NICOTINE PHARMACOLOGY and PRINCIPLES of ADDICTION This module focuses on the pharmacology of nicotine and principles of addiction.

NICOTINE ADDICTION U.S. Surgeon General’s Report (1988) Cigarettes and other forms of tobacco are addicting. Nicotine is the drug in tobacco that causes addiction. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. In 1988 the U.S. Surgeon General released a report entitled The Health Consequences of Smoking: Nicotine Addiction. This landmark document summarized the scientific evidence supporting the concept that tobacco products are effective nicotine-delivery systems capable of inducing and sustaining chemical dependence. The major findings of the report were as follows: Cigarettes and other forms of tobacco are addicting. Nicotine is the drug in tobacco that causes addiction. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. The last point is significant in that we, as health care providers, must treat tobacco use and dependence as a serious medical condition. It is a chronic form of brain disease, not just a “bad habit.” Nicotine addiction is a complex disorder that requires treatment directed at both the biological and the behavioral aspects of the disease. U.S. Department of Health and Human Services. (1988). The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General (DHHS Publication No. PHS 88-8406). Washington, DC: U.S. Government Printing Office. Retrieved December 19, 2005, from http://www.cdc.gov/tobacco/sgr/sgr_1988/. U.S. Department of Health and Human Services. (1988). The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General.

CHEMISTRY of NICOTINE N Nicotiana tabacum Natural liquid alkaloid Pyridine ring Pyrrolidine ring As discussed in the Epidemiology of Tobacco Use module, tobacco and tobacco smoke have numerous constituents. From a pharmacologic perspective, the most important constituent is nicotine. Nicotine, composed of a pyridine ring and a pyrrolidine ring, is one of the few natural alkaloids that exists in the liquid state. Nicotine is a clear, weak base (pKa = 8.0) that turns brown and acquires the characteristic odor of tobacco following exposure to air (Benowitz, 1992; Taylor, 2001). Nicotine mimics the effects of acetylcholine at the acetylcholine receptor site. Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Taylor P. (2001). Agents acting at the neuromuscular junction and autonomic ganglia. In Hardman JG, Limbird LE (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw Hill. Nicotiana tabacum Natural liquid alkaloid Colorless, volatile base pKa = 8.0

PHARMACOLOGY Pharmacokinetics Effects of the body on the drug Absorption Distribution Metabolism Excretion Effects of the drug on the body Pharmacokinetics Pharmacology is divided into two areas: pharmacokinetics and pharmacodynamics. Pharmacokinetics is defined as the effects that the body has on a drug—specifically, the drug’s absorption, distribution, metabolism, and excretion. Each of these factors significantly influences how a drug affects a given individual. Pharmacodynamics is defined as the effects of a drug on the body. The effects can be either positive (therapeutic effects) or negative (adverse reactions or side effects). The next several slides cover nicotine pharmacokinetics and pharmacodynamics. Then we’ll discuss nicotine addiction as a form of chronic brain disease requiring a multifaceted therapeutic approach. ♪ Note to instructor(s): For a comprehensive review of the metabolism and disposition kinetics of nicotine, refer to Hukkanen, Jacob, & Benowitz (2005). Hukkanen J, Jacob P III, Benowitz NL. (2005). Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79–115. Pharmacodynamics

nicotine is readily absorbed. NICOTINE ABSORPTION Absorption is pH dependent In acidic media Ionized  poorly absorbed across membranes In alkaline media Nonionized  well absorbed across membranes At physiologic pH (7.3–7.5), ~31% of nicotine is unionized To understand nicotine pharmacology, it’s important to know that absorption of nicotine is pH dependent. Because nicotine is a weak base (pKa = 8.0): In acidic media… nicotine is ionized and poorly absorbed across membranes. In alkaline media… nicotine is nonionized and well absorbed across membranes. Under physiologic conditions (pH = 7.3–7.5), approximately 31% of nicotine is nonionized and readily crosses cell membranes (Benowitz, 1992; Hukkanen et al., 2005). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Hukkanen J, Jacob P III, Benowitz NL. (2005). Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79–115. At physiologic pH, nicotine is readily absorbed.

NICOTINE ABSORPTION: BUCCAL (ORAL) MUCOSA The pH inside the mouth is 7.0. Acidic media (limited absorption) Cigarettes Alkaline media (significant absorption) Pipes, cigars, spit tobacco, oral nicotine products Most American cigarette smoke is acidic. As a result, limited nicotine is absorbed across the buccal (oral) mucosa. In contrast, air-cured tobacco (found in pipe tobacco and cigars) produces smoke with an alkaline pH, which allows for buccal absorption of nicotine. Even pipe or cigar smokers who don’t inhale experience considerable nicotine absorption through the buccal mucosa (Benowitz, 1992). Smokeless tobacco products (snuff and chew) and nicotine gum and lozenge are buffered to an alkaline pH to facilitate absorption of nicotine (Benowitz, 1999). If the pH of the mouth is lowered by drinking acidic beverages (e.g., coffee, juice, or cola), absorption of nicotine from nicotine gum is reduced substantially (Henningfield et al., 1990). This fact is important when counseling patients on the proper use of nicotine gum, lozenge, and oral inhaler. Notably, the tobacco industry documents reveal that the industry alters the ammonia and acid aldehyde chemistry to manipulate the pH of its products, rendering them more addictive. Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz NL. (1999). Nicotine addiction. Prim Care 26:611–631. Henningfield JE, Radzius A, Cooper TM, Clayton RR. (1990). Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum. JAMA 264:1560–1564. Beverages can alter pH, affect absorption.

NICOTINE ABSORPTION: SKIN and GASTROINTESTINAL TRACT Nicotine is readily absorbed through intact skin. Nicotine is well absorbed in the small intestine but has low bioavailability (30%) due to first- pass hepatic metabolism. Nicotine is readily absorbed across intact skin. This allows for transdermal administration of nicotine as a therapeutic adjunct to tobacco cessation (Taylor, 2001). Conversely, the bioavailability of nicotine in the gastrointestinal tract is limited. Absorption across the gastric mucosa is poor as a result of low gastric pH. In the small intestine, nicotine is well absorbed due to increased pH; however, the systemic bioavailability is low (30%) because it undergoes significant first-pass hepatic metabolism (Benowitz, 1992). Oral nicotine formulations (e.g., sublingual tablets and lozenges) are not subject to first-pass hepatic metabolism. Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Taylor P. (2001). Agents acting at the neuromuscular junction and autonomic ganglia. In Hardman JG, Limbird LE (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw Hill.

NICOTINE ABSORPTION: LUNG Nicotine is “distilled” from burning tobacco and carried in tar droplets. Nicotine is rapidly absorbed across respiratory epithelium. Nicotine is “distilled” from burning tobacco and carried in droplets to the small airways of the lung. The droplets are composed of water, tar, and alkaloids, including nicotine (Benowitz, 1999). When tobacco smoke reaches the alveoli, nicotine is rapidly absorbed across respiratory epithelial cells due to the following factors (Benowitz, 1999): The pH of the lung is 7.4 (a larger fraction of nicotine is nonionized). The alveolar surface area of the lung is large. The capillary system in the lung is extensive. Benowitz NL. (1999). Nicotine addiction. Prim Care 26:611–631. Lung pH = 7.4 Large alveolar surface area Extensive capillary system in lung

NICOTINE DISTRIBUTION Nicotine reaches the brain within 11 seconds. Arterial Inhalation of tobacco smoke is an effective means of delivering nicotine to the central nervous system. After inhalation, nicotine is rapidly absorbed across pulmonary epithelium into the arterial circulation, traveling via the carotid arteries to the central nervous system. Nicotine readily penetrates the blood-brain barrier, resulting in transient exposure of the brain to high levels of nicotine. Nicotine has been estimated to reach the brain within 11 seconds of inhalation. Following systemic distribution, brain nicotine levels decline rapidly (Benowitz, 1990). This graph depicts the arterial and venous concentrations of nicotine achieved during cigarette smoking. Within 1 minute after smoking a cigarette, arterial levels of nicotine are nearly seven times the corresponding venous levels (Henningfield et al., 1993). These rapid, high levels of nicotine in the central nervous system produce an almost immediate effect, thereby reinforcing the behavioral act of smoking, which further stimulates repeated administration. Benowitz NL. (1990). Clinical pharmacology of inhaled drugs of abuse: Implications in understanding nicotine dependence. In Chiang CN, Hawks RL (eds.), Research Findings on Smoking of Abused Substances (NIDA Research Monograph 99). Rockville, MD: National Institute on Drug Abuse. Retrieved December 19, 2005, from www.drugabuse.gov/pdf/monographs/download99.html. Henningfield JE, Stapleton JM, Benowitz NL, Grayson RF, London ED. (1993). Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug Alcohol Depend 33:23–29. Venous Henningfield et al. (1993). Drug Alcohol Depend 33:23–29.

NICOTINE METABOLISM N H CH3 N 70–80% cotinine ~ 10% other metabolites 10–20% excreted unchanged in urine N CH3 N Nicotine is metabolized extensively in the liver and to a lesser extent in the kidney and lung. Approximately 70–80% of nicotine is metabolized to cotinine, an inactive metabolite (Benowitz et al., 1983), and about 4% is metabolized to nicotine-oxide. The metabolism of nicotine to cotinine is a two-step process likely involving CYP2A6 and aldehyde oxidase. Cotinine is further metabolized to 3′-hydroxycotinine, which undergoes renal elimination. However, nicotine, cotinine, and 3′-hydroxycotinine also undergo glucuronidation. A small fraction (10–20%) of an administered dose of nicotine is excreted as unchanged drug in the urine (Benowitz, 1996; Benowitz & Jacob, 1997; Benowitz et al., 1994). ♪ Note to instructor(s): The daily intake of nicotine can be estimated from a measured plasma cotinine level using the following equation: Daily dose of nicotine (in mg) = plasma cotinine concentration (ng/ml)  0.08 Example: An average cotinine concentration of 300 ng/ml in a typical smoker corresponds to a daily intake of 24 mg nicotine (Benowitz & Jacob, 1994). A smoker absorbs, on average, approximately 1 mg of nicotine per cigarette (Benowitz & Jacob, 1984). It can then be estimated that a plasma cotinine level of 300 ng/ml corresponds to a daily intake of 24 cigarettes. 300 ng/ml  0.08 = 24 mg = 24 cigarettes (1 mg = 1 cigarette) Benowitz NL. (1996). Pharmacology of nicotine: Addiction and therapeutics. Annu Rev Pharmacol Toxicol 36:597–613. Benowitz NL, Jacob P III. (1984). Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499–504. Benowitz NL, Jacob P III. (1994). Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 56:483–493. Benowitz NL, Jacob P. (1997). Individual differences in nicotine kinetics and metabolism in humans. In Rapaka RS, Chiang N, Martin BR (eds.), Pharmacokinetics, Metabolism, and Pharmaceutics of Drugs of Abuse (NIDA Research Monograph No. 173; DHHS Publication No. 97-4141). Rockville, MD: National Institute on Drug Abuse. Benowitz NL, Jacob P, Fong I, Gupta S. (1994). Nicotine metabolic profile in man: Comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268:296–303. Benowitz NL, Kuyt F, Jacob P III, Jones RT, Osman AL. (1983). Cotinine disposition and effects. Clin Pharmacol Ther 34:604–611. 70–80% cotinine ~ 10% other metabolites Metabolized and excreted in urine Adapted and reprinted with permission. Benowitz et al. (1994). J Pharmacol Exp Ther 268:296–303.

NICOTINE EXCRETION Half-life Nicotine t½ = 2 hr Cotinine t½ = 19 hr Occurs through kidneys (pH dependent; h with acidic pH) Through breast milk The half-life of nicotine in the body is approximately 2 hours. This rapid metabolism of nicotine to inactive compounds underlies tobacco users’ need for frequent, repeated administration of nicotine. With regular tobacco use, significant nicotine levels accumulate during waking hours. The half-life of cotinine (nicotine’s major metabolite) is much longer (18–20 hours). For this reason, cotinine can be used as a more reliable marker of tobacco use and exposure to second-hand smoke. Nicotine and other metabolites are excreted in the urine. Urinary excretion is pH dependent; the excretion rate is increased in acidic urine. Nicotine accumulates in breast milk (Hukkanen et al., 2005) and can be detected in the blood and urine of infants of nursing smokers (Benowitz, 1999; Taylor, 2001). Benowitz NL. (1999). Nicotine addiction. Prim Care 26:611–631. Hukkanen J, Jacob P III, Benowitz NL. (2005). Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79–115. Taylor P. (2001). Agents acting at the neuromuscular junction and autonomic ganglia. In Hardman JG, Limbird LE (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw Hill.

NICOTINE PHARMACODYNAMICS Nicotine binds to receptors in the brain and other sites in the body. Central nervous system Cardiovascular system Exocrine glands Now let’s turn to nicotine pharmacodynamics, which refers to the effects that nicotine has on the body. Nicotine is a potent agent that affects numerous organ systems, including the cardiovascular, endocrine, musculoskeletal, and neurologic systems, as shown in this diagram. Following absorption, nicotine binds to receptors in the brain and other sites in the body, inducing a variety of predominantly stimulant and, to a lesser extent, sedative effects (Taylor, 2001). Taylor P. (2001). Agents acting at the neuromuscular junction and autonomic ganglia. In Hardman JG, Limbird LE (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw Hill. Gastrointestinal system Adrenal medulla Other: Neuromuscular junction Sensory receptors Other organs Peripheral nervous system Nicotine has stimulant and sedative properties.

NICOTINE PHARMACODYNAMICS (cont’d) Central nervous system Pleasure Arousal, enhanced vigilance Improved task performance Anxiety relief Other Appetite suppression Increased metabolic rate Skeletal muscle relaxation Cardiovascular system  Heart rate  Cardiac output  Blood pressure Coronary vasoconstriction Cutaneous vasoconstriction Pharmacodynamic effects of nicotine on the central nervous system (Benowitz, 1992): Pleasure: Tobacco users commonly report they find tobacco use pleasurable. Arousal, enhanced vigilance: Tobacco use may help with thinking, concentration, and mood elevation. Improved task performance: Nicotine has been shown to increase vigilance and performance for some types of tasks (e.g., repetitive/monotonous tasks). Relief of anxiety: Many tobacco users report reduced anger, tension, and stress after administration. It is not known whether the improvements in mood or task performance are due to relief of nicotine withdrawal symptoms or a direct effect of nicotine on the brain. Pharmacodynamic effects of nicotine on the cardiovascular system: Nicotine’s effects on the cardiovascular system include increased heart rate, cardiac output, and blood pressure as well as cutaneous and coronary vasoconstriction (Benowitz, 1992). After a cigarette is smoked, the smoker’s blood pressure rises by 5–10 mmHg for 15–30 minutes, and the heart rate increases an average of 10–20 beats/min for up to 60 minutes (Benowitz et al., 1988). Studies suggest there is a flat dose-response to the cardiovascular effects of nicotine. This so-called ceiling effect might be due to a rapid but partial development of tolerance to the cardiovascular effects of nicotine (Benowitz, 1997). Other pharmacodynamic effects of nicotine: Nicotine is an effective appetite suppressant and causes modest acute increases in the metabolic rate (Benowitz, 1992). Most people who quit using tobacco will gain weight, although the average person will gain less than 10 pounds (Fiore et al., 2000). Weight gain after tobacco cessation is a major concern for many patients, especially females. Nicotine also causes relaxation of some skeletal muscle (Benowitz, 1992). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Benowitz NL. (1997). The role of nicotine in smoking-related cardiovascular disease. Prev Med 26:412–417. Benowitz NL, Porchet H, Sheiner L, Jacob P III. (1988). Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum. Clin Pharmacol Ther 44:23–28. Fiore MC, Bailey WC, Cohen SJ, et al. (2000). Treating Tobacco Use and Dependence. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service.

NEUROCHEMICAL and RELATED EFFECTS of NICOTINE Dopamine Norepinephrine Acetylcholine Glutamate Serotonin -Endorphin GABA Pleasure, reward Arousal, appetite suppression Arousal, cognitive enhancement Learning, memory enhancement Mood modulation, appetite suppression Reduction of anxiety and tension On a neurochemical level, nicotine induces a variety of central nervous system, cardiovascular, and metabolic effects. Nicotine stimulates the release of many neurotransmitters, which have been associated with the following effects (Benowitz, 1999): Neurotransmitter Effects Dopamine Pleasure, reward Norepinephrine Arousal, appetite suppression Acetylcholine Arousal, cognitive enhancement Glutamate Learning, memory enhancement Serotonin Mood modulation, appetite suppression -Endorphin Reduction of anxiety and tension GABA Reduction of anxiety and tension Nicotine induces a constellation of effects that reinforce tobacco use behavior. Benowitz NL. (1999). The biology of nicotine dependence: From the 1988 Surgeon General’s Report to the present and into the future. Nicotine Tob Res 1(Suppl):S159–S163. Benowitz. (1999). Nicotine Tob Res 1(Suppl):S159–S163.

WHAT IS ADDICTION? ”Compulsive drug use, without medical purpose, in the face of negative consequences” Alan I. Leshner, Ph.D. Former Director, National Institute on Drug Abuse National Institutes of Health Many people believe that addiction is a result of weakness in character and an inability to change one’s behavior. But is it really that simple? Research contradicts this position. Nicotine addiction is a form of chronic brain disease resulting from an alteration in brain chemistry (Leshner, 1997, 1999). Dr. Alan Leshner, the former director of the National Institute on Drug Abuse, simply defines drug addiction as “compulsive use, without medical purpose, in the face of negative consequences” (Leshner, 1997). But how does human behavior fit into this equation? Leshner Al. (1997, April). Drug abuse and addiction are biomedical problems. Hosp Pract (special report):2–4. Leshner AI. (1999). Science-based views of drug addiction and its treatment. JAMA 282:1314–1316.

BIOLOGY of NICOTINE ADDICTION: ROLE of DOPAMINE stimulates dopamine release is not just a bad habit. Pleasurable feelings Many smokers believe that smoking/dipping/chewing is simply a bad habit. Research has shown that nicotine addiction is a chronic condition, one with a biological basis. Experts in drug abuse and addiction believe that nicotine addiction is a form of chronic brain disease. Nicotine stimulates the release of brain neurotransmitters, including dopamine, which activates the dopamine reward pathway. This induces feelings of pleasure, which reinforce repeat administration of the drug. With chronic administration, tolerance to the behavioral and cardiovascular effects of nicotine develops over the course of the day. Tobacco users regain sensitivity to the effects of nicotine after overnight abstinence from smoking. When tobacco users abruptly discontinue nicotine they experience symptoms of withdrawal. These withdrawal symptoms serve as a powerful stimulus to repeat nicotine administration (Benowitz, 1992). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Discontinuation leads to withdrawal symptoms. Repeat administration Tolerance develops

DOPAMINE REWARD PATHWAY Ventral tegmental area Prefrontal cortex Dopamine release Drugs such as cocaine, heroin, amphetamine, and nicotine exert profound effects on the brain. These agents have in common the ability to stimulate the release of the neurotransmitter dopamine in the midbrain. Dopamine induces feelings of euphoria and pleasure and is responsible for activating the dopamine reward pathway (Leshner, 1997). The dopamine reward pathway, as depicted in this simplified diagram, is a network of nervous tissue in the middle of the brain that elicits feelings of pleasure in response to certain stimuli. The important interconnected structures of the reward pathway include the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex (area of the brain responsible for thinking and judgment). The neurons of the VTA contain the neurotransmitter dopamine, which is released in the nucleus accumbens and in the prefrontal cortex. Behaviors that naturally stimulate the reward pathway include eating to relieve hunger, drinking to alleviate thirst, or engaging in sexual activity. On a primitive, neurochemical level, stimulation of the reward pathway reinforces the behavior so that it will be repeated. Obviously these behaviors are necessary for continued survival of the organism. The reward pathway can also be stimulated by drugs of abuse such as cocaine, opiates, amphetamine, and nicotine. When these unnatural stimuli trigger the reward pathway the same pleasurable feelings are elicited. Researchers believe that, with chronic drug use, the brain becomes chemically altered—transforming a drug user into a drug addict (Leshner, 1997). Consider cigarette smoking as an example. Immediately following inhalation, a bolus of nicotine enters the brain, stimulating the release of dopamine, which induces nearly immediate feelings of pleasure and relief of symptoms of nicotine withdrawal. This rapid dose-response reinforces and perpetuates the smoking behavior. This slide is made available to the public through the National Institute on Drug Abuse Web page, at www.nida.nih.gov/Teaching/largegifs/slide-9.gif. Adapted with permission by Dr. Rochelle D. Schwartz-Bloom, Duke University. Leshner Al. (1997, April). Drug abuse and addiction are biomedical problems. Hosp Pract (special report):2–4. Stimulation of nicotine receptors Nucleus accumbens Ventral tegmental area Nicotine enters brain

CHRONIC ADMINISTRATION of NICOTINE: EFFECTS on the BRAIN Nonsmoker Smoker Human smokers have increased nicotine receptors in the prefrontal cortex. High Low Image courtesy of George Washington University / Dr. David C. Perry Chronic administration of nicotine results in an increased number of nicotine receptors in specific regions of the brain (Perry et al., 1999). This upregulation of nicotine receptors leads to the development of tolerance, by which repeated doses of a drug produce less of an effect than did the initial exposure. Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ. (1999). Increased nicotinic receptors in brains from smokers: Membrane binding and autoradiography studies. J Pharmacol Exp Ther 289:1545–1552. Perry et al. (1999). J Pharmacol Exp Ther 289:1545–1552.

NICOTINE PHARMACODYNAMICS: WITHDRAWAL EFFECTS Depression Insomnia Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness Increased appetite/weight gain Decreased heart rate Cravings* Most symptoms peak 24–48 hr after quitting and subside within 2–4 weeks. ♪ Note to instructor(s): Refer students to the Withdrawal Symptoms Information Sheet handout. This handout describes several symptoms, when they occur postcessation, and how to cope with withdrawal. In addition to being an educational aid for students, it can be copied and distributed to patients who are quitting. When nicotine is discontinued abruptly, the following withdrawal symptoms develop (American Psychiatric Association, 1994; Hughes et al., 1991; Hughes & Hatsukami, 1998): Depression Insomnia Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness Increased appetite/weight gain Decreased heart rate (not measurable through self-report) Cravings* *Cravings is a symptom of tobacco withdrawal that was included in the third edition and revised third edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders; however, this symptom was omitted from the fourth edition (DSM-IV) classifications. Other symptoms of quitting have been described in the literature, and many of these are addressed in the Withdrawal Symptoms Information Sheet. Tobacco users usually experience a strong desire or craving for tobacco. In general, withdrawal symptoms peak 24–48 hours after cessation and gradually dissipate over the next 2–4 weeks. Strong cravings for tobacco may persist for months to years after cessation (Benowitz, 1992; Hughes et al., 1991). American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association. Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW. (1991). Symptoms of tobacco withdrawal: A replication and extension. Arch Gen Psychiatry 48:52–59. Hughes JR, Hatsukami D. (1998). Errors in using tobacco withdrawal scaoe (letter to the editor). Tob Control 7:92–93. HANDOUT American Psychiatric Association. (1994). DSM-IV. Hughes et al. (1991). Arch Gen Psychiatry 48:52–59. Hughes & Hatsukami. (1998). Tob Control 7:92–93. * Not considered a withdrawal symptom by DSM-IV criteria.

NICOTINE ADDICTION CYCLE To alleviate the symptoms of withdrawal, smokers re-dose themselves throughout the day. This figure depicts the typical nicotine addiction cycle a cigarette smoker experiences on a daily basis. ♪ Note to instructor(s): Orient the students to the following elements on this figure: The jagged line represents venous plasma concentrations of nicotine as a cigarette is smoked every 40 minutes from 8 am to 9 pm. The upper solid line indicates the threshold concentration for nicotine to produce pleasure or arousal. The lower solid line indicates the concentrations at which symptoms of abstinence (i.e., withdrawal symptoms) from nicotine occur. The shaded area represents the zone of nicotine concentrations (neutral zone) in which the smoker is comfortable without experiencing either pleasure/arousal or abstinence symptoms. After smoking the first cigarette of the day, the smoker experiences marked pharmacologic effects, particularly arousal. No other cigarette throughout the day produces the same degree of pleasure/arousal. For this reason, many smokers describe the first cigarette as the most important one of the day. Shortly after the initial cigarette, tolerance begins to develop. Accordingly, the threshold levels for both pleasure/arousal and abstinence rise progressively throughout the day as the smoker becomes tolerant to the effects of nicotine. With continued smoking, nicotine accumulates, leading to an even greater degree of tolerance. As a result, the smoker experiences greater withdrawal symptoms between successive cigarettes. Late in the day, each individual cigarette produces only limited pleasure/arousal; instead, smoking primarily alleviates nicotine withdrawal symptoms. Cessation of smoking overnight allows resensitization of drug responses (i.e., loss of tolerance). Most dependent smokers tend to smoke a certain number of cigarettes per day (usually more than 10) and tend to consume 10–40 mg of nicotine per day to achieve the desired effects of cigarette smoking and minimize the symptoms of nicotine withdrawal (Benowitz, 1992). Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Reprinted with permission. Benowitz. (1992). Med Clin N Am 2:415–437.

NICOTINE ADDICTION Tobacco users maintain a minimum serum nicotine concentration in order to Prevent withdrawal symptoms Maintain pleasure/arousal Modulate mood Users self-titrate nicotine intake by Smoking/dipping more frequently Smoking more intensely Obstructing vents on low-nicotine brand cigarettes As shown in the previous slide, tobacco users tend to carefully titrate, or regulate, their tobacco intake to maintain a relatively constant level of nicotine in the body, in order to Prevent withdrawal symptoms Maintain pleasure/arousal Modulate mood (e.g., to handle stress or anxiety) Although many tobacco users might not think about it consciously, they are able to alter nicotine delivery in a number of ways, including By smoking or dipping more frequently By smoking more intensely (e.g., inhaling deeper or longer, smoking cigarette down to the filter) By obstructing the vents (with fingers or lips) on “light” cigarettes, thereby increasing the amount of nicotine delivered to the lung Benowitz NL. (1999). Nicotine addiction. Prim Care 26:611–631.

ASSESSING NICOTINE DEPENDENCE Fagerström Test for Nicotine Dependence (FTND) Developed in 1978 (8 items); revised in 1991 (6 items) Most common research measure of nicotine dependence; sometimes used in clinical practice Responses coded such that higher scores indicate higher levels of dependence Scores range from 0 to 10; score of greater than 5 indicates substantial dependence In research, and sometimes in clinical practice, it is useful to be able to measure a patient’s level of nicotine dependence. The most commonly used scale for assessing nicotine dependence is the Fagerström Test for Nicotine Dependence (FTND). The FTND, which originally was an 8-item scale called the Fagerström Tolerance Questionnaire, consists of the following 6 items (Heatherton et al., 1991): How soon after you wake up do you smoke your first cigarette? Within 5 minutes, 6–30 minutes, 31–60 minutes, after 60 minutes Do you find it difficult to refrain from smoking in places where it is forbidden? Yes, No Which cigarette would you hate most to give up? The first one in the morning, Any other How many cigarettes per day do you smoke? 10 or less, 11–20, 21–30, 31 or more Do you smoke more frequently during the first hours after waking than during the rest of the day? Do you smoke if you are so ill that you are in bed most of the day? ♪ Note to instructor(s): Refer students to the FTND handout, which lists the items, describes the scoring, and presents cutoffs for categories of dependence. The scale is perhaps the most commonly used research measure of nicotine dependence, but it also can be used in clinical practice. As shown on the scoring sheet, the responses are coded such that higher scores indicate higher levels of nicotine dependence. The total scores, after summing the items, range from 0 to 10. Although there are no established cutoffs for score interpretations, many researchers and clinicians generally consider scores of greater than 5 indicative of substantial dependence. Modified versions of the scale have been developed and tested for use with spit tobacco users (Severson & Hatsukami, 1999) and adolescents (Prokhorov et al., 1998). Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. (1991). The Fagerström Test for Nicotine Dependence: A revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction 86:1119–1127. Prokhorov AV, Koehly LM, Pallonen UE, Hudmon KS. (1998). Adolescent nicotine dependence measured by the modified Fagerström Tolerance Questionnaire at two time points. J Child Adol Subst Use 7:35–47. Severson HH, Hatsukami DK. (1999). Smokeless tobacco cessation. Prim Care 26:529–551. HANDOUT Heatherton et al. (1991). British Journal of Addiction 86:1119–1127.

CLOSE TO HOME © 2000 John McPherson. Patients often describe tobacco cessation as the most difficult achievement of their life. Tobacco users can be very creative in the methods they choose for quitting, as is illustrated in this cartoon. CLOSE TO HOME © 2000 John McPherson. Reprinted with permission of UNIVERSAL PRESS SYNDICATE. All rights reserved.

FACTORS CONTRIBUTING to TOBACCO USE Environment Tobacco advertising Conditioned stimuli Social interactions Physiology Genetic predisposition Coexisting medical conditions Tobacco Use Nicotine is a powerful drug capable of inducing a variety of pharmacologic effects, including an alteration in brain chemistry. However, tobacco addiction is more than just a brain disease. It is a complex process involving the interplay of many factors (pharmacologic, environmental, and physiologic) that influence an individual’s decision to use tobacco (Benowitz, 1992). As such, treatment of addiction requires a multifaceted approach (Lerman et al., 2005; Leshner, 1999). This slide depicts important factors that influence tobacco use behavior. Environmental factors: Tobacco industry advertising: For years, the tobacco industry has engineered major marketing plans to design more addictive cigarettes and to defy the public regarding the hazards of smoking. Their multibillion-dollar marketing effort is an important contributor to tobacco use. Conditioned stimuli: All drug-taking behavior is learned, a result of conditioning. Drug-taking behavior is reinforced by the consequences of the pharmacologic actions of the drug. At the same time, smokers begin to associate specific moods, situations, or environmental factors with nicotine’s reward effects. The association between such cues and anticipated drug effects and the resulting urge to smoke is another type of conditioning. For example, people often smoke cigarettes in specific situations, such as after a meal or with coffee or alcoholic beverages. The association between smoking and these other events, repeated many times, causes the environmental situations to become powerful cues for the urge to smoke. A nondrug example of this type of conditioning is the desire to eat popcorn at the movies or hot dogs at baseball games. Other aspects of smoking (e.g., manipulation of smoking materials, taste, smell, feel of smoke in the throat) become associated with the pleasurable effects of smoking. Even unpleasant moods can become conditioned cues for smoking. For example, a smoker may learn that not having a cigarette provokes irritability, a common nicotine withdrawal symptom. Smoking a cigarette relieves withdrawal symptoms. After repeated similar experiences, a smoker may come to regard irritability from any source, such as stress or frustration, as a cue for smoking. Conditioning is a major factor that causes relapse. As such, it must be addressed as a component of behavioral therapy for nicotine addiction. Social interactions: Having family or peer-group members who smoke increases the likelihood of tobacco use and, therefore, addiction. Among adolescents, peer pressure is often a reason for initiating tobacco use. Pharmacologic factors: As discussed previously, there is a pharmacologic basis for a nicotine-dependent individual’s decision to use tobacco. Physiologic factors: Experts now believe that some individuals have a genetic predisposition for nicotine addiction. Additionally, the impact of coexisting medical conditions (especially psychiatric conditions) increases an individual’s likelihood of using and becoming dependent on tobacco. Benowitz NL. (1992). Cigarette smoking and nicotine addiction. Med Clin N Am 76:415–437. Lerman C, Patterson F, Berrettini W. (2005). Treating tobacco dependence: State of the science and new directions. J Clin Oncol 23:311–323. Leshner AI. (1999). Science-based views of drug addiction and its treatment. JAMA 282:1314–1316. Pharmacology Alleviation of withdrawal symptoms Weight control Pleasure

TOBACCO DEPENDENCE: A 2-PART PROBLEM Physiological The addiction to nicotine Medications for cessation Treatment Behavioral The habit of using tobacco Behavior change program Treatment Tobacco dependence is a chronic brain disease and is a condition that requires a two-prong approach for maximal treatment effectiveness. Prolonged tobacco use of tobacco results in tobacco dependence, which is characterized as a physiological dependence (addiction to nicotine) and behavioral habit of using tobacco. Addiction can be treated with FDA-approved medications for smoking cessation, and the behavioral habit can be treated through behavior change programs, such as individualized counseling and group or online cessation programs. The Clinical Practice Guideline for treating tobacco use and dependence (Fiore et al., 2000), which summarizes more than 6,000 published articles, advocates the combination of behavioral counseling with pharmacotherapy in treating patients who smoke. ♪ Note to instructor(s): Specific methods for treating tobacco use and dependence are covered in detail in the Assisting Patients with Quitting and Aids for Cessation modules. Fiore MC, Bailey WC, Cohen SJ, et al. (2000). Treating Tobacco Use and Dependence. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service. Treatment should address the physiological and the behavioral aspects of dependence.

NICOTINE PHARMACOLOGY and ADDICTION: SUMMARY Tobacco products are effective delivery systems for the drug nicotine. Nicotine is a highly addictive drug that induces a constellation of pharmacologic effects. Nicotine activates the dopamine reward pathway in the brain, which reinforces continued tobacco use. Tobacco users who are dependent on nicotine self-regulate tobacco intake to maintain pleasurable effects and prevent withdrawal. To summarize: Tobacco products are effective delivery systems for the drug nicotine. Nicotine is a highly addictive drug that induces a constellation of pharmacologic effects. Nicotine activates the dopamine reward pathway in the brain, which reinforces continued tobacco use. Tobacco users who are dependent on nicotine self-regulate their tobacco intake to maintain pleasurable effects and prevent withdrawal.

NICOTINE PHARMACOLOGY and ADDICTION: SUMMARY (cont’d) Nicotine dependence is a form of chronic brain disease. Tobacco use is a complex disorder involving the interplay of the following: Pharmacology of nicotine (pharmacokinetics and pharmacodynamics) Environmental factors Physiologic factors Treatment of tobacco use and dependence requires a multifaceted treatment approach. Nicotine dependence is a form of chronic brain disease. Tobacco use is a complex disorder involving the interplay of the following: Nicotine pharmacology, including pharmacokinetics and pharmacodynamics Environmental factors Physiologic factors Treatment of tobacco use and dependence requires a multifaceted approach. This topic is covered in the remainder of the program.