Nearly all tobacco users are aware that tobacco use poses substantial health risks. Most know and will acknowledge tobacco use will shorten their lives and that they have a 50% chance of death secondary to a tobacco-caused disease. They may not have conceptualized this, though, as playing “Russian Roulette” with a 2-barreled revolver.
Appreciating the nature of tobacco dependence requires clinicians to first recognize the fundamental and powerful way that nicotine, particularly when delivered via the cigarette, influences behavior and causes nicotine dependence. (If nicotine dependence does not exist, tobacco dependence cannot be produced.)
Most people who are tobacco dependent believe that all it takes to stop smoking is enough willpower. However, in light of seminal advances in neuroscience of the past decade, this position is no longer valid. For example, adolescent smoking is commonly understood to be a child’s simple, natural quest for independence and a manifestation of rebelliousness. We now understand that the adolescent’s decision to initiate the behavior is generally made during a time of intense Central Nervous System (CNS) development. Exposing the developing brain to periodic surges of nicotine results in usually permanent alterations in brain structure and function. At the most basic level, nicotine-caused changes in brain receptor number, density, sensitivity, and permeability alter the brain’s response to its normal neurotransmitters. More insidiously, nicotine exposure changes neuronal gene expression, second messenger system functions, modulation mechanisms, and even arborization patterns, creating an environment that is “engineered” to function best in the presence of nicotine, not the brain’s endogenous ligands. While not absolutely deterministic, these changes substantively influence the likelihood that the individual will maintain tobacco use indefinitely.
With this understanding, discontinuing tobacco use and the smoking behavior requires stabilizing altered neuronal physiology to control the resulting compulsion to smoke; willpower, alone, generally is not sufficient. Effective tobacco-dependence treatment requires optimal medical management as well as patient and family education and support. Just like any other chronic disturbance in biology, effective management is often iterative, requiring long-term interventions characterized by adaptation and response to change.
Neurobiology of Nicotine Addiction
Nicotine in tobacco smoke increases the number of nicotinic acetylcholine receptor sites in the brain by 2- to 3-fold.77-83Moreover, this nicotine receptor proliferation is not necessarily reversible in humans.84 Nicotinic receptors are located in all areas of the mammalian brain, but they are particularly concentrated in both the mesolimbic dopaminergic pathway and the locus ceruleus. These sites are of critical importance to the organism’s basic survival functions, cognitive processing, and memory. Because of nicotine’s ability to “highjack” these fundamental functions – while simultaneously improving cognition and memory – it is one of the most potent neuropharmacologic drugs of dependence, exceeding the abuse potential heroin, cocaine, or d-amphetamine.85
Nicotine’s effects are potentiated by the rapidity with which it reaches the brain. Following a deep inhalation of tobacco smoke, as much as a ten-fold arterial-venous concentration difference can develop within just a few seconds.86Consequently, the brain can essentially “discern” individual puffs of a cigarette. The rapid surge in arterial nicotine concentration delivered to the brain is an important stimulus for neuronal alterations, and is the main determinant of the beneficial and rewarding effects of nicotine.
The Beneficial Effects of Nicotine
The mesolimbic system is normally activated in response to drinking water, eating food, and engaging in sexual activity – activities essential for the survival of both the individual and the species. Sensory cortical and cognitive areas of the brain interface with the mesolimbic system through axonal projections that extend onto the ventral tegmental area, or VTA. Nerve terminals in the VTA are cholinergic, with the dominant form of post-synaptic cholinergic receptor of the α4β2 nicotinic subtype. Post-synaptic efferents extend outward to the nucleus accumbens, where the nerve terminals are dopaminergic. Dopamine release into the synaptic cleft activates accumbal D2receptors on post-synaptic neurons, resulting in an action potential that is propagated toward the pre-frontal cortex, generally responsible for generating visceral emotions such as safety, threat, satisfaction, or fear. In this manner, sensory input from the outside world, for example, from the visual system, translates into “positive or negative” survival stimuli that are important to help keep the organism safe from harm.
The nicotinic α4β2 acetylcholine receptors in the VTA are particularly sensitive to changes in nicotine concentration. Tobacco-dependent people modulate emotions and reward, in part, by modulating accumbal dopamine levels. When dopamine levels rise with nicotine intake, the individual becomes more cognitively aroused, feels more alert and vigorous, and perceives the sensation of pleasure, or gratification.87-94 When brain dopamine levels fall, the opposite occurs. The individual no longer exposed to exogenous stimulation by nicotine may feel moody, depressed, and dysphoric.93
Abrupt discontinuation of cigarette smoking (i.e. stopping “cold turkey”) produces a number of profound physiologic effects. For example, EEG alterations are accompanied by slowing of cognitive performance and difficulty concentrating.95,96 By far the most common, and perhaps the most motivating, effects of withdrawal include anxiety, irritability, frustration, and depressed mood. Rather than a manifestation of weakness of character, these symptoms are a manifestation of altered nicotinic and dopaminergic physiology within survival pathways of the CNS.
All nicotine withdrawal symptoms are promptly reversed by resumption of tobacco use.97 Fortunately, administration of pharmaceutical nicotine also relieves the adverse effects of withdrawal.96, 98-100 Therapeutically, physicians are in a position to help patients achieve the same salutary effect without relying on the toxic tobacco smoke vehicle to do it.
Medications to Treat Tobacco Dependence
Understanding tobacco use as the behavioral manifestation of a biological problem helps to inform a rational approach to the pharmacologic management of tobacco use and dependence. The medications discussed in the Tool Kit should be thought of as members of three distinct classes: 1) Nicotine medications, such as patch, gum, or nasal. All nicotine medications are nicotinic acetylcholine receptor agonists. 2) Dopaminergic/ Noradrenergic reuptake inhibitors, of which there is only one at present, bupropion. 3) α4β2 nicotinic receptor partial agonists, of which there is only one at present, varenicline. See “Pharmacologic Treatment” for further information and details on all tobacco-dependence medications, including effectiveness, side effects, and safety. Case Examples, marked as “Medication Prescribing Examples”, are available in Tobacco-Dependence Treatment Process and Approach to show how to use the Stepwise Tobacco-Dependence Treatment Guide in this Tool Kit to help select starting medication(s), dose(s), and combinations, depending on pre-treatment patient characteristics.)
Though the exact mechanisms of action for each class are not fully understood, there are several generalities that prove useful when developing a treatment plan. Nicotine agonists act mainly through direct stimulation of the VTA, indirectly resulting in maintenance of accumbal dopamine levels, even in the absence of the dramatic nicotine surges produced by the cigarette. Tricyclic (nortriptyline) and tetracyclic (bupropion) antidepressants work primarily by improving the dopaminergic milieu within the nucleus accumbens.101 The newest class of medications FDA approved for the treatment of tobacco dependence (varenicline) functions as a partial agonist for the α4β2 nicotinic receptors in the VTA. These medications should not be viewed as equivalent or interchangeable. Each has a specific pharmacology, with substantial differences in mechanism of action. Biologic variability within a population of tobacco-dependent patients likely accounts for the observed variability in effectiveness of these medications, and warrants an individualized approach to therapy, where treatment choices are evaluated for relevance, re-evaluated for effect, and adjusted as needed to achieve predefined targets.
The growing understanding of the biological basis for tobacco use, brought about by the neuroscience and neurogenetic research of the past 20 years, has led to radically revised concepts of tobacco use, changing it from a “bad habit” to what it really is: a chronic medical disease. This enhanced understanding of the biological basis for tobacco use, in turn, has led to totally new concepts in treatment, illustrating the imperative need to incorporate medications, if tobacco dependence is to be effectively treated. The sections Tobacco-Dependence Treatment Process and Approach and Pharmacologic Treatment cover this in depth and breadth.