Blood-Pressure Drug May Help Hard-Core Smokers Kick Habit

A widely used high-blood-pressure drug has emerged as the first of what experts foresee as a growing number of nicotine-free chemicals capable of weaning smokers from their habit.

In the process of testing the drug, clonidine, drug-dependence researchers have concluded that, because of the success of anti-smoking programs, most of those who still smoke probably represent a hard core of addicted users for whom conventional cessation strategies will have only limited effect.

In addition, the research on the drug--commonly sold under the brand name Catapres--confirmed a 1986 finding that smoking is highly likely to be associated with a medical history of depression.

The observations about clonidine, published in today’s issue of the Journal of the American Medical Assn., come in the wake of Monday’s annual smoking report by U.S. Surgeon General C. Everett Koop that underscored the addictive potential of tobacco, linking it in habit-forming potential to heroin and cocaine.

The new clonidine study, led by a prominent New York expert on depression, appears to underscore what researchers say is a growing sense of how intractable smoking behavior can be. An editorial published with the new study predicts that clonidine will open the way for development of a family of nicotine-free drug treatments to help smokers quit.

Until now, only chewing gum, stick-on patches and nasal spray--all containing nicotine--have been available as pharmacologic smoking treatments. In an effort to eliminate nicotine products from smoking treatment, researchers have experimented with another blood pressure drug, mecamylamine (brand name: Inversine) and two anti-depressants, fluoxetine and doxepin--all with only modest success. Some research subjects have reported side effects common to psychoactive drugs. And researchers at UCLA are still testing an inhalant made from the active ingredient in lemon juice, though results are not expected for several months.

But to Dr. John Hughes, a University of Vermont expert on tobacco addiction, the new study of clonidine--which appears the most promising of all the nicotine-free agents tested so far, he said--represents a direction that has developed, virtually from scratch, since 1985.

“Three years ago, if you’d mentioned the idea that drugs (to treat smoking) are going to become more common, people would have said, ‘You’re crazy,’ ” Hughes said in a telephone interview. “(Today) we’re right on the border of really starting to understand the mechanism of tobacco dependence. As we understand that, we’ll see a lot more rational medication therapy going on.”

Hughes and Dr. Daniel Freedman, a UCLA psychiatry and addiction expert, said researchers have begun to focus on an area of the brain called the locus ceruleus, which has also been identified as having a role in addiction to other psychoactive drugs. As an anti-hypertension medication, clonidine is thought to interfere with the brain’s control over the manufacture of natural adrenaline and to prevent dangerous increases in blood pressure. Since some of the same adrenaline function is believed responsible for addictive behavior, researchers think clonidine’s blood pressure effect is applicable to addiction treatment.

In the study of clonidine, a team of researchers at the New York State Psychiatric Institute and Columbia University tested the drug on 77 smokers trying to quit. Forty-five of them were given daily doses of the drug in the same amounts used for blood pressure treatment while the rest received a placebo. The clonidine group as a whole was able to give up smoking far more readily than the placebo group; clonidine was especially effective in women, for whom it was successful 72% of the time.

Overall, clonidine was effective for 64% of the subjects after four weeks’ use. Dr. Alexander Glassman, who headed the research, said the different success rates between men and women may have been due to statistical quirks.

Six months after the clonidine treatment, Glassman said, the drug-treated group showed about the same success in staying off tobacco as patients elsewhere who were given nicotine gum or another nicotine product. Six months after the study, 27% of the group that received clonidine was still not smoking compared to 5% of those who got the placebo.

Success rates in smokers who reported histories of depression were significantly lower than in those who did not. A total of 75% of subjects who were free of depression successfully completed clonidine treatment, while 52% of those who had been through periods of depression earlier in their lives did so.

“We figured that it was going to be tough enough to get people to stop smoking without their being depressed or drug abusers,” said Glassman. “But what we didn’t expect was the effect of depression. Our sample was heavily addicted (to tobacco) and it follows Koop’s concerns. These are hard-core smokers.

“I think what’s happening is that, nowadays, the people who can quit easily quit and the ones that are left behind (as smokers) are not randomly selected. The easy ones quit and the hard ones remain. What we’ve found is that those hard ones are heavily loaded with depression.

First of a Series

“Ten years from now, there may be other drugs that will be discovered. This is the first of probably a series. Once you find an area of the brain you can play with, people will find better substances.”

Hughes and other smoking experts said development of workable drug therapies will become more important in the next few years because they expect that the growing anti-smoking movement will increasingly ostracize smokers and that virtually all tobacco users aside from the truly addicted will quit. The remaining smokers will require stronger and more effective treatments, predicted Hughes, and they be willing to tolerate side effects, which include mood alteration and other problems associated with psychoactive products.

In a related development, today’s issue of the journal included a report from the U.S. Preventive Services Task Force that concludes that the success rates of broad, conventional quit-smoking programs are most dependent on a multidisciplinary approach, with emphasis on follow-up care in the event of relapse. The task force concluded that reinforcement of anti-smoking messages--as opposed to a single treatment method--is more successful.

Glassman said the National Institute on Drug Abuse has agreed to sponsor another follow-up study to see how well drug-treated smokers do 18 months after they quit. He said the six-month results in the new study did not represent a group large enough to justify sweeping conclusions about long-term effects.

Glassman’s study of clonidine relied entirely on pills, but the company that developed the drug said it is starting a large national trial in which a stick-on patch containing clonidine is being tested. A spokesman for Boehringer Ingelheim Corp., which provided some of the support for Glassman’s study, said that if results of the stick-on patch are encouraging, the company will ask for U.S. Food and Drug Administration approval to promote and market its clonidine product.

No test to compare the effectiveness of the pills with the stick-on patch is planned. The Boehringer Ingelheim spokesman noted that the pill form is no longer protected by patent laws and generic pill versions of clonidine are widely available. The company retains patent rights to the stick-on patch and Dr. Ted Hughes, the spokesman, said the firm is primarily interested in the commercial prospects of the product to which it owns exclusive rights.

Potent Blood Pressure Medicine

While clonidine is widely available and physicians could legally prescribe it for smokers, drug experts emphasized that it is a highly potent blood pressure control agent whose side effects can be fatal if doses are abruptly stopped. FDA-approved labeling for clonidine includes a warning that the drug may lead to dependence.

Common side effects include drowsiness, dizziness, headache, fatigue and constipation. Depression has been observed in some people taking clonidine.

While Glassman said the different effects on people with and without depression histories were intriguing, he and other researchers noted that the study linking smoking and depression is only tenuous, at best.

Three years ago, a Columbia University study led by researcher Denise Kandel found that adolescents who suffered from depression were far more likely to become smokers than teen-agers with normal mental health histories. Kandel said the effect remained after the adolescents had reached 25 and she said she is about to begin a follow-up study on the group at ages 33 and 34.

She said the earlier study indicated that tobacco may have a key difference from other drugs of abuse. She said that in the cases of alcohol and marijuana, in particular, teen-age use increased quickly until the early 20s, when it subsided fairly rapidly.

With tobacco, however, she said, use escalated among teen-agers but then reached a plateau from which smoking levels didn’t substantially decrease.

“When people start smoking, they find it very hard to stop,” she said. “The difference you find between marijuana and alcohol and smoking is very striking.”