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Widespread Blinding Failures Put Validity of Nicotine Replacement Studies in Serious Question

Does NRT really double a smoker's chances? While real-world quitting surveys find no advantage, their simplicity has been attacked as unscientific by double-blind clinical trial NRT researchers. Now the clinical trial's integrity is in question as a new study reports blinding failures in 71% of NRT studies assessing blindness.

John R. Polito

Charleston, SC June 4, 2004 -- Imagine deeply believing the "double your chances" NRT marketing slogan and hearing about a study offering a 50/50 chance of receiving three months of free nicotine patches. Once in the study, imagine being able to sense that the flow of nicotine to your brain had ended, as you grew confident that the patch on your arm was empty when placed there. Would frustrated expectations have destroyed your resolve to continue?


A study in the June 2004 edition of Addictive Behaviors identified 73 double-blind placebo controlled NRT trials and found that only 17 had conducted blinding assessments. During assessments participants were asked to surmise whether they had been using a real nicotine delivery device or an empty placebo.

According to the authors, 12 of the 17 studies (71%) reported blinding failures as "subjects accurately judged treatment assignment at a rate significantly above chance."

Entitled "The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials," the study was led by Marc Mooney at the University of Minnesota's Tobacco Use Research Center. It found that almost two-thirds of placebo patch quitters were "confident" that they had not received the real nicotine patch.

The study lists a number of prior studies foreshadowing that attempts to use placebo controls in clinical NRT trials might not produce accurate assessments of NRT's true merits.

The authors assert that nicotine is a psychoactive drug providing cues making it easier to discriminate and cite a 1996 study in which smokers were "trained to reliably distinguish various doses of nicotine from placebo."

It cites a series of studies indicating that using nicotine will "reliably reduce withdrawal symptoms," 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."


Although current NRT marketing asserts that NRT "doubles a smoker's chances of quitting versus cold turkey," smokers might be surprised to learn that "real" cold turkey quitters were not invited to formal NRT studies to compete against NRT quitters.

Instead, the industry's "double your chances" assertion is based entirely upon clinical odds ratio victories generated by performance of quitters receiving months of free nicotine products, over those who wanted to receive months of free nicotine products but were instead randomly assigned to receive placebo products.

Does cutting back on nicotine intake prior to ending its use alter any quitter's underlying dream of freedom? Instead, could frustrated expectations and rewarded expectations have handed NRT an unearned victory? Could a billion dollar nicotine replacement industry have been built almost entirely upon known blinding failures?


Aside from "real-world" quitting surveys in California, London and Quebec in which those choosing to quit cold turkey performed just as well as those using a growing array of expensive NRT products, a March 2003 meta-analysis that combined and averaged all seven over-the-counter (OTC) patch and gum studies provides highly visible evidence that the merits of NRT may have been vastly overstated.

The study found that only 7% of OTC patch and gum users and 3% of placebo group quitters were still not smoking at six months. Although it again provided NRT with its much heralded "double your chances" victory margin, according to June 2000 U.S. Clinical Practice Guideline evidence tables, the 3% placebo rate is at least three times lower than historic six-month "on-your-own" quitting rates.

The authors of the March 2003 study speculate that the extremely low rate could be due to less dependent smokers having already successfully quit, with remaining smokers comprising a "hardened" heavily dependent population. But the hardening argument is in obvious conflict with real-world findings.

The Journal of the American Medical Association published the results of the California smoker survey on September 11, 2002. It contains graphs indicating absolutely no long-term NRT advantage for light smokers (less than 15 cigarettes per day) or heavy smokers (more than 15 per day).

The California survey review boldly concludes that, "NRT appears no longer effective in increasing long-term successful cessation in California smokers."


How long were the pharmaceutical industry and researchers aware of serious blinding concerns? According to the "Blind Spot" study they began toying with trying to fool placebo group quitters by putting small amounts of nicotine (.5 or 1 mg.) into pieces of placebo gum as early as 1982.

The study indicates that the practice was also used in a number of nicotine patch studies where patches worn by placebo group members released up to 3 mg. of nicotine, the nicotine equivalent of smoking three cigarettes a day. No formal clinical study can be found testing the effects upon placebo group cessation rates of using nicotine as a masking agent.

Although the new study asserts that a dozen failures are not sufficient in number, depth of analysis or uniformity to allow definitive conclusions about their "consequences," it warns researches that "the validity of NRT clinical trial results could be questioned" if future studies fail to make proper blinding assessments.

In that the pharmaceutical industry funded a large percentage of NRT studies, what the "Blind Spot" study leaves unaddressed is why the 71% failure rate would be any lower in the 56 studies that chose not to conduct blinding assessments or, at least, to not publish their results.

Fact References

1. Blind Spot Study: Mooney M, et al, The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials. Addict Behav. 2004 June;29(4):673-84 (link to full-text copy in PDF format)

2. Fact: GlaxoSmithKline "double your chances over cold turkey" assertion: GlaxoSmithKline May 3, 2004 Press Release

3. Fact: Four real-world quitting surveys finding no advantage for NRT: (1) Pierce, JP, et al., Impact of Over-the-Counter Sales on Effectiveness of Pharmaceutical Aids for Smoking Cessation. Journal of the American Medical Association, September 11, 2002;288:1260-1264 (link to full text in PDF format); (2) Boyle, RG, et al, Does insurance coverage for drug therapy affect smoking cessation? Health Affairs 2002 Nov-Dec;21:162-8 (link is to study abstract);(3) SmokeFree London, Tobacco in London - Facts and Issues, June 2003, Figure 14, PDF page 17 (link is to report in PDF format); (4)Gomez-Zamudio, M, et al, Role of pharmacological aids and social supports in smoking cessation associated with Quebec's 2000 Quit and Win campaign, Preventive Medicine 2004 May;38(5):662-7 (link to study abstract).

4. Fact: 7% OTC NRT six-month quit smoking rate, 3% placebo rate: Hughes, JR, Shiffman, S, et al., A meta-analysis of the efficacy of over-the-counter nicotine replacement. Tobacco Control, March 2003;12:21-27 (link to full text copy)

5. Fact: 3% OTC NRT meta-analysis placebo rate at least three times lower than historic rates: USDHHS Clinical Practice Guideline, June 2000 (link to 196 page PDF document - . Also see Polito, JR, Does the Over-the-counter Nicotine Patch Really Double Your Chances of Quitting?, WhyQuit, April 2002 (link to online article averaging Guideline evidence tables)

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Written 05/19/04 and page reformatted 08/11/18 by John R. Polito