To achieve the greatest confidence that a PREP will reduce risks for persons who cannot stop smoking, well-validated methods for predicting risk, including external exposure indicators, and the best available biomarker assays should be used.

NICOTINE PHARMACOLOGY (SEE SECTION II, CHAPTER 9)

Nicotine is the addictive component of tobacco products, and the strength of this addiction affects the individual’s ability to stop smoking (U.S. DHHS, 1988). Nicotine is also a component of most PREPs, and therefore, evaluation of the harm reduction potential of PREPs requires evaluation of nicotine’s relative toxicity, especially during long-term use (see Chapter 4).

Structurally, nicotine is very similar to acetylcholine (Ach) and interacts with specific nicotinic receptors (nAchRs) in the central and peripheral nervous systems. The interaction between nicotine and its receptor affects the release of numerous neurotransmitters and results in upregulation of the nicotinic receptors leading to the physiological, cognitive, and sensory effects associated with tobacco use, addiction, and withdrawal. Nicotine also has well-documented effects on metabolism and on the cardiovascular, gastrointestinal, and hormonal systems (see Chapter 9).

Pharmacological nicotine replacement therapy (NRT) has proven to be a remarkably well-tolerated and effective strategy for many, leading to cessation of cigarette smoking at least in the short- to medium-term (Benowitz et al., 1998; Fiore et al., 2000). Although the experience is much more limited, it is also a potential strategy for reducing the number of cigarettes smoked by smokers who cannot or will not quit (Fagerström et al., 1997; Rennard et al., 1990; Shiffman et al., 1998; Transdermal Nicotine Study Group, 1991).

There are important considerations in evaluating nicotine products for possible tobacco harm reduction. First, nicotine is addictive, and although the daily exposure may be reduced by NRT use, continued usage implies psychological dependence, if not physical addiction. It is arguable whether this should be a concern, given the assumption of an undisputed reduction of risk compared to smoking. However, it would seem reasonable to include surveillance of the dependency potential and abuse liability of each NRT product. Furthermore, the effects of long-term nicotine intake on such factors as drug and alcohol consumption, the progression of coincidental diseases, the impact of aging on cognitive and other physiological functions, and susceptibility to other forms of addictive behavior are largely unknown. For example, observations suggesting that nicotine impairs endothelial function, a property it shares with cigarette smoking,



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