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Nicotine Patch Inventor Fudges Patch Study Findings

July 12, 2009   John R. Polito

This article reviews how clinical trial smoking cessation researchers snagged victory from the jaws of defeat and the potential cost of doing so.

Reading the official study summary (abstract) of a just published clinical trial on the value of using the nicotine patch for two weeks prior to quitting smoking, and an additional 10 weeks thereafter, the study's lead author, Duke Medical University Professor Jed E. Rose, PhD, leaves readers with the clear impression that the results were a resounding success, that pre-quitting patch use "approximately doubled" quitting rates. But a reading of the full nine page study makes Rose's victory assertion sadly laughable. If official U.S. quitting evidence standards are applied, there was no victory.

Published online by Nicotine & Tobacco Research on June 30, 2009 and funded by U.S. tobacco giant Philip Morris, USA, the study's title - "Precessation treatment with nicotine patch significantly increase abstinence rates relative to conventional treatment" - is unambiguous in declaring victory.

Interestingly, the study's participants were taught how to quit smoking by use of Philip Morris USA's "Quit Assist" quit smoking guide. The only quitting method openly attacked in the 27 page guide is cold turkey, the method responsible for generating up to 90% of long-term successful ex-smokers.

"I tried to quit cold turkey, but I would explode for no reason over the stupidest little thing, like 'Where's the milk? I guess the nicotine in the gum relaxed me," a featured quitter is quoted as saying.

Co-inventor of the 1988 patented nicotine patch, although the study's financial disclosure indicates that Dr. Rose did not have a financial stake in this study when it was published, it's unclear whether one existed at the time the study was conducted and written. Readers are told, "Dr. Rose has received royalties from sales of certain nicotine patches and is named as inventor on nicotine skin patents that expired in 2008."

The study randomly assigned 400 smokers to one of four study conditions. Two groups were assigned to 2 weeks of nicotine patch use while continuing to smoke, while the other two were assigned to 2 weeks of supposedly user "blind" placebo patch use (patches containing no nicotine) while also continuing to smoke.

All four groups were given active nicotine patches at the two-week mark and instructed to quit smoking. The quitting portion of the study involved ten weeks of identical and open (no blinding) stepped-down nicotine patch use in all four groups (6 weeks of 21mg patches, 2 weeks of 14mg patches, and 2 weeks of 7 mg patches).

Two different definitions of "quit"

Clinical trials commonly employ two different standards for determining and declaring successful quitters: 7-day point prevalence and continuous cessation. Seven-day point prevalence normally defines successful quitting as having not smoked any nicotine within the past seven days, as assessed at periodic study points during the study, usually when quitting product use ends and at long term follow-up (six months and/or one year).

Successful continuous cessation is defined as a study quitter having had zero smoking lapses, not even a puff, since the study's original quit smoking date.

Use of the 7-day point prevalence standard presents a clearer and fairer representation of which study participants have actually quit at any given study assessment point. Continuous cessation fails to count participants who needed a day or two of false starts before successfully adapting to either ending all nicotine use or to successful transfer of their chemical dependency to a new means of dopamine pathway stimulation (replacement nicotine or varenicline).

This study's 2 week pre-quitting period is a tad unusual in that half of participants continued smoking while wearing nicotine patches, while the other half smoked while being led to believe that they too were wearing nicotine patches. The active patch group, wearing 24 hour patches, was effectively given a 2 week head start in learning to adjust to incorporating the patch's slower yet continuous delivery of 21 milligrams of nicotine, daily, into their blood streams, the nicotine equivalent of smoking roughly one pack of cigarettes a day.

On quitting day, the placebo group was compelled to instantly transfer from smoked nicotine to patch nicotine, with zero lapses if to be counted as having successfully quit using a continuous cessation standard.

But successful nicotine delivery device transfer isn't as easy as industry marketing suggests. Years of extremely quick and highly precise delivery conditioned smokers to expect to rapidly satisfy insula driven urges, craves and anxieties. Eight to ten seconds after their first puff, nicotine would arrive and stimulate brain dopamine pathways, providing almost instant feedback as to whether the smoker needed to inhale more nicotine, had smoked enough, or had smoked too much.

Although providing a lesser degree of control, oral forms of nicotine delivery (the gum, lozenge or smokeless tobacco) take significantly longer to penetrate mouth tissues, making feedback much slower. This increases the risk of those new to oral nicotine getting too much by chewing or sucking too long or too hard. It can cause nicotine overdose and a nausea sensation, which in new users can breed frustration, false starts and relapse to smoking.

Transdermal nicotine via the patch obviously takes the longest to enter the bloodstream. As with the quit smoking pill Chantix (varenicline), the degree of dopamine pathway stimulation is predetermined by product strength and the only control over stimulation is in using or ending use of the product.

Normally challenged by an abrupt end to the arrival of all nicotine, placebo group participants in most clinical trials normally experience a significantly more intense experience, at least until peak withdrawal is achieved within 72 hours. But within 3 days their blood is nicotine-free and their brain is heavily engaged in down-regulating nicotinic receptor counts, as it attempts to restore receptor sensitivities to pre-nicotine levels.

Sensing a brief emotional train wreck, dopamine deprived placebo quitters should be expected to experience more false starts and initial lapses, with more second effort attempts being seen (catching up). Likewise, researchers here knew that allowing the active patch pre-quitting groups a 2 week head start in learning to get comfortable adding 21mg of transdermal nicotine to their daily diet disadvantaged the placebo group. Frankly, the quitting definition featured in this study - continuous cessation - exploits the active group's two-week adjustment advantage.

U.S. government's definition of having "quit"

It's why official U.S. cessation policy, as reflected in the 2008 U.S. Clinical Practice Guideline abandons continuous cessation as the primary evidence standard and instead focuses on 7-day point prevalence stop smoking rates in compiling, comparing and presenting quitting method evidence.

The 2008 U.S. Guideline update states that, "As in the 1996 and 2000 Guidelines, a point prevalence outcome measure (7-day point prevalence, when available), rather than continuous abstinence, was used as the chief outcome variable. Point prevalence was preferred for several reasons. First, this was the modal reporting method among the analyzable studies. Second, continuous abstinence data may underestimate the percentage of individuals who are abstinent at particular followup timepoints, although some data suggest that these rates are similar. Finally, most relapse begins early in a quit attempt and persists. A point prevalence measure taken at 6 months certainly would capture the great majority of those relapse events. Therefore, whenever possible, 7-day point prevalence abstinence data were used. If point prevalence data were not available, the preferred alternative was continuous abstinence data."

The full-text of the Rose-Philip Morris study reports both the active group's continuous abstinence victory at the end of the ten-week quitting period, and the ever so slight placebo group advantage in 7-day point prevalence rates. But the authors and journal editors consciously permitted the study's title and summary to claim total victory and in doing so went against established government standards regarding ranking and presentation of study evidence.

Knowing that the active group was given two weeks longer to adjust to incorporating patched nicotine into their dependency diet, it is deeply disturbing that all involved with this study failed to select a title that alerted readers to the fact that two weeks of nicotine patch use prior to quitting smoking is likely a waste of both time and money, or at a minimum that the study's evidence was conflicting.

This is certainly no innocent researcher mistake as Dr. Rose is credited with 41 published papers, many of which are superb inquiries into the depths of dependency. Clearly this wasn't Rose's finest hour as this paper appears to be little more than an attempt to increase nicotine patch sales.

The discussion section of the study asserts that the reason for choosing continuous over point prevalence was that, "Continuous abstinence may be a better predictor of long term success" that "failing to adhere to a quit date may indicate a greater vulnerability to relapse over the long term."

May? May? Although no footnote was provided to any study evidence supporting this "may" theory, just two paragraphs earlier the authors explained why selecting continuous over point prevalence would have seriously undercounted placebo group quitting. It states:

"While continuous abstinence rates at 10 weeks and at 6 months were enhanced by precessation nicotine patch treatment, point abstinence differed only at 1 week postquit; by 10 weeks, there was no significant difference (a similar result was recently reported by Bullen et al, 2008). This was due to the control group 'catching up' with the precessation nicotine group rather than the precessation group 'falling behind' ..."

Ten week continuous and 7-day point prevalence findings

According to the study's full-text, "Continuous abstinence at 10 weeks was significantly higher in the precessation nicotine patch conditions than in the placebo conditions." "Continuous abstinence rates at 10 weeks averaged 22% in the precessation nicotine patch groups versus 11% in the placebo patch groups."

When continuous cessation rate quitters where analyzed it was noted that at the end of patch use, treatment "mainly benefited smokers with lower levels of dependence, based upon Fagerstrom Test for Nicotine Dependency score [FNTD]." "In contrast, for smokers with higher FNTD scores, abstinence rates did not differ significantly between patch conditions."

Contrary to the study's continuous cessation findings and contrary to the study patch victory title assertion, the full-text discloses a one percentage point placebo group victory when considering the actual percentage of study participants who had not smoked within the previous 7 days. Quoting from page 6:

"Results showed that precessation nicotine treatment increased 1-week point abstinence (36% vs. 23%) but did not significantly affect 10-week point abstinence (30% vs. 31%)."

Six month continuous and 7-day point prevalence findings

While the study discloses this ever so slight placebo point prevalence victory at 10 weeks, in reviewing six-month follow-up findings, while Figure 3 does show 6 month placebo group point prevalence performance, it does not show point prevalence performance for the entire pre-quitting nicotine patch group, making comparison between groups impossible. Instead, the study states, "Point (7-day) abstinence at 6 months was also analyzed and did not show a significant difference between precessation patch conditions."

One might think that given that Philip Morris is funding this research that all involved in the paper's publication would have demanded full transparency, including informing readers of the actual figures that the authors determined were "not significant."

There is one additional reason why researchers having strong pharmaceutical industry financial ties (which the express language of this study's financial disclosure suggests is probably NOT the case here) might intentionally omit negative six-month point prevalence rates from their study. By doing so they force future researchers attempting to locate, combine and average similar quitting method studies (the preparation of a "meta-analysis") to rely upon much higher yet less meaningful continuous abstinence rates. The end result is meta-analysis evidence tables, similar to those contained in the U.S. Guideline, that compare placebo performance to pharmacolgy but have little or no foundation in actual quitting realities or science.

A 2008 paper published in Addiction cites this paper as having been presented at the annual meeting of the Society for Research on Nicotine and Tobacco in Austin, Texas in 2007.

Nearly all news accounts of this study are like a July 9, L.A. Times story that appears to have relied upon a Duke University press release. As with most cessation study news accounts, there is no indication here that the Times reporter actually read the full-text of the study, a factor those authoring study press releases seem to be increasingly relying upon (see Pfizer's initial Chantix press releases).

The Times article makes no reference to point prevalence rates, nor does a July 9 Science Daily article.

Pre-quitting portion of the study was not blind

The paper asserts that "patch assignment was conducted double blind." While it may have been "conducted" double blind, participant awareness of assignment to the placebo patch was anything but blind. According to the study's own assessment of blinding integrity, "of 165 subjects receiving placebo patches, 27 believed they had received active patches, 112 believed they had not, and 26 were unsure." Yes, four times as many placebo group members correctly identified their assignment as could not.

Although this paper provides a rare glimpse into blinding inside nicotine patch studies, a June 2004 study entitled "The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials" alerted researchers to serious blinding concerns. It found widespread blinding failures, noted that smokers could be "trained to reliably distinguish various doses of nicotine from placebo," that "most have quit several times before entering clinical trials, and many are only too familiar with the syndrome" and that "the use of a double-blind design provides no guarantee that ... participants remain blind to their treatment assignment."

As I asserted in November in Canada's leading medical journal, "pharmacotherapies for smoking cessation [are] grounded in a false premise, namely that researchers were somehow able to hide the onset of nicotine withdrawal symptoms from control group members, whose previous quitting history had taught them exactly how withdrawal felt (a rising tide of anxieties, anger, dysphoria, concentration difficulty and sleep fragmentation within 24 hours of quitting), and that researchers found a way to mask the reduction of withdrawal syndrome for intervention group members."

The scientific foundation of the validity of nearly all pharmacology quitting trials is based upon the sham and farce that experienced nicotine addicts won't recognize the agony of withdrawal. Although the gold standard in most clinical research areas, drug addiction is probably the only pharmacology study area where use of placebo controls serves as a license to steal.

Researchers violate study participant's human rights

Principle 32 of the World Medical Association's (WMA) Declaration of Helsinki commands that the "benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention" and that placebos should not be used unless "compelling and scientifically sound methodological reasons" are demonstrated.

More than 100 placebo controlled cessation trials are currently underway here in the U.S. Why? How many thousands of U.S. study participants ran out of time and were killed by their addiction to smoking nicotine because researchers violated their human rights and provided them the least effective intervention known, placebo? Placebo use will continue until our universities refuse to approve such studies and medical journals refuse to publish results.

President Obama has promised that under his administration science will be driven by facts not profits. Clearly, with more than 400,000 annual smoking related deaths, no research area is in greater need of getting the fox out of the hen house than nicotine dependency recovery, where love of money has destroyed truth.

To his credit, Dr. Rose shared data within this study that clearly indicates that blinding had failed. What he failed to do was alert readers, researchers and the media that the scientific foundation of this paper was in serious question, as nearly 70% of the placebo group correctly identified their assignment. Although less than seen in traditional clinical trials, where the placebo group isn't later re-assigned to receive pharmacology, to some degree this trial measured frustration and fulfillment of participant expectations, not treatment efficacy.

Clinical trial recruiting advertisements, such as currently used at Duke Medical University, can't help but create expectations in smokers by advising them of the medication involved in the study, how long free medications will be received and how much participants can expect to be paid. The informed consent process also creates expectations and sometimes reveals risk information that aids first-time users of the quitting product in determining active group assignment.

If smokers want to learn the truth about what works and what doesn't they'd be well advised to ignore findings from any study using placebo controls. Instead, they should examine real-world findings, nearly all of which show that those using quitting pharmacology products fail to prevail against cold turkey quitters.

The most recent such results were reported last month when GlaxoSmithKline, the maker of Nicorette gum, was forced to report that its own quitting survey found that cold turkey quitters trounced pharmacology quitters. Other findings include: results from the UK's national stop smoking program (Statistics on NHS Stop Smoking Services in England, April to December 2007 - see Table 6); a 2006 unpublished U.S. National Cancer Institute survey of 8,200 quitters, as reported in the Wall Street Journal, Page A1, February 8, 2007; a study of "Smoking status of Australian general practice patients and their attempts to quit"; English smoking treatment services: one-year outcomes published in Addiction (See Table 6); a 2005 study by Alberg AJ entitled Nicotine replacement therapy use among a cohort of smokers; Tobacco In London, Facts and Issues (see Figure 14); a 2002 study by Boyle RG entitled Does insurance coverage for drug therapy affect smoking cessation?; and a 2002 Journal of the American Medical Association paper by Pierce JP entitled Impact of Over-the-Counter Sales on Effectiveness of Pharmaceutical Aids for Smoking Cessation.

One-third of screened participants excluded

Dr. Rose's conclusion that smoking nicotine while also wearing the patch was "well tolerated" is anything but conclusive. As seen in Pfizer's five primary Chantix studies, Rose only studied "healthy" smokers. One-third of the population that applied to participate in this study (206 of 608 screened applicants) were rejected.

The study excluded nearly all groups that would be expected to face elevated health risks posed by potential increases in central nervous system stimulation, potential drug interactions, use of a fetal teratogen, and a known atherosclerosis and tumor promoter.

Excluded were all using medications having psychoactive properties, smokers older than 65 and younger than 21, smokers of fewer than 15 cigarettes per day, smokers of low nicotine cigarettes, smokers with hypertension, hypotension, coronary artery disease, cardiac rhythm disorder, history of skin allergy, any major medical condition, current psychiatric disease, pregnancy or nursing mothers, current alcohol or drug abuse, current smokeless tobacco use, or use of any other smoking cessation treatment.

On the heals of hundreds of extremely serious adverse events seen among Chantix users, including 98 deaths by suicide, university health reporters, journal editors and media health reporters must be held accountable for reliance upon rose colored press releases and for failing to read, analyze and report on the full-text of studies.

We know that in some cases nicotine patch use alone by "at risk" populations could be a matter of life or death. A June 2009 Kentucky study reports that ICU nicotine patch use by coronary artery bypass graft surgery patients resulted in a 6-fold increase in risk of death (OR 6.06; 95% CI 1.65 to 22.21). What we don't yet know is the nicotine patch use mortality rate when smokers across the nation are bombarded with pharmaceutical industry advertising proclaiming that patch use while smoking is safe. But headline grabbing papers like this it may already be happening.

How many smokers will experience serious adverse events because Duke Medical University's press release failed to make alert them to the fact that only healthy smokers were included in the study? How many will be harmed because the editors of Nicotine & Tobacco Research failed to require that the study's summary advise readers that 30% of screened applicants were considered at-risk and rejected?

This Philip Morris funded study is a classic example of dropping the research ball. It's as if this 2007 paper has been revived and published in an attempt to sell additional nicotine patches. It's as if it is being used as an advertisement to tell smokers that if you previously tried quitting with the nicotine patch and failed that you probably did it wrong, that you need to buy some more and give it another try, but this time two weeks longer, while continuing to smoke.

Smoking while quitting? It's music to the nicotine addict's ears!

But if so, there's a glaring problem with this study's marketing message. Only two studies have analyzed success rates among second-time nicotine patch users and as both Philip Morris USA and Dr. Rose are surely aware, the results were devastating. One study found a 100% six-month smoking relapse rate (Tonnesen 1993) and in the other 98.4% failed (Gourlay 1995 - see Table III).

I, John R. Polito, am solely responsible for the content of this article.
Any errors brought to my attention will be immediately corrected.

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Written 07/12/09.
Reformatted 08/16/2018 by John R. Polito