Quitting smoking: Still a challenge, but newer tools show promise

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ABSTRACTSmoking continues to be a major public health problem with devastating consequences in terms of morbidity and mortality. Physicians are strongly encouraged to engage patients in a serious, concerted, and consistent effort to overcome nicotine addiction. Brief counseling in combination with medications has been shown to be effective. This article provides physicians guidelines for helping patients to quit this addictive disorder.


  • Nicotine dependence is a life-threatening, biochemically based disease, driven by changes in midbrain receptors and reward mechanisms.
  • The state of the art in smoking cessation involves encouragement, persistence, and evidence-based pharmacotherapy.
  • Physicians should be assertive in addressing nicotine dependence, approaching patients with encouragement to quit, consistent monitoring and support, telephone “quit lines,” and counseling, as well as persistence and optimism. The combination of proactive, engaged, brief counseling and pharmacotherapy will yield the best results.



Tobacco is a dirty weed,
I like it.
It satisfies no normal need,
I like it.
It makes you thin, it makes you lean,
It takes the hair right off your bean.
It’s the worst darn stuff I’ve ever seen.
I like it.

Graham Lee Hemminger. The Penn State Froth, November 1915: 19. Courtesy of Paul J. Dzyak, Jr., Paterno Library, Pennsylvania State University, State College, PA.

All physicians recognize the harm in tobacco smoking and try to convince patients to quit for health reasons, but quitting is challenging and frustrating for both doctor and patient. Physicians can improve quitting outcomes by applying their knowledge of the physiologic basis of nicotine addiction and newer tools that are making a real difference in smoking cessation.


Tobacco use remains the single largest preventable cause of death and disease in the United States: 443,000 US adults die of smoking-related illnesses each year, or one every 8 seconds.1 Tobacco smoking is currently responsible for 18% of all deaths and 37% of all preventable deaths. One-third of all smokers die early, with men losing 13 years of life and women losing 15 years. (See The rise and partial fall of smoking for a historical overview.)

Smoking, the leading cause of lung cancer, is also implicated in cancers of the mouth, larynx, esophagus, stomach, kidney, bladder, and cervix and has been linked to leukemia. (Though nicotine is responsible for the addictive properties of tobacco, it does not cause cancer itself: other substances in tobacco smoke, many of them byproducts of combustion, are carcinogenic.)

Running a close second to cancer as a smoking-related cause of death is cardiovascular disease, including stroke, myocardial infarction, microvascular dementia, peripheral vascular disease, and aortic aneurysm. Pulmonary and respiratory diseases, including chronic obstructive pulmonary disease, pneumonia, and asthma, are the third most common fatal smoking-related ailments.

Other medical consequences include erectile dysfunction, infertility, pregnancy complications, and low birth weight. Smoking also causes adverse surgical outcomes, poor wound healing, hip fractures, low bone density, peptic ulcer disease, and cataracts.

Smoking is estimated to cost the United States $96 billion in direct medical expenses and $97 billion in lost productivity annually.2

On the positive side, quitting smoking has health benefits at any age, and smokers who quit before age 35 have death rates similar to those in people who have never smoked.1,3


Most smokers want to quit, and many try to—but few succeed. In the 2010 National Health Interview Surveys, 68.8% of adult smokers said they wanted to stop smoking, and 52.4% had tried to in the past year, but only 6.2% had succeeded.4 Many recovering alcoholics and drug addicts say that quitting tobacco was much harder than abstaining from other substances of choice.

Why is it so hard to quit?

Smoking is a classic addiction

Addictions are usually diagnosed by behavioral signs, and nicotine addiction has many of the clinical hallmarks, eg:

  • Tolerance, with a trend toward increasing the potency of the dose and the frequency of smoking over time
  • Mental preoccupation with smoking, as it often becomes woven into one’s daily schedule and is associated with almost everything the smoker does throughout the day. Having no cigarettes in the house can generate anxiety that is relieved only by obtaining more
  • Squandering scarce financial resources on nicotine products, over time amounting to substantial sums, and since smoking rates are higher in poor people than in the affluent, these are people who can least afford it
  • Withdrawal symptoms, characterized by jitteriness, irritability, headache, insomnia, anxiety, and increased appetite.

People continue to smoke despite adverse consequences such as falling asleep while smoking and setting fire to the bed or to the house, or losing digits to peripheral vascular disease. Being unable to quit and to stay off smoking is a hallmark of tobacco dependence. Relapses are often triggered by being near other smokers or seeing a billboard advertising cigarettes. Eventually, the nicotine addict comes to value and crave nicotine more than health or life itself.

Nicotine stimulates ‘reward’ centers in the brain

Nicotine is an alkaloid found in many plants (including potatoes) but in especially high concentrations in tobacco. In mammals, it is a stimulant, rapidly producing dependence and addiction.

Figure 1.

Inhaled by smoking, nicotine is absorbed across the large alveolar surface, avoids first-pass metabolism, and is transported rapidly to the brain (Figure 1). In fact, nicotine reaches the brain less than 20 seconds after inhalation, which is slightly faster even than when drugs are injected intravenously.5

Tobacco smoke contains approximately 4,800 compounds, many of which activate neurotransmitter systems such as dopamine, norepinephrine, acetylcholine, glutamate, serotonin, beta-endorphin, and gamma-aminobutyric acid. The most significant of these is the dopamine reward system known as the mesoaccumbens pathway. This system is activated within seconds of smoking and produces a sense of pleasure.

Nicotine binds to nicotinic acetylcholine receptors, primarily to alpha-4, beta-2 receptors in the ventral tegmental area of the midbrain. Once this binding occurs, a neurochemical message is conveyed to the nucleus accumbens via the release of dopamine in the mesoaccumbens pathway—the final common reward pathway triggered by all drugs of abuse. Since these structures and pathways of the brain are anatomically central, the addiction is driven by the basal ganglia and midbrain, the phylogenetically oldest parts of the brain. Nicotine therefore drives its addicts to continue smoking by producing strong neurochemical rewards and by causing strongly negative reactions when discontinued.

Genetically mediated susceptibility probably contributes to addiction. People whose neurochemical pathways are easily stimulated by this drug are probably at far greater risk of addiction. Paradoxically, people who are rapid metabolizers of nicotine are at greater risk than slow metabolizers.6 (Nicotine is metabolized by cytochrome P450 2A6 in the liver.)

Tolerance and withdrawal

Tolerance develops with long-term use, mediated by up-regulation (increased numbers) of alpha-4, beta-2 cholinergic receptors in the ventral tegmental area. Any reduction in nicotine level causes distress because receptors are unoccupied; with more receptors, nicotine intake must increase to keep physiologic balance and avoid withdrawal. Since the half-life of nicotine is only about 2 hours, the smoker must smoke almost constantly to satisfy receptors hungry for the stimulating drug. If drug levels drop, withdrawal occurs very quickly.

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal. The cycle of pleasure, eventual tolerance, withdrawal, craving, and compulsion is biologically driven, like the drives of thirst, reproduction, and hunger. Nicotine hijacks species-sustaining reward mechanisms, leading to the malignant, compulsive disease of nicotine addiction.

Treatment doomed to fail?

Because nicotine addiction involves the midbrain, cessation strategies that rely on higher cerebral function are not likely to succeed. Counseling, common sense, and willpower simply cannot overcome the dopaminergic stimulating power or assuage the withdrawal sickness of nicotine dependence. Telling patients that smoking is bad for them misses the mark in most cases. Patients want to quit, but the drive to smoke is too powerful. Attempts to cut down rather than abstain from smoking also fail.

Nicotine is a formidable adversary for the patient and for the doctor or other health professional. Until recently, treatment was usually ineffective.

So, what does work against nicotine addiction?

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