Addicted to Nicotine
A National Research Forum

Section I: History and Pharmacology
Jack E. Henningfield, Ph.D., Chair

NICOTINE DELIVERY SYSTEMS

John Slade, M.D.
Robert Wood Johnson Medical School
University of Medicine and Dentistry of New Jersey

Introduction

Tobacco use, specifically use of the cigarette and the cigar, is rising among young people in the United States, and smoking rates among adults have been stagnant throughout most of the 1990s.

The cigarette kills half of those who continue to use it. Among those living who use cigarettes regularly, 500 million will be fatally poisoned by these devices. If present trends continue, the annual death toll from tobacco in 2020 will exceed 10 million, and this number will not be diminished if no one begins using cigarettes from this day forward: These future victims are already smoking.

The tobaccos of commerce are indigenous to the Western Hemisphere. Native Americans used Nicotiana tabacum and N. rustica extensively for pharmacologic purposes, both ritually and recreationally, throughout the Americas prior to the era of European exploration. The Spanish, Portuguese, and English adopted their cultivation and curing practices in developing commercial products. The major forms of tobacco adopted by Europeans were cigar, chew, snuff, and pipe tobacco. Cigar smoke tends toward the alkaline, and alkalinizing agents were often used in chew and snuff mixtures. An alkaline environment favors the free-base form of nicotine, which is readily absorbed across mucous membranes. The main sites of nicotine absorption for all of these products are the mucous membranes of the mouth and nose.

Beginning around 1839, a novel approach to curing tobacco was developed on the farm of Abisha Slade, south of the Dan River, between Moon and Rattlesnake Creeks, in Caswell County, North Carolina. It involved the use of high temperatures and charcoal. Mr. Slade taught many of his colleagues in Virginia and North Carolina the new technique as well, and further refinements by others led to what is recognized today as the flue-curing process. The high sugar content of flue-cured tobacco resulted in a more acidic smoke than varieties containing less sugar, such as those used to make cigars. This characteristic results in nicotine being ionized and held in solution in the aerosol droplets of smoke. The smoke from flue-cured (also called "bright" or "Virginia") tobacco is less irritating and easier to inhale than the smoke from, for example, a conventional dark cigar tobacco because of the lower content of unionized, free-base nicotine. Most of the nicotine in smoke from flue-cured tobacco (and from a conventional American-blend cigarette) is readily absorbed only if it is inhaled.

A contrasting approach to the development of a nicotine delivery device that facilitated inhalation was developed on Java just after the turn of the 20th century. Cloves, which contain the potent local anesthetic eugenol, came to be mixed with dark tobaccos. Clove cigarettes are today the major delivery device used in Indonesia for inhaled nicotine.

Machinery to make cigarettes inexpensively, tobacco blends that facilitated inhalation, modern railroad networks, mass media advertising methods, the safety match, and, quite probably, the promotion of competition fostered by the dissolution of the Tobacco Trust in 1911, combined, by the time RJ Reynolds introduced Camel cigarettes in 1913, to create the conditions that led to the cigarette epidemic.

By midcentury, health concerns about cigarettes led manufacturers to modify their products in ways that provided the appearance of safety. Without regulatory oversight, manufacturers added filters and made brazen claims of health benefit. Among the prominent filters of the 1950s was the Micronite Filter for Kent cigarettes. The original Kent filter was crocidolite asbestos, and the company had reports from two independent electron microscopy labs by 1954 that asbestos was present in the smoke from these cigarettes. Nonetheless, Lorillard continued to use asbestos for another 2 or 3 years. Overall cigarette consumption, which had fallen on the early news of lung cancer risk, rebounded on the strength of unproven filter claims.

In the wake of the 1964 Report of the Surgeon General's Advisory Committee, the industry redoubled its efforts to provide products that appeared less dangerous while continuing to offer no actual proof of safety. The era of the "low-tar" or "light" cigarette, supported by the test method of the Federal Trade Commission (FTC), which continues to this day, had begun. The chief scientist at RJ Reynolds told management in 1965 that a test method such as this would mislead consumers. Unrestrained by effective regulation, the industry developed products that had hopeful test results taken when machines smoked them, but that performed like their high-tar predecessors when actually used by consumers. The mix of toxins changed as blends and additives were adjusted to maintain nicotine delivery and flavor under the "low-tar" dictates of public relations. These changes in cigarette design have been associated with a shift in the cell type of lung cancer from small cell to adenocarcinoma. For all practical purposes, the "light" brands are no less addictive and no less poisonous than those that do not make this claim.

Not only have "light" cigarettes not been significantly less toxic than the products they have supplanted, these products have successfully competed with abstinence, making it less likely that people stop smoking altogether.

The regular, hard-pack version of Marlboro has a nicotine content of 13.5 mg, and its FTC nicotine rating is 1.1 mg, while the "light" hard-pack version has a nicotine content of 13.0 mg and an FTC nicotine rating of 0.8 mg. The regular version features 13 percent filter ventilation and the "light" version 22 percent. A consumer may actually obtain as much as 3 mg or more of nicotine from either of these products.

Cigar use has rebounded in recent years in association with a marked increase in industry-generated promotional activity. In 1997, 22 percent of high school students, including 11 percent of females and 31 percent of males, were current users of cigars. A cigar may contain more than 400 mg of nicotine, and the nicotine can be delivered across the buccal mucosa or be absorbed in the lung, depending on whether smoke is inhaled.

Moist snuff products exhibit a range of pH (and, hence, free-base nicotine availability), which correlates, for U.S. Tobacco, the leading manufacturer, with what company officials have called a "graduation strategy." The company sells sweet, low-delivery products to novices and high-potency products to those who are addicted, while making intermediate offerings available in the product mix as well.

A number of novel, cigarette-like devices have recently been developed by several of the major cigarette makers. Philip Morris and RJ Reynolds are testing these products in ways that resemble conventional assessments of new drugs. It appears that emissions from these products are similar to emissions from at least some existing brands of so-called ultra low-tar cigarettes. It is not yet clear which specific cigarette brands these products might directly compete with.

Four nicotine delivery devices are now approved by the Food and Drug Administration as temporary aids to achieving abstinence from tobacco use: patch, gum, nasal spray, and vapor inhaler. As an example, nicotine gum is available with two levels of nicotine content, 2 mg and 4 mg, which deliver about 0.8 mg and 1.5 mg of nicotine, respectively, at the most.

What We Know

• All commercial tobacco products are effective nicotine delivery devices.

• Tobacco products are designed to have specific nicotine delivery characteristics.

• All commercial tobacco products are toxic when used as intended.

• So-called light cigarettes are not less toxic, and consumers have been deceived.

• Novel tobacco products that resemble cigarettes have deliveries that are similar to those of some commercially available cigarettes.

• Medicinal forms of nicotine are less reinforcing than tobacco products, and nicotine patches are not reinforcing at all.

What We Need To Know More About

• How are tobacco products made, and what considerations have gone into their design?

• What are the most appropriate ways to test tobacco products for regulatory and public education purposes?

• What steps can be taken to reduce the toxicity of tobacco products?

• What steps can be taken to reduce the addictiveness of tobacco products?

• What are the thresholds for establishing and sustaining nicotine dependence?

• What are the effects of systematically lowering the nicotine content of tobacco products?

• What criteria might be appropriate for allowing health claims to be made for novel nicotine delivery devices that resemble cigarettes?

• Should more direct competition between tobacco products and medicinal nicotine delivery devices be encouraged?

Recommended Reading

Slade, J. Nicotine delivery devices. In: Orleans, C.T., and Slade, J., eds. Nicotine Addiction: Principles and Management. New York: Oxford University Press, 1993. pp. 3-23.

Slade, J., and Henningfield, J.E. Tobacco product regulation: Context and issues. Food Drug Law J 1998 supplement, in press.

Warner, K.E.; Slade, J.; and Sweanor, D.T. The emerging market for long-term nicotine maintenance. JAMA 278(13):1087-1092, 1997.