THERAPEUTICS FOR NICOTINE ADDICTION 尼古丁成瘾治疗

107 THERAPEUTICS FOR NICOTINE ADDICTION REESE T. JONES NEAL L. BENOWITZ About 25% of adults in the United States smoke tobacco cigarettes.Most continue smoking because they are addicted to nicotine. That nicotine is central to maintaining tobacco use is well established (49). When asked, 70% of cigarette smokers report that they would like to quit. Each year, less than 1%will actually succeed without any therapeutic inter- ventions. Few other conditions in medicine present nicotine addiction’s mix of lethality, prevalence, cost, and relative therapeutic neglect, despite effective and readily available treatment interventions. Health care providers too often fail to assess or treat tobacco addiction despite substantial evi- dence that even brief therapeutic interventions are effective (2). Worldwide potential benefits of prevention and adequate treatment are staggering (96). More than 1.2 billion people regularly smoke tobacco. During the twentieth century, only approximately 0.1 billion people died of tobacco use–related illnesses. If current smoking patterns continue, 1 billion additional people will die of smoking-related illness during this century. Half will die during middle age. About 4 million people died of tobacco-related disease in 1998. Projections indicate 10 million tobacco-related deaths yearly by the year 2030, with 70% of those deaths in devel- oping countries. Reducing the number of current smokers by 50% would avoid 25 million premature deaths in the first quarter of this century and about 150 million more by midcentury (96). Understanding the role of nicotine in sustaining tobacco addiction offers a basis for optimal and rational treatments for preventing or stopping smoking (49). Nicotine addic- tion has much in common with other addictions, so consid- eration of therapeutics should help in development of thera- Reese T. Jones: Department of Psychiatry, University of California, San Francisco, California. Neal L. Benowitz: Departments ofMedicine, Psychiatry, and Biopharma- ceutical Sciences, University of California, San Francisco; Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, San Francisco, California. pies for less common addictions to stimulants such as cocaine and amphetamines or to other drugs. Nicotine ad- diction resulting from tobacco cigarette smoking is empha- sized. Other routes for nicotine delivery, chewing tobacco, buccal and nasal snuff, and smoked pipes and cigars, deliver substantial amounts of nicotine but with different pharma- cokinetics, although the pharmacology is otherwise similar. Nicotine is addicting when it is delivered by any route, but special attributes and the ubiquity of cigarette delivery systems warrant special attention. WHY DO PEOPLE SMOKE? Although the pharmacologic effects of nicotine are essential to sustaining tobacco smoking, the beginnings of tobacco addiction result from nonpharmacologic learned or condi- tioned factors, social settings, personality, and genetics (4). Taking nicotine enhances an addicted smoker’s mood and performance. Nicotine is rewarding. Smoking is an ex- tremely effective way of rapidly and conveniently delivering concentrated doses of nicotine to the brain (4,5). Nicotine smokers appear able to discriminate small, rewarding effects from each individual puff and to titrate nicotine dose from each cigarette. From the typical 10 puffs per cigarette, a one pack-per-day smoker receives 73,000 distinct drug rein- forcements per year. Although nicotine can enhance mood directly, what is even more important for understanding nicotine addiction therapeutics is that when nicotine is taken by an addicted smoker, the negative consequences of prior nicotine use are diminished. A nicotine withdrawal syndrome is relieved (4). Most smokers say they want to stop smoking (2,13). Most adults have made several attempts to quit and require four or more attempts before quitting permanently. Relapse typically occurs because of disrupted emotional state, work performance, enjoyment of leisure activities, and interper- sonal relationships. Life-threatening smoking-related illness should motivate one to quit, yet 50% of smokers after a Neuropsychopharmacology: The Fifth Generation of Progress1534 myocardial infarction continue to smoke (13,49). Smokers with lung or throat cancer or those suffering from chronic obstructive lung disease behave similarly. Tobacco-taking behavior is made more likely to recur, reinforced by the pharmacologic actions of nicotine (49). With each successive cigarette, a beginning smoker, usually an adolescent, learns to associate certain moods, situations, and environmental factors with the rewarding effects of nic- otine. Associations between cues associated with smoking, anticipated nicotine effects and the resulting urge to use tobacco (craving) become all important in maintaining smoking. Smoking is more likely in certain situations: after a meal, with coffee or alcohol, and with friends who smoke (49). Associations between events and smoking repeated thou- sands of times make for powerful cues facilitating an urge to smoke. Manipulation of smoking paraphernalia, taste, smell, and sensations from smoke in upper airways become associated with pleasurable effects. Unpleasant or dysphoric moods come to serve as conditioned cues for smoking. For example, an adolescent smoker, usually within the first year of smoking, learns that not having a cigarette available is associated with feelings of irritability and learns that just a few puffs from a cigarette diminish irritability and other dysphoric nicotine withdrawal symptoms. After hundreds of repeated experiences, irritability from any source serves as a cue for smoking. Left to nature, it is unlikely that many people would make or find a cigarette, light it, and smoke it (49). Condi- tioning and learning linking nicotine pharmacology and en- vironmental contingencies are facilitated by advertising en- couraging, often in subtle ways, the use of tobacco. In the beginning, teenage smokers teach each other. Quickly, links between the pharmacologic actions of nicotine and associ- ated behaviors become powerful (7). Conditioning loses its power only gradually without nicotine delivered in the right dose and context. Conditioning is a major factor in relapse to nicotine use after quitting. Dealing with it is important in any therapeutics for nicotine addiction. Many smokers report that smoking improves concentra- tion and elevates mood. Cigarette smoking or nicotine ad- ministration improves attention, reaction time, and prob- lem-solving, particularly in recently abstinent smokers (55, 74). Smokers typically report enhanced pleasure and re- duced anger, tension, depression, and stress after a cigarette. Whether enhanced performance and improved mood after smoking are mostly or entirely the result of the relief of abstinence symptoms or rather are intrinsic effects of nico- tine on the brain remains unclear (49). Improvement in the performance of nonsmokers after nicotine suggests at least some direct enhancement (8). NICOTINE PHARMACOKINETICS AND METABOLISM Some special attributes of smoked nicotine delivery are im- portant for understanding mechanisms and therapeutics of tobacco addiction (5,49). Nicotine, a tertiary amine struc- turally similar to acetylcholine, binds to nicotinic choliner- gic receptors in the brain and elsewhere. During smoking nicotine, steam distilled from the burning tobacco is inhaled into the small airways and alveoli on small droplets of tar, buffered to a physiologic pH, absorbed rapidly into the pulmonary capillaries, and thence into systemic arterial blood. Initial arterial blood levels of nicotine are two to six times greater than venous levels (11). Within 10 to 20 sec- onds after each puff, relatively high levels of nicotine reach the brain. Nicotine levels in plasma and in brain tissue then decline rapidly because of rapid distribution into peripheral tissues. During a typical smoker’s day, peak and trough plasma and brain nicotine levels vary considerably before and after each cigarette, but nicotine gradually accumulates over 6 to 8 hours of repeated smoking because of nicotine’s 2-hour half-life (5). By midafternoon, relatively constant, steady- state, venous plasma levels, 20 to 40 ng/mL, are reached, but with transient 50-ng/mL increments in arterial and brain levels after each cigarette. During sleep, plasma con- centration of nicotine falls progressively but is still measur- able on awakening when the first cigarette of the next day is smoked, typically within 30 minutes of awakening. Thus, smoking results in exposure of brain to nicotine 24 hours of each day but with regular brain level perturbations after each puff and each cigarette (5,12). Smokers regulate smoked nicotine intake to maintain their preferred range of concentrations by varying puff and inhalation timing, volume, and number (49). Nicotine in- take and resulting plasma levels vary. Smokers can compen- sate for differing machine-determined nicotine yields to ob- tain a preferred dose of nicotine whether smoking a high- or low-yield brand (39). Nicotine delivered by cigarettes offers smokers individualized control of nicotine dose unat- tainable by other nicotine delivery systems (49). The special attributes of smoked nicotine dosimetry are relevant when designing animal experiments to model human tobacco de- pendence properly (53) and when considering nicotine re- placement therapies (NRTs). In contrast to smoking, chew- ing tobacco and snuff deliver nicotine through oral or nasal mucosa. Plasma and brain nicotine concentrations rise more gradually, reach plateau levels after about 30 minutes, and then decline slowly over the next few hours (5). NICOTINE RECEPTOR–BASED NEURAL MECHANISMS RELEVANT TO THERAPEUTICS Nicotine binds stereoselectively to a diverse family of nico- tinic cholinergic receptors widely distributed in brain, auto- nomic ganglia, adrenal medulla, and neuromuscular junc- tions (15,16). Nicotine’s effects on nicotinic cholinergic receptors in the brain enhance release of an array of neuro- transmitters; dopamine, norepinephrine, acetylcholine, se- Chapter 107: Therapeutics for Nicotine Addiction 1535 rotonin, vasopressin, �-endorphin, glutamate, �-aminobu- tyric acid, and others (12,49). Nicotinic cholinergic receptors have varied functional characteristics, different chemical conductances for sodium and calcium, and vari- able sensitivity to different nicotinic agonists (17,92). Re- ceptor diversity probably accounts for the diverse effects of nicotine experienced by smokers (19). The undoubtedly complex relationships between specific nicotinic cholinergic receptor subtypes and release of specific neurotransmitters are still to be fully characterized (92). Neurotransmitter re- lease is assumed to mediate nicotine effects such as arousal, relaxation, cognitive enhancement, relief of stress, and depression. A brain nicotinic cholinergic receptor is a ligand-gated ion channel, with five subunits. Most brain nicotinic cholin- ergic receptors are composed of � and � subunits. The � subunits are responsible for ligand binding. The � subunits mediate other aspects of receptor function (29). The nico- tinic cholinergic receptor, consisting of �-4 and �-2 sub- units, accounts for 90% of high-affinity nicotine binding in rat brain and may play a critical role in stimulant and rewarding effects (21). The �-2 subunit is critical for dopa- mine release, judging from studies of knockout mice lacking that subunit who have less nicotine-induced dopamine re- lease and do not self-administer nicotine as do wild-type mice (76). When nicotine binds to nicotine receptors, allosteric changes lead to different functional states including a resting state, an activated state (channel open), and two desensitized states (channel closed) (10). Receptor change to the desensi- tized state probably accounts for tolerance and for the obser- vation that tolerance to nicotine is associated with increased numbers of nicotinic cholinergic receptors in animals dur- ing chronic nicotine treatment and in brains of human smokers (24–27). Nicotine’s effects on brain dopaminergic and noradren- ergic systems are important in reinforcing self-administra- tion (49). The mesolimbic dopamine system is assumed to mediate pleasurable and other rewards from nicotine as with other drugs of abuse. Nicotinic receptors are on the nerve terminal membranes in the nucleus accumbens and on membranes of the dopamine-secreting neurons innervating nucleus accumbens located in the midbrain. Unlike cocaine and amphetamine, which exert effects by binding to pre- synaptic dopamine transporters on nerve terminal mem- branes, nicotine’s effects depend more on modulating the flow of impulses to the terminal field (17). As happens after repeated exposure to other stimulants, repeated exposure to nicotine results in sensitization of its effects on dopamine release in the accumbens. There appears to be co-stimula- tion of N-methyl-D-aspartate (NMDA) receptors for gluta- mate because the development and the expression of the sensitized dopamine response is attenuated or blocked by the administration of NMDA-receptor antagonists. In this respect, some consequences of repeated nicotine exposure on these pathways are similar to those of other stimulant drugs. The consequences of nicotine’s modulating effects on multiple neuronal systems remains to be determined (49). Sustained exposure to nicotine desensitizes some but not all nicotinic cholinergic receptors and results in a state in which nicotine is needed to maintain normal neurotrans- mission. As nicotine levels decrease, diminished neurotrans- mitter release or altered modulation of neurotransmitter sys- tems (17) contributes to a relative deficiency state and in humans, symptoms of lethargy, irritability, restlessness, in- ability to concentrate, depressedmood, and other symptoms making up the nicotine withdrawal syndrome. Plasma con- centrations of nicotine in smokers are sufficient to desen- sitize mesolimbic dopamine neuron nicotinic receptors reinforcing nicotine self-administration. Thus, self-adminis- tration of eight to ten nicotine bolus doses (puffs) during the smoking of each cigarette would cause gradually decreasing dopamine release in the nucleus accumbens. With each suc- cessive cigarette and gradually rising levels of brain nicotine, desensitization would increase. If so, tobacco smokers con- tinue to smoke during the latter half of each smoking day under conditions in which nicotine is less likely to stimulate neurotransmitter release than while smoking the first ciga- rettes of the day. Thus, other mechanisms likely contribute to the rewarding properties of nicotine in the latter portion of the daily cycle of smoking (49). Nicotine increases or decreases brain serotonin levels, de- pending on concentration and pattern of exposure (16). A possible role for serotonin release in reward mechanisms is suggested by selective serotonin (5-HT3) antagonists that reduce nicotine reinforcing effects. Chronic exposure to nic- otine results in reduced capacity to synthesize 5-HT in sero- tonergic terminals. Postmortem human studies indicate that tobacco smoking is associated with reductions in hippocam- pal 5-HT and 5-hydroxyindole acetic acid (16). Functional consequences of the nicotine-induced changes in 5-HT re- main to be established but could partially explain anxiety reduction commonly reported by smokers. Increased 5-HT release could result in anxiety and related symptoms com- mon during the early stages of nicotine withdrawal (49). Nicotine-mediated release of norepinephrine plays a role in the release of adrenocorticotropic hormone (ACTH) and cortisol. Nicotine, acting on �-7 cholinergic receptors, re- leases glutamate, enhances fast excitatory synaptic trans- mission possibly contributing to improved learning and memory (28,36), and regulates dopaminergic function. Ac- tivation of the locus ceruleus produces behavioral arousal with nicotine-increased burst firing an adaptive reaction to stressful situations (49). Activation of nicotinic cholinergic receptors in the adrenal medulla releases epinephrine and perhaps �-endorphin, a factor contributing to nicotine’s systemic actions (12). In addition to brain receptor-mediated effects, nicotine activates afferent nerves, an effect possibly accounting for the importance of sensory phenomena in cigarette smoking satisfaction and important in shaping conditioned aspects of smoking behaviors. For example, intravenous nicotine Neuropsychopharmacology: The Fifth Generation of Progress1536 produces burst firing of locus ceruleus neurons before in- jected nicotine reaches the brain (47). After an initial rapid onset, brief activation that can be blocked by a peripheral nicotine antagonist, a second longer-lasting activation, me- diated by central nicotinic receptors, occurs (31). NATURAL HISTORY OF NICOTINE DEPENDENCE Most nicotine addicts begin smoking during adolescence. Adolescent smoking has been increasing since the 1990s. In the United States, about 3 million adolescents smoke. Each day, 6,000 more begin. Most perceive themselves to be dependent on nicotine within their first year of smoking. Adolescent daily smokers appear to inhale doses of nicotine similar to doses inhaled by adults. When asked, about 50% report wanting to quit, and 71% report having tried and failed (49). Adolescents report withdrawal symptoms similar to those reported by adults (32). Without treatment interventions, smoking quitting rates in adolescent smokers in the United States are comparable to those of addicted adult smokers. Young, still experiment- ing smokers are likely to become regular smokers; however, the proportion of adolescents who go on to regular smoking and what influences the progression remain obscure. The first symptoms of nicotine dependence occur within weeks of the onset of occasional use, often before daily smoking begins (7). As many as one-third to one-half of adolescents experimenting with cigarettes become regular smokers. Interventions to prevent progression to tobacco addic- tion in adolescents are less effective than in adult smokers (33). Adolescents have less interest in treatment, high treat- ment dropout rates, and low quitting rates (20). Reviews of adolescent tobacco smoking conclude that better charac- terization of nicotine dependence (35) and assessment of pharmacotherapies are needed, given the almost epidemic proportions of smoking in adolescents. RISK FACTORS Comorbidity Some smokers report that smoking helps relieve their depression and other mood disorders. Others become se- verely depressed when they stop smoking (16,52). Smokers are more likely to have experienced major depression, and those who have are less likely to quit smoking (37). Several mechanisms may link smoking and depression (16). Depression sensitizes patients to the dysphoric effects of stressful stimuli. Smokers exposed to stressful stimuli be- come conditioned to nicotine’s diminishing of the adverse effects. Nicotine-related decreases in 5-HT formation and release in the hippocampus could be a factor. Stopping ad- dicting drugs, including tobacco, has been hypothesized to result in a negative affect state with dysphoria, malaise, and inability to experience pleasure that has been termed hedonic dysregulation (84). Smokers may be protected from such consequences by the antidepressant properties of nicotine. Consistent with a notion that nicotine may be self-ad- ministered by some smokers to manage affective disorders is an uncontrolled study reporting that transdermal nicotine lessened depression in nonsmokers with major depression (56). Another intriguing connection is that cigarette smok- ing inhibits