NICOTINE ADDICTION
Section snippets
WHAT IS ADDICTION?
Approximately 45 million Americans currently smoke tobacco products. Seventy percent of smokers state they would like to quit, and 30% make a serious attempt to quit each year,1 that is, they quit for at least 1 day. Only 3% of smokers, however, successfully quit each year. Unfortunately, the rate of appearance of new daily smokers, primarily among children or adolescents, matches the quit rate, so the prevalence of cigarette smoking has not declined for many years.38
The key concept in
EVIDENCE THAT NICOTINE IS ADDICTING
Loss of control of tobacco use is evident to most health care professionals who have tried to get patients with smoking-related diseases to quit. However, it is worthwhile to review the various lines of evidence for tobacco addiction, and the role of nicotine in sustaining tobacco addiction. The first line of evidence for tobacco addiction is that most smokers state they would like to quit smoking, and many have made several quit attempts that have failed. Most studies indicate that smokers on
CENTRAL NERVOUS SYSTEM MECHANISMS OF NICOTINE ADDICTION
(S)-Nicotine binds stereoselectively to nicotinic cholinergic receptors that are present in the brain, autonomic ganglia, the medulla, and neuromuscular junctions. Most relevant to nicotine addiction are the neuronal nicotinic cholinergic receptors. These are found throughout the brain, with the greatest number of binding sites in the cortex, thalamus, and interpeduncular nucleus, and substantial binding in the amygdala, septum, brain stem motor nuclei, and locus coeruleus.24 The nicotinic
PHARMACODYNAMICS OF NICOTINE ADDICTION
The release of various neurotransmitters results in behavioral arousal, sympathetic neural activation, and a number of other effects that are believed to be rewarding.5 The release of specific neurotransmitters has been speculatively linked to the reported reinforcing effects of nicotine (Fig. 1). For example, enhanced release of dopamine and norepinephrine may be associated with both pleasure and appetite suppression, the latter of which may contribute to lower body weight. Release of
ABSORPTION OF NICOTINE FROM TOBACCO
Nicotine is distilled from burning tobacco and carried proximally on tar droplets that are inhaled and deposited in the small airways and alveoli. The absorption of nicotine across biologic membranes depends on pH. The pH of smoke from the flue-cured tobaccos found in most cigarettes is acidic (pH 5.5 to 6.5). At this pH, the nicotine is primarily ionized. In the ionized state, it does not cross cell membranes rapidly. Consequently, there is little buccal absorption of nicotine from cigarette
NICOTINE KINETICS AND ADDICTION: THE CIGARETTE IS AN OPTIMAL DRUG DELIVERY SYSTEM
Smoking is a unique form of systemic drug administration, because nicotine is delivered to the pulmonary rather than to the portal or systemic venous circulations. It takes 10 to 19 seconds for nicotine to pass from the cigarette to the brain.6 The lag time between smoking and the entry of nicotine into the brain is shorter than that observed when nicotine is injected intravenously. Nicotine enters the brain quickly, but the brain levels decline rapidly thereafter as the drug is distributed to
REGULATION OF NICOTINE INTAKE
That smokers regulate their intake of nicotine has been clearly demonstrated. Smokers change the way they puff a cigarette depending on nicotine yield, as determined by the cigarette smoking machine.46, 74 They puff lower yield cigarettes more frequently or more intensely than higher yield cigarettes, presumably to obtain more nicotine. Smokers who switch from higher yield to lower yield cigarettes consume more nicotine from the lower yield cigarettes than is predicted by smoking machine tests.
ASSESSING NICOTINE ADDICTION
The first section of this article discussed the definitions of addiction and the criteria developed by the Surgeon General and the American Psychiatric Association to determine addiction. Translating definitions of addiction to practical criteria that can be used to assess addiction at the bedside has been problematic. The most widely used assessment tool has been the Fagerström Tolerance Questionnaire (Table 4).33 These questions were developed to assess the level of tolerance to nicotine, but
ACKNOWLEDGMENT
The author would like to thank Kaye Welch for editorial assistance.
References (74)
Cigarette smoking and nicotine addiction
Med Clin North Am
(1992)- et al.
Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area
Brain Research
(1994) Behavioral pharmacology of cigarette smoking
- et al.
Higher levels of nicotine in arterial than in venous blood after cigarette smoking
Drug Alcohol Depend
(1993) Genetics of smoking: A brief review
Behav Ther
(1986)- et al.
Prevalence and demographic correlates of symptoms of last year dependence on alcohol, nicotine, marijuana and cocaine in the U.S. population
Drug Alc Depend
(1997) - et al.
Allosteric modulations of the nicotinic acetylcholine receptor
Trends Neurosci
(1993) Cigarette smoking among adults—United States, 1993
MMWR
(1994)Diagnostic and Statistical Manual of Mental Disorders, ed 3, Revised (DSM-IIIR)
(1987)Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
(1994)
Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1
JAMA
Pharmacologic aspects of cigarette smoking and nicotine addiction
N Engl J Med
Pharmacology of nicotine: Addiction and therapeutics
Annu Rev Pharmacol Toxicol
Smokers of low yield cigarettes do not consume less nicotine
N Engl J Med
Daily intake of nicotine during cigarette smoking
Clin Pharmacol Ther
Nicotine renal excretion rate influences nicotine intake during cigarette smoking
J Pharmacol Exp Ther
Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking
J Pharmacol Exp Ther
Nicotine metabolic profile in man: Comparison of cigarette smoking and transdermal nicotine
J Pharmacol Exp Ther
Influence of smoking fewer cigarettes on exposure to tar, nicotine, and carbon monoxide exposure
N Engl J Med
Deficient C-oxidation of nicotine
Clin Pharmacol Ther
Reduced tar, nicotine, and carbon monoxide exposure while smoking ultralow-but not low-yield cigarettes
JAMA
Circadian blood nicotine concentrations during cigarette smoking
Clin Pharmacol Ther
Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum
Clin Pharmacol Ther
Suppression of nicotine intake during ad libitum cigarette smoking by high dose transdermal nicotine
J Pharmacol Exp Ther
Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain
J Neurochem
Nicotine dependence and major depression: New evidence from a prospective investigation
Arch Gen Psychiatry
DSM-III-R nicotine dependence in young adults: Prevalence, correlates and associated psychiatric disorders
Addiction
Racial and ethnic differences in serum cotinine levels of cigarette smokers
JAMA
Nicotinic binding in rat brain: Autoradiographic comparison of [3H]acetylcholine, [3H]nicotine and [125I]a-bungarotoxin
J Neurosci
Sensitivity to nicotine and brain nicotinic receptors are altered by chronic nicotine and mecamylamine infusion
J Pharmacol Exp Ther
Nicotine dependence in schizophrenia: Clinical phenomena and laboratory findings
Am J Psychiatry
Smoking habits of long-term survivors of surgery for lung cancer
Thorax
The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General. DHHS (CDC) Publication No. 88-8406
ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: A novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization
J Pharmacol Exp Ther
Nomenclature and classification of drug and alcohol-related problems: A shortened version of a WHO memorandum
Br J Addict
Nicotine-induced activation of locus coeruleus neurons—An analysis of peripheral versus central induction
Naunyn-Schmiedeberg's Arch Pharmacol
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Address reprint requests to Neal L. Benowitz, MD, University of California, San Francisco, Box 1220, San Francisco, California 94143-1220, e-mail: [email protected]
This work was supported by Grants No. DA02277 and DA01696 from the National Institutes of Health.
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Departments of Medicine, Psychiatry, and Biopharmaceutical Sciences, University of California, San Francisco; and the Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, San Francisco, California