Flavor improvement does not increase abuse liability of nicotine chewing gum

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Abstract

Because the taste of nicotine gum has impeded compliance with dosing recommendations, nicotine gum with improved taste (mint, orange) was developed and marketed. Prior to marketing, the Food and Drug Administration (FDA) required a rigorous abuse liability assessment to examine whether enhanced palatability of nicotine gum would increase its abuse liability. Subjective, physiological, and psychomotor effects of mint flavor and original nicotine gum were tested in adult smokers (22–55 years old); a group of younger subjects (18–21 years old) was also included to allow for assessment of abuse liability in young adults specifically. Amphetamine and confectionery gum served as positive controls for abuse liability and palatability. Subjects rated palatability of mint gum higher than original nicotine gum, but substantially lower than confectionery gum. Palatability decreased with increasing dose of nicotine. Neither original nor mint gum increased ratings of traditional abuse liability predictors [Good Effect, Like Effect, Morphine–Benzedrine Group (MBG) scales of Addiction Research Center Inventory (ARCI)], while amphetamine increased ratings of all these measures. Both flavors of nicotine gum decreased craving during 2 h of abstinence. These effects were more pronounced in the adult group and mint gum was more effective than original gum. Younger subjects reported fewer withdrawal symptoms and lower ratings for drug effects and flavor. Improved flavor of nicotine gum does not increase abuse liability, but may be associated with enhanced craving reduction.

Introduction

Sixty-eight percent of the 47 million smokers in the United States indicate they are interested in quitting (Centers for Disease Control and Prevention, 1997). Nicotine replacement therapy (NRT) products (e.g., gum, patch, inhaler, and nasal spray) are marketed as smoking cessation aids and deliver nicotine through various routes of administration other than cigarette smoke inhalation, thereby reducing withdrawal symptoms in abstinent smokers. NRT products have proven efficacious; they approximately double long-term (6–12 months) quit rates when compared to placebo (e.g., Law and Tang, 1995, U.S. Department of Health and Human Services, 2000).

When nicotine gum was developed in the 1970s, providing nicotine in a safe and effective manner while minimizing risk to children who might have inadvertent access to the gum was a key challenge Ferno, 1977, Ferno et al., 1973, Jarvik and Henningfield, 1993. A peppery flavoring was added to reduce nicotine's unpleasant taste and burning sensation, thereby providing an acceptable formulation for persons motivated to quit smoking, yet not so pleasant as to be attractive to children and nonsmokers Ferno, 1977, Ferno et al., 1973. That is, flavoring was chosen with the objective of providing a satisfactory medicine without fostering abuse of the product; the choice of flavor was effective in this regard Nemeth-Coslett and Henningfield, 1986, West et al., 2000.

The gum's aversive taste is an important clinical issue; among smokers trying to quit who use nicotine gum as a smoking cessation aid, the major clinical problem is undermedication resulting from failure to use adequate levels per day Rose, 1996, Henningfield and Stitzer, 1991, Fortmann et al., 1988, and the taste of nicotine gum is an important impediment to compliance with recommended dosing regimens Rose, 1996, Jarvik and Henningfield, 1993. The reputation of bad taste may also keep some smokers from trying the gum. Improved taste of nicotine gum therefore may increase both its efficacy and the number of smokers using it, and in response to consumer feedback the pharmaceutical industry has developed and marketed nicotine gums with more appealing flavors (e.g., mint, orange). Prior to the marketing of a nicotine-containing gum with enhanced palatability, concerns were raised about a potential increase in abuse potential. That is, with enhanced palatability, the product may appeal to gum-chewers in general, especially of a younger age, and thus lead to nicotine abuse/dependence in nonsmokers. In addition, the enhanced palatability may increase perception of positive nicotine effects, a potentially important interaction in light of the growing availability of nicotine replacement products and the current efforts of the pharmaceutical industry to develop oral nicotine replacement products in addition to the gum already marketed (e.g., sublingual tablet, Molander and Lunell, 2001). For these reasons, the U.S. Food and Drug Administration (FDA) required an abuse liability study of flavored nicotine gum as part of the approval process. Thus, the present study was designed to determine the abuse liability, subjective effect, and physiological response profile of a mint-flavored nicotine gum as compared to the original nicotine gum in adults (22–55 years old) and young adults (18–21 years old). Several doses of mint-flavored and original nicotine gum (0, 2, 4, and 8 mg) were compared to each other and amphetamine, a drug with known abuse liability. A commercial non-nicotine-containing mint gum was included to serve as a comparison for flavor ratings. In a broader perspective, the abuse liability study described here is a unique application of abuse liability testing, addressing the potential interaction between increased palatability of an oral drug vehicle and a drug's effects. This application is especially relevant in the context of the continuing efforts of the pharmaceutical industry to develop new nicotine delivery systems with improved appeal and palatability.

Section snippets

Subjects

Twenty-four subjects between 18 and 50 years old (12 in the 18–21-year-old group and 12 in the 22–50-year-old group) completed the study. Table 1 shows demographic information and smoking variables for both groups. The groups did not differ in any of the demographic characteristics displayed, with the exception of age. All subjects were non-treatment-seeking smokers; all smoked 15 or more cigarettes per day and had a baseline afternoon expired carbon monoxide level of 15 ppm or higher. All

Palatability

Fig. 1 shows ratings of “Do you like the gum's taste?” at timepoint 110, after 5 min of chewing. In the interest of clarity, only one timepoint is shown. Ratings decreased with time during the 15 min of chewing (P<.001) and the 110 timepoint was chosen because the differences between mint and original gum were most clear at this timepoint. Overall, subjects rated the mint gum higher on “Do you like the gum's taste?” than the original nicotine gum and they rated confectionery gum substantially

Discussion

This study was designed to assess the abuse liability of mint-flavored nicotine gum, as required by the FDA. Results suggest that mint flavoring increases the palatability of nicotine gum but does not increase its abuse liability in adults (22–50 years) or young adults (18–21 years). Mint flavor gum was given higher subjective ratings (e.g., mean Like Taste rating after 5 min of chewing was 34 for placebo on a scale from 0 to 100) as compared to the original flavor gum (mean rating 20), but

Acknowledgements

The authors thank John Yingling, Erin Moffett, Tim Mudric, and Michael di Marino for technical assistance and statistical analyses. This study was supported by SmithKline Beecham Consumer Healthcare.

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    Present affiliation: Department Psychology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298, USA.

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