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Electronic Letters to:

Philip Tønnesen, Kim Mikkelsen, and Linda Bremann
Nurse-Conducted Smoking Cessation in Patients With COPD Using Nicotine Sublingual Tablets and Behavioral Support
Chest 2006; 130: 334-342 [Abstract] [Full text] [PDF]
*eLetters: Submit a response to this article

Electronic letters published:

[Read eLetter] It's unlikely this NRT study was blind
John R. Polito   (15 August 2006)

It's unlikely this NRT study was blind 15 August 2006
John R. Polito,
Nicotine Cessation Educator

Send letter to journal:
Re: It's unlikely this NRT study was blind

johnpolito{at} John R. Polito

Nicotine is a psychoactive chemical producing a powerful dopamine/adrenaline high and it has been shown that smokers can be trained to reliably distinguish various doses of nicotine from placebo (Perkins 94, Perkins 96, Perkins 97). NRT has been shown to reliably reduce withdrawal and cravings (Hughes 84) and smokers with a quitting history should be expected to recognize their withdrawal syndrome (Hughes 87).

Medical journal editors and peer review continue to ignore that while double-blind randomized clinical trials of NRT continue to enjoy nearly two-fold six-month odds ratio victories over placebo, NRT has yet to produce a single real-world performance survey victory after more than two decades of widespread use (see survey references in 13th World Conference on Tobacco and Health Drenched in Nicotine at ).

I submit that it is unlikely that this study was blind, that nicotine expectations did impact efficacy, and that in real-world nursing practice those using sublingual nicotine tables will never ever prevail over nurses assisting those motivated to quit smoking without NRT.

Dr. Tonnesen openly acknowledges via email that in this study subjects were not asked about blinding, and asserts that "in most smoking cessation studies this question is not routinely asked." "It's not my impression that the patients could guess if they got active nicotine or placebo," contends Dr. Tonnesen. "We asked that question in a former study testing the nicotine inhaler (n=232) and found that on active 46% on active and 58% on placebo identified the treatment correctly, 13% on active and 15% on placebo guessed wrong, and 42% on active and 27% on placebo did not know which treatment they had received. I assume we would have found the same figures here. So, participants are not very good in guessing with no significant difference between groups. (JAMA 1993;269:1268-1271; P. Tønnesen,, Jesper Nørregaard, Kim Mikkelsen et al. A double-blind trial of a nicotine inhaler for smoking cessation)."

It has been more than two years since Mooney et al published a review of 73 allegedly double-blind NRT studies and declared that studies assessing blindness were not generally blind as claimed in that "subjects accurately judged treatment assignment at a rate significantly above chance" (see, 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).

An overly gracious Mooney's warned that:

"The NRT literature has been largely silent on the topic of blindness failure, even since the publication by Hughes and Krahn (1985) calling for researchers to address the problem. Based on the relatively few identified studies, definitive conclusions about the frequency and consequences of blindness failure are not justified. 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."

Why would any medical journal publish a new NRT study asserting to the world that it was "double-blind" when: (1) there was no attempt to assess blindness; (2) the journal knew or should have known that serious NRT blinding concerns have long existed; and (3) Mooney warned in advance that failure to assess blinding would justify questioning the study's core integrity?

Below is a comparison of Tonnesen's 1993 blinding data to that from Dar's 2005 study (see, Dar, R et al., Assigned Versus Perceived Placebo Effects in Nicotine Replacement Therapy for Smoking Reduction in Swiss Smokers, Journal of Consulting and Clinical Psychology, 2005, Vol. 73, No. 2, 350, 353):

Received Nicotine -- Received Placebo

Guessed Nicotine:

46% T 13% T

39% D 16% D

Guessed Placebo:

15% T 58% T

26% D 55% D

Didn't Know:

42% T 27% T

35% D 29% D

The Dar study did not involve smoking cessation but smokers challenged to reduce daily smoking by use of NRT. The 2005 Dar paper was a secondary analysis of a 2002 paper by Etter which found that nicotine was slightly more effective than placebo in reducing cigarette consumption in smokers not yet ready to quit("at 6 months, cigarette consumption decreased by a median of 10 cigarettes per day in the nicotine group, 7.5 in the placebo group"). To quote from the study's discussion:

"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."

Journal editors must begin demanding that all submitted NRT studies include thorough blinding evaluations. We should encourage researchers to conduct at least one blinding assessment early in the study (within two weeks) to preclude as much performance bias as possible, and not wait an entire year thus introducing serious recollection bias, with possible intervening quit attempts.

It's hard to believe that the pharmaceutical industry is being allowed to continue to falsely tell smokers that NRT doubles their chances over quitting cold turkey when no quitter motivated and wanting to abruptly end all nicotine use has ever been invited to compete against those seeking free nicotine in any NRT study. It's time for researchers and journals to stop pretending that NRT efficacy has anything whatsoever in common with real-world effectiveness.

Copyright © 2008 by the American College of Chest Physicians.