Blinding failures in 12 of 17 NRT studies

John (Gold)
John (Gold)

May 20th, 2004, 4:32 am #1

Have Profits Blinded the NRT Industry?
Does nicotine replacement therapy (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.
Charleston, SC (PRWEB) May 20, 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?

NRT'S BLIND SPOT

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 may 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."

BLIND TO MISSING TURKEYS

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 battle 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.

Could frustrated expectations and rewarded expectations have handed NRT an unearned "double your chances" victory? Could a billion dollar nicotine replacement industry have been built almost entirely upon known blinding failures?

CLUES THE BLIND COULD FOLLOW

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 boldy concludes that, "NRT appears no longer effective in increasing long-term successful cessation in California smokers."

GRASPING FOR BLINDNESS

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.

# # #

About the author: John R. Polito is founder and a director at WhyQuit, the Internet's oldest free quitting forum devoted to the science and psychology of nicotine cessation, and presents free bimonthly recovery programs at the College of Charleston.

Contact Info:

John R. Polito
Nicotine Cessation Educator
1325 Pherigo Street, Mt. Pleasant, SC 29464
(843) 849-9721
[url=mailto:johnpolito@comcast.net]johnpolito@comcast.net[/url]

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 is to study astract - http://www.ncbi.nlm.nih.gov/entrez/quer ... s=15135549

2. Fact: Recent pharmaceutical industry "double your chances over cold turkey" assertions: GlaxoSmithKline May 3, 2004 Press Release - http://www.quit.com/news.aspx?id=209; Pfizer January 16, 2004 Press Release - http://www.pfizer.ca/english/newsroom/p ... easeID=113

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 is to free full text in PDF format - http://www.fchn.org/fmh/wmchh/articles/ ... s_aids.pdf ); (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 - http://content.healthaffairs.org/cgi/co ... t/21/6/162 );(3) SmokeFree London, Tobacco in London - Facts and Issues, June 2003, Figure 14, PDF page 17 (link is to report in PDF format - http://www.lho.org.uk/HIL/Lifestyle_and ... Issues.pdf ); (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 - (link is to study abstract - http://www.ncbi.nlm.nih.gov/entrez/quer ... s=15066370 )

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 is to free full text - http://tc.bmjjournals.com/cgi/content/f ... o5/Oz4yutI

5. Fact: 3% OTC NRT meta-analysis placebo rate at least three times lower than historic rates: USDHHS Clinical Practice Guideline, June 2000. Link is to a 196 page PDF document - http://www.surgeongeneral.gov/tobacco/t ... co_use.pdf . Also see Polito, JR, Does the Over-the-counter Nicotine Patch Really Double Your Chances of Quitting?, WhyQuit, April 2002. Link to online article - http://whyquit.com/whyquit/A_OTCPatch.html

The above study review will go out as a press release at 5 a.m. EST, Thursday, May 20. As always I invite our English and journalism majors, and all interested in this topic, to send your editing recommendations, comments and/or suggestions to [url=mailto:john@whyquit.com]john@whyquit.com[/url] . As always, sincere thanks! John
Quote
Share

Joel
Joel

November 27th, 2005, 9:25 pm #2

It seems that John's work is starting to get other professionals in the field of tobacco control to question the wisdom or such a heavy reliance on pharmacotherapies for smoking cessation:

Wednesday, November 23, 2005 Nicotine Replacement Therapy Success May Largely Be Due to Placebo Effect; Research Questions Pharmacotherapy as Basis for National Cessation Plan 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; 29:673–684).

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.

About the author:
Name:Michael Siegel Location:Boston, Massachusetts I am a physician who specialized in preventive medicine and public health. I am now a professor in the Social and Behavioral Sciences Department, Boston University School of Public Health. I have 20 years of experience in tobacco control, primarily as a researcher. My areas of research interest include the health effects of secondhand smoke, policy aspects of regulating smoking in public places, effects of cigarette marketing on youth smoking behavior, and the evaluation of tobacco control program and policy interventions.

http://tobaccoanalysis.blogspot.com/200 ... ccess.html
Quote
Share

John (Gold)
John (Gold)

November 29th, 2005, 11:18 am #3

Thanks Joel. This is a link to the full text of Mooney's Blind Spot study:
Some may wonder why we care. Let me briefly share just one of many concerns. If half of adult smokers are failing to quit before the ultimate bad news arrives, how many serious quitting attempts did they have in them before paying the ultimate price?
There is a massive difference in repeat cold turkey quitting attempts and repeat NRT attempts. With each cold turkey attempt the quitter was a bit more likely to discover the Law of Addiction and the power of a puff through the school of hard-quitting-knocks. But what lesson could possibly be learned by repeat failure with NRT?
Unlike cold turkey quitting, the odds actually decline with subsequent NRT use. This link is to a 1993 nicotine patch recycling study where those who'd relapsed to smoking during a prior patch study a year earlier were brought back for a second patch attempt. Guess how many of them succeeded in quitting smoking for six months during their second patch attempt? Zero, none, nill, nada!
With over 50% of all smokers having now tried NRT at least once,and untold millions having made more than one NRT attempt, how many are needlessly dying because no one told them that their odds of success had dropped to near 0%? It's deadly serious when toying with nicotine robs them of all hope and yet no one tells them. In fact, if you listen closely to the marketing, they are today actually targeting NRT users for second time use (the gum now tastes like gum, keep using NRT and eventually you'll succeed).
Still just one rule ... no nicotine today, Never Take Another Puff!
John (Gold x6)
Quote
Share

BillW Gold.ffn
BillW Gold.ffn

November 29th, 2005, 10:39 pm #4

So there you have it, Ladies and Gentlemen:
If you use NRT
YOU WILL GO BLIND!
Well, not really, but you will just maintain your addiction to nicotine while, at the same time not getting enough. This combination of both eternally prolonged withdrawal symptoms and maintained active addiction is what causes the lack of success of NRT. The Worst of Both Worlds.
BillW, who never ever succeeded on NRT, but is now nicotine free and healing for Three years, nine months, two weeks, six days, 39 minutes and 11 seconds. 41670 cigarettes not smoked, saving $8,125.81. Life saved: 20 weeks, 4 days, 16 hours, 30 minutes.
Quote
Share

Starshinegrl Gold
Starshinegrl Gold

March 8th, 2006, 7:32 pm #5

Quote
Share

John (Gold)
John (Gold)

November 6th, 2008, 9:24 am #6

Blinding is the foundation upon which more than 200 pharmacology cessation clinical trials have been built. Today, the Canadian Medical Association Journal published the my letter on this topic, the meat of which asserts that: "pharmacologic treatment of chemical dependency may be the only known research area in which blinding is impossible." Hopefully it will stir researcher debate but I'm not holding my breath. This is the link:
I recently learned that World Medical Association Declaration of Helsinki principle 32 states, unless compelling and sound reasons are demonstrated, it violates a study participant's human rights to use placebo controls in clinical studies instead of the "best current proven intervention" (see http://www.wma.net/e/policy/b3.htm ).
I hope that the reason researchers continue to violate quitter human rights in pitting pharmacology products against placebo isn't that it's always easiest to beat. Participants joined these studies seeking weeks or months of free NRT or other dopamine pathway stimulating chemicals. Imagine their frustration upon again sensing full-blown withdrawal.
Remember, placebo is not a real quitting method and it certainly does not reflect a quitter who fully expects to endure and navigate their withdrawal syndrome. In the end there's only one way to restore and again enjoy natural dopamine pathway sensitivities. In the end, all who successfully arrest their dependency have one thing in common, they stopped putting nicotine into their bloodstream. Yes, still just one rule ... no nicotine today!
Breathe deep, hug hard, live long,
John (Gold x9)
Quote
Share