"Does Chantix really work?" "Tell me the truth, what are my chances?" Frankly, your actual chances of quitting smoking with Chantix (whose chemical name is varenicline) are not promising - at best about 1 in 5. This article explores new quitter frustrations before closing with hope.
Five clinical trials of Chantix, a new prescription pill quit smoking aid manufactured by Pfizer, were published in July and August 2006. Three are comparable in that they involved a 12-week treatment period using 1mg of Chantix twice daily. In the Chantix study headed by Gonzales, 21.9% of Chantix users were still not smoking at one year. In Oncken the rate was 22.4% and in Jorenby 23%.
That's an average one-year rate of 22% or, on the flip side, a relapse rate of 78%. But these rates were achieved under highly artificial clinic study conditions. History and common sense teach that use under real-world conditions will generate a much higher failure rate. The question is, how high?
Pfizer funded and co-authored the five studies and was involved in all study elements including design and monitoring. Pfizer appears to have spared no expense in creating what may be the most intense clinic quitting experiences ever. Frankly, it is surprising that the intensity of support and interaction did not produce even higher rates. Real-world quitters, alone with their pills, or even participating in Pfizer's GetQuit support plan, will be fighting under entirely different battlefield conditions. What was it like inside an early Chantix study?
How many real-world quitters using Chantix will get it for free, will be reimbursed travel expenses associated with visiting their health provider to obtain it, will attend sixteen clinic visits involving brief one-on-one sessions with counselors trained in motivation and coping skills development, will receive eight follow-up telephone support calls from their provider, two full physical exams, ponder the significance of a stream of questions in provider administered surveys, have their urine and blood checked seven times, sense the seriousness associated with undergoing six EKGs, and watch their weight, vital signs and expired carbon monoxide breath tests recorded sixteen times?
How much of Chantix's 22% one-year quitting rate is due to Chantix and how much attributable to the 26 times in the Jorenby study that participants spent one-on-one time with their Chantix provider? How many real-world quitters will have the support benefit of 26 sessions with their prescribing physician? Any? If so, at what cost?
"Those Who Don't Know Cessation Study History are Destined to Repeat It."
Chantix enters the quitting product market as a prescription aid at a time when nicotine replacement therapy or NRT is the clear frontrunner. Nicotine gum was first approved by the FDA for prescription use in 1984 and followed by the nicotine patch in 1991. Both the gum and patch were approved for over-the-counter (OTC) sales in 1996, the same year as prescription nicotine nasal spray was approved. The nicotine inhaler and bupropion (Zyban) joined as prescription products in 1997. In 2002 the lozenge become the first nicotine delivery device to enter the market directly as an OTC product.
There is a night and day difference between the intensity of Chantix-like randomized clinical trials and the OTC studies we've seen. The OTC studies were needed to validate the U.S. Food and Drug Administration (FDA) allowing the nicotine gum and patch to go from prescription to OTC in '96. OTC study participants sometimes received little more than the instructions that came inside the box.
A 2002 study by pharmaceutical industry consultants combined and averaged the
seven over-the-counter nicotine patch and gum studies found that just 7% were still not smoking at six-months - a 93% relapse rate. Although still a well-kept industry secret, the one-year OTC NRT rate is likely a bit less than 5%. Yes, a 95% failure rate and near 100% failure for second time users.
But NRT's extremely dismal quitting rate did not become visible until forced to stand on its own and be evaluated for OTC use. Until then, NRT was allowed to hide behind an intensity-rich clinic experience which nourished quitting motivations far longer than normal. Let's look back to a few of the more heralded early nicotine gum studies which had heavy education and/or support elements too. How did their results compare to Chantix's initial 22% one-year rate?
Is Chantix a Step Forward or Backward?
A 1976 nicotine gum study headed by Russell found that 23% were still not smoking at 1 year, the1980 Raw study produced a whopping 38% rate, in 1982 Jarvis found a 31%
rate, in 1983 Schneider 30%, in 1984 Hialmarson 29%, in 1986 Daughton 31%, in
1987 Kornitzer 32%, and in 1989 Tonnesen boasted a 44% one year quit smoking
rate.
The history of nicotine gum studies provided Pfizer confidence that intensively supportive Chantix (varenicline) studies should generate rather hefty and newsworthy one-year quitting rates. But it also knew that naked and alone, outside clinic doors, that nicotine gum proved at least three times less effective (using the low of 23% above to OTC NRT's 7% six-month rate).
Clearly, taking a Chantix pill twice daily is vastly easier than chewing piece after piece of nicotine gum, often after the onset of a crave episode. True, but aside from the discouraging cost of a 12-week supply ranging from $321 to $516 (U.S.), Chantix users face the possibility of a host of discouraging side effects that, without counseling, explanation or ongoing support may have them abandoning its use.
In the Oncken study, 79% titrated to 1mg of Chantix twice daily reported adverse events: 35% experienced nausea (42% when non-titrated), 37% insomnia, 19% abnormal dreams, 11% constipation and 10% flatulence.
When Chantix stands alone will its quitting rate be at least three times lower than the 22% average generated in Pfizer's three comparable studies? We don't yet know. Let's hope that the above nicotine gum rates are not comparable as it could mean that Chantix's real-world rate might actually be worse than gum's.
When OTC NRT's dismal six-month 7% quitting rate is contrasted to the boasts within pharmaceutical industry NRT marketing commercials, clearly both smokers and children were seriously deceived about the ease of quitting with replacement nicotine. Let's hope Pfizer turns a new page and places honesty and openness above corporate profits.
So what is the bottom line? What are your chances with Chantix? Clearly we do not yet know Chantix's odds when used as a stand-alone aid but if gum's performance is any indication they could be less than 1 in 20. If you can find a way to duplicate the intensity of Chantix's formal clinic conditions should you expect to experience 1 in 5 odds of success or 22% at one year? Not necessarily.
Chantix Study Eligibility Criteria
A second factor that could significantly diminish Chantix's real-world performance rate is associated with the substantial percentage of smokers who applied to participate in each study and were denied.
In Gonzales 1,843 smokers were screened and 458 were excluded (25%), in Oncken
980 were screened and 333 excluded (34%), and in Jorenby 1,413 were screened and 386 excluded (27%). But why?
A partial list of those excluded includes those suffering from cardiovascular disease, alcohol abuse, major depression, panic disorder, systolic blood pressure greater than 150 or diastolic pressure greater than 95, a history of cancer, a body mass index (calculated as weight in kilograms divided by height in meters squared) of less than 15 or higher than 38; weight less than 45kg, those with a "clinically significant medical disease," those over age 75 or younger than age 18, those smoking fewer than 10 cigarettes per day, and those known to have recently relapsed during NRT or Zyban quitting attempts.
Most within these groups reflect populations that have historically been the most challenging to assist in quitting, including youth who often smoke fewer than ten per day. Out in real-world conditions most will not be excluded from using Chantix, thus driving down Chantix real-world performance rates. If you are within one of excluded groups, your group was not studied and, as yet, we have no idea of your odds of success with Chantix.
Does Chantix Present Dependency Transfer Concerns?
Can Chantix users get hooked on it, or more accurately, permanently transfer their nicotine dependency to it? Varenicline is a partial agonist that produces up to 60% of the dopamine release generated by nicotine, while actually blocking nicotine molecules from occupying nicotinic acetylcholine receptors (the alpha 4, beta 2 subtype), thereby preventing nicotine from releasing dopamine. Is 60% of the dopamine production generated with nicotine sufficient to foster or maintain chemical dependency?
When nicotine gum was first introduced in '84 there was no mention of the possibility of getting hooked on the cure. Today GlaxoSmithKline consultants estimate that nearly 40% of nicotine gum "users" are dependent upon it, or as the consultants put it, "are persistent users."
The varenicline studies make no mention of possible dependency transfer concerns. A November 2003 study found that as many as 6.7% of nicotine
gum "quitters" were still chronic users at six months, three months beyond FDA use guidelines. An aside, if only 7% of OTC gum users quit for six months and 6.7% are then hooked on it, what percentage breaks free from nicotine by using it?
Is there a similar dependency transfer concern with varenicline but possibly to some lesser degree? If so, why wouldn't Pfizer want to fully disclose those concerns up front so that smokers can make fully informed decisions. If none, in light of nicotine gum, patch, lozenge and inhaler dependency issues, why wouldn't Pfizer want to reassure smokers?
A related question, arising from what may be the sloppiest portion of the Chantix studies, is how widespread was NRT use within the five studies and how much of Chantix's 22% one-year rate is attributable elevated dopamine output generated by NRT, once Chantix's elevated dopamine output ceased at the end of the 12-week treatment period?
We know that records were kept of "use of nicotine containing products." We also know, from the Oncken study, that once Chantix treatment ended after twelve weeks that "use of nicotine replacement therapy did not disqualify subjects from being considered abstinent." The obvious questions becomes, how many actively feeding nicotine addicts did Pfizer count among the cured and why was the NRT use data not published or released?
Were Chantix Studies Really Blind?
It's hard to imagine any smoker who has not heard the NRT marketing assertion that it "doubles" their chances of quitting. If Pfizer and Chantix follow the path taken in marketing NRT, regardless of how low Chantix's quitting rate eventually becomes, smokers will only be told its victory margin over the study's placebo group, not the actual percentage of users succeeding.
In fact, it's already happening. Pfizer's May 11, 2006 Chantix press release fails to disclose that nearly 4 out of 5 Chantix clinical study participants relapsed to smoking. Instead it boasts, "In two identically designed studies, patients receiving a 12-week course of Chantix therapy (1 mg twice daily) nearly quadrupled the likelihood of quitting than those taking placebo."
Let's examine these massive Chantix placebo victories. In Pfizer's Chantix (varenicline) clinical trials those screened and not excluded were randomly assigned into at least one of two study arms: the active group which would receive Chantix and the control group which would receive an identical looking placebo pill.
Each of the five Chantix studies represents that it was double blind. If true, neither participants nor reserachers should have been able to determine participant assignment to receive either a placebo pill or the active chemical varenicline. Surprisingly, the studies do not mention whether or not researchers actually conducted blinding assessments to test and validate the study's blind.
Blinding is extremely important to the study's core validity. If randomized participants can determine their group assignment then the study's final odds ratio victory (if any) may reflect frustrated and/or fulfilled expectations rather then the actual merits of the chemical tested. Blinding failures actually occurred in NRT studies and it is almost impossible to believe that they didn't happen in Chantix studies too.
Nicotine is a psychoactive chemical that generates a potent dopamine/adrenaline high. The pharmaceutical industry has known since at least a 1994 study that smokers can
quickly be trained to reliably distinguish various doses of nicotine from placebo. Smokers with any quitting history have experienced their own withdrawal syndrome and should be expected to recognize both its onset and intensity.
The Chantix studies found that varenicline significantly diminished a smoker's withdrawal syndrome. Cravings were consistently reduced when varenicline, 1.0 mg twice daily, was compared with placebo. All three comparable studies found that varenicline significantly reduced the urge to smoke compared to placebo.
Approximately 90% of participants in the Chantix studies had previously attempted quitting, failed and had some degree of memory of what it felt like to sense the onset of the anxieties and craves associated with their withdrawal syndrome.
A June 2004 study by Mooney reviewed 73 allegedly double-blind NRT studies and
declared that the limited number of studies assessing blindness were not generally blind as claimed in that "subjects accurately judged treatment assignment at a rate significantly above chance."
Mooney warned researchers that, "To determine the prevalence of failure, clinical trials of NRT should uniformly test the integrity of study blinds. Moreover, if blindness failure is observed, subsequent efforts should be made to determine if blindness failure is related to study outcome and, if so, to provide an estimate of treatment outcome adjusted for blindness bias. Without these methods and analyses, the validity of NRT clinical trial results could be questioned."
The blinding analysis in a 2005 study by Dar found that 3.3 times as many placebo group members correctly guessed that they had received placebo (54.5%) as guess nicotine (16.4%). Although the Dar study focused on smoking reduction, Tonnesen's 1993 nicotine inhaler quitting
study produced strikingly similar placebo group findings in that 3.8 times as many in the placebo group correctly guessed placebo (58%) as guessed nicotine (15%). Among inhaler users, Tonnesen found that 3.5 times more correctly guessed inhaler (46%) as guessed placebo (13%), while 42% on active and 27% on placebo did not know which treatment they had received.
Participants were recruited to the Chantix studies by being told that the study involved evaluation of a medication. Most seeking participation knew their withdrawal syndrome and clearly hoped the medication would diminish the rising tide of anxieties and craves they now associated with withdrawal.
Pfizer knew that NRT studies were plagued by blinding failures and that frustrated and rewarded expectations likely played a substantial role in both relapse and cessation. Pfizer also knew that Chantix placebo group members would not receive anything different than received by NRT placebo group members - an inert placebo. For them, the exact same set of elements was in play - the expectation of relief, the onset of withdrawal and frustrated expectations. It knew that the active group would sense a "significant" reduction in their withdrawal syndrome and thus likely be more inclined to remain and take advantage of the study's heavy and lengthy support structure.
Mooney warned researchers more than two years ago that a study's core validity could be questioned if full blinding assessments were not conducted. If the Chantix studies failed to stop and assess blinding, why? Did Pfizer know in advance that its varenicline studies would not be blind and that blinding bias would impact performance?
Quoting from the Dar 2005 study, "The present secondary analysis of the data elucidates these placebo effects by showing that reduction of smoking was strongly related to participants beliefs about their drug assignment. Smoking reduction was larger in those who believed that they had received nicotine compared with those who believed they had received placebo, regardless of actual drug assignment. Moreover, after adjustment to perceived drug assignment, the association between actual drug assignment and smoking reduction was no longer statistically significant."
Approximately 80% of the placebo group members in the varenicline studies relapsed to smoking within two weeks. A brief blinding assessment within two weeks could have quickly and easily revealed each participant's assignment belief. As far as we know, no blinding assessment was conducted.
It makes one wonder who at the FDA is actually reading studies like Mooney and demanding quality cessation study design prior to drug approval. In fact, the FDA's May 11, 2006 press release suggests that the studies were in fact blind. Interestingly, the FDA's press release fails to mention that 4 out of 5 Chantix users relapsed.
Will Chantix Marketing Attack Cold Turkey Quitting?
The U.S. Federal Trade Commission (FTC), charged with enforcing truth in advertising, has allowed the NRT industry to make outlandish marketing claims and distort NRT's true effectiveness (if any). One of the worst offenses is the assertion that NRT competed against and defeated cold turkey quitters within NRT studies. The representation is false, deceptive and it just didn't happen.
The only subjects applying for these studies were a population self-seeking medication, medication that would delay full and abrupt neuronal re-sensitization - the opposite of a quitter who abruptly ends use of chemicals intended to foster unnatural dopamine levels. There were no cold turkey quitters in any clinical NRT study. There were no cold turkey quitters in any clinical Chantix study, just a frustrated placebo group whose expectations that medication would diminish their withdrawal syndrome went totally unfulfilled.
A key industry tactic in convincing about half of U.S. smokers to buy NRT has been a two-decade campaign that bashes and trashes abrupt nicotine cessation quitting as almost impossible, while asserting that few cold turkey quitters succeed. Pfizer should be encouraged to start being honest with quitters when teaching them about their own natural cessation instincts as more than 40 million living U.S. success stories is obviously more than "few."
Pfizer needs to remember two important facts. First, as suggested by the these two tables, during 2006 80-90% of all successful long-term quitters are again expected to be cold turkey quitters (see American Cancer Society Cancer Facts & Figures 2003, Table 3; and Doran, May 2006).
Second, NRT quitters have never once prevailed over those quitting without it in any real-world quitting survey published to date (see the California JAMA survey, Quebec Quit & Win, Minnesota Insurance Survey, London, Western Maryland,
Ferguson's UK NHS Smoking Cessation Services survey, Australia Family Practice
Survey).
Maybe real-world Chantix evaluation will someday prove it superior at one year over those quitting without it but from what we already know we shouldn't hold our breath. Until then what we can probably count on is the pharmaceutical industry working study design to its economic advantage, spinning results to foster unrealistic expectations, hiding each study's actual relapse rates, ignoring obvious blinding failures, boasting about odds ratio victories flowing from them, and proclaiming victory over foes who were not present.
The next time you hear a pharmaceutical industry commercial suggest that quitting cold turkey is nearly impossible, take your own survey of all long-term ex-smokers who have been off of all sources of nicotine for at least one year. Once you complete your own survey we invited you to explore WhyQuit and the wonderful world of abrupt nicotine
cessation. There is still only one rule that if followed offers a 100% guarantee of success to all ... no nicotine just day at a time, Never Take Another Puff!
XXX
No Copyright - This Article is Public Domain
John R. Polito is solely responsible for the content of this article.
Any factual error will be immediately corrected upon receipt of credible authority
in support of the writer's contention. E-mail comments to
john@whyquit.com
Last updated Sept. 2, 2006 at 1742 EST
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