Reginald V. Fant

Pharmacotherapy for nicotine dependence.

Approximately 50% of long‐term cigarette smokers die prematurely from the adverse effects of smoking, including on cancer, cardiovascular disease, lung disease, or other illness. This risk can be substantially reduced by smoking cessation, with greater benefits occurring the earlier in the smoking career that cessation occurs. However, cessation provides benefits at any stage, including after the onset of smoking‐related disease, by improving the prognosis and quality of life. Clinicians can have a significant impact on reducing tobacco use by their patients by following the US Public Health Service Clinical Practice Guidelines. Proven strategies include structured methods of advising cigarette smokers to quit and guidance to facilitate their efforts, as well as the use of various pharmacotherapies. Pharmacotherapies for tobacco dependence include nicotine replacement medications in the form of gum, transdermal patch, lozenge, sublingual tablet, nasal spray, and vapor inhaler formulations. The only nonnicotine medication that has been approved by the US Food and Drug Administration is bupropion. Combination therapies, long‐term medication therapies, and harm reduction strategies may further improve outcome with approved medications. Further, new medications such as varenicline and rimonabant are likely to reach tobacco users who are refractory to current treatments. Increasing the treatment options, increasing availability, and reducing the perceived cost of these medications may have an additional public health impact.

Pharmacodynamic effects of new de-nicotinized cigarettes

The effects of cigarette smoking result from the delivery of nicotine, other components of smoke, and sensory stimulation. In the present study, pharmacological effects of new tobacco-derived de-nicotinized cigarettes (controls) were compared with standard cigarettes. The de-nicotinized cigarettes had the appearance, draw and taste of standard cigarettes but contained and delivered virtually no nicotine (< 0.06 mg), but delivered tar and carbon monoxide (CO). They were compared with cigarettes that delivered nicotine, CO and tar. Subjects (n = 20: 10 men, 10 women) participated in four experimental sessions in which they smoked either a standard cigarette or a de-nicotinized cigarette after either 3 or 12 h of tobacco deprivation. Heart rate, blood pressure, and EEG were recorded before, and for 1 h after, ad lib smoking. Plasma nicotine concentrations verified that de-nicotinized cigarettes did not deliver nicotine. The de-nicotinized cigarettes did not increase heart rate or activate the EEG. The subjects preferred the cigarettes that delivered nicotine compared to the de-nicotinized cigarettes. However, both types of cigarettes reduced subjective measures of tobacco craving and withdrawal. These data extend previous research that suggested the process of smoking and components of tobacco smoke other than nicotine mediate some effects of cigarette smoking. The de-nicotinized cigarettes may prove useful in evaluating effects of smoking independent of the delivery of nicotine.

Pharmacokinetics and pharmacodynamics of moist snuff in humans

INTERVENTION Four brands of moist snuff and a non-tobacco mint snuff were tested. Subjects reported to the laboratory for five experimental sessions. After baseline measurement of dependent variables, each subject placed 2 g of one of the brands of snuff (or one Skoal Bandits pouch) between the cheek and gum for 30 minutes. The subjects remained in the experimental laboratory for an additional 60 minutes. SUBJECTS Ten volunteers who were daily users of smokeless tobacco. MAIN OUTCOME MEASURES Plasma nicotine concentration, cardiovascular effects, and subjective effects. RESULTS Large amounts of nicotine were delivered rapidly to the bloodstream. The amount of nicotine absorbed and the rate of absorption were related to the pH of the snuff product in aqueous suspension. Cardiovascular and subjective effects were related to the amount of nicotine absorbed. CONCLUSIONS Snuff products are capable of rapidly delivering high doses of nicotine, which can lead to dependence. Long-term use of snuff can lead to a number of adverse health effects including oral cancers, cardiovascular diseases, and gingival diseases. For these reasons, it is important that the public health community considers oral snuff use as a burden on public health in the same way that cigarette smoking is recognised.

Combination Nicotine Replacement Therapy for Smoking Cessation Rationale, Efficacy and Tolerability

Currently available nicotine replacement therapy (NRT) medications provide effective treatment for tobacco dependence, typically doubling success rates compared with placebo. A strategy for further improving the efficacy of NRT is to combine one medication that allows for passive nicotine delivery (e.g. transdermal patch) with another medication that permits ad libitum nicotine delivery (e.g. gum, nasal spray, inhaler). The rationale for combining NRT medications is that smokers may need both a slow delivery system to achieve a constant concentration of nicotine to relieve cravings and tobacco withdrawal symptoms, as well as a faster acting preparation that can be administered on demand for immediate relief of breakthrough cravings and withdrawal symptoms.This article reviews 5 published studies that have examined the effectiveness of combination NRT compared with monotherapy in providing withdrawal relief and smoking cessation, and examines other factors relevant to the promotion of combination NRT for treating tobacco dependence.The data show that there are conditions under which combinations of NRT products provide greater efficacy in relieving withdrawal and enabling cessation than monotherapy, but the findings are not robust and additional research is warranted to better understand the magnitude and generality of the benefits of combination therapy. There are also regulatory and commercial obstacles that must be considered. Nonetheless, combination NRT has the potential to provide effective treatment of tobacco dependence in persons whose dependence is refractory to currently available treatments.

A pharmacokinetic crossover study to compare the absorption characteristics of three transdermal nicotine patches

We compared the pharmacokinetic profiles of the highest marketed doses of three different patch systems using a crossover study design. Specifically, each of the 25 subjects was assigned to receive the Pharmacia-Upjohn (McNeil) 15-mg, 16-h patch, the Novartis 21-mg, 24-h patch, and the Alza (SmithKline Beecham) 21-mg, 24-h patch. Subjects used each patch for 3 consecutive days, applying a new patch each morning. Plasma nicotine concentrations were measured 15 times during the first 24-h period and at 48, 48.5, 49.5, and 51 h following initial patch application. Measures of total nicotine absorbed (AUC), maximum plasma nicotine concentration (C(max)) and minimum plasma nicotine concentration (C(min)), were higher for the 21-mg, 24-h patches than for the 15-mg, 16-h patch during both the first day of dosing and during the modeled steady-state period (48-72 h after initial application). Within the 21-mg, 24-h patch systems, the Alza patch produced significantly higher AUC and C(max) values during acute dosing and during steady state, but there was no difference between C(min) values. The time to reach C(max) (T(max)) was fastest for the Alza patch system; the Pharmacia-Upjohn patch produced a faster T(max) than the Novartis patch. These results indicate that there are significant differences between the pharmacokinetics of the currently marketed patch systems, which may be important for effective relief of withdrawal symptoms and cigarette craving.

Nicotine concentration, smoke pH and whole tobacco aqueous pH of some cigar brands and types popular in the United States

The present study examined characteristics relating to nicotine delivery of 17 cigar brands, which included small cigars, cigarillos, and large premium cigar brands. The cigars selected for analysis were intended to represent the range of cigar products currently available and in popular use. In addition to cigar characteristics previously studied such as size, nicotine content, and pH of their tobacco, the present study examined smoke pH on a puff-by-puff basis. The tobacco content of the cigars ranged in weight from 0.53 to 21.5 g. There was considerable variation in total nicotine content, which ranged from 5.9 to 335.2 mg per cigar. The aqueous pH of the tobacco from the cigars also varied widely with values ranging from 5.7 to 7.8. The smoke pH values of the smallest cigars was generally acidic, changed little across puffs, and more closely resembled the profiles previously reported for typical cigarettes. Interestingly, the smoke pH of smaller cigars and cigarillos became acidic after the first third of the cigar was consumed and then remained acidic thereafter, whereas larger cigars became acidic during the first third, then became quite alkaline during the last third. Because of wide variations in nicotine content of the tobacco across brands and of similarly wide variations in smoke pH, cigar size is not an accurate predictor of the nicotine delivery capacity of a particular cigar brand, although, in general, larger cigars are capable of providing larger total nicotine delivery with extraordinarily high delivery levels being possible from many of the large premium cigars. These results demonstrated that the popular cigars in this study contained enough nicotine for the development of dependence when smoking as few as one or two of the larger cigars per day.

Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status.

Increasing the diversity and availability of medications for the treatment of tobacco dependence and/or withdrawal, to aid in the achievement of smoking cessation, is crucial to meet the diverse needs of tobacco users. Despite a general awareness that smoking is harmful and widespread interest in smoking cessation, nearly 50 million adults in the US and 1.3 billion worldwide continue to smoke. Nicotine replacement therapies are effective in the treatment of tobacco dependence and withdrawal, but do not meet the needs of all tobacco users. Improvement of tobacco dependence and/or withdrawal treatments is likely to rely on novel pharmacological approaches that include new chemical entities and new formulations of current drugs. In addition, new indications for treating tobacco dependence and withdrawal show promise for reducing tobacco use and associated disease.This article focuses on a range of novel pharmacological approaches for the treatment of tobacco dependence and/or withdrawal, including oral and pulmonary nicotine delivery and the following non-nicotinic medications: antidepressants, an α4β2 nicotine partial agonist, an α2-noradrenergic agonist, cytochrome P450 (CYP) 2A6 inhibitors, opioid antagonists and GABAergic medications. In addition to existing medications, this article addresses novel medications in the clinical development stage and those that have been evaluated previously. Novel medications in the clinical development stage include at least three nicotine vaccines and the cannabinoid receptor acting drug rimonabant. Medications evaluated previously include lobeline, mecamylamine and an anticholinergic drug regimen comprising atropine, scopolamine and chlorpromazine. Having not been approved by major drug regulatory authorities for the treatment of tobacco dependence and/or withdrawal, these medications have been evaluated in an experimental capacity.

Nicotine replacement therapy.

Physicians can help their patients quit smoking by recommending to all of their patients that they quit smoking with the help of nicotine replacement medications. Currently available forms of nicotine medications include gum, patch, nasal spray, and vapor inhaler. Nicotine replacement medications aid smokers in their cessation efforts by relieving the physiologic symptoms of nicotine withdrawal. Because nicotine medications do not deliver the myriad toxins and carcinogens cigarettes deliver, these medications are safe when used as directed. This article discusses the rationale behind nicotine replacement therapy in the context of tobacco dependence, the available medications, and the public health benefits of these medications.

Flavor improvement does not increase abuse liability of nicotine chewing gum.

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.

Tobacco use as drug addiction: the scientific foundation.

Tobacco use is strongly driven by the pharmacological actions of nicotine in the central nervous system. This review will summarize some of the seminal research findings relating to nicotine dependence and will highlight fundamental questions that must yet be answered. The evidence that nicotine is an addictive drug was summarized in the 1988 Report of the Surgeon General which concluded that nicotine fulfills the criteria for a dependence-producing drug. More recently, research has further characterized the pharmacological effects of nicotine in the brain and elucidated the basic pathophysiology of nicotine addition. Moreover, research shows that nicotine replacement therapy, such as nicotine patch or gum, can prevent or reverse withdrawal symptoms. It is also clear that the form of nicotine delivery is a major determinant of addiction potential and that cigarettes and smokeless tobacco products are both highly engineered drug delivery devices that act not only to provide users with controllable doses of nicotine, but also to maximize the addictive effects of nicotine. Along with the understanding of the dependence process has come a rapidly expanding arsenal of treatment for the disorder. There are many major questions about the nature and course of nicotine addiction that remain unanswered and must be addressed if we are to continue to improve our ability to prevent tobacco dependence as well as to provide more effective and acceptable options for treatment and disease prevention in those who are already addicted.