American College of Physicians: Internal Medicine — Doctors for Adults ®


Research spurs new views of nicotine

Possible therapeutic effects add twist to tobacco debate

From the February 1997 ACP Observer, copyright 1997 by the American College of Physicians.

By Patricia Braus

New research about smoking is helping answer lingering questions about the powerful attachment between smokers and their cigarettes, but it is also pointing to certain beneficial effects of nicotine--and raising serious questions about smoking cessation efforts.

There is no question that smoking remains a deadly behavior. The American Lung Association estimates that cigarettes are currently responsible for about 20% of deaths each year in the United States from conditions like lung cancer, heart disease and stroke. More recently, researchers have linked new hazards to smoking, including the risk of exposure to secondhand smoke and the increased risk among smokers of macular degeneration.

However, the central ingredient in cigarettes—nicotine—has been found to lower the risk of Parkinson's disease, reduce anxiety and possibly effectively treat conditions like Alzheimer's disease. While no one is extolling the virtues of smoking, discussions over the long-maligned chemical nicotine are growing more complex.

"There are two views," said John Rosecrans, PhD, a professor of pharmacology and toxicology at the Virginia Commonwealth University School of Medicine in Richmond. "There's the one view that nicotine is this dependent agent, like cocaine or morphine. The other view is that nicotine is not this terrible subject, that it has some therapeutic potential."

To date, much of mainstream medicine—including the federal government—has viewed nicotine in terms of the damage it can cause. By the late 1980s, when evidence pointed to nicotine as the agent in cigarettes that builds dependence, the U.S. Surgeon General declared nicotine to be an addictive substance. And more recently, the FDA embarked on an effort to regulate what commissioner David Kessler, MD, called the "pediatric disease" of smoking through a series of limits on the sales and distribution of cigarettes to minors.

But researchers continue to uncover new information about the nature of nicotine's bonds to the human brain. For example, they have been able to substantiate some of the claims made by smokers. "Smoking decreases anxiety," explained Joanna Fowler, PhD, a senior chemist at Brookhaven National Laboratory in Upton, N.Y. "Some people think it improves cognition."

But as she is quick to add, "The problem is, the smoke contains carbon monoxide and carcinogens." Within hours of quitting, for example, smokers commonly experience powerful withdrawal symptoms that include anxiety, anger, difficulty concentrating, insomnia and irritability. Researchers have traced a vast network of reactions that include an increase in the expression of nicotine receptors in the brain, changes in the way the brain metabolizes glucose, changes in the brain's electroencephalographic patterns and changes in the level of neurotransmitters such as dopamine.

Some surprises

Despite the clear health risks that smoking poses, the effects of nicotine itself on the brain may not be all bad. Young people with attention deficit hyperactive disorder (ADHD), for example, a condition marked by difficulty in concentration, find some relief from smoking and tend to smoke twice as much as other people. "It's a known experimental finding that nicotine helps people focus," explained Eric C. Westman, ACP Member, an internist and medical director of the Nicotine Research Program at Duke University and Durham Veteran's Administration Medical Center. "It is assumed that nicotine helps people with ADHD."

Researchers have also shown that nicotine can help people reduce the uncontrollable behavior such as tics and outbursts experienced by in people with Tourette's syndrome, and initial studies exploring the link between use of nicotine patches and memory recall in people with Alzheimer's may yield new insights. In addition, Dr. Westman observed that nicotine can help reduce episodes of ulcerative colitis.

"We've had our blinders on because of smoking, and we haven't been exploring nicotine as a therapeutic drug," Dr. Westman said. "I think it is very promising."

The fact that fewer smokers than non-smokers develop Parkinson's disease, for example, has been well established. "We know that the risk of Parkinson's is about half in smokers versus the nonsmoker," Dr. Fowler said.

Because Parkinson's disease is characterized by the disruption of normal dopamine expression, the abnormally high levels of dopamine observed in smokers may play a role in their resistance to Parkinson's, Dr. Fowler suggested.

One of the latest links in the connection between nicotine and dopamine was discovered recently, when Dr. Fowler and her research group were using positron emission tomography (PET) scans to track the aging process in the brains of normal adults. Typically, older people have less of the brain enzyme monoamine oxidase, or MAO, which breaks down the neurotransmitter dopamine. Dopamine is a key neurotransmitter in motor activity, and a key element that is missing in Parkinson's patients.

Dr. Fowler assumed that her oldest subjects would have the highest levels of MAO in their brains. But the results, reported in the February 1996 issue of Nature, showed that cigarette smokers had 40% less of the MAO enzyme than non-smokers. With lower levels of the MAO enzyme, smokers were essentially able to retain high levels of dopamine, a factor that could potentially help them ward off Parkinson's disease. "In certain of these normal people, it looked like they were taking drugs to inhibit MAO," said Dr. Fowler. Increased knowledge about the effects of smoking on the MAO enzyme may increase researchers' knowledge about Parkinson's disease.

Addiction or habit?

New research about nicotine has rekindled another debate that focuses on tobacco's downside: whether or not smoking—and more specifically, nicotine—is addictive or habit forming.

The potency of nicotine's effects on the brain was underscored this past summer when a study published in Nature showed that nicotine stimulates the same part of the brain in rats that is stimulated by the drugs cocaine, amphetamine and morphine. The researchers, led by Gaetano Di Chiara, MD, at the University of Cagliari in Italy, injected nicotine into the veins of rats and then charted what occurred in the brain. Researchers found that dopamine was released and that cells were activated in a specific part of the forebrain called the shell of the nucleus accumbens. Dr. Di Chiara's group had earlier reported the same two responses in rats injected with hard drugs. Dr. Di Chiara told Science News in July that dopamine reinforces a desire for drugs such as nicotine.

Dr. Di Chiara's study was widely seen as additional evidence that nicotine is an addictive substance, but the results have not been universally accepted. Leo Abood, PhD, a professor of pharmacology at the University of Rochester School of Medicine and Dentistry, noted that the doses of nicotine used in the study were 50 to 100 times what a smoker would normally use. "Its relevance to smoking is questionable," he said.

Dr. Abood is one of many researchers who reject the idea that nicotine dependence is an addiction like any other. For one, smokers don't crave nicotine on its own the same way drug users crave cocaine and other hard drugs; Dr. Abood pointed out that there is no evidence that smokers have ever tried to consume raw nicotine to satisfy their supposed addiction, although it has been available as an insecticide for decades. Critics of addiction theories also point out that nicotine patches have not been abused by smokers trying to quit; by contrast, Dr. Abood said, imagine the potential for abuse if hard drugs such as morphine or cocaine were made available in patches.

Still, the effectiveness of nicotine replacement therapy such as nicotine patches shows that nicotine does play a critical role in the dependence of smokers on cigarettes. Smokers using nicotine patches are twice as likely to quit as smokers who go it alone, according to the 1996 Clinical Practice Guidelines on smoking cessation from the Agency for Health Care Policy and Research (AHCPR). In addition, nicotine gum boosts the rate of successful quitting by 40% to 60%.


Other research points to a definite physiologic link between smokers and nicotine, particularly in individuals suffering from depression. Psychiatrist Alexander Glassman, MD, first noticed a link between depressed people and cigarettes in the late 1980s, when he was involved in a clinical trial of a drug to help smokers quit. "The people who came to us had an astonishing rate of depression," said Dr. Glassman, professor of psychiatry at Columbia University College of Physicians and Surgeons.

Since then, the connection between smoking and depression has been solidly established. From 30% to 50% of patients who use smoking cessation services have a history of depression, according to the AHCPR smoking cessation guidelines. From his work in smoking cessation, Dr. Glassman estimates that about 50% of female smokers and 25% of male smokers have a history of depression.

Some believe the link between smoking and depression may be genetic. A study of more than 1,500 female twins found that individuals with a family history of smoking and major depression were likely to both develop major depression and smoke. In the January 1993 study in the Archives of General Psychiatry, researchers suggested that genetic variation might make some individuals more receptive to the powerful effects of nicotine in the brain. The researchers also suggested that genetic factors could create personality traits that raise the risk for both major depression and smoking.

An even more important reason for the link between depression and smoking may stem from the pleasure that smoking can bring. As Dr. Fowler's research suggests, smoking triggers higher dopamine levels in the brain; elevated levels of dopamine have been linked to feelings of well-being and pleasure and have been found in users of heroin and cocaine. Such emotions may be particularly welcome by individuals suffering from depression. Interestingly, newer antidepressants such as phenelzine sulfate act as MAO inhibitors and help regulate dopamine levels.

The link between depression and nicotine raises critical red flags for physicians helping depressed patients stop smoking. Dr. Glassman warned that these individuals, for example, successfully quit about half as often as non-depressed smokers and are two-and-a-half times more likely to become depressed when they do eventually quit. In addition, Dr. Glassman said that these patients can develop major depression when their nicotine levels drop too dramatically. Even when placed on nicotine patches, he explained, some depressed patients become suicidal because their nicotine levels drop too quickly. As a result, some patients require antidepressants in addition to nicotine replacement therapy.

The general population

But in a testament to the power of nicotine, most people—depressed or not—have a hard time kicking the habit. Although 34% of smokers try to quit every year, only 2.5% are successful each year, according to 1996 data from the American Lung Association.

A major barrier to quitting is overcoming the ingrained behaviors that accompany smoking. Researchers estimate that someone who smokes two packs a day inhales a puff every minute and a half; targeting nicotine dependence alone does not give smokers something to do with their hands when they wake up in the morning, desperate for a smoke.

The latest research has found that smokers who try to quit without counseling or contact with a health provider have the least success. A total of 7.6% of smokers who received no individual or group counseling about smoking cessation successfully quit smoking, compared to 15.1% of those who received individual counseling and 15.3% who received group counseling about smoking, according to AHCPR's guidelines.

Even getting support over the telephone is successful. In the early 1990s, Group Health of Puget Sound launched a massive smoking prevention program that covers smoking cessation services for a small co-pay. The program covers nicotine patches or gum only if patients participate in a smoking cessation program that is offered in person or via the telephone. In 1987, 22% of those who had participated in a smoking cessation program were smoke free one year after the program started; by 1990, 30% of participants in the program could make that claim. According to Tim McAfee, MD, associate director of the department of preventive care and medical director of tobacco services at Seattle's Group Health Cooperative of Puget Sound.

But the power of nicotine to change the way smokers feel about themselves continues to make the job of helping patients quit smoking a frustrating one. Nicotine patches and gum have not proven to be wonder drugs for smokers trying to quit, and experts say they are unlikely to offer the complete solution. Many experts hope that evidence of the potent, chemical nature of tobacco addiction, along with the myriad ways it affects smokers, will help physicians to see smoking as more than simply a habit or a risk factor.

"Tobacco addiction is a chronic disease," said Michael Fiore, MD, an internist and director of the Center for Tobacco Research and Intervention at the University of Wisconsin Medical School and chairman of the panel that developed the AHCPR guidelines on smoking cessation. "Unlike diabetes, hypertension or hyperlipidemia, physicians can spend three minutes treating tobacco addiction and have the potential to help 5% to 10% of smokers quit. The time we spend counseling and prescribing nicotine replacement therapy is time very well spent."

Patricia Braus is a Rochester, N.Y.-based freelance writer specializing in health care.

AHCPR's five strategies to help patients stop smoking

For years, physicians have been hearing about new strategies to help patients quit smoking. But for physicians who have seen patients try and fail to quit repeatedly, the question of what really works best still looms large.

Practice guidelines released last April by the Agency for Health Care Policy and Research (AHCPR) recommended strategies for physicians to help their patients quit smoking. In creating the guidelines, the agency's panel reviewed approximately 3,000 articles to determine the best strategies for helping patients quit.

The recommendations focus on the following five strategies:
1. At every visit, ask patients if they use tobacco.
2. If so, urge them to quit in a "clear, strong, and personalized manner."
3. Ask smokers if they are ready to quit.
4. Help smokers quit by providing nicotine replacement therapy in most cases.
5. Arrange and schedule follow-up contact by telephone or in person, contacting patients at least once during the first week.

Some bristle at the idea of asking patients at every physician visit if they smoke. Alan Foster, director of the employee assistance program at the University of Rochester, fears that constant reminders about smoking could have the wrong affect on smokers. "I would be afraid that if I constantly nagged a patient," he said, "they would get out of there."

In reality, though, many physicians do not even raise smoking as an issue. A study published in the June 1995 issue of the Journal of Family Practice found that only half of smokers who saw a primary care physician were asked whether they smoked over the past year.

There's evidence, however, that most patients do not resent the question. "There's a myth that if you talk to your patients it might reduce patient satisfaction," said researcher Helen Halpin Schauffler, PhD, associate professor of health policy at the University of California at Berkeley School of Public Health. "We found that people whose doctors have talked to them about lifestyle risk showed more patient satisfaction." At Seattle's Group Health Cooperative of Puget Sound, for example, physicians ask patients about smoking at every visit. "It gets treated like a vital sign," said Tim McAfee, MD, medical director of tobacco services for the program. "Since 70% of smokers are planning on quitting in the next six months, they appreciate the attention."

And there is evidence that patients could use the help. According to the AHCPR guidelines, patients who received help from health providers—including doctors, social workers, dentists and psychologists—had the highest rates of success in quitting (25%), while those who tried to quit on their own had the lowest (8.2%). But the findings also show that doctors need not feel solely responsible for getting patients to quit. They can depend on health educators, nurses and other health workers to provide additional support for patients trying to stop smoking.

For a free copy of AHCPR's guidelines on smoking cessation, call 800-358-9295 or go to AHCPR's web site at Copies are also available through the Instant Fax service, which can be used with a touch-tone telephone. Dial 301-594-2800, push 1, and wait for further instructions.

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