As the pharmaceutical giant Pfizer was reminded in May, arriving first has its rewards, but they come with the risks of venturing into uncharted territory. This past spring the Federal Aviation Administration banned pilots and air traffic controllers from taking the company’s popular smoking-cessation aid, varenicline, which is sold in the U.S. as Chantix. Amid 6.5 million prescriptions written worldwide since 2006, the drug had spawned highly publicized reports of acute psychiatric episodes that included seizures, psychosis and suicidal depression. In May the nonprofit Institute for Safe Medication Practices documented 988 such “adverse events,” prompting the aviation ban.
The Food and Drug Administration has now added strong warning language to varenicline’s medication guide, and Pfizer is reviewing evidence that might help explain the rare but severe incidents. Although the bad publicity may dampen sales of the drug, observers say that some adverse events are not unexpected when a new drug hits the market, especially one that is the first of its kind. Varenicline is not just a novel smoking-cessation tool; it is the first of an entire class of medications specifically designed to target a powerful family of receptors on the surface of brain cells. Known as neuronal nicotinic acetylcholine receptors, they can mediate pain, mood, memory, attention and other cognitive functions.
Abbott Laboratories, Targacept and AstraZeneca have nicotinic receptor drugs in clinical trials for memory impairment, adult attention-deficit hyperactivity disorder and pain. The National Institute on Drug Abuse is testing varenicline itself as a treatment for cocaine and alcohol dependence. Preclinical studies are looking at other new nicotinic receptor compounds for Parkinson’s disease, Alzheimer’s disease, depression, ulcerative colitis and inflammation as well, attesting to the broad influence of this receptor family.
The effects of nicotinic receptors are so pervasive, in fact, that some of the mechanisms involved are not completely understood. “It’s a story that’s still evolving, and it’s very complicated, so going in with a drug like varenicline, I’m not surprised that there are side effects,” says Lorna Role, who studies the receptors’ biology at Columbia University and Stony Brook University. This type of acetylcholine receptor, which also responds to nicotine, acts as “a volume control” for other neurotransmitters, according to Role. “A little nicotine turns up transmitter release,” she explains. “It’s been shown to increase the release of dopamine, glutamate, GABA—every major neurotransmitter.”
Activating a subtype of nicotinic receptor known as alpha4beta2 causes dopamine to be released in a part of the brain involved in reinforcing reward, for example, and that receptor is the primary target of varenicline. The drug works as a “partial agonist,” meaning it binds to the receptor, producing moderate stimulation intended to stave off nicotine withdrawal. In so doing, it blocks nicotine from getting to the receptor as well, which prevents a smoker from receiving a dopamine surge from a cigarette.
In cell studies, varenicline also acts as a potent full agonist for another receptor subtype called alpha7 that is associated with some of the positive cognitive effects of nicotine, such as enhanced focus. Variations in the alpha7 receptor gene are implicated in the difficulties schizophrenics tend to have with shutting out sounds or other stimuli. “I was hopeful that varenicline could be used for schizophrenia,” Role says, “then the first report came out of it causing a psychotic episode, and it was hands off.”
Given the complexity of the neuropsychological systems affected by nicotinic receptors, most of the episodes involving varenicline may never be explained. Pfizer representatives point out that smokers as a group have higher than average rates of anxiety and depressive disorders, suggesting that mild or undiagnosed preexisting mental illness might have played a part in some of the reactions to the drug. Moreover, symptoms such as agitation and suicidal thinking are well-documented side effects of tobacco withdrawal, notes Anjan Chatterjee, a director of medical affairs for Pfizer: “So it’s hard to decide, is it the smoker’s past history, or is it varenicline?”
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6 Comments
Add CommentWhy wasn't this drug tested on people of color? Is it because Pfizer knows it effects the melanin which is the dark pigment in skin and the brain regions where the dark grey matter is located. Why not use the cheap and tested for 50 year base for this drug which is cytisine? Silly me, I know why because it wouldn't make Pfizer the millions this one has on the blood of the unwarned initial users of this highest reported side effect drug ever.
Reply | Report Abuse | Link to thisPart of the problem is that the drug trials were sanitized. Those with any history of mental symptoms, drug use, and alcohol abuse were eliminated. The remaining smokers have a much higher rate of these concerns. Also, the dosage is one size fit all unlike comparable drugs in this class.
Reply | Report Abuse | Link to thisI took this drug a year ago and after 6 weeks I was living a nightmare for the next couple of months.
Chantix is a very dangerous drug, some of it's severe side effects could be permanent, we just do not know yet. There is a 50/50 shot that patients will experience severe side effects; that means that you might be ok or you might want to claw your face off. There are millions of people that are taking Chantix right now in different countries.There are plans to use Chantix for other medical issues, but no plans to perform more much-needed trials. Pfizer needs to stop this madness as soon as possible.
Reply | Report Abuse | Link to thisMy mother took Chantix successfully in two rounds and quit smoking after 30 some years. I decided to try it, having failed to quit smoking on numerous attempts. It did cut cravings. It also gave me extreme nausea as the doctor warned. However, after 2 weeks on the drug I began to have night terrors and panic attacks from triggers I had long overcome. Some history- I was brutally attacked about 10 years ago. At that time I had what was called PTSD, took celexa for about 4 years for anxiety, and with strong will power and cognitive therapy overcame the fears. I have lived a normal life for a long time. Now, since taking the drug, I feel like I am starting over. Literally, the 'terrors' came back (flashbacks of event in extreme vividness). Perhaps the drug is good for restoring memories, but that's not something I needed or anticipated. My doctor thinks it was a rare side-effect, but after reading your article I wonder. He knew my medical history and should have not recommended the drug. In my view, a life of persistent feelings of terror mixed with intrusive suicidal ideation and depression (being unable to close my eyes without seeing the attack) is worse than smoking and its health effects for me.
Reply | Report Abuse | Link to thisI took Chantix for almost three months. I thought it was a wonder drug! After being a smoker for over 20 years,I just didn't want a cigarette any more. I was so happy.I felt physically great. When my third month was up I began to get progressively angrier. I have gone through withdrawl before, this was not the same. I hated everyone around me including my sweet children. I could not rationalize my feelings I thought I was litterally going insane. I have never had trouble with anxiety, depression or anger before. Two weeks after quiting Chantix I became the happy optimist once again.
Reply | Report Abuse | Link to thisIf little is known about the mechanism of the receptors that varenicline affects then why was this drug introduced and approved in the first place. I would say it's all about Big Pharma's pursuit of the almighty dolllar but it goes further then that; this drug was approved and endorsed by the Government and the National Institute of Health based upon dubious test results. The NIH in its endorsement of pharmaceuticals, particularly veranicline was based on a 6 month end point and it was not much more effective then buproprian. Any study on addiction should have at least one years as an end point and as one scientist pointed out; if smoking in and off itself is a chronic illness then the end point should be 5 years.
Reply | Report Abuse | Link to thisAlmost any television advertisement for any other drug lists all the potential deadly effects that may result from the use of the advertised drug; however I do not recall any serious adverse events described in the original Tortoise and Hare Commercial.
In addition I am tired of hearing about nicotine withdrawal causing suicidal thoughts. If it is indeed the nicotine withdrawal then they are admitting that their drug does not work as it is supposed to replace the dopamine agonist effect of nicotine. They can't have it both ways; it reduces your craving for nicotine because you are receiving the dopamine blast from our product; but because you committed suicide it was withdrawal from nicotine.
Please do me a favor and stop trying to save me from myself by introducing more poison. The arrogance of the medical and scientific community and the government's complicity in the introduction of a drug that effects a part of the brain that they do not fully understand borders on criminal negligence. It's one thing to introduce a drug that benefits truly ill people; it's another thing to introduce an unproven drug to eliminate a habit that annoys the Nanny Nation.