Trials that Matter: Varenicline: A Designer Drug to Help Smokers Quit

In June 2000 pharmaceutical influence rewrote U.S. cessation policy mandating pharmacology use by all patients attempting cessation, instantly destroying almost all non-pharmacology programs. Decline in the U.S. smoking rate has come to a halt. Cessation pharmacology history, when combined with these trials, strongly suggests Chantix[1] and Champix[2] are about to become part of the problem, not the solution.

After more than two decades pharmacology cannot point to a single real-world performance survey victory over those quitting without it - see California (2003), Minnesota (2002), London (2003), Quebec (2004), Maryland (2005), UK NHS (2006) and Australia (2006).[3] On the clinical side, Mooney's June 2004 NRT blinding review found that NRT studies were generally not blind as claimed in that nicotine is a psychoative drug and participants correctly guessed group assignment at rates significantly above chance.[4]

Ninety percent of varenicline study participants had a history of at least one failed attempt, knew their withdrawal syndrome, and 80% of placebo group members relapsed within two weeks. Placebo group withdrawal syndrome expectations and frustrations didn't change because of the name of the chemical promising relief. We have no reason to believe varenicline studies were blind.

As noted, up to 30% of excluded applicants reflected hard to treat populations (weight, alcohol abuse etc.) and would have substantially diminished varenicline performance. Also, if Guideline Table 13 is applied to these studies then program contact time has an argument for laying claim to nearly 100% of varenicline user cessation rates.

The author's list omits the shocking study revelation that, "during the follow-up period, use of nicotine replacement therapy did not disqualify subjects from being considered abstinent." That's a 40-week period. Was Pfizer evaluating varenicline or NRT?

Shiffman taught us that OTC NRT products have a 93% six-month relapse rate, while Tonnesen and Gourlay found that the relapse rate for repeat NRT users is closer to 99%. At least seven early nicotine gum studies produced rates higher than seen here. We have no reason to believe Chantix, when used as a stand along quitting aid, will perform better than NRT.

If you are in search of effective patient quitting resources I encourage you to examine the content of the programs pharmaceutical industry influence sought to destroy in June 2000. A few survived and found their way to the Internet. Look at the work of Joel Spitzer, a 30- year Chicago cessation counselor.[5]

John R. Polito Nicotine Cessation Educator

[1] Polito JR, Will Chantix really help me quit smoking, WhyQuit News, Aug. 25, 2006 - http://whyquit.com/pr/082506.html

[2] Polito JR, Champix - an 8 in 10 failure rate or worse?, WhyQuit News, Oct. 14, 2006 - http://whyquit.com/pr/101406.html

[3] Polito JR, Cold turkey twice as effective as NRT or Zyban, WhyQuit News, May 19, 2006 - http://whyquit.com/pr/051906.html

[4] Mooney M, The blind spot in the nicotine replacement therapy literature: assessment of the double-blind in clinical trials, Addict Behav. 2004 Jun;29(4):673-84

[5] Spitzer J, Joel's Library, www.whyquit.com/joel

Conflict of Interest:

Pro bono editor of WhyQuit.com, an abrupt nicotine cessation forum

TO THE EDITOR:

Drs. Schroeder and Sox in their recent editorial (1) provide a brief, but important summary of three clinical trials of varenicline for smoking cessation recently published in JAMA (2, 3, 4). However, in summarizing the trial designs and results for two of the trials (2, 3) the authors mistakenly reported the dosing regimen used. In the 2 studies comparing varenicline to placebo and to bupropion, the dose was titrated up to 1.0 mg twice daily (2, 3) rather than 0.5 mg twice daily as reported by the authors. Schroeder and Sox go on to provide a fairly thorough summary of the relapse prevention study design and outcomes, but the error that they reported in the dosing regimen for the first 2 varenicline trials led them to incorrectly conclude for this 3rd trial that "The dose of varenicline was 1.0 mg twice daily, double the dose in the other 2 varenicline trials." In fact, varenicline dosing for all 3 trials reported in JAMA was the same for the first 12 weeks; 0.5 mg once daily for days 1 to 3, 0.5 mg twice daily for days 4 to 7 and 1.0 mg twice daily from day 8 through 12 weeks or the end of treatment (2, 3, 4).

In their summary and conclusions, Schroeder and Sox pose some thoughtful questions to consider regarding potential differences in outcomes for varenicline treatment, or any cessation treatment, conducted in real world vs clinical trial environments. One of their conclusions regarding the results from the relapse prevention trial was that ""¦it (varenicline) had a relatively small margin of superiority over placebo (43.6% vs 36.9%)." While they did describe the design of the study earlier, this statement without some clarifying comments regarding the somewhat uncommon study design seems to suggest that an unusually high placebo rate was achieved in the trial, which was not the case. All participants in the relapse prevention trial received 12 weeks of open label varenicline treatment prior to being randomized to either 12 additional weeks of varenicline treatment or 12 weeks of placebo (4). Thus, long term (24 weeks) vs standard term (12 weeks) varenicline treatment would be another way to put the results of this trial in context.

1. Schroeder SA, Sox HC. Trials that matter: varenicline: a designer drug to help smokers quit. Ann Intern Med. 2006;145:784-785.

2. Gonzales D, Rennard SI, Nides M, et al, for the Varenicline Phase 3 Study Group. Varenicline, an 4 2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;296:47-55.

3. Jorenby DE, Hays JT, Rigotti NA, et al, for the Varenicline Phase 3 Study Group. Efficacy of varenicline, an 4 2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296:56-63.

4. Tonstad S, Tonnesen P, Hajeck P, Williams KE, Billing CB, Reeves KR. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trail. JAMA. 2006;296:64-71.

Conflict of Interest:

Dr Gonzales has received research contracts from Pfizer, GlaxoSmithKline, Sanofi-Aventis, Nabi Biopharmaceutical, and Addex Pharmaceuticals; consulting fees and honoraria from Pfizer, Sanofi-Aventis, and GlaxoSmithKline; and owning 5 shares of Pfizer stock. Dr Tonstad reports receiving honoraria for advisory boards and for lectures from Pfizer, GlaxoSmithKline, and Sanofi-Aventis. Dr Jorenby reports receiving research support from Pfizer, Nabi Biopharmaceutical, and Sanofi-Aventis and consulting fees from Nabi Biopharmaceutical.