BASIC AND HUMAN PHARMACOLOGY
It is some 550 years since the eponymous Jean Nicot sent tobacco and seeds from Portugal to Paris, passing Nicotiana tabacum from the Americas to Northern Europe by way of the Iberian peninsula. Nicotine itself was subsequently extracted and synthesized, culminating in the identification of the spatial orientation of the natural (S) isomer in the late 1970s (Domino, 1999). Up to 10% of the nicotine in tobacco smoke is the (R) isomer, probably arising from racemization during combustion (Benowitz, 1986). Nicotine has gained particular prominence as the addictive constituent of most tobacco based products and, to a lesser extent, as an effective insecticide.
Nicotine, 3-(1-methyl-2-pyrrolidinyl) pyridine, has a molecular weight of 162.23 and is a volatile, colorless base (pKa=8.5) that turns brown and acquires the typical odor of tobacco on exposure to light. Roughly 69% of its pyrrolidine nitrogen is ionized (positively charged) at pH 7.4 and 37°C, whereas its pyridine nitrogen is un-ionized. This feature of nicotine renders its absorption and renal excretion highly pH dependent, because uncharged lipophilic bases pass easily over lipoprotein membranes and charged organic bases do not. For example, nicotine is primarily ionized at the pH (5.5) of smoke from the flue-cured tobaccos in most American cigarettes, and buccal absorption is minimal (Gorrod and Wahren, 1993). By contrast, smoke from air-cured tobaccos in pipes, cigars, and many European cigarettes is less acidic and is well absorbed through
the mouth (Armitage et al., 1978; Gori et al., 1986). Nicotine constitutes about 95% of the total alkaloid content of commercial cigarette tobacco (Gorrod and Jenner, 1975).
The mechanisms by which nicotine exerts its actions at a molecular level are complex. Dale (Dale, 1914) noticed the structural similarity between nicotine and acetylcholine (Ach) and the resemblance of the effects of nicotine in vivo to those of Ach after pretreatment with the muscarinic antagonist atropine. The muscarinic effects of Ach are now recognized to be mediated via one of the five heptahelical muscarinic receptors (M1-M5). Ligation of these receptors may activate downstream signaling pathways via their interaction with diverse G proteins. Nicotinic receptors (nAchRs), by contrast, are ligand gated ion channels (Domino, 1999; Lena and Changeux, 1998). These pentamers are comprised of various combinations of α, β, γ, and δ subunits. Recent studies have demonstrated that specific configurations of these subunits mediate the diverse effects of nicotine. Although this area of research is evolving, the neuronal subunits that appear to be primarily responsible for the effects of nicotine contain α3,4,7 and β2 and 4 subunits. The α4β2 subtype is particularly prevalent in the brain and may be responsible for the self-administration of nicotine. Mice deficient in the β2 subunit do not self-administer nicotine (Cordero-Erausquin et al., 2000), suggesting that this subunit in particular may be important in reinforcing the effects of nicotine. In addition, some preliminary evidence suggests that the α7 subunit may play a significant role in withdrawal and sensory gating functions of schizophrenics (Adler et al., 1998; Nomikos et al., 2000; Panagis et al., 2000). Localization studies have identified nAchRs in the brain, neuromuscular junctions, autonomic ganglia, and adrenal medulla (Gundisch, 2000). Ligation of nAchRs by nicotine opens the channel, and the ionic influx activates signal transduction pathways, culminating in release of a number of different neurotransmitters, which have been related to nicotine’s pharmacodynamic effects. These include dopamine (pleasure and appetite suppression), serotonin (appetite suppression and mood modulation), epinephrine and norepinephrine (arousal and appetite suppression), Ach (arousal and cognitive enhancement), vasopressin (memory improvement), glutamate (improvement in learning), β-endorphin (mood modulation and analgesia), and δ-aminobutyric acid. Nicotine also increases nAchR expression. For example, prenatal nicotine exposure upregulates the pulmonary expression of the α7 receptor subunit and consequently affects fetal lung development in monkeys (Sekhon et al., 1999). Nicotine caused lung hypoplasia and reduced surface complexity of developing alveoli in this model. Collagen surrounding the large airways and vessels was increased, as was the number of type II cells and neuroendocrine cells in neuropepithelial
bodies. Many animal studies have also demonstrated that nicotine administration upregulates expression of nAchRs in the brain. Similarly, ligand-binding studies have demonstrated an increase in binding sites for nicotine analogues in the cerebral cortex and hippocampus of smokers compared to nonsmokers (Perry et al., 1999), although the extent to which this may contribute to the differential central effects of nicotine observed in smokers is unknown.
Dopamine is believed to be the dominant neurotransmitter in the maintenance of drug-taking behavior (DiChiara, 1999; Koob, 1992). The area of the brain that is responsible for the reinforcing effects of all drugs of abuse is the mesolimbic pathway, which contains the ventral tegmental area (VTA), nucleus accumbens, amygdala, cingulate gyrus, and frontal lobe and is rich in dopamine. The VTA and nucleus accumbens seem particularly important in nicotine’s reinforcing effects. Activation of nAchRs in the VTA and other parts of the midbrain, modulates the ascending mesolimbic dopamine system, including the nucleus accumbens (George et al., 2000; Yu et al., 2000). Nicotine self-administration behavior is diminished by either surgical or chemical ablation of dopaminergic pathways or by treatment with dopamine antagonists (Kameda et al., 2000). Nicotine evokes an increase in dopamine levels in brain microdialysis studies (Fu et al., 2000). In addition, monoamine oxidase A and B, responsible for the metabolism of dopamine, are reduced by a compound in tobacco smoke that also results in higher levels of neurotransmitters (Quattrocki et al., 2000).
The release or inhibition of other transmitters may also play a role in nicotine addiction. They may be responsible for mood modulation, the modest enhancement of performance, and the weight-reducing effects of nicotine (Benowitz, 1999; Chiodera et al., 1990; Chowdhury et al., 1989; U.S. DHHS, 1988). Mood modulation by nicotine has been a controversial topic, since laboratory studies do not validate the smoking-induced enhancement of mood self-reported by smokers. Furthermore, individuals experience greater positive affect when smoking after a period of abstinence. The relief of negative affect by tobacco use may be more a function of abating withdrawal symptoms (Cinciripini et al., 1997; RCP, 2000). Finally, in addition to its traditional pre- and postsynaptic actions at synapses and at chemoreceptors in the carotid and aortic bodies, nicotine also evokes the release of epinephrine from the adrenal medulla and may act directly to activate ion channels distinct from nAchRs. For example, nicotine has been shown to block directly inward rectifier potassium channels, an effect of potential relevance to cardiac arrhythmogenesis (Wang et al., 2000b).
Although buccal absorption is influenced by the pH of tobacco or tobacco smoke, tobacco smoke from all sources is rapidly absorbed from the large surface area of the small airways and the alveoli, following dissolution in the pulmonary fluid at pH 7.4 (Zevin et al., 1998). Nicotine is also readily absorbed from the skin; this property has been exploited in the use of patch delivery in nicotine replacement therapy (NRT) for cigarette smokers (Figure 9–1). Nicotine is well tolerated as a dermal application, even in individuals who suffer from irritant skin disorders (Benowitz, 1995).
Following ingestion, as with chewing tobacco, the pH dependence of nicotine ionization favors its absorption by the small intestine, rather than the stomach, although a timed-release preparation, which permits colonic absorption (Green et al., 1999), has also been developed for use in ulcerative colitis as discussed below. Although the peak levels of nicotine attained after chewing tobacco may approximate those after smoking, the shape of the curve of plasma concentration versus time is quite different (Figure 9–2). Thus, after smoking a cigarette, plasma levels of nicotine rise rapidly to a peak, which is maintained transiently after the cigarette is inhaled, rather than the more gradual and sustained elevation after oral
ingestion. The evoked liking, systemic response, and addiction potential of the former pattern of nicotine delivery exceed those of the latter (Benowitz et al., 1988). It takes roughly 10–15 seconds for nicotine, inhaled by puffing a cigarette, to reach the brain, and puffing is associated with a marked arterial-venous gradient of nicotine (Benowitz, 1995; Benowitz et al., 1988; Guthrie et al., 1999). This rapid central nervous system (CNS) delivery permits the smoker to adjust the nicotine dosage to a desired effect, reinforcing self-administration and facilitating the development of addiction (Benowitz, 1995). This contrasts with the slower increase and lesser increment in brain nicotine attained after transdermal delivery, which facilitates the development of tolerance (see below). The average cigarette contains 10–15 mg of nicotine and delivers, on average, roughly 1–2 mg of nicotine systemically to the smoker. However, smoking habit— puff intensity, duration, and so forth—can markedly alter nicotine bioavailability. By comparison, the systemic doses of nicotine from other delivery systems are roughly 1 mg from a 2 mg gum; 5–22 mg per day from transdermal patches; 0.5 mg per dose from one spray per nostril; 3.6 mg from 2.5 grams of snuff, held in the mouth for 30 minutes and 4.5 mg from 7.9 grams of chewing tobacco chewed for 30 minutes (Benowitz and Jacob, 1999).
Following its absorption, nicotine circulates with roughly 60% in the ionized form. It is poorly (around 5%) protein bound (Benowitz et al., 1982) and widely distributed, at least in rats and rabbits, particularly in liver, lungs, and brain (Benowitz et al., 1990).
Distribution and Metabolism
The presence of both aromatic and aliphatic carbon and nitrogen atoms in nicotine affords multiple sites for metabolic oxidation and subsequent conjugation reactions (Figure 9–3). The disposition of nicotine has been reviewed in depth elsewhere (Benowitz and Jacob, 1999; Gorrod and Schepers, 1999). Briefly, roughly 80% of the metabolic inactivation of nicotine involves oxygenation of the 5'-carbon to yield cotinine. This appears to involve an intermediate cytochrome P-450 (CYP)- derived 1',5'-imminium ion, which is further metabolized by aldehyde oxidase to yield cotinine (Brandange and Lindblom, 1979; Gorrod and Hibberd, 1982; Murphy, 1973). This iminium ion is an alkylating agent and has been speculated to have relevance to the carcinogenicity of tobacco, although this is not established (Hibberd and Gorrod, 1983). Oxidation of this radical may also yield nornicotine or 4-(3-pyridyl)-4-oxo-N-methylbutylamine. CYP2A6 and, to a lesser extent, 2B6 appear to play the predominant roles in nicotine carbon oxidation in humans (Benowitz and Jacob, 1999; Nakajima et al., 2001; Nakajima et al., 2000; Yamazaki et al., 1999). Although roughly
15% of a nicotine dose is excreted in human urine unchanged, all of the primary metabolites, including cotinine, are subject to further oxidation reactions. Oxidation appears to involve only the alicyclic pyrrolidine nitrogen in biological systems (Gorrod and Schepers, 1999). Nicotine-1'-N-oxide may be reduced to nicotine in man by gut bacteria (Dajani et al., 1975).
Phase two metabolites can be formed by methylation, glucuronidation, sulfation, or glutathione conjugation reactions with primary oxidation metabolites. Formation of such polar, water soluble molecules facilitates excretion. Although great interindividual variation is noticeable, glucuronides may account for roughly 40% of the urinary nicotine metabolites in humans. This variability may also be apparent among ethnic groups. Thus, the most abundant phase 2 metabolite in the urine of North Americans is the N-glucuronide of cotinine, whereas in Europeans the O-glucuronide of trans-3'-hydroxycotinine predominates (Gorrod and Schepers, 1999). Similarly, the metabolism of nicotine is slower in African Americans than in Caucasians, due to both slower oxidative metabolism of nicotine to cotinine and slower N-glucuronidation (Benowitz et al., 1999; Caraballo et al., 1998; Perez-Stable et al., 1998). Asian Americans also metabolize both nicotine and cotinine more slowly than do Caucasians. Nicotine clearance declines with age (Molander et al., 2001). Although there is some evidence for differences between men and women in the pharmacodynamic response to nicotine (Pomerleau et al., 1991), this does not appear to reflect systematic differences in nicotine pharmacokinetics. Nicotine readily crosses the placental barrier, although there is no apparent conversion of nicotine to cotinine by placental tissues or microsomal fractions (Pastrakuljic et al., 1998). Although the potential for fetal toxicity must be considered in women undergoing NRT (as discussed below), this consideration usually occurs in the context of relativity. Thus, the hazard to the fetus of maternal cigarette smoking is well established (Oncken et al., 1998; Robinson et al., 2000), whereas the theoretically much smaller risk of NRT remains entirely notional.
Clearance of nicotine falls with hepatic blood flow during sleep (Gries et al, 1996) and a circadian pattern in both circulating nicotine and cotinine is evident (Figure 9–4). Although the half-life of nicotine is about 2–3 hours when based on plasma levels, it approximates 11 hours when based on urinary excretion (Benowitz and Jacob, 1994, 1999), so circulating levels tend to accumulate during the day. The afternoon levels of nicotine in the plasma of smokers generally range from 10 to 50 ng/ml, whereas steady-state levels with patches range from 10 to 20 ng/ml and with the nasal spray from 5 to 15 ng/ml (Benowitz and Jacob, 1999).
Sophisticated approaches to analysis not just of nicotine and cotinine, but of minor oxidative metabolites and many phase 2 metabolites, have
now been established, albeit in few laboratories. These encompass sensitive and specific methodologies, such as tandem mass spectrometry (Byrd et al., 1994). These tools will afford a more comprehensive approach to investigating genetic (e.g., nAchR or CYP2A6 polymorphisms; McKinney et al., 2000; Nakajima et al., 1996) and environmental factors (e.g., CYP2A6 induction or repression by alcohol or other drugs; Niemela et al., 2000), which might contribute to interindividual variability in nicotine pharmacokinetics. For example, they will include the integration of assessment of nitrosamines formed from nicotine into long-term studies of the safety of NRT.
Nicotine is excreted by both glomerular filtration and tubular secretion. Acidification of urine greatly increases its renal clearance, which impedes tubular reabsorption by ionizing the nicotine (Benowitz and Jacob, 1999). Urinary excretion of cotinine is less influenced by pH since it is more basic. However, renal clearance of both compounds is influenced highly by urinary flow rates (Benowitz and Jacob, 1999).
The factors that mediate the effects of nicotine are complex, confounded as they are in the cardiovascular system by direct and reflex effects, acute effects and long-term desensitization, and secondary effects due to sympathoadrenal activation. Acute delivery of nicotine in a cigarette results in a transient tachycardia, cutaneous vasoconstriction, and a rise in blood pressure (Cryer et al, 1976). By contrast, desensitization of vascular or central receptors by nicotine may contribute to the lower blood pressure observed in chronic smokers (Charlton and While, 1995).
The mechanisms involved in mediating the adverse effects of cigarette smoking and of smokeless tobacco on the cardiovascular system are poorly understood, but are thought to include induction of an adverse lipoprotein profile (Allen et al., 1994), induction of a chronic inflammatory response (Strandberg and Tilvis, 2000) including oxidative tissue injury (Morrow et al., 1995; Patrignani et al., 2000; Reilly et al., 1996; Traber et al., 2000), activation of platelets and other hemostatic variables (Benowitz et al., 1993; Ludviksdottir et al., 1999; Whiss et al., 2000), and impairment of endothelial function (Raitakari et al., 2000). Following the introduction of NRT, there was considerable concern about the cardiovascular safety of this intervention, especially in patients with preexisting cardiovascular disease. However, NRT has been shown to be effective, without an apparent cardiovascular hazard, not only in the general
population (Benowitz and Gourlay, 1997), but also in patients with established coronary vascular disease (Greenland et al., 1998; Joseph et al., 1996; Nitenberg and Antony, 1999). Controlled studies have demonstrated that switching from cigarette smoking to NRT is associated with amelioration of the lipoprotein and hemostatic profiles (Allen et al., 1994; Ludviksdottir et al., 1999; Winther and Fornitz, 1999) and a reduction in platelet activation (Nowak et al., 1987).
Although evidence of a clinical cardiovascular hazard of NRT has yet to emerge, several observations suggest that aspects of the cardiovascular effects of nicotine merit further research. For example, cigarette smoking impairs endothelial function (Celermajer et al., 1993; Raitakari et al., 1999), which appears to be a surrogate marker of future clinical vascular disease (Dugi and Rader, 2000). Interestingly, nicotine has been reported to impair flow mediated brachial arterial endothelial function (Chalon et al., 2000) and bradykinin stimulated endothelial function in dorsal hand veins of volunteers (Sabha et al., 2000). On the other hand, short term administration of nicotine gum did not alter the coronary constrictor response to the cold pressor test—reflective of the effects of sympathadrenal activation—in patients with established coronary artery disease (Nitenberg and Antony, 1999). Although exposure of mice deficient in apoenzyme E (Apol E) to cigarette smoke accelerates atherogenesis (Gairola and Daugherty, 1999), there have been no analogous studies of nicotine and no studies of atherosclerotic plaque progression in individuals receiving long-term NRT.
Switching to NRT in the short term does not appear to correct the systemic markers of inflammation in cigarette smokers (Nilssen et al., 1996), and there are conflicting reports of the direct effects of nicotine on free radical generation in vitro (Gouaze et al., 1998; Guatura et al., 2000; Wetscher et al, 1995). Interestingly, many cigarette smokers also drink alcohol (Swahn and Hammig, 2000), and alcohol is a potent prooxidant in humans (Meagher and FitzGerald, 2000). While ethanol increases the clearance of nicotine, the acute hemodynamic effects of ethanol and nicotine are additive (Soderpalm et al., 2000), perhaps reflecting a common mechanism. However, there are no reports of the effects of NRT on contemporary markers of oxidative stress or a comprehensive assessment of its effects on markers of inflammation.
Nicotine is a CNS stimulant. Paradoxically, it is perceived to be relaxing in stressful situations and to enhance gating of relevant stimuli. The smoker does not react as much as the nonsmoker to external distrac-
tions—hence its use by those trying to relax or concentrate. Stress increases the smoker’s nicotine consumption. An increase in respiratory rate and heart rate has been observed with NRT. Sleeplessness has also been reported in patients using NRT (Gourlay et al., 1999). Nicotine overdose is remarkably difficult to achieve with NRT (Labelle and Boulay, 1999), however, it occasionally complicates the use of nicotine-containing insecticides. In these cases, central symptoms—initially tremors, nausea, vomiting, and possibly convulsions—give way to signs of central depression and neuromuscular blockade (Saxena and Scheman, 1985).
Memory and Cognition
Although there is considerable interest in the potential effects of nicotine on cognition (Emilien et al., 2000; Waters and Sutton, 2000), this has not been formally evaluated in individuals receiving NRT. Activation of nAchRs containing the α7 subunit results in Ach release and calcium activation, and both effects have been implicated in memory formation and cognition (Kem, 2000). Recent interest has been focused by co-immuno-precipitation of the amyloid A β(1–42)-fragment and the α7nAchR from the dendtritic plaques of Alzheimer’s disease (AD) lesions (Wang et al., 2000a). The β-fragment of amyloid A binds to the receptor and prevents its activation by nicotine, potentially implicating defective nAchR activation in the pathogenesis of AD. Again, although there is some evidence for a slowing of deterioration of AD in individuals who smoke (Debanne et al., 2000; Doll et al., 2000; Jarvik, 1991; Lopez-Arrieta et al., 2000; Merchant et al., 1999), along with a considerable literature relating to the use of cholinesterase inhibitors for this condition, NRT has not been formally evaluated in AD.
The Biological Basis of Addiction. Although tobacco products contain several thousand chemicals, nicotine is considered to be the principal constituent in tobacco that leads to the persistent use of tobacco products (U.S. DHHS, 1988). However, other yet unknown constituents in tobacco may also have a role in the maintaining the use of tobacco. For example, smokers experience a reduction of monoamine oxidase (MAO) activity in the brain (Berlin et al., 1995) as a result of some constituent in smoke (Fowler et al., 1996); inhibition of MAO may result in antidepressant activity (Oxenkrug, 1999) and contribute to the high prevalence in smoking among individuals with depressive disorders. Physical addiction to nicotine is associated with euphoriant and other psychoactive effects, the development of tolerance, and the experience of withdrawal symptoms
when the tobacco product is no longer used (U.S. DHHS, 1988). In addition, the rate of absorption and therefore the speed of delivery of nicotine to the brain also play a significant role in the addictive potential of nicotine (Henningfield and Keenan, 1993). These factors contribute to the reinforcing effects or persistent use of nicotine and also may be responsible for day-to-day regulation of nicotine levels in tobacco users.
Psychoactive and reinforcing effects from nicotine are the result of the release of a number of neurotransmitters and hormones (Benowitz, 1999; U.S. DHHS, 1988; Watkins et al., 2000). This cascade of events is associated with mood modulation, cognitive and motor performance enhancements, and weight reduction. These effects may contribute to the initiation and maintenance of tobacco use. Chronic administration of nicotine can lead to neuroadaptation. One of the effects of neuroadaptation is the development of tolerance. Adaptation occurs so that the brain can maintain a state of homeostasis despite an increased release of neurotransmitters. This process includes receptor inactivation and desensitization and an increase or upregulation in receptor number (Benowitz, 1999). The extent of these changes could vary depending on the receptor subtype and site (Watkins et al., 2000). Tolerance may lead to individuals’ using more of the tobacco product or switching to higher nicotine-containing products.
Neuroadaptation may subsequently lead to withdrawal symptoms when the tobacco user is no longer exposed to the product. Withdrawal symptoms include negative affect (e.g., irritability, frustration or anger, anxiety, dysphoric or depressed mood), restlessness, difficulty in concentrating, insomnia, decreased heart rate, and increased appetite or weight (APA, 1994). These symptoms occur among regular users of cigarettes and smokeless tobacco (Hughes and Hatsukami, 1992). They are less pronounced with nicotine gum use, but this distinction blurs with prolonged use of the gum (Hughes et al., 1986b; West and Russell, 1985). Approximately 49% of self-quitting smokers and 87% of tobacco cessation program attendees meet Diagnostic and Statistical Manual of Mental Disorders (DSM) IIIR (APA, 1987, 1994) criteria for nicotine withdrawal syndrome (Hughes and Hatsukami, 1992). These withdrawal symptoms peak during the first week of abstinence and return to baseline levels by four weeks (Hughes et al., 1990a). The intensity of these symptoms is further reduced over the course of time. The only exception to this pattern is increased weight. Weight may continue to increase over six months, and a reduction may not be seen at all or only after several months of abstinence (Hughes et al., 1990a).
A major determinant of whether nicotine is likely to be addictive is the amount and speed of nicotine delivery. The route of delivery also determines the pattern of nicotine delivery (as discussed earlier). For
example, each puff of a cigarette delivers a bolus dose of nicotine, resulting in a rapid peak, which then falls to a trough level. The time between these bolus doses allows for resensitization of brain nAchRs, so that each delivery can remain reinforcing (Benowitz, 1999). In addition, this route of administration allows the delivery of a greater number or frequency of reinforcements. Other delivery routes result in a slow and persistent absorption of nicotine. Subjective effects, the desire to use more of a drug, and the actual self-administration of a drug are functions of absorption rate (Henningfield and Keenan, 1993). Therefore, whereas cigarettes have high abuse potential, nicotine patches have lower abuse potential.
It is also important to note that addiction to nicotine is not just a biological phenomenon, but also one in which learning or conditioning has taken place. Nicotine self-administration comes under the control of stimuli that have been associated with smoking or tobacco use. These stimuli can precipitate a strong desire for nicotine, withdrawal symptoms, or drug effects. Exposure to these stimuli may lead to the same biological effect on neural substrates as observed from the direct actions of the drug (Childress et al., 1999). Furthermore, stimuli associated with tobacco use, such as the sensory aspects of smoking, can become reinforcing as well; that is, they become secondary reinforcers. In addition a tobacco user develops expectancies regarding the use and effects of the substance, leading to a psychological reliance on the drug.
The susceptibility to nicotine addiction is thus a result of both the biological effects of the drug and learning history. In addition, environmental factors (e.g., access to tobacco, restrictions on tobacco, social modeling) and genetic or organismic factors (e.g., rate of nicotine metabolism, psychiatric disorders, personality factors) may play a significant role. Specific populations might be more vulnerable to nicotine addiction. Genetic twin studies have shown heritability estimates that range from 28 to 84%, with a mean estimate of 53% (Hughes, 1986). Genetic heritability has been associated with the onset as well as the persistence of smoking (Heath et al., 1998, 1999). Examples of what is inherited may be differences in sensitivity to nicotine (Pomerleau, 1995), the rate of nicotine metabolism (Tyndale et al., 1999), or other mechanisms such as genetic polymorphisms in the dopamine transporter and subtypes of dopamine receptors (Lerman et al., 1999; Shields et al., 1998). In addition, individuals with comorbid disorders tend to have a high prevalence of smoking. For example, high prevalence of smoking is found in individuals with depressive disorders, schizophrenia, and alcohol or drug abuse disorders (Breslau, 1995; Hughes et al., 1986a). The mechanisms responsible for susceptibility to smoking may differ across disorders. The nicotine-associated release of neurotransmitters is similar to those found with antidepressants and may be responsible for the association between smoking and depression and
for the recurrence of depressive disorders after smoking cessation. Furthermore, studies have shown a genetic linkage between smoking and depression (Kendler et al., 1993), and observations have been made that depression can predate smoking or smoking predate depression (Breslau et al., 1993, 1998). For individuals with schizophrenia, the sensory gating effects of nicotine via the α7 nicotinic receptor may provide some symptomatic relief (Dalack et al., 1998; Freedman et al., 1997). A genetic link also seems to exist for alcohol and nicotine addiction (Hughes, 1986), along with commonality in the release of dopamine across all drugs leading perhaps to increased sensitivity to the reinforcing effects of drugs or the potential for substitution. Furthermore, nicotine can be used to offset the aversive effects of drug use (Benowitz, 1999).
Assessment of Addiction. Various measures and methods have been developed to measure dependence on a drug and its abuse or addiction potential (see Table 9–1). These measures and methods are important in examining harm reduction products since addiction to a drug is one of the determining factors associated with its harmful consequences. The addictive potential of a drug can be determined by examining the number of individuals, within the general population and among those exposed to the drug, who are regular users of the drug or are considered dependent on a drug, using specific criteria. Determination of the abuse potential of nicotine replacement agents has also relied on examining whether users of the product escalate their use over time or continue its use beyond a recommended period. However, deciphering whether this persistent
TABLE 9–1 Measures of Dependence or Addiction and Abuse Liability
Measures for Dependence or Severity of Dependence
Daily or regular smoking (cotinine level)
International Diagnostic Code
Surgeon General’s report, 1988
Fagerström Tolerance Questionnaire
Fagerström Nicotine Dependence Test
Methods to Assess for Addiction or Abuse Liability Surveys
Daily use or dependence among the general population
Daily use or dependence among those exposed to the drug
Escalation of drug use
Psychoactive or subjective effects
Conditioned place preference
medication use is a result of the desire to prevent relapse to cigarettes or an addiction to the product can be difficult. The “addictiveness” of a drug can also be determined by the extent to which relapse occurs among those individuals who have tried to stop using it. In addition, various animal and human laboratory methods have been developed to assess the abuse liability of a drug, including measurement of psychoactive or stimulus effects and determination of whether a drug is a reinforcer (positive or negative) leading to preference for a drug or drug self-administration (Bozarth, 1987; Balster, 1991; U.S. DHHS, 1988).
According to Food and Drug Administration (FDA) guidelines, abuse liability is determined by two primary factors (see deWit and Zacny, 1995). One is the likelihood of repeated use, which is determined by the drug’s psychoactive, positive reinforcing effects and the extent to which it can relieve withdrawal symptoms as a result of chronic use. Repeated use may also be determined by the degree of unpleasant effects associated with drug use. The second factor is the incidence of adverse short- and long-term consequences as a result of use. Drugs with a greater number of adverse consequences are thought to be more likely to have abuse liability than those with fewer adverse effects.
Measures and Surveys of Dependence. Surveys and instruments have been used to assess the amount and frequency of use (e.g., daily use, regular use) and whether an individual is dependent on a drug based on specific diagnostic criteria. These measurement tools have been used to determine the extent to which dependence occurs within a general population and among those who have been exposed to or have experimented with the drug. In addition, these diagnostic tools for dependence have been used to determine whether dependence on nicotine is a dose-related phenomenon. Both DSM-IIIR and DSMIV (APA, 1987,1994) and the World Health Organization (WHO) International Diagnostic Code-10 (IDC-10) (WHO, 1991) are the commonly used criteria to assess for nicotine dependence. According to the DSM and the IDC-10, substance dependence, including nicotine, results in several behavioral and cognitive characteristics and physiological manifestations (see Table 9–2). The primary criteria for dependence based on these definitions include a strong desire to take the drug for periods longer than intended, problems controlling its use, use despite negative consequences or having a higher priority than other activities or obligations, tolerance, and physical withdrawal (APA, 1994; WHO, 1991). Not all criteria have to be met, nor is any one criteria critical to satisfy a diagnosis of dependence. In the 1988 Surgeon General’s report The Health Consequences of Smoking: Nicotine Addiction, the primary criteria for drug dependence included (1) highly controlled or compulsive use of a drug, (2) psychoactive effects from the drug, and (3) drug-reinforced behavior. Additional criteria, similar to those listed in DSM-IV and IDC,
TABLE 9–2 Criteria for Substance Dependence from DSM IV
A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifest by three (or more) of the following, occurring at any time in the same 12-month period
Tolerance—need increased amounts of substance to achieve desired effect, or diminished effect with continued use of same amount
Sometimes, physical withdrawal
Substance often taken in larger amounts or over a longer period than intended
A strong desire to take the drug
Persistent or unsuccessful efforts to cut down or control substance use
Difficulty controlling use
Great deal of time spent in activities necessary to obtain the substance or recover from its effects
Important social, occupational, or recreational activities given up or reduced because of substance use
Higher priority given to drug use than to other activities and obligations
Substance use continued despite knowledge of having a persistent or recurrent physical or psychological problem likely to have been caused or exacerbated by the substance
Persisting use despite harmful consequences
SOURCE: Adapted from RCP, 2000.
were also included. The number or type of symptoms experienced varies across different drugs of abuse. The major difference between nicotine and some other drugs of abuse is the lack of intoxication in regular tobacco users that results in behavioral and cognitive disruption (U.S. DHHS, 1988). However, this makes nicotine no less an agent of addiction or dependence than other drugs (Stolerman and Jarvis, 1995). In fact, many cigarette smokers exhibit at least as many indicators of dependence as other drug users and abusers (CDC, 1995b; U.S. DHHS, 1988). Assessment of nicotine dependence using these criteria can be made by a number of diagnostic structured instruments including the Composite International Diagnostic Interview-Substance Abuse Module, the National Institute of
Mental Health-Diagnostic Interview Schedule (NIMH-DIS), and the NIMH-DIS for children (see Colby et al., 2000, for review).
Other methods have been used to assess addiction or dependence on nicotine or tobacco products. For example, population surveys such as the National Household Survey on Drug Abuse (NHSDA) assess for symptoms of tobacco dependence and include such items as how many current tobacco users (1) reported daily use of the product, (2) have tried to cut down, (3) were unable to cut down or quit or experienced difficulty quitting, (4) felt a need for more tobacco for the same effect, (5) felt dependent, or (6) felt sick or experienced withdrawal symptoms when stopping smoking and met at least one or more of these indicators (CDC, 1995a, b; CDC, 1994). Researchers have used meeting a specified number of these symptoms as proxy measures for the DSM-IV criteria for substance dependence. In some assessments, individual items, such as experiencing withdrawal symptoms or difficulty quitting have been of particular focus as indicators of dependence (CDC, 1994, 1995a, b).
Other reports assessing nicotine dependence determine the number of smokers who meet criteria for high level nicotine dependence according to the Fagerström Tolerance Questionnaire (FTQ; Fagerström, 1978; Fagerström and Schneider, 1989) or the revised version, the Fagerström Test for Nicotine Dependence (FTND) (Heatherton et al., 1991). Several adolescent versions have also been developed (Prokhorov et al., 1996, 1998; Rojas et al., 1998). Although this scale is continuous, a cut-off score of 6–7 or higher has been used to separate low and high level of dependence.
Based on the measures of dependence described above, the percentage of cigarette users that report dependence on their tobacco product varies according to the population examined (e.g., total populations, daily smokers, ever smokers, and so forth) and the definition of dependence used. According to the NHSDA, a population survey of noninstitutionalized civilians 12 years and older, the proportion of respondents who reported experiencing at least one indicator of dependence was 75.2% among those individuals who used cigarettes one or more times during the 30 days preceding the survey and 90.9% among daily users (reporting daily use for≥ 2 consecutive weeks during the 12 months preceding the survey) (CDC, 1995b). In another study, the estimated prevalence of dependence according to the DSM-IIIR criteria (APA, 1987) among Americans 15–54 years old sampled for the National Comorbidity Survey was about 24.1% (Anthony et al., 1994). The lifetime prevalence of dependence among middle-aged male ever smokers in Japan was 42, 26, and 32% according to IDC-10, DSM-IIR, and DSM-IV criteria, respectively (Kawakami et al., 1998). In another study, very high rates were observed with 90% of a general sample of middle-aged male smokers meeting
DSM-III criteria for dependence (Hughes et al., 1987). Kandel and associates (1997) used the indicators listed in the NHSDA (see above) including items assessing for frequency and quantity of use and problems related to use in order to diagnose nicotine dependence. The criteria for diagnosis were based on the DSM-IV method in which smokers must experience three or more of seven indicators of dependence. The findings showed that while 8.6% of the general population 12 years and older met criteria for nicotine dependence, 28% of those who had used tobacco products in the past year experienced nicotine dependence. A few studies have also been conducted with adolescents. The study conducted by Kandel and associates (1997) using the NHSDA examined the prevalence of nicotine dependence by age. They observed that about 19.9% of adolescents who smoked any cigarette met criteria for nicotine dependence, compared to rates ranging from 26.4 to 32.7% among smokers between the ages of 18 and 49 years and 23.7% among those 50 and older. In a study conducted in New Zealand, about 20% of a general sample of 18-year-olds were dependent on tobacco and more than half (56.4%) of the sample who smoked daily met DSM-IIIR criteria for nicotine dependence.
In another survey that used the FTQ with a score of 7 or more (indicative of a high level of dependence, not dependence per se), only 19% of Japanese male ever-smokers age 35 and older met this criteria (Kawakami et al., 1998), but 36% of U.S. males did (Hughes et al., 1987). Among adolescent smokers, the prevalence of high level of dependence according to the FTND or FTQ has also been wide-ranging. Many of the studies assessed prevalence of high level of dependence in special populations of adolescents. The highest percentage of adolescents with a score of 7 or more on the FTQ was observed among a heavy-smoking group who participated in a nicotine patch trial, with an observed rate of 68% (Smith et al., 1996). The lowest rate was 20% using a modified FTQ with a cutoff score of 7 or higher, which was observed in vocational technical high school student smokers (Prokhorov et al., 1996). This proportion was lower than the 50% rate that the investigators observed among adult smokers.
An indicator of the addiction potential of a drug is the development of daily or regular use or dependence among those who have been exposed to it. There is strong evidence to show that a significant number who are exposed to cigarettes may become daily smokers or dependent on them. Among high school students participating in the 1997 Youth Risk Behavior Survey (YRBS), of the 70.2% who tried cigarette smoking, 35.8% went on to smoke daily. This rate of escalation from trying cigarette smoking to regular use of tobacco is similar to the 33–50% observed in other studies (U.S. DHHS, 1994). The development of dependence among those who tried tobacco products is similarly high. In one population-
based study of adult smokers, about 31.9% of those who tried tobacco became dependent on it based on the DSM-III criteria (Anthony et al., 1994). In another study of young adults aged 21–30, of the 74% who had smoked tobacco at least once, 27% developed DSM-IIIR criteria for tobacco dependence (Breslau et al., 1993). Similar data are not available for smokeless tobacco users. Existing data are limited to the number of individuals who report having used smokeless tobacco in the past month versus the number who report lifetime use of smokeless tobacco; this method of calculation represents about 18% for smokeless tobacco users. This figure is compared to 37% for cigarette smokers using a similar method of calculation (U.S. DHHS, 2000).
Relapse rates among those who tried to quit have been considered another indicator of dependence on or addiction to a drug. Relapse is high among a general population of smokers who have tried to quit smoking, with only 2.5% being able to sustain abstinence for a year (CDC, 1994). One study showed that among self-quitters, about two-thirds reported smoking within two days postquit (Hughes et al., 1992). The rate of relapse among a population of smokers who have undergone clinical treatment tends to be about 75%, with a significant number of these relapses occurring within the first few weeks. These rates and patterns of relapse are similar to those observed with smokeless tobacco (Hatsukami and Severson, 1999) and other drugs of abuse (Hunt and Matarazzo, 1973; Maddux and Desmond, 1986; Wallace, 1989). High rates of relapse are also observed among youth that smoke. Based on results from the YRBS, among high school students who smoked daily, 72.9% had ever tried to quit smoking and only 13.5% were former smokers (CDC, 1998).
Most research on the dependence on nicotine replacement products has examined the persistence of use or escalation of use over time. No data are available on the prevalence of daily use in the general population or on dependence on these products according to diagnostic criteria for dependence or FTND scores. The rate of persistent use of nicotine replacement products among smokers enrolled in clinical trials who were assigned these products is much lower than the rate of persistent use of cigarettes, ranging from 9% for nicotine gum to 18% for nicotine nasal spray (Hughes, 1998). With nicotine nasal spray the rates of persistent use are higher, and there is evidence to show that a small number escalate the amount of use over time (deWit and Zacny, 1995). In general, addiction to these products is significantly less than addiction to cigarettes due to the relatively slow absorption of nicotine, the side effects that sometimes results from use, and the cost per unit of purchase.
In summary, research shows that nicotine delivered via cigarettes and smokeless tobacco is likely to lead to a high prevalence of use and dependence. One third to one-half of individuals who experiment with
cigarette products are likely to become regular users and dependent on them. No data are available on the initiation of nicotine replacement product use among tobacco-naïve individuals or rates of diagnosable dependence, although these rates are likely to be low (Shiffman et al., 1998). The number of new NRT users among those attempting to quit was approximately 10% per year prior to over-the-counter (OTC) nicotine replacement products and 26% per year after OTC availability (Shiffman et al., 1998). Therefore, increased availability has led to increased use of these products among smokers, however, the rate of use still remains quite low. Furthermore, among smokers who use nicotine replacement products, persistent use tends to be low. Future research endeavors should concentrate on developing uniform methods and measures for assessing nicotine dependence so comparisons can be made across products and studies. The present measures are limited to assessing the extent of dependence and limited by being designed to diagnose other drugs of abuse and not specifically to diagnose nicotine dependence. In addition, as new products evolve, rates of initiation, regular use or persistent use and dependence, or progression to dependence as a result of experimentation should be assessed.
Models of Addiction. Several methods have been developed using clinical and animal models to determine the addiction potential or abuse liability of a drug. These include models of self-administration, drug discrimination, and conditioned drug placement. Models to examine withdrawal have also been developed. For humans, subjective responses to drugs can also be determined, although these responses may not necessarily be associated with actual drug-taking behavior.
When a drug is reinforcing, it is more likely to be self-administered or preferred compared to a control drug that has no abuse potential. The subject is exposed to a drug, typically, at varying doses and then required to choose between this particular drug and a control drug or an alternative reinforcer (e.g., sucrose for animals, money for humans), or between different doses of the drug.
In self-administration models, the animal is required to perform a particular maneuver, such as lever pressing, to obtain the drug, which is typically administered intravenously. This lever pressing could be based on a fixed ratio (a specific number of responses are required prior to drug delivery), a progressive ratio (more responses are required after each drug delivery), or an interval schedule (a certain time interval is necessary before drug delivery), or a combination of these. Scheduled reinforcement in response to environmental stimuli associated with drug administration are called second-order schedules (Goldberg et al., 1981). Drugs can be made
available for a fixed amount of time or throughout the day. Drugs that are reinforcing prompt the subject to work more or pay a higher cost for them than for the control; reinforcing drugs also lead to a greater persistent responding for them even when they are no longer available (Henningfield et al., 1991). Typically the dose-response curve is U-shaped (Risner and Goldberg, 1983; Rose and Corrigall, 1997) with low and high doses resulting in reduced drug self-administration. Low doses may produce limited or undetectable effects and high doses may produce adverse effects.
Drug discrimination models involve training the subject to discriminate the stimulus properties of drug A from drug B. A third drug may be introduced, and the animal or human subject is asked to decide whether the drug is more like drug A or drug B (Bigelow and Preston, 1989; Preston, 1991). Subjects can also be trained to discriminate among several sets of drugs or different doses of a drug. This model allows determination of the mechanism of action of a drug. For example, if one wanted to determine whether an opioid has µ agonist or κ agonist activity, an experiment can be developed in which the subject is trained to discriminate between drugs that are known to have each of these activities. After this period of training, the drug in question is introduced and the subject has to indicate whether the drug is more like drug A (e.g., a µ agonist) or drug B (a κ agonist). This model can be also used to determine whether a drug has the stimulus properties of a particular pharmacological class of drugs that are abused. A similar method is used in a drug preference procedure, in which subjects are exposed to drug A and drug B, and are required to self-administer each of these drugs during separate experimental sessions. After the drug exposure or sampling period, subjects are then asked to choose between drugs A and B, to determine their preference for one drug or another (de Wit, 1991). Drug A or B can be two different doses of a drug, different types of drugs, or an active and placebo drug.
The conditioned place preference model also is used to determine the abuse liability of a drug. Animals are trained that the drug is available only in a particular place (e.g., a specific chamber). Then a determination is made of how frequently the animal is willing to go to this place. If it is chosen significantly more frequently than the other place which is associated with a control drug or no drug administration, the experimental drug may have abuse potential (Bozarth, 1987).
Drug withdrawal models have typically involved observing signs and symptoms during a period of abstinence after repeated admin-
istration of a drug (U.S. DHHS, 1988; Hughes et al., 1990; Malin et al., 1992). These withdrawal symptoms can be precipitated by antagonist drugs or allowed to occur naturally. Although the occurrence of withdrawal signs and symptoms does not necessarily indicate that that the drug will be abused, it may be one indicator of the potential for abuse.
Finally, among humans, subjective responses to drugs can be determined (Jasinski and Henningfield, 1989; Fischman and Foltin, 1991; Jaffe and Jaffe, 1989). Subjects can be asked to indicate the intensity of experiencing different subjective effects, such as the degree of euphoria, liking of a drug, “high,” desire for a drug, or “head rush.” Comparisons can be made across different drugs and across doses within a particular drug. Subjects can also be asked to rate the effects of a drug using various standardized measures that have been developed to assess a drug profile (e.g., stimulant-like effects, depressant effects) such as the Addiction Research Inventory (Haertzen et al., 1963).
Self-administration paradigms have been used to demonstrate that a wide range of species (monkeys, mice, dogs, and rats) exhibit preference for administering nicotine over a control vehicle (Henningfield and Goldberg, 1983; RCP, 2000; Rose and Corrigall, 1997; Swedberg et al., 1990; U.S. DHHS, 1988). Studies have shown that these animals are willing to lever-press several hundred times in order to receive an injection of nicotine (Goldberg et al., 1981; Risner and Goldberg, 1983). However, unlike other drugs such as cocaine, the range of environmental conditions under which nicotine serves as a reinforcer is more restricted (Henningfield and Goldberg, 1983). In laboratory studies, human smokers have also been found to lever-press for intravenous doses of nicotine (Henningfield and Goldberg, 1983) as well as to self-administer greater number of doses of nicotine nasal spray (Perkins et al., 1997) and nicotine gum (Hughes et al., 1990b) compared to the respective placebo conditions. Clinical trials for the nicotine spray (Sutherland et al., 1992) and gum (Hughes et al., 1991) have also observed greater self-administration of active compared to placebo doses. Most human studies, however, have focused on assessing smoking behavior, looking at various indices of exposure, including number of cigarettes, number of puffs, puff volume, puff duration, inhalation duration, and intercigarette interval as well as biochemical indices of exposure such as cotinine or nicotine concentrations. Smoking behavior has been examined in response to changes in dose of cigarettes, preloading with nicotine or administering nicotinic antagonists and other drugs that may affect the reinforcing effects of nicotine (U.S. DHHS, 1988). Self-administration of nicotine is dose related in
both humans and animals, although there is lesser dose-dependency than other drugs in animals, and the curve is somewhat flat for humans (Corrigall, 1999). Nonetheless, reduced nicotine self-administration in humans is observed with nicotine preloading and compensation with changing nicotine doses in cigarettes. Speed of nicotine delivery also plays a role in the extent to which nicotine is self-administered. Rapid bolus injections of nicotine result in greater self-administration than a slow infusion (Wakasa et al., 1995). Self-administration can be blocked by mecamylamine, a nonspecific nAchR antagonist or by dopamine receptor antagonists (see earlier discussion of the biological basis of addiction). Self-administration can be facilitated not only by the dosing characteristics of cigarettes or nicotine but also by the sensory characteristics of cigarettes (Henningfield and Goldberg, 1983; Rose and Corrigall, 1997).
Smokers tend to report dose-related subjective effects such as drug liking, drug strength, head rush, and feeling dizzy or aroused as a result of inhaled, buccal (smokeless tobacco), intravenous, or nasal spray nicotine administration (Fant et al., 1999; Henningfield et al., 1985; Jones et al., 1999; Perkins et al., 1994a, 1994b). Smokers who have a history of drug dependence exhibit a similar dose-related increase in “liking” and other subjective responses for intravenously administered nicotine as observed for cocaine, amphetamine, morphine, pentobarbitol, and heroin (Jasinski et al., 1984; Jones et al., 1999; Keenan et al., 1994). Findings from another study also revealed that intravenous nicotine was misidentified as cocaine or amphetamine by the study participants who had histories of drug use (Henningfield et al., 1985; Jones et al., 1999). Subjective responses to nicotine gum, patch, spray and inhaler have been less pronounced than responses to cigarettes or intravenous nicotine (deWit and Zacny, 1995; Henningfield and Keenan, 1993; Schuh et al., 1997).
The occurrence of withdrawal symptoms after cessation of continuous nicotine infusion in rodents has been demonstrated (Malin et al., 1992). In humans, withdrawal symptoms upon cigarette smoking cessation has also been well established (Hughes et al., 1990a). However, fewer studies have been conducted with other tobacco products or nicotine replacement agents. Cessation of smokeless tobacco use generally produces less intense withdrawal symptoms than cessation of cigarette smoking (Hatsukami et al., 1987; Keenan et al., 1989). However, in a population of smokeless tobacco users enrolled in clinical trials, the severity and number of withdrawal symptoms from smokeless tobacco were comparable to those experienced by cigarette smokers who were trying to quit (Hatsukami et al., 2000). Nicotine gum withdrawal symptoms also tend to be significantly less intense in number and severity than cigarette withdrawal symptoms (Hatsukami et al., 1991, 1993, 1995), and higher doses of gum produce greater withdrawal than lower doses of gum (Hatsukami
et al., 1991). On the other hand, among those who have used the product for a prolonged period, nicotine gum may be comparable to cigarettes in the number of withdrawal symptoms experienced (Hughes et al., 1986b; West and Russell, 1985).
In summary, various laboratory studies have observed that nicotine is self-administered, produces psychoactive effects, and produces withdrawal symptoms. The route of delivery can determine the extent to which nicotine-containing products can produce these effects and lead to addiction, with cigarettes showing the highest potential for addiction.
Future studies on new products should routinely measure the abuse potential of a drug by using the various methods that have been described. Furthermore, these paradigms could be considered to test medications focused at reducing frequency of tobaccco use.
Nicotine exerts its effects on the gastrointestinal (GI) tract mainly via the activation of parasympathetic ganglia. Generally, it increases tone and contractility, and nausea, vomiting, and diarrhea can result from an overdose. However, GI irritation, other than mild nausea, rarely complicates NRT (Wong et al., 1999). Salivation evoked by cigarette smoking also rarely accompanies the doses used in NRT. Nicotine slows gastric emptying and reduces gastric and pancreatic secretions.
Given the association of smokeless tobacco with oral cancer (Schildt et al., 1998; Winn, 1997), there was initial concern that this might pose a risk with NRT. Follow-up studies of intermediate duration do not substantiate this concern (Wallstrom et al, 1999). In recent years, the observation that ulcerative colitis appears to be ameliorated in smokers has prompted the evaluation of NRT for this condition and controlled studies support its efficacy (Guslandi, 1999; Sandborn, 1999) and a delivery system permitting controlled release of nicotine in the colon has been developed.
Other Effects of Nicotine
There is much speculation about the existence of gender-specific effects of nicotine and their implications for NRT strategies. There is some evidence of differences in the pharmacodynamic effects of nicotine between genders and of an influence of timing in the menstrual cycle on the response to NRT and the success of attempts to quit (Pomerlau et al., 1991; Gritz et al., 1996). Women appear to have more pronounced withdrawal symptoms during the late luteal phase of the menstrual cycle, and it has been suggested that fear of weight gain, confidence in the ability to quit,
and readiness to quit smoking might be differentially related to gender. Maternal smoking has adverse effects on the fetus, including the risk of spontaneous abortion, abruptio placentae, reduced weight at birth, and deformities (Haustein, 1999). In animal models, maternal consumption of nicotine results in hyperactivity in the neonate (Tizabi et al., 2000). Maternal smoking has been associated with sudden infant death syndrome and appears to result in an intellectual deficit, apparent in children at least as old as 6–7 years of age (Frydman, 1996).
Chronic smokers tend to have lower blood pressure than nonsmokers (Charlton and While, 1995). Maternal smoking has been associated with a reduced incidence of preeclampsia, but the mechanism is unclear (Lain et al., 1999). Nicotine does cross the placental barrier unchanged and maternal passive smoking raises nicotine levels in breast milk and in suckling infants. No linkage of nicotine consumption to birth deformities has been established; however, its contribution to the other effects of smoking during pregnancy is less clear (Haustein, 1999). For example, nicotine inhibits placental aromatase, reduces uteroplacental blood flow, and may adversely affect endothelial function in animal models (Torok et al., 2000). Presently, the experience with short-term NRT has not been associated with reports of adverse effects on fetal outcome, however; the number of individuals evaluated in this setting has been small.
Cigarette smoking is associated with lower body weight and quitting is associated with weight gain. Involvement in a weight control program amplifies the efficacy of NRT (Danielsson et al., 1999). Although the mechanisms are likely to be complex, nicotine is of some substantial relevance to this effect of smoking. Aside from its stimulatory effect on basal metabolic rate, nicotine reduces the synthesis of neuropeptide Y (NPY) in the arcuate neurons which project into the paraventricular nucleus (PVN). Injection of NPY into the PVN results in hyperphagia and obesity in rats (Frankish et al., 1995). Smoking is associated with insulin resistance, which improves after cessation (Kong et al., 2000). Elevated leptin levels have been related to weight loss in smokers, and levels appear to correlate with the degree of insulin resistance (Assali et al., 1999). Crossover studies in volunteers suggest that plasma leptin levels correlate with changes in insulin sensitivity and that intermediate levels are found in subjects on NRT (Oeser et al., 1999).
Nicotine has diverse effects on other hormonal systems in the brain that are presently poorly understood. For example, chronic nicotine administration stimulates mediobasohypothalamic tyrosine hydroxylase and suppresses pro-opiomelanocortin mRNAs. Suppression of forebrain β-endorphins may be relevant to maintaining nicotine self-administration (Rasmussen, 1998). Similarly, smoking is extremely prevalent among schizophrenics and may modulate the response to certain antipsychotics,
such as clozapine (McEvoy et al., 1999). It has been speculated that this behavioral response may represent an attempt at self-medication, and some evidence for a disease-related abnormality in central nAchR sensory gating in schizophrenia has begun to emerge (Breese et al., 2000; Dalack et al., 1998).
Much less information is available concerning the effects of nicotine on other systems. Examples of potentially important observations include impairment of the immune response (Sopori et al., 1998), adverse effects on bone formation (Fung et al., 1999), and testicular hypogonadism (Kavitharaj and Vijayammal, 1999; Reddy et al., 1998), all observed with nicotine in model systems. The relevance of these observations, if any, to the doses of nicotine achieved in humans during NRT is unknown and should be evaluated.
Finally, cigarette smoking may result in drug interactions. While polycyclic hydrocarbons in cigarette smoke induce CYP isozymes of potential relevance to carcinogenesis, nicotine itself can induce CYP2E1, CYP2A1/ 2A2, and CYP2B1/2B2 in animal studies. Cutaneous vasoconstriction due to nicotine can delay the absorption of transdermal and subcutaneously administered medication, including insulin and heparin, and the stimulant effects of nicotine can diminish the analgesic effects of some opioids and the sedative effects of benzodiazapines (Zevin and Benowitz, 1999). Cigarette smoking reduces the hypotensive response to β-blockers (Fox et al., 1984), but the contribution of nicotine to this effect is unknown. Smoking reduces portal blood flow velocity and volume in humans and may modulate the disposition of drugs subject to hepatic metabolism (Rapaccini et al., 1996).
NRT has proven an effective strategy in the cessation of cigarette smoking that is remarkably well tolerated at least in the short to medium term. Although the experience is much more limited, NRT also holds promise as a strategy for reducing the number of cigarettes smoked by those who cannot or will not quit.
Both of these observations prompt considerations for future research. Thus, for those who quit smoking but continue to take NRT indefinitely, are there reasons to be concerned? First, nicotine can be addictive and although the daily exposure may be lower on NRT than when the individual was smoking, continued use implies psychological dependence, if not physical addiction. It is arguable whether this should be a concern, given the marked reduction of risk compared to smoking. However, it would seem reasonable to include surveillance of the dependence potential and various methods to determine abuse liability of various nicotine
products. Furthermore, the implications of long-term nicotine intake for such factors as the safety of drug and alcohol consumption, progression of incidental diseases, impact of aging on cognitive and other physiological functions, and susceptibility to other forms of addictive behavior are largely unknown. For example, observations suggesting that nicotine impairs endothelial function, a property it shares with cigarette smoking, raise concerns about its effect on atherogenesis during long-term usage. Such an effect may take many years to emerge and highlights the importance of continued postmarketing surveillance of NRT. This is also true of carcinogenesis. For example, nicotine may be metabolized to nitrosamines (e.g. nicotine-derived nitroketone) with carcinogenic potential (Hecht, 2001; Hoffman et al., 1991). However, the methodology to assess their formation is just emerging, and the concentration-effect relationships and individual patterns of susceptibility are far from established. Studies of long term nicotine administration on surrogate variables that more closely resemble the mechanism under consideration (e.g., imaging of plaque progression) and attendant studies in animal models seems timely. Increasingly, the application of genomic and proteomic approaches is likely to clarify the differential effects of smoking and NRT on the expression and translation of genes related to the development of smoking-related diseases. Finally, the picture of nicotine’s effect on inflammation and the immune response is confused and limited. More research is needed to clarify its effects on cytokine generation, the formation of nitric oxide and eicosanoids and oxidative injury. Research should continue to explore other potential therapeutic efficacies of NRT, including its use in ulcerative colitis, analgesia, weight reduction, Parkinson’s disease, and cognitive disorders associated with aging and schizophrenia. Broadly speaking, the experience with long-term experience with nicotine via Swedish snus is reassuring with respect to safety, but formal evaluations of such risk from long-term use under controlled conditions have been scant (Idris et al., 1998; Raw and Macneil, 1990).
Continued use of NRT in conjunction with ongoing, albeit reduced, smoking prompts additional questions. For example, the constituents of cigarette smoke that mediate tissue injury are largely unknown, and it is also unknown if modulating the coincident nicotine level might influence their absorption, metabolic disposition, mechanism of action, or elimination. Design of such studies will rely on the development of more refined and tractable methodology to investigate the in vivo kinetics and dynamics of other constituents of cigarette smoke and their interactions with nicotine.
Finally, although ethnicity already seems relevant, other factors that determine interindividual differences in nicotine efficacy, safety, and addictive potential remain largely unexplored. Particular attention might be
paid to genetic variation in proteins relevant to nicotine pharmacokinetics and dynamics and their interaction with environmental variables. As with other drugs, one anticipates increasing individualization of nicotine dosage and/or delivery when given as a therapeutic agent. Insight into the interaction of genetic and environmental factors that influence initiation (Gynther et al., 1999; Heath et al., 1999) of cigarette smoking, latency until the practice becomes habitual (Stallings et al., 1999), and the quantity then smoked (Koopmans, 1999) has been increasing. Clarification of how these factors interact is also likely to afford insights of value in predicting the individual likelihood of response to the use of NRT as a strategy for quitting or reducing tobacco exposure.
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