Nicotine


Chantixby James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Chantix (Varenicline) is one of the most popular smoking cessation drugs available by prescription.  However, a number of problems with this drug have been identified and this has led to many restrictions on its use.  These problems include an increased incidence of depression, suicidal thoughts, lightheadedness and fainting.

Results of a recent study published in the Canadian Medical Association Journal add another potential problem for Chantix.  These investigators conducted a meta-analysis of 14 published papers describing the beneficial and negative effects associated with Chantix when used to treat nicotine addiction.  The investigators included only double-blind randomized controlled trials in their analysis.  This means that subjects and investigators did not know who was receiving Chantix vs. placebo (simply a sugar pill with no active ingredients) and subjects were assigned to the Chantix or placebo group randomly.  This reduces the chance that subjects at risk for cardiovascular problems were assigned more frequently to the Chantix group.  The investigators analyzed data from 8,216 subjects.  Their study revealed a small but statistically significant increase in the risk for cardiovascular problems such as heart attacks or strokes in the subjects taking Chantix.  Although there was a difference, it was small.  In the Chantix group 52 of 4908 (1.06%) subjects experiences a so called adverse cardiovascular event while in the placebo group 27 of 3308 (0.82%) subjects experienced the same kind of event.

There are some points worth discussion here.  Firstly, it is not surprising that Chantix might be associated with cardiovascular complications.  Chantix is a nicotine replacement therapy.  Therefore, Chantix shares many of the same pharmacological actions of nicotine.  Cigarette smoking does increase the risk of cardiovascular disease partly because cigarette smoke contains nicotine (cigarette smoke also contains carbon monoxide and other toxins which are not present with Chantix).  Nicotine increases blood pressure and increase blood clots which can cause heart attacks and strokes and Chantix may do this as well.  Secondly, although the increased risk for adverse events in the Chantix group was small, the overall sample size was also small (<5,000 subjects).  Worldwide, there are millions of people using Chantix to help kick the smoking habit and therefor a much larger number of patients might be at risk worldwide.

Finally, it is important to remember that all drugs cause side effects (some worse than others).  When deciding whether or not a drug should be used, the doctor and patient must consider the risk vs. the benefit.  Chantix might produce a small increase in the risk for a heart attack or stroke in a patient trying to kick the nicotine habit.  But, what is the heart attack/stroke risk for that patient if he/she continues to smoke?  Many smokers become former smokers without the need for drugs like Chantix but there are also many smokers who have quit hundreds of times.  This is the subset of people who are most likely to benefit from nicotine replacement treatments.  Larger studies will likely reveal the real risk/benefit ratio of Chantix when used to treat nicotine addiction.

In the meantime, the wise person will discuss these issues with their doctor before using Chantix to help kick the smoking habit.

 

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by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Nicotine is a highly addictive drug and kicking the smoking habit has proven to be extremely difficult for many cigarette smokers.

Several smoking cessation strategies work reasonably well in the short term (3 months or so) but relapse rates are greater than 80% after 1 year.  There are a variety of reasons why smokers relapse but a strong relapse predictor is body weight gain, particularly in women.

Nicotine does decrease body weight and it does so by several mechanisms.  Nicotine acts in the brain to inhibit the brain regions that regulate appetite.  Nicotine also acts on fat cells to stimulate fat breakdown and it also stimulates energy expenditure (metabolism) by cells throughout the body.  Without nicotine onboard, appetite increases, fat breakdown and metabolism decrease and before you know it, the ex-smoker has put on 10 or more pounds.  After a peak in the mirror, the ex-smoker becomes a former ex-smoker.  If there was some way to prevent the weight gain, smoking relapse rates would likely fall and this would be beneficial for the individual smoker and for the overall health profile of the U.S population.

Science Magazine cover

A new study published in Science magazine may provide some hope that the appetite and body weight gain can becontrolled in the abstinent smoker.  These studies were done in mice where food intake and body weight were monitored after treatments which stimulated or blocked receptors for nicotine were tested.

Nicotine does have specific targets (receptors) in the brain where it produces its addictive actions.  The nicotinic receptors are found on neurons in the ventral tegmental area that use dopamine as a neurotransmitter and these neurons are in the reward pathways in the brain.  However, receptors for nicotine are also found in a region of the brain called the hypothalamus which is responsible for regulating appetite (among other things).  The study in Science revealed that the nicotinic receptors were found on a subset of neurons called POMC neurons and nicotine and a related drug activated these neurons.  POMC is an abbreviation for a protein known as pro-opiomelanacortin.  This in an interesting protein because it breaks down into three important smaller proteins: endorphin (the body’s natural opiate), melanocortin and adrenoccorticotrophin (which stimulates the adrenal gland).  The connection between endorphin and adrenocorticotrophin and nicotine induced appetite regulation was not investigated in this study.  However, it looks like melanocortin may be a key player here because when receptors for melanocortin were “knocked down” nicotine was no longer able to suppress feeding in these mice.

These studies were done in mice and there is a long way to go before these results can be translated into safe and effective treatments for nicotine addiction in human smokers.

These studies were also done in nicotine naïve mice; they were not nicotine addicted.  It is known that nicotine changes the nervous system in nicotine-addicted mice and humans so the role of melanocortin in appetite regulation needs to be studied in nicotine addicted mice.  However, these studies do provide new and important data about the complex mechanisms that regulate appetite and feeding behaviors and how these mechanisms may overlap with the reward pathways in the brain.  This could eventually lead to effective suppression of appetite in nicotine abstinent smokers leading to more appealing reflections in the mirror.

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