High-Risk Haplotypes in Smokers

It’s getting harder to interpret genetics studies, and that’s a good thing.

Reporting the results of published studies concerned with genetic risk factors has always been a tricky proposition. Beyond the inevitable, and too often ideological nature/nurture split, there has been an unfortunate history of false positives in the rush to make news with a “gene for” alcoholism or schizophrenia or belief in God.

But single gene theories are mostly a thing of the past, and results tend to be broader and more tentative, as befits the state of our knowledge about genes and risk in a post-epigenetic landscape. Nonetheless, there’s no denying that genes play a strong role in all kinds of behaviors and processes. A large group of U.S. tobacco researchers went looking for associations between genetic risk factors and the ability to stop smoking successfully, and published their results in the American Journal of Psychiatry. The group came down strongly in favor of the proposition that genetic variations in the chromosome 15q25 region help dictate who manages to quit smoking and who does not.

The genetic variants in question are for nicotine receptors, and are called CHRNA5-CHRNA3-CHRNB4. They compose a “high-risk haplotype” that Li-Shiun Chen and coworkers believe to be involved in the ability to quit. (A haplotype is a combination of DNA sequences on a chromosome that are transmitted as a unit). People with these genetic variants “quit later than those at low genetic risk; this difference was manifested as a 2-year delay in median quit age.” However, this association tended to wash out at very high levels of smoking. Nonetheless, “pharmacological cessation treatment significantly increased the likelihood of abstinence in individuals with the high-risk haplotype,” compared to the low-risk group.

The suspicious haplotypes did not reliably predict tobacco abstinence across all groups that were studied. And any pharmacological treatment at all vastly increases abstinence rates, compared to placebo, while those who smoke the fewest cigarettes per day have the best shot at abstinence no matter what. In one sense, all the study is saying is that anti-craving drugs are more likely to be effective in smokers “who are biologically predisposed to have difficulty quitting.” Other smokers may not need them at all as a quitting aid—which is very much as common sense would have it. But further research in this area may allow medical workers to genetically identify smokers who will definitely require a pharmacological booster shot to overcome their crippling addiction.

In brief, the study says that success in quitting may be directly modulated by certain types of genetic variation among smokers. And genetic variations influencing quitting success may be different from gene variants controlling for “severity of nicotine dependence” (how many cigarettes you smoke), and whether you get addicted in the first place. It is all very complicated. But it’s the sort of thing that gives researchers hope when they contemplate deploying forms of personalized medicine in addiction treatment.

Study limitations abound. The work looked at only one genetic locus, while the success of smoking cessation might depend on multiple gene sites. The placebo arm was relatively small, and the smoking reports were obtained through a combination of biochemical confirmation and self-reporting.

Baker, T. (2012). Interplay of Genetic Risk Factors (CHRNA5-CHRNA3-CHRNB4) and Cessation Treatments in Smoking Cessation Success American Journal of Psychiatry DOI: 10.1176/appi.ajp.2012.11101545

Graphics Credit: (Li-Shiun Chen)

Medical Cigarettes

Is it “Inhumane” to Take Cigarettes Away from Schizophrenics?

In an article for Brain Blogger a couple of years ago, I looked into the astonishing fact that, as a typical study of in-patient smoking among schizophrenics in Britain revealed, about 80-90% of the patients diagnosed with schizophrenia were cigarette smokers. Given that the running rate in the general population hovers around 20-25% on average, this is really quite amazing. It seems clear that nicotine is doing something for a schizophrenic that makes cigarettes into a form of self-medication that almost all schizophrenics apparently discover at one time or another.

A review of relevant studies through 1999, undertaken by Lyon and published in Psychiatric Services, shows unequivocally that schizophrenic smokers are self-medicating to improve processing of auditory stimuli and to reduce many of the cognitive symptoms of the disease. “Neurobiological factors provide the strongest explanation for the link between smoking and schizophrenia,” Lyons writes, “because a direct neurochemical interaction can be demonstrated.” According to Lyon, “Several studies have reported that smokers require higher levels of antipsychotics than nonsmokers. Smoking can lower the blood levels of some antipsychotics by as much as 50%…. For example, Ziedonis and associates found that the average antipsychotic dosage for smokers in their sample was 590 mg in chlorpromazine equivalents compared with 375 mg for nonsmokers.”

In particular, smoking seems to help quell auditory and visual hallucinations. The process known as “sensory gating” refers to lower response levels to repeated auditory stimuli. A schizophrenic’s response to a second stimulus is greater than a normal person’s, and this is also impacted by cigarettes. Sensory gating may be involved in the auditory hallucinations common to schizophrenics. Receptors for nicotine are involved in sensory gating, and several studies have shown that sensory gating among schizophrenics is markedly improved after smoking.

There is an additional reason why smoking is an issue of importance for health professionals. Dr. Bill Yates at Brain Posts recently examined a small study by Michael Allen and colleagues in the American Journal of Psychiatry in which 40 schizophrenic patients were admitted to a psychiatric emergency service, where they were given standard antipsychotic therapy. In addition, the researchers randomly assigned either a 21mg nicotine patch or a placebo patch to the subjects upon admission. As Dr. Yates summarized the results:

--Nicotine patches reduced agitation by 33% in the first four hours and 23% at 24 hours. And the reduction was greater than with either the antipsychotic alone, or in conjunction with the placebo patch.

--Subjects with lower nicotine dependence scores tended to show the most response compared to placebo.

--The effect of nicotine replacement on agitation reduction approached the level seen with standard antipsychotic therapy.

As Yates notes, this finding is “pretty dramatic.” It seems to show that acute nicotine withdrawal only makes the situation worse in a clinical setting. The study authors also argue that stronger patches combined with nicotine gum might quell agitation more quickly and effectively. “Encouraging patients with psychotic disorders and mood disorders to quit smoking is an important general health strategy,” Dr. Yates writes. “However, this study suggests that attempting this during an acute psychotic break is probably counter productive and may be inhumane.”

Photo Credit:http://drugabuse.gov/

The Day After

How’s that no-smoking pledge going?

This post is not meant for most of you. Those of you who never smoked, or smoked and quit successfully—move along, maybe check out my earlier posts about smoking this month.

But for those of you who have decided to take the 35th annual Great American Smokeout seriously—for those of you who decided today, or yesterday, or recently, to quit smoking—I have a few remarks, if you have a moment. I’m fairly trustworthy on this subject. I’m a science writer, I follow the field of addiction science, and I smoked a pack of Camel filters a day for about 25 years. In addition, I quit smoking using the most recently available smoking cessation aids—nicotine patches and anti-craving medication, in this case Zyban, a.k.a. Wellbutrin.

I had decided, after the usual smoker’s run of unsuccessful independent quitting attempts, that the only real hope I had for success was to throw myself into the hands of my primary care physician. Happily, Dr. Joe is a young example of the last of the breed, a lingering remnant of a tribe that used to be known as family doctors. When I told Dr. Joe of my plans to quit smoking, he was overjoyed. Too overjoyed, it seemed to me. As it turned out, there were grounds for my suspicion. Dr. Joe had recently returned from a smoking cessation seminar at the Mayo Clinic in Rochester, Minnesota, with a grab bag of refinements and alternative approaches for setting up a no-smoking regimen. Furthermore, he made it clear that, if necessary—if I forced him to it through relentless noncompliance—he was fully prepared to order regular blood workups to detect and quantify my nicotine levels.

Of course, I instantly regretted setting a foot into this ring, but once Dr. Joe started flinging prescriptions for patches and pills my way, I realized I was in it up to my wallet (Insurance companies weren’t paying for nicotine cessation products, ever, at that time).

Most smokers know the current drill. A few weeks with nicotine patches or gum or nasal spray, combined with a short course of Zyban or Chantix to further reduce cravings, and then you are expected to fly out of the nest and spread the good news.  Most smokers know that even this controversial armamentarium is not going to completely spare them from a rare and special kind of suffering: addictive craving for nicotine.  It’s a mean, rough ride, as everyone knows.

But if you take a few of the major potholes out of the road, smooth over the really big bumps just a little, fill in the low spots a bit as well, you have a fighting chance—especially if you have tried and failed before (almost nobody pulls it off on the first attempt).

Here are the key features of the program, as my doctor worked it up for me:

--Stronger patches. Mayo Clinic and other institutions had made an important discovery, my doctor said. People weren’t wearing strong enough patches. There was a system of matching up patch strength to amount and duration of smoking, and then a step-down procedure, to less and less powerful patches, and it was all listed on the packages, but because of great nervousness over medical complications by a very few individuals who overdid the patch and then chain-smoked on top of that, the result was that the patches as marketed weren’t strong enough, many doctors felt. The advice was to start strong, with the strongest patch available (and perhaps there was even a patient or two who doubled up, ahem). 

--Longer patches. Start strong—and go long. The whole nicotine replacement plan is supposed to last a month or two. Phooey, said Dr. Joe. No telling in advance how long the process will take. There is no set timetable. How long would I be wearing patches and tapering the dose? As long as it took, Dr. Joe inferred, for me not to need them anymore. He seemed prepared to keep me on patches the rest of my life, if it kept me from picking up a cigarette. In the end, when I took off my final, tiny patch, I had been using them for a little less than six months. The recommended five-star treatment plan in the literature and on the packages calls for only 10 weeks, tops.

--Pharmaceuticals. It is admittedly hard to separate out placebo effects from drug effects, in the case of something as elusive as cigarette urges. But I do believe that Zyban took the edge off the worst of my cigarette cravings. It did not eliminate them, anymore than the patches eliminated them. But the medication effectively dissipated the grip of that moment of panic, when you have risen from your chair and set about finding your coat and car keys for a run to the gas station to buy a pack of cigarettes. Or at least that’s the way it felt to me.

--Exercise. Trite? You bet, and you can be sure that I winced and offered a tired smile when I heard my doctor bore in on the subject. Since I knew him to be a crazed bicyclist, I was prepared to disregard most of what he had to say. But his insistence sent me back to the research literature on exercise and its effect on dopamine, serotonin, acetylcholine, and endorphin levels. So I took him up on that firm suggestion as well, and found that, at the least, it helped with a period of rocky sleep in the beginning.

--Diet. No huge changes, just watching the sweets in an effort to avoid surging blood sugar levels. Fruit helps, since constipation is a common side effect of nicotine cessation—just the opposite of how it works with heroin. I continued to drink coffee, but for a while it didn’t taste as good.

--Relaxation. Quitting smoking makes you tense. You think I’m being funny? Quitting smoking makes you tense all over, mentally and physically. During the first few days you’ll notice that your body is clenched, held rigidly. Your posture is likely to be anything but relaxed; your physical movements can be jerky and awkward. A few minutes a day spent sitting with eyes closed, in a relaxed upright posture, thinking of nothing or concentrating on your breathing or meditating either formally or casually, can bring partial relief from all that tension. And on some days, that can be crucial.

--Determination. Unfortunately, it wasn’t until everyone around me—my wife, children, parents, close friends, work associates—had all, I sensed, basically given up on me, silently condemning me to the category of Lifetime Smoker, that I finally managed to make a successful run at a major life problem. There are better ways to work up your determination. Find and employ them.

With time, an involved partner, nicotine replacement, and the right medication, the deal can be done. There has never been a better time in history to be a smoker who has decided to quit.

Graphics Credit: http://adoholik.com/

Rethinking the Patch

Quitters do better on 6-month regimen.

It may sound like dream propaganda for the makers of nicotine patches. And it is. Moreover, at least one of the study authors has worked in the past as a consultant for GlaxoSmithKline, maker of Nicoderm CQ, one of the best-selling brands of transdermal nicotine patches.

So there is every reason to dismiss a recent study by researchers at the University of Pennsylvania School of Medicine, published in the Annals of Internal Medicine, which strongly suggests that the currently recommended regimen of two months isn’t long enough. It should be tripled. Which also triples sales.

There’s only one catch: There is reason to believe that the results are legitimate, and that smokers who are trying to quit would be more successful if they stuck with the patch for longer periods than currently recommended on the manufacturer’s box.  For some time now, tobacco addiction researchers, and centers such as Mayo Clinic’s Stop Smoking facilities, have recognized the need for extending the manufacturer’s suggested period of use.

Referring to the patch on its Stop Smoking web site, Mayo Clinic says: “You typically use the nicotine patch for eight to 12 weeks. You may need to use it longer if cravings or withdrawal symptoms continue.”

And from the field come reports of abstaining smokers independently choosing to use the patch longer, often by cutting the patches into eighths or sixteenths in order to accomplish a long, slow taper at the end of the process. By following this route, a nicotine addict need not be aware of the precise day or moment when his nicotine fix from the patch has dropped to placebo levels—further evidence that nicotine addiction is a chronic condition that may not respond to treatments of only two to three months in duration. 

One early development during the marketing of the patch that helped set the short-term use pattern were reports in the 1990s of heart attacks by patch users. Subsequent research showed that rare cardiac problems had arisen in patients who had continued heavy smoking while on the patch, and that there was little evidence of a direct link between nicotine patches and heart attacks. (Recent heart attack victims are advised to wait six weeks and use patches with caution.)

The study concludes: “Transdermal nicotine for 24 weeks increased biochemically confirmed point-prevalence abstinence and continuous abstinence at week 24, reduced the risk for smoking lapses, and increased the likelihood of recovery to abstinence after a lapse compared with 8 weeks of transdermal nicotine therapy.”

One limitation of this particular study, acknowledged as such by the authors, is that “participants were smokers without medical comorbid conditions who were seeking treatment.” In other words, the study cohort consisted of highly motivated smokers.

And another problem is cost: Few health insurance companies cover the full cost of patches, including Medicaid. The additional cost per quitter, the study found, was about $2,400 for the extended regimen.

Nonetheless, any uptick in success rates for smoking cessation programs should be noted and taken under consideration.

Photo Credit: www.drugabuse.gov

E-Cigarettes: Another Look

FDA remains conflicted over safety concerns.

The Food and Drug Administration (FDA) issued a controversial Safety Alert over electronic cigarettes, known as “e-cigarettes,” then held a press conference to explain itself. The agency’s muddled response to the issue has prompted increased advertising and online sales for Asian e-cigarette manufacturers, as well as a countering burst of criticism about the newest nicotine delivery system under the sun.

The FDA conducted a small-scale lab analysis of two different brands of e-cigarettes, and found “carcinogens and toxic chemicals such as diethylene glycol, an ingredient used in antifreeze.” The FDA’s Division of Pharmaceutical Analysis also found evidence of small amounts of cancer-causing nitrosamines. “These products do not contain any health warnings comparable to FDA-approved nicotine replacement products or conventional cigarettes,” the agency bulletin said. Therefore, the agency “has no way of knowing, except for the limited testing it has performed, the levels of nicotine or the amounts or kinds of other chemicals that the various brands of these products deliver to the user.”

The agency did not seek to ban e-cigarettes, as Canada did in March. However, in a written statement to CNN in March, the FDA admitted it had been detaining or refusing importations of electronic cigarettes for more than a year.

Debate has raged recently over the safety of e-cigarettes, which are battery-operated cigarette substitutes that technically dodge no-smoking bans, since no actual smoke is emitted. When a smoker inhales on the e-cigarette, the battery warms liquid nicotine stored in a plastic filter, producing a smokeless but inhalable form of synthetic nicotine. Upon exhalation, there is a small puff of vapor that quickly evaporates (See my earlier post, "E-Cigarettes and Health").

Michael Levy, director of compliance for the FDA’s division of drug evaluation and research, said he believes the products are illegal. However, “There is pending litigation on the issue of FDA’s jurisdiction over e-cigarettes,” he said.

Proponents of the e-cigarette claim that the devices are self-evidently safer than smoking cigarettes, and can help people stop using tobacco products. Critics respond that the safety of synthetic nicotine drug-delivery devices has not been established. Moreover, the range of fruit and candy flavors offered by e-cigarette manufacturers suggests to Jonathan Inickoff of the American Academy of Pediatrics Tobacco Consortium that the devices seem “tailor-made to appeal to kids,” while addicting them to nicotine and turning them into future cigarette smokers.

With half a million Americans dying prematurely each year from smoking, according to figures from the Centers for Disease Control (CDC), some doctors and tobacco researchers have pointed out that nitrosamines are also found in everything from nicotine patches to bacon. According to one researcher, “FDA should be encouraging, not maligning the manufacture and sale of electronic cigarettes, and working with manufacturers to assure the highest possible quality control.”

For a robust discussion of the e-cigarette question, see www.e-cigarette-forum.com


Photo Credit: www.politech.wordpress.com

addiction drugs smoking nicotine

The Patch and How to Use It

Take the Fagerstrom test.

The U.K. Guardian, in partnership with the British Medical Journal, recently offered its readers a short version of the Fagerstrom test, a questionnaire used for assessing the intensity of physical addiction to nicotine. The Guardian article then made recommendations about which patch strength smokers should be using, based on their scores.

Here is a longer version of the Fagerstrom test, with scoring assessment, followed by the Guardian’s recommendations about patches:

Fagerstrom Test for Nicotine Dependence *

1. How soon after you wake up do you smoke your first cigarette?
-- After 60 minutes
(0)
-- 31-60 minutes
(1)
-- 6-30 minutes
(2)
-- Within 5 minutes
(3)

2. Do you find it difficult to refrain from smoking in places where it is forbidden?
-- No
(0)
-- Yes
(1)

3. Which cigarette would you hate most to give up?
-- The first in the morning
(1)
-- Any other
(0)

4. How many cigarettes per day do you smoke?
-- 10 or less
(0)
-- 11-20
(1)
-- 21-30
(2)
-- 31 or more
(3)

5. Do you smoke more frequently during the first hours after awakening than during the rest of the day?
-- No
(0)
-- Yes
(1)

6. Do you smoke even if you are so ill that you are in bed most of the day?
-- No
(0)
-- Yes
(1)

* Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for
Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. British Journal of Addictions. 1991; 86:1119-27

0-2 Very low dependence

3-4 Low dependence

5 Medium dependence

6-7 High dependence

8-10 Very high dependence

[Scores under 5: “Your level of nicotine dependence is still low. You should act now before your level of dependence increases. “]

[Score of 5: “Your level of nicotine dependence is moderate. If you don’t quit soon, your level of dependence on nicotine will increase until you may be seriously addicted.”]

[Score over 7: “Your level of dependence is high. You aren’t in control of your smoking–-it is in control of you!”]

The U.K. Guardian’s scoring assessment

Which patch to use:

--2 points = light nicotine dependence. Start with the 7 mg nicotine patch.

--3 or 4 points = moderate nicotine dependence. Start with the 14 mg nicotine patch.

--5 or 6 points = heavy nicotine dependence. Start with the 21 mg nicotine patch.

Graphic Credit: Electronic Illustrators Group

smoking addiction nicotine

Nicotine Addiction in the U.K.

Study group urges harm reduction strategy for heavy smokers

Britain's Royal College of Physicians (RCP) called upon the government to treat cigarette smoking like any other drug addiction, and faulted its members for failing to offer sufficient help to heavy smokers trying to kick the habit.

Because of that failure, the Academy called for greater access to nicotine substitution products, and the development of safer and more effective nicotine delivery systems for smokers who cannot quit.

The Academy’s report, "Harm Reduction in Nicotine Addiction: Helping People Who Can’t Quit," called for a sweeping overhaul of the country’s nicotine marketing structure "so that harm reduction strategies are in place."

The report’s principle suggestion: "Change nicotine product regulation to make it easier to produce and market medicinal nicotine products."

Jean King, Cancer Research UK's director of tobacco control, said the report highlighted the "stark fact" that cigarettes are freely available, while medicinal nicotine products are heavily regulated.

The report also calls for continued development of new forms of “user-friendly medicinal nicotine substitutes,” as well as relief from burdensome regulations that impede the marketing of new nicotine alternatives—chewing gums, nasal sprays, and patches.

“Smokers smoke because they are addicted to nicotine,” said Professor John Britton, chair of the Academy’s Tobacco Advisory group. “There are millions of smokers who can’t quit, or else are unlikely to quit, and those people need nicotine products that can satisfy their addiction without killing them.”

This methadone-style approach to nicotine addiction is sure to prove controversial. Will it save lives, or will it simply keep nicotine addicts from getting clean? Reuters reports that some British scientists are concerned that an emphasis on cigarette substitution products is at odds with a policy of helping people completely break their addiction to nicotine—which the Royal Academy maintains is still their primary focus.