It may be that double-blinded, placebo-controlled trials of nicotine replacement therapy (NRT) products for smoking cessation are not as blinded as we previously thought. And that the blindness failure may bring into question the validity of NRT clinical trial results as well as the wisdom of heavy reliance on pharmacotherapy in the national smoking cessation action plan that was recently developed and played a large role in the proposed DOJ tobacco lawsuit remedies.
Two recent studies have examined the possibility that clinical trials of NRT may not be truly blinded and that the blindness failure may actually result in a bias toward finding a significant effect of NRT on smoking cessation when a true effect may not exist.
First, a 2004 study in Addictive Behaviors found that relatively few (17 of 73 studied) NRT trials have even made an attempt to assess the blinding success of their studies. And of the few which did, more than half found a blindness failure. Only 3 of these studies attempted to determine whether blindness bias was present (see: Mooney M, White T, Hatsukami D. The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials. Addictive Behaviors 2004; 29:673Â684).
According to the study authors: "The NRT literature has been largely silent on the topic of blindness failure ... 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."
Note that since the methods and analyses being suggested by the authors have generally not been used in the existing literature, the inference is that the authors are questioning the validity of current NRT clinical trial results.
Second, a 2005 study in the Journal of Consulting and Clinical Psychology actually re-analyzed the results of an earlier study of the effectiveness of NRT therapy in reducing cigarette consumption. The authors found that blindness failure occurred. Of those subjects who received nicotine, 38.5% guessed that they were receiving nicotine, but 26.3% guessed that they were actually receiving placebo. Of the subjects who received placebo, 16.4% actually thought that they had received nicotine (see: Dar R, Stronguin F, Etter J-F. Assigned versus perceived placebo effects in nicotine replacement therapy for smoking reduction in Swiss smokers. Journal of Consulting and Clinical Psychology 2005; 73:350-353).
More importantly, the authors found that perceived drug group assignment was strongly related to smoking reduction in the study. In fact, the relationship between perceiving that a subject was getting nicotine and successful smoking reduction was so strong that this effect completely explained the original study's finding of a significant effect of NRT therapy in reducing cigarette consumption.
The authors concluded 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."
The Rest of the Story
Essentially, what these studies are suggesting is that because nicotine is a psychoactive drug, it is quite possible that smokers may be able to distinguish between nicotine and placebo quite quickly, and this ability to distinguish the two is far greater than by chance. This phenomenon is called blindness failure.
Next, these studies suggest that the blindness failure may be introducing a bias into the study. It is possible that smokers' judgments about whether they have received nicotine or placebo may be related to the study outcomes: namely, smoking cessation or reduction in cigarette consumption. The more recent study found this to be the case, and the effect was large enough to explain the entire observed positive effect of NRT therapy in that study. This effect is called blindness bias.
Next, the studies suggest that because of the likely presence of blindness bias in this type of research, analytic methods must be used to adjust for this blindness bias. This is called bias adjustment. In the case of the Dar et al. study, this adjustment actually negated the observed effects of NRT in the original study.
Finally, these studies imply that because the current literature on the effect of NRT therapy does not adequately examine blindness failure, determine whether blindness bias occurred, and conduct bias adjustment in reporting the results, the validity of the existing NRT clinical trial results is subject to question.
I think it is important to point out that if it is true that blindness bias explains some of the observed effect of NRT products, this doesn't mean that the use of the products does not improve smoking cessation. It just implies that the reason for the effectiveness of the therapy may not be the nicotine itself, but rather, the belief that the subject is receiving something that will help them. In other words, it would imply that the observed effect is essentially a placebo effect.
For example, this would mean that giving someone a placebo but telling them it is nicotine would be as effective as giving someone nicotine. And for the proportion of subjects who receive nicotine but think it is placebo (26% in the above study), they would be expected to fare worse than subjects who are given placebo but told it was nicotine (I'm not suggesting lying to patients as an intervention - I'm just using this example to illustrate and explain this point).
I think the rest of the story casts some doubt on the heavy reliance upon pharmacotherapy in the proposed national smoking cessation action plan. I think it's entirely possible that the putative effects of NRT therapy, if applied on a national level, have been considerably exaggerated and that the ability of the proposed smoking cessation plan to cause five million Americans to quit within one year, as claimed, may be overstated.
I do think it is important for readers to know that the chair of the committee that prepared the smoking cessation action plan has a rather large conflict of interest in making pharmacotherapy the cornerstone of the plan because he "has served as a consultant, given lectures sponsored by, or has conducted research sponsored by GlaxoSmithKline, Pharmacia, Pfizer, and Sanofi-Synthelabo" and in 1998, he was named to a university chairmanship made possible by an unrestricted gift to his university from GlaxoWellcome. He has also received funding from the Robert Wood Johnson Foundation."
With that said, I should disclose my own conflict of interest in writing this post: I have received funding in the past from the Robert Wood Johnson Foundation and own some Pfizer stock. Of course, it should be noted that there probably is not a true conflict of interest here as it would, if anything, bias me towards overstating the potential role of pharmaceutical products, not challenge the existing belief that these products should form the cornerstone for a national smoking cessation action plan.
My own feeling, based on my years of experience in tobacco control, is that pharmacotherapy in general is over-emphasized and that most smokers who quit successfully long-term are those who quit cold turkey without any particular pharmaceutical aids. It is also important to note that smokers who relapse after having tried NRT therapy tend to do dismally in future cessation attempts with NRT. All in all, I think that the benefits and importance of drugs in the smoking cessation process have been over-emphasized, and I urge readers to read extensively on the web site of John Polito, who I find has the most insightful understanding of the smoking cessation process and the potential role of NRT products as anyone I know in the tobacco control field.