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Original Investigation
September 4, 2018

Effect of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial

Author Affiliations
  • 1Masonic Cancer Center, University of Minnesota, Minneapolis
  • 2Behavioral Medicine Laboratories, University of Minnesota Medical School, Duluth
  • 3Family Medicine and Community Health, University of Minnesota Medical School, Minneapolis
  • 4Department of Behavioral Science, University of Texas MD Anderson Cancer Center, Houston
  • 5Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island
  • 6Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida
  • 7Health Sciences Research, Mayo Clinic, Scottsdale, Arizona
  • 8Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina
  • 9Oregon Research Institute, Eugene
  • 10Department of Psychiatry, University of Pennsylvania, Philadelphia
  • 11Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland
  • 12Department of Medicine, University of California, San Francisco
  • 13Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina
JAMA. 2018;320(9):880-891. doi:10.1001/jama.2018.11473
Key Points

Questions  Is there a difference in biomarkers of smoke exposure between reducing nicotine content of cigarettes immediately vs gradually?

Findings  In this randomized clinical trial of 1250 smokers, immediate compared with gradual reduction to very low nicotine content cigarettes or with a control smoking group significantly reduced exposure (area under the concentration curve) to breath carbon monoxide (difference, 4.06 ppm and 3.38 ppm for immediate vs gradual reduction group and immediate reduction vs control group, respectively), acrolein (difference, 17% and 19%), and phenanthrene tetraol (difference, 12% and 14%); there were no significant differences between the gradual and control groups.

Meaning  Immediate reduction in nicotine content of cigarettes provided the greatest reduction in biomarkers of smoke exposure over time.

Abstract

Importance  The optimal temporal approach for reducing nicotine to minimally or nonaddictive levels in all cigarettes sold in the United States has not been determined.

Objectives  To determine the effects of immediate vs gradual reduction in nicotine content to very low levels and as compared with usual nicotine level cigarettes on biomarkers of toxicant exposure.

Design, Setting, and Participants  A double-blind, randomized, parallel-design study with 2 weeks of baseline smoking and 20 weeks of intervention was conducted at 10 US sites. A volunteer sample of daily smokers with no intention to quit within 30 days was recruited between July 2014 and September 2016, with the last follow-up completed in March 2017.

Interventions  (1) Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; (2) gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or (3) maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes.

Main Outcomes and Measures  Between-group differences in 3 co-primary biomarkers of smoke toxicant exposure: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons) calculated as area under the concentration-time curve over the 20 weeks of intervention.

Results  Among 1250 randomized participants (mean age, 45 years; 549 women [44%]; 958 [77%] completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, −4.06 parts per million [ppm] [95% CI, −4.89 to −3.23]; P < .0055), 3-HPMA (ratio of geometric means, 0.83 [95% CI, 0.77 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.88 [95% CI, 0.83 to 0.93]; P < .0055). Significantly lower levels of exposure were observed in the immediate reduction vs control group for CO (mean difference, −3.38 [95% CI, −4.40 to −2.36]; P < .0055), 3-HPMA (ratio of geometric means, 0.81 [95% CI, 0.75 to 0.88]; P < .0055), and PheT (ratio of geometric means, 0.86 [95% CI, 0.81 to 0.92]; P < .0055). No significant differences were observed between the gradual reduction vs control groups for CO (mean difference, 0.68 [95% CI, −0.31 to 1.67]; P = .18), 3-HPMA (ratio of geometric means, 0.98 [95% CI, 0.91 to 1.06]; P = .64), and PheT (ratio of geometric means, 0.98 [95% CI, 0.92 to 1.04]; P = .52).

Conclusions and Relevance  Among smokers, immediate reduction of nicotine in cigarettes led to significantly greater decreases in biomarkers of smoke exposure across time compared with gradual reduction or a control group, with no significant differences between gradual reduction and control.

Trial Registration  clinicaltrials.gov Identifier: NCT02139930

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