product. Possible symptoms include depressed mood, agitation, anxiety, hostility, changes in behavior, suicidal thoughts and behavior, and attempted suicide.29

A double-blind, placebo-controlled, randomized multicenter trial was conducted in which healthy smokers received either SR bupropion 150 mg twice daily or a placebo daily for 7 weeks and were subsequently seen for counseling and followup for a total of 52 weeks. The primary end points were biochemically confirmed continuous abstinence at weeks 7 and 52. The authors specifically conducted this trial in the primary care setting to verify the general applicability of the results to the intended end users. Results of this study showed bupropion was efficacious, with an absolute 25% of participants continuously abstinent at 1 year; it doubled the odds of continuous abstinence from week 4 to 7 and from week 4 to 52 compared with placebo.46

A meta-analysis47 involving 49 trials utilizing bupropion for smoking cessation showed that bupropion significantly increased the incidence of long-term cessation when used as a sole agent in 36 separate trials. Other trials that used bupropion as an add-on agent with NRT did not show additional benefit in improving cessation rates.47

Images For smoking cessation, the manufacturer recommends a dosage of 150 mg once daily for 3 days and then twice daily for 7 to 12 weeks or longer, with or without NRT. Patients are instructed to stop smoking during the second week of treatment and are encouraged to use counseling and support services along with the medication. For maintenance therapy, consider SR bupropion 150 mg twice daily for up to 6 months.29

Varenicline (Chantix) Varenicline acts at sites in the nicotine-affected brain in two ways: by providing nicotine effects to ease withdrawal symptoms and by blocking the effects of nicotine from cigarettes if they resume smoking. Specifically, varenicline is a partial agonist that binds selectively to α42-nicotinic acetylcholine receptors with a greater affinity than nicotine. When bound to the receptor, the drug blocks nicotine from binding and also evokes a response but to a lesser degree than nicotine. The stimulation of the receptor results in release of dopamine and thus provides a type of “reward” that can decrease craving and withdrawal symptoms.48

The recommended dosage for varenicline is 0.5 mg daily for 3 days, increase to 0.5 mg twice daily for 3 days, and then increase to 1 mg twice daily for a standard 12-week treatment. If abstinence has not been achieved after the 12-week treatment, then a second 12-week treatment may be prescribed.48

Varenicline is listed as a first-line agent in the 2008 clinical guidelines on treating tobacco use and dependence. Eleven trials comparing varenicline with placebo, three of which also had a comparison with bupropion, were reviewed in a meta-analysis.49 Varenicline resulted in a twofold to threefold increased likelihood of long-term smoking cessation compared with nonpharmacologic treatment. Most studies were only 12 weeks, so efficacy beyond this time period needs further study.

Since 2006, when varenicline was approved by the FDA, alarming numbers of adverse effects, including suicidal thoughts, erratic behavior, and aggressive behavior, have been reported. The large number of reports led to the release of a Public Health Advisory by the FDA in February 2008.50 The advisory stressed the importance of screening for any type of psychiatric illness or any behavior changes after starting varenicline. A boxed warning along with an update of the medication guide from the manufacturer was required by the FDA.51

The FDA sponsored two epidemiologic studies that evaluated the neuropsychiatric adverse events linked to the use of varenicline. These studies had multiple limitations, and although the studies did not show an increased risk of hospitalization secondary to neuropsychiatric events, it is important for both healthcare professionals and patients to be aware of the possible risks associated with the use of varenicline.52

Specific warnings stress patients should report any history of psychiatric illness and any changes in behavior or mood immediately to their prescribing practitioner.50 There have also been concerns with the risk of cardiovascular events associated with the use of varenicline, and the FDA requested a systematic review of all randomized clinical trials to identify if there was an associated cardiovascular risk with the use of varenicline.53

Clinical Controversy

Concerns have been voiced regarding cardiovascular adverse events related to varenicline use. The FDA reviewed a clinical trial that showed a small increase in cardiovascular events in varenicline-treated patients with cardiovascular disease compared with placebo-treated patients.53 In light of the fact that cigarette smoking substantially increases the risk of cardiovascular diseases,38 and varenicline has been shown to cause a twofold to threefold increase in the likelihood of long-term smoking cessation,51 the benefits in most cases may outweigh the risks. It is important for healthcare providers to educate patients with cardiovascular disease of the risks and benefits of varenicline to allow them to make an informed decision.

Seven hundred patients who smoked and also suffered from cardiovascular disease were randomized to either varenicline or placebo and followed for 12 weeks of therapy and another 40 weeks following treatment. It was shown varenicline was more effective in helping patients to achieve smoking cessation and maintain abstinence for up to 1 year than placebo. It was found that varenicline may be associated with a small increase in risk of cardiovascular events, but the benefit of smoking cessation in this patient population is very important and must be considered when evaluating the risk-to-benefit ratio.53

Prochaska and Hilton54 published a meta-analysis that included all 22 trials published up to May 2012. The study focused on events occurring during drug exposure. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5,431) in the varenicline groups and 0.47% (18/3,801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval –0.10 to 0.63; P = 0.15), based on all 22 trials, was neither clinically nor statistically significant.

Comparison of NRT and Non-Nicotine Options

A systematic review and multiple treatment meta-analysis was performed using a Baysean model to evaluate the effect of high-dose and standard-dose NRT, combination NRT, bupropion, and varenicline.55The primary outcome included smoking abstinence at 4, 12, 26, and 52 weeks following the set quit date. The standard- and high-dose NRT patch, bupropion, and varenicline were shown to be superior to placebo and controls on a consistent basis. Varenicline was shown to be statistically more effective in achieving smoking abstinence compared with the other agents except at 6 months when compared with high-dose NRT patches and combination therapy. It is difficult to identify which agent is more effective over another at this time, since other considerations such as cost and specific patient factors must also be taken into account.55

Second-Line Medications

Second-line medications are pharmacotherapies for which there is evidence of efficacy for treating tobacco dependence, but which have a more limited role than first-line medications because (a) the FDA has not approved them for treatment of tobacco dependence and (b) there are more concerns about potential side effects than with first-line medications.29 Second-line treatments should be considered for use on a case-by-case basis after first-line treatments have been used or considered.

Clonidine Clonidine has been found to be efficacious as a smoking cessation treatment. It can be used off-label as a second-line agent to treat tobacco dependence. A meta-analysis56 of six trials showed that clonidine increased smoking cessation rates by 11% (OR 1.89; CI 1.30 to 2.14). There was a high incidence of dose-dependent side effects, particularly dry mouth and sedation.56 It should be noted that abrupt discontinuation of clonidine can result in symptoms such as nervousness, agitation, headache, and tremor, accompanied or followed by a rapid rise in blood pressure and elevated catecholamine levels.

Doses have varied significantly, from 0.15 to 0.75 mg/day orally and from 0.1 to 0.2 mg/day transdermally, without a clear dose–response relationship to cessation. Most commonly reported side effects include dry mouth, drowsiness, dizziness, sedation, and constipation. Clonidine will lower blood pressure in most patients; thus, blood pressure should be monitored.29

Nortriptyline Nortriptyline is also considered to be efficacious as a second-line agent for tobacco dependence. Therapy is initiated 10 to 28 days before the quit date to allow it to reach steady state at the target dose. Trials have initiated treatment at a dose of 25 mg/day, increasing gradually to a target dose of 75 to 100 mg/day. Duration of treatment used in smoking cessation trials has been approximately 12 weeks. Most commonly reported side effects include sedation, dry mouth, blurred vision, urinary retention, light-headedness, and tremor.29

Future Treatments Work continues on the development of vaccines to treat nicotine addiction. Vaccines are designed to produce antibodies that bind to nicotine and prevent it from entering the brain. As a result, the positive stimulus in the brain that is normally caused by nicotine is no longer present, thereby taking away the physical motivation for smoking.57

Currently there are four vaccines in development, but only NicVAX and NIC002 have any information published in the peer-reviewed literature. Based on the published Phase I/II trials and one unpublished Phase III trial, these vaccines were able to induce an immune response even when the patient was currently smoking, and tolerability was favorable. However, these studies have not been shown to improve abstinence rates over placebo. Further research is needed to determine if these vaccines will become an option for smoking cessation in the future.57

Personalized Pharmacotherapy Personalized pharmacotherapy might be a future option in improving the smoking cessation rates that continue to be low. Genome-wide association studies attempted to identify several genetic determinants of smoking behavior, and a phenotype may have been discovered that might identify patients who are at higher risk for developing nicotine dependence.58 Examples of areas being studied include identifying genes directly related to nicotine reward and metabolism pathways,39 identifying ways to anticipate response to various smoking cessation treatments based on cytochrome P450 systems, and nicotine metabolite ratios, all of which could lead to selecting the most effective smoking cessation treatment for each individual patient.58


Caffeine is the most widely consumed behaviorally active substance in the world, generating an increased sense of well-being, happiness, energy, alertness, and sociability.59 Caffeinism is the term coined to describe the clinical syndrome produced by acute or chronic overuse of caffeine. The syndrome usually is characterized by CNS and peripheral manifestations, most notably anxiety, psychomotor alterations, sleep disturbances, mood changes, and psychophysiologic complaints. As many as one in five adults consume doses of caffeine generally considered large enough to cause clinical symptoms.59

Pharmacologically, the risk of developing meaningful clinical manifestations becomes high when intake exceeds 500 mg/day. This places 20% to 30% of North Americans at risk.59 Caffeine has been proposed as a “model of drug abuse” despite the facts that its sale is largely unrestricted and that heavy consumption of caffeine-containing beverages is not considered to be drug abuse. The information below represents a broad overview of dependence, withdrawal, and tolerance. The reader interested in more information is urged to consult the exhaustive review by Juliano et al.59

Epidemiology of Caffeine Use and Abuse

Approximately 173 million consumers drink tea and 183 million consumers drink coffee.60 The National Coffee Association reports that 40% of 18- to 24-year-olds are drinking coffee each day, while 54% of adults aged 25 to 39 reported drinking coffee daily.

The majority of caffeine users progress to a pattern of frequent or daily consumption. Participants in a study reported consuming a mean of 547.8 mg of caffeine per day. They reported daily consumption of soft drinks (74%), roasted or ground coffee (56%), cocoa/chocolate (36%), bag or leaf tea (34%), instant tea (10%), instant coffee (7%), and caffeine-containing medications (6%). Most participants (81%) reported having their first caffeinated product within 60 minutes of waking. The mean age of onset of regular caffeine consumption was 15.9 years. Results of a recent study showed that, according to their parents, children aged 5 to 7 years old consumed approximately 52 mg of caffeine per day, and children aged 8 to 12 years old consumed approximately 109 mg.61

Energy Drinks

A number of energy drinks containing caffeine, taurine, vitamins, and sugar have found their way onto the American market. Sold under brand names such as Red Bull, Monster Energy, Rockstar, and Full Throttle, these products are especially popular with adolescents and emerging adults. Over half of college students surveyed reported drinking at least one energy drink per month.62 They are generally marketed to enhance alertness or provide a short-term energy boost. Common energy drinks contain approximately 80 mg caffeine per 8 oz (~250 mL) serving, but commercially available energy drinks are often sold in 16-oz (~500 mL) containers and can contain up to 505 mg of caffeine.62

Additionally, several manufacturers have marketed alcoholic beverages that have caffeine as an additional ingredient. Some have other ingredients such as guarana, taurine, and ginseng. The Center for Science in the Public Interest has chosen to call these beverages “alcospeed.”63 A novel website calling itself the “Energy Fiend—The Caffeine Fix”64 lists 577 caffeinated beverages and their respective caffeine content. At least 130 contained more than the 0.02% caffeine limit for soft drinks imposed by the FDA.

Differential Diagnosis

Caffeine intoxication is the only official diagnosis associated with caffeinism in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).10 Caffeine-induced anxiety can manifest as restlessness, nervousness, excitement, insomnia, diuresis, flushing, GI disturbance, muscle twitching, irritability, and jitteriness. If caffeine-induced insomnia requires specific treatment, caffeine-induced sleep disorder is an appropriate DSM-IV-TR diagnosis.10

Because excessive caffeine consumption is so widespread, a thorough history of caffeine use should be included in the routine assessment of all new patients in primary care medical settings. In this manner, the practitioner can use the information gathered to uncover high levels of caffeine intake and then use the information to pinpoint the cause of clinical signs and symptoms typical of caffeinism. Clinical manifestations of caffeinism almost always lessen in intensity or disappear completely within 1 to 2 weeks after removing the drug.

Pharmacology of Caffeine

Caffeine is rapidly and completely absorbed from the GI tract, reaching a peak blood level within 30 to 45 minutes of oral ingestion. It easily crosses the blood–brain barrier, and levels achieved in the brain are proportional to the dose administered.

The half-life of caffeine in humans is approximately 3.5 to 5 hours. Serious problems rarely result from overdoses of caffeine. In fact, the amount of caffeine needed to cause death in an average adult male is 5 to 10 g, the equivalent of 50 to 100 cups of regular brewed coffee. Thus, the risk of overdose from dietary sources of caffeine is virtually nonexistent.

Caffeine increases the heart rate and force of contraction. It also has a strong diuretic effect. The key factor promoting caffeine use and dosage increases can be the drug’s reinforcing effect on pleasure and reward centers of the brain. Caffeine’s pharmacologic actions appear comparable (although less potent) with those of other stimulants, such as amphetamines and cocaine.

Caffeine Dependence

Research has shown that abstinence from caffeine induces a distinct withdrawal syndrome. Evidence for this was presented by Strain et al.65 In a structured psychiatric interview, subjects who self-identified as having problems with caffeine use were evaluated for features of a DSM-IV-TR diagnosis of drug dependence. Those judged as caffeine dependent manifested at least three of four criteria (i.e., tolerance, withdrawal, persistent desire, or an unsuccessful attempt to reduce consumption and persistent use despite adverse psychological or physical consequences). Of 99 people screened, 27 were evaluated by means of a structured psychiatric interview modified for the diagnosis of caffeine dependence; 16 of those subjects (59%) met the criteria. In a second phase of the study, 11 of the 16 caffeine-dependent individuals participated in a 2-day double-blind crossover study of caffeine deprivation. Nine showed evidence of caffeine withdrawal during the placebo phase.

CLINICAL PRESENTATION Excessive Caffeine Intake


    • The patient may not be in acute distress.


    • The patient may complain of nausea, vomiting, diarrhea, and psychomotor agitation, and can appear restless, nervous, and excited.


    • The patient can present with facial flushing, diuresis, and muscle twitching.

    • Tachycardia or cardiac arrhythmias can also occur.

Laboratory Tests

    • Caffeine serum concentrations are rarely used clinically.

Caffeine Withdrawal

The frequency of the caffeine withdrawal syndrome is not well known, but it may be common. Withdrawal can occur when individuals who previously consumed caffeine on a regular basis suddenly discontinue its intake.66 The syndrome is characterized by the occurrence of headache, drowsiness, fatigue, and sometimes impaired psychomotor performance, difficulty concentrating, nausea, excessive yawning, and craving. These symptoms usually appear within 18 to 24 hours of discontinuation, corresponding to the time required for the drug to leave the body.

The caffeine withdrawal headache is somewhat unique, starting with a sense of fullness in the head and progressing to throbbing and diffuse pain that is made worse by movement. The maximum intensity of the pain occurs 3 to 6 hours after beginning.

When caffeine is reintroduced, relief of withdrawal symptoms tends to occur within 30 to 60 minutes. At present, this appears to be the most effective “treatment” for the caffeine withdrawal syndrome.

Effect on Sleep

Caffeine interferes with sleep in most nontolerant individuals.59 Tolerant people are much less likely to self-report sleep abnormalities, or they may sense that the insomnia has disappeared altogether. To illustrate, 53% of those consuming less than 250 mg/day agreed that caffeine before bedtime would prevent sleep, compared with 43% of those consuming 250 to 749 mg/day, and only 22% of those taking 750 mg/day or more. Even though the higher-level consumers denied that caffeine interferes with their sleep, studies done in the sleep laboratory confirm that caffeine consumers do have greater sleep latency, more frequent awakenings, and altered sleep architecture, and that these effects are dose related.

Caffeine During Pregnancy

Over the years there has been much discussion on whether or not caffeine intake during pregnancy is harmful to the developing fetus. Results of research have been mixed, but, in general, caffeine has not been shown to be a potent and consistent teratogen. Kuczkowski67 published an evidence-based review highlighting the implications of caffeine intake in pregnancy and offering recommendations for practitioners providing peripartum care to expectant mothers who consume caffeine. The author concluded that, for the healthy pregnant adult, moderate daily caffeine intake at a dose level up to 400 mg/day is not associated with adverse effects such as general toxicity, cardiovascular effects, effects on bone status and calcium balance, changes in adult behavior, increased incidence of cancer, or effects on fertility. The study did not identify any significant positive associations between maternal caffeine consumption and cardiovascular malformations.

The March of Dimes advises women to limit their caffeine intake to less than 200 mg/day. This recommendation was prompted by the results of a population-based prospective cohort study published in March 200868 showing that pregnant women consuming 200 mg or more of caffeine a day had double the risk of miscarriage compared with those who had no caffeine. Criticism of this study was swift to follow, and its conclusions have been called into question.

A Cochrane systematic review69 points out that authors of some observational studies have concluded that caffeine intake is harmful to the fetus. The review concludes that there is insufficient evidence from RCTs to support any reason to avoid caffeine during pregnancy. Unfortunately, this review is based on only one published controlled trial.

Caffeine and Headaches

A Norwegian study70 investigated the association between caffeine consumption and headache in the general adult population. Results were based on cross-sectional data from 50,483 (55%) out of 92,566 invited participants aged greater than or equal to 20 years. A weak but significant association (OR 1.16; 95% CI 1.09 to 1.23) was found between high caffeine consumption and infrequent headaches. In contrast, headache for greater than 14 days/mo was less likely among individuals with high caffeine consumption compared with those with low caffeine consumption. The authors speculate that their results may indicate that high caffeine consumption changes chronic headache into infrequent headache due to the analgesic properties of caffeine. Alternatively, chronic headache sufferers tend to avoid intake of caffeine to not aggravate their headaches, whereas individuals with infrequent headache are less aware that high caffeine use can be a cause.


Desired Outcomes

Many people drink coffee, tea, and other caffeinated beverages without problems. When adverse health effects do occur (e.g., insomnia, headaches, anxiety, palpitations), it may be necessary to cut down on the amount of caffeine ingested or to eliminate it altogether to achieve the goal of elimination of these symptoms.


Caffeinism is treated by reducing or discontinuing the drug. It may be necessary to wean the patient off the drug gradually because going “cold turkey” can produce such serious symptoms that the drug must be restarted. Decaffeinated beverages can be substituted slowly for the caffeinated type. However, relapses are less likely to occur when the drug is discontinued all at once, probably because of the considerable self-discipline required to continue weaning the drug when one knows that an increase in dose will cause the symptoms to abate.




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