# Presentation: 709011

## Science and Future Research Directions for Reduced Nicotine Content Cigarettes Tobacco Control UpdateNational Cancer Advisory Board, February 6, 2008

- Dorothy K. Hatsukami
- University of Minnesota
- Transdisciplinary Tobacco Use Research Center
- Comprehensive Cancer Center

## Why study reduced nicotine content cigarettes?

- All tobacco products contain nicotine.
- Nicotine is the addictive agent in tobacco products.
- Nicotine is responsible for the progression from initiation to regular smoking and difficulty with cessation.

## Establishing a nicotine threshold for addiction-- The implications for tobacco regulation

- Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction. The implications for tobacco regulation. (1994). *N Engl J Med, 331*(2), 123-125.

- Goal:
- To prevent nicotine addiction in youth.
- Threshold for addiction:
- Dose to establish and maintain addiction
- 	~ 5 mg/day.
- Proposal:
- A gradual reduction of nicotine content of cigarettes over 10-15 years.

## Potential Risks of Nicotine Reduction Strategy

- Compensatory oversmoking
- Black market
- Starter product for non-smokers

## Reduced Nicotine Content (RNC) cigarettes vs. commercial low yield cigarettes
Safety of progressive nicotine reduction
Consumer acceptability of reduced nicotine content cigarettes 
Lowering level of nicotine addiction
Promoting smoking cessation

- Safety of progressive nicotine reduction
- Consumer acceptability of reduced nicotine content cigarettes
- Lowering level of nicotine addiction
- Promoting smoking cessation

- Nicotine Yield Reduction Studies: Key Issues

- Benowitz, N. L., Hall, S. M., Stewart, S., Wilson, M., Dempsey, D., & Jacob, P., 3rd. (2007). Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. *Cancer Epidemiol Biomarkers Prev, 16*(11), 2479-2485.
- CA78603

## Nicotine Content Reduction Study: Pilot Study Design

- Reduced Nicotine Content and Low Yield Commercial Cigarettes
- Uncontrolled, sequential, within-subject design
- Smokers of at least 10 cigarettes/day, not intending to quit in next 6 months
- Usual brand and 5 test cigarette brands
- Nicotine yield reduced at weekly intervals
- Brief cessation counseling at the end of the tapering phase
- 4 week follow-up

| Usual Brand |  |  | Cigarette 1 |  |  | Cigarette 2 |  |  | Cigarette 3 |  |  | Cigarette 4 |  |  | Cigarette 5 |  |  | Follow-up |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 0 |  | 1 |  |  | 2 |  |  | 3 |  |  | 4 |  |  | 5 |  |  | 6 |  |  |  |  | 10 |
| Weeks of Study |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |

## Characteristics of Research Cigarettes

|  | Machine-Determined Nicotine Yield 
(mg) | Machine-Determined 
Tar Yield 
(mg) |
| --- | --- | --- |
| RNC Study Research Cigarette |  |  |
| Nicotine Content |  |  |
| 12mg | 0.9 | 10.9 |
| 8mg | 0.6 | 10.9 |
| 4mg | 0.3 | 7.8 |
| 2mg | 0.2 | 9.2 |
| 1mg | 0.1 | 10.2 |

## Characteristics of Research Cigarettes

|  | Machine-Determined Nicotine Yield 
(mg) | Machine-Determined 
Tar Yield 
(mg) |
| --- | --- | --- |
| Commercial Cigarettes |  |  |
| Pall Mall Light 100s | 0.9 | 12 |
| Merit Kings | 0.6 | 8 |
| True Kings | 0.4 | 4 |
| Now 100s | 0.2 | 2 |
| Carlton 100s | 0.1 | 1 |

## RNC Study Cigarettes Per Day

## RNC Study Plasma Cotinine

## RNC Study Carboxyhemoglobin

## RNC Study Urine Total NNAL

**FOLLOW-UP**

**Usual**

## RNC Study Fibrinogen

**Usual**

## Summary

- Gradual reduction of nicotine content in cigarettes results in a progressive (70%) reduction of nicotine exposure.
- There is little evidence of smoking compensation, and no evidence of increased exposure to toxicants, or evidence of adverse effects on cardiovascular biomarkers.
- RNCs are acceptable to smokers, although not as good as usual brand cigarettes.

## Summary

- After the end of the study, cigarette consumption was substantially reduced and  dependence scores were lower, consistent with achieving a lower level of dependence.
- Approximately 25% of subjects achieved abstinence at 4 weeks after end of taper.
- Reduction of nicotine, CO and possibly TSNA exposure was observed with commercial cigarettes,  but only at the two lowest exposure levels (ultra-low yield cigarettes).

## Regulation of the nicotine content of cigarettes and the use of a nicotine reduction strategy to prevent or reduce the level of nicotine addition appears to be safe and feasible, at least in the short term.  Long-term studies are needed.

- Conclusion

## Cessation Studies using Reduced Nicotine Content Cigarettes : Key Issues

- Among a population of dependent smokers interested in quitting, what are the effects of denicotinized cigarettes on:
- Reducing dependence?
- Promotion of cessation?
- Toxicant exposure and toxicity?
- Consumer perception of the health risks?

## Quest: Nicotine and Toxicant Modification

- From:  http://www.questcigs.com/home.asp,
- accessed November 14, 2002

## Study Design: Quest vs. Nicotine Lozenge

- P50 DA/CA13333

- Abstinence
- 6 weeks

- Smokers
- (N = 167)

- Quest 2
- 0.3 mg Nic
- N = 53

- Quest 3
- 0.05 mg Nic
- N = 54

- Commit Lozenge
- 4 mg
- N = 60

## Advertisement

- ....University of Minnesota is looking for participants for a research study.  This study examines a novel approach to quitting by using a new tobacco product as  a steps towards becoming smoke free.  The study will look at health effects of this new product.

## Effects of Switching on Dependence Scores

## Effects of Switching on Withdrawal Symptoms

## Abstinence rates: Intent-to-treat 4 week continuous abstinence (Weeks 9-12)

| Quest 3
(0.05 mg nicotine)
N=54 | Quest 2
(0.3 mg nicotine)
N=53 | Nicotine lozenge
4 mg
N=60 |
| --- | --- | --- |
| 
43.4% | 
21.2% | 
28.3% |
| p=0.04
 |  |  |

## Cigarettes per Day

## Effects of Switching on CO

## Effects of Switching on Total NNAL (NNK Metabolite)

- Effects of Switching on Total NNAL (NNK Metabolite)

## Effects of Switching on Perceived Risk of Lung Cancer

## Summary

- Among smokers interested in quitting, denicotinized cigarettes:
- Reduced dependence
- Facilitated abstinence
- Reduced toxicant exposure
- Did not change perceived risk for disease

## Conclusion

- Denicotinized cigarettes hold significant promise in helping smokers quit.
- Sensory aspects of smoking play a role in tobacco addiction.
- Larger, longer-term trial and follow-up is needed.

## Goals of Conference on Nicotine Regulation

- Present the current science on topics related to nicotine regulation.
- Discuss whether or not reducing nicotine levels may be feasible as a policy measure and under what conditions.
- Establish a research agenda to determine the feasibility and practicality of nicotine reduction as a policy measure.

## Conference Conclusions and Recommendations

- Science base exists to support further investigation.
- Strong support to consider reducing nicotine levels as a potential method to reduce harm.
- However, the best approach to accomplish this goal is not yet known.

## Research Questions

- What important constituents and design features contribute to addiction potential?
- Can a threshold dose for nicotine addiction be identified?
- As nicotine is reduced in cigarettes, can tobacco users use medications for cessation to reduce compensatory smoking and nicotine withdrawal?

## Research Questions

- Are there any unintended consequences from nicotine reduction in tobacco?
- How do reduced nicotine cigarettes affect vulnerable populations (e.g., low SES, individuals with mental health disorders, and others)?

## Framework Convention on Tobacco Control
Article 9: Regulation of the contents of tobacco products
Proposed legislation to provide FDA with authority to regulate tobacco products
Section 907(a)(4) authorizes issuance of a product standard by FDA “for the reduction of nicotine yields of the product”
The legislation forbids FDA from taking nicotine levels to zero, but allows FDA to issue a standard to lower nicotine yields to levels that cannot create or sustain addiction

- Article 9: Regulation of the contents of tobacco products
- Proposed legislation to provide FDA with authority to regulate tobacco products
- Section 907(a)(4) authorizes issuance of a product standard by FDA “for the reduction of nicotine yields of the product”
- The legislation forbids FDA from taking nicotine levels to zero, but allows FDA to issue a standard to lower nicotine yields to levels that cannot create or sustain addiction

- Potential for Tobacco Product Regulation

## What does the future hold?

- Science can inform public health and help guide how regulatory agencies control ingredients, toxicant emissions, and any aspect of tobacco product design and manufacture that affects nicotine delivery.
- Novel treatment mechanisms and methods to help smokers quit can be determined.