Jack E. Henningfield

The reemergence of smokeless tobacco

Smokeless tobacco (snuff and chewing tobacco) is reemerging as a popular form of tobacco, particularly among male adolescents. In different regions of the United States, from 8 to 36 percent of male high-school students are regular users. The use of smokeless tobacco has been shown to cause oral-pharyngeal cancer. The strongest link is with cancers of the cheek and gum. White mucosal lesions (leukoplakia) are found in 18 to 64 percent of users, often at the site where the tobacco was held. Other associations have been suggested for cancers of the esophagus, larynx, and pancreas. Nitrosamines, found in high concentrations in smokeless tobacco, most likely have a role in its carcinogenicity. Other health problems include periodontal disease, acute elevations of blood pressure, and dependence. In early 1986, after action at the state level, Congress enacted a federal law requiring health-warning labels on packages of smokeless tobacco and a ban on electronic advertising. Other regulatory measures under consideration include raising state and federal excise taxes, tightening controls on advertising, and prohibiting sales to minors. In view of the recent growth of this problem, policy makers are taking the opportunity to intervene with preventive measures to protect a new generation of tobacco users.

The Fagerstrom Test for Nicotine Dependence and the Diagnostic Interview Schedule: do they diagnose the same smokers?

Two common assessment tools for nicotine dependence are the Fagerstrom Test for Nicotine Dependence (FTND) and the Nicotine Dependence section of the Diagnostic Interview Schedule [(DIS)-III-R or -IV based on the Diagnostic and Statistical Manual (DSM)-III-R and -IV, respectively]. The FTND emphasizes morning smoking and overall heaviness of smoking. The DSM emphasizes adverse consequences, desire to cut down, and mood changes during withdrawal. We tested (1) how the DSM-III-R diagnosis of Nicotine Dependence is related to FTND score; and (2) how the (a) DSM-III-R or (b) elevated FTND score is related to longer smoking histories, greater psychiatric symptomatology, and tobacco liking scores. Retrospective chart reviews were conducted on 370 smokers, the majority (55.9%) of whom had a current DSM-III-R diagnosis of Substance Dependence other than nicotine. All subjects had completed the FTND, the DIS-III-R, the Symptom Checklist-90-Revised (SCL-90-R), and a survey on drug liking. Agreement statistics were calculated between the DSM-II-R diagnosis of Nicotine Dependence and various cutoff scores values that were assigned as thresholds for nicotine dependence on the FTND. At no cutoff score did the two instruments reliably agree; the highest kappa (at a cutoff of FTND > or = 7) was 0.205. At cutoffs above 5, the FTND diagnosed fewer cases than the DSM-III-R. Multiple regression analysis showed that DSM diagnosis was associated with greater psychiatric symptomatology on the SCL-90-R, while FTND scores were associated with greater tobacco liking. The FTND and the DSM-III-R appear to measure different aspects of the tobacco dependence process. Specifically, the FTND may provide a stronger measure of physical dependence, while the DSM may tap other domains such as awareness of dependence, behaviors resulting from that awareness, and psychiatric symptomatology. Disagreements between the FTND and the DSM are likely to become greater with the changes in the DSM-IV.

Toward a comprehensive long term nicotine policy

Global tobacco deaths are high and rising. Tobacco use is primarily driven by nicotine addiction. Overall tobacco control policy is relatively well agreed upon but a long term nicotine policy has been less well considered and requires further debate. Reaching consensus is important because a nicotine policy is integral to the target of reducing tobacco caused disease, and the contentious issues need to be resolved before the necessary political changes can be sought. A long term and comprehensive nicotine policy is proposed here. It envisages both reducing the attractiveness and addictiveness of existing tobacco based nicotine delivery systems as well as providing alternative sources of acceptable clean nicotine as competition for tobacco. Clean nicotine is defined as nicotine free enough of tobacco toxicants to pass regulatory approval. A three phase policy is proposed. The initial phase requires regulatory capture of cigarette and smoke constituents liberalising the market for clean nicotine; regulating all nicotine sources from the same agency; and research into nicotine absorption and the role of tobacco additives in this process. The second phase anticipates clean nicotine overtaking tobacco as the primary source of the drug (facilitated by use of regulatory and taxation measures); simplification of tobacco products by limitation of additives which make tobacco attractive and easier to smoke (but tobacco would still be able to provide a satisfying dose of nicotine). The third phase includes a progressive reduction in the nicotine content of cigarettes, with clean nicotine freely available to take the place of tobacco as society’s main nicotine source.

Estimation of available nicotine content of six smokeless tobacco products.

Correspondence to : Jack E Henningfield, NIDA Addiction Research Center, PO Box 5180 (or 4940 Eastern Ave), Baltimore, MD 21224, USA Abstract Objective To determine if nicotine con tent and pH vary among a series of smokeless tobacco products and if nic otine dosage would be altered selectively. Methods The pH level and nicotine con centration were determined in six smoke less tobacco products. The tests were performed on four sets of samples bought in three regions of the US. Free, un ionised nicotine, available for absorption, was estimated mathematically with the Henderson-Hasselbalch equation. Results Nicotine concentrations of the tobacco products were 7.5 mg nicotine per gram of wet (undried) tobacco for Skoal Bandits Wintergreen and ranged from 10.3 to 11.4 mg/g for the other five products. The pH levels were 6.9 for Skoal Bandits Wintergreen, 8.6 for Copenhagen Snuff, and ranged from 7.4 to 7.6 for the other products. These data enabled the identification of four levels of available nicotine across products, with free nic otine estimates in aqueous solutions ranging from 7% to 79%. Conclusions Nicotine dosing capability shows wide variation across products and is determined by the nicotine content and pH level. Manipulation of pH appears to be the primary means of nicotine dose control. Human bioavailability testing would be required to determine actual amounts and rates of nicotine absorbed per gram of the various products and to determine the influence of factors such as tobacco cut and other chemical additives.

NIH electronic cigarette workshop: Developing a research agenda

BACKGROUNDnElectronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood.nnnPURPOSEnThis paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes.nnnRESULTS AND CONCLUSIONSnThe research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences.

Tobacco dependence and withdrawal: Science base, challenges and opportunities for pharmacotherapy

Several pharmacotherapies for tobacco dependence and withdrawal have been approved by the Food and Drug Administration to aid smoking cessation. These medicines double to triple the odds of cessation compared to placebo, with the diversity in chemical entity (e.g., nicotine, varenicline, bupropion) and route (e.g., nicotine gum and transdermal patch) providing options for people who find a given medication unacceptable or ineffective. Treatments in development include vaccines, combinations of existing products, and new indications, such as reduced tobacco use and exposure. These therapies have been developed on the foundation of research on the neuropharmacology of tobacco dependence and withdrawal. Ongoing research is expected to contribute to more efficacious use of existing therapies and the development of new approaches. This article addresses these developments as well as the challenges to medication development. Challenges include understanding the population-based and individual differences in the vulnerability to dependence and responsiveness to various treatment options, which could contribute to effective treatment to patient matching. Research on the CNS effects of administration and withdrawal of nicotine and other tobacco product constituents is expanding, providing the basis for more effective therapeutic approaches and new medications development. Additionally, whereas medications are approved on the basis of standardized assessments of efficacy and safety in clinical trials, the public health impact of medications depends also on their appeal to smokers and their effectiveness in actual use settings. Research on more effective medication use along with policies that support improved access and utilization are vital to conquering the tobacco epidemic.

Human cocaine-seeking behavior and its control by drug-associated stimuli in the laboratory.

Second-order schedules of drug self-administration were developed to incorporate the effects of drug-related environmental stimuli into an animal model of drug abuse, making it more similar to human situations. Ironically, little is known about how human subjects behave under these schedules. In this study, human volunteers with a history of cocaine use worked on a second-order schedule in which every 100th lever response produced an auditory–visual brief stimulus (2 s). The first stimulus produced after 1 h was extended to 10 s and paired with an intravenous injection of cocaine (25 mg). Up to three injections were allowed per session. In different phases of the experiment, presentation of the brief stimulus was discontinued and/or saline solution (placebo) was injected instead of cocaine. Injections of cocaine were found to maintain responding even when the brief stimulus was not presented. Placebo injections alone did not maintain responding. In contrast, the brief stimulus maintained high levels of responding under placebo conditions, even though self-reports indicated that subjects could clearly discriminate that they were not receiving cocaine. These results demonstrate that drug-related environmental stimuli can maintain persistent drug seeking during periods of drug unavailability. As this procedure directly measures the effects of stimuli on drug seeking, it may provide a valuable complement to indirect measures, such as self-reports of craving, that are often used with human subjects. The similarity of the response patterns in humans and animals also supports the use of second-order schedules in animals as a valid model of human drug seeking.

A factor analysis of the fagerstrom tolerance questionnaire.

A factor analysis of 1309 Fagerstrom Tolerance Questionnaires (FTQ) was performed with LISCOMP software, which utilizes tetrachoric correlations to account for the dichotomous responses of the FTQ. Three factors with eigenvalues greater than 1.0 were obtained, accounting for 56.6% of the variance. Factor 1 was loaded by questions How soon on waking do you smoke your first cigarette?, Do you find it difficult to refrain from smoking in places it is forbidden?, How many cigarettes a day do you smoke?, and Do you smoke if you are so ill that you are in bed most of the day? Factor 2 was loaded by questions Which cigarette would you hate to give up? and Do you smoke more during the morning than during the rest of the day? Factor 3 was loaded exclusively by question What brand do you smoke? The question Do you inhale always, sometimes, or never? loaded exclusively on a fourth factor, however its eigenvalue did not reach significance. Support is provided for the modification of the eight-item FTQ to the six-item Fagerstrom Test for Nicotine Dependence (FTND). Based on the wording of the questions that loaded on each factor, we propose that Factor 2 assesses the degree of urgency to initiate smoking after overnight abstinence and that Factor 1 reflects the persistence of smoking during waking hours.

Brand differences of free-base nicotine delivery in cigarette smoke: the view of the tobacco industry documents

The recent availability of internal tobacco industry documents provides significant insight into industry knowledge and manipulation of tobacco smoke delivery. One critical area of research is the role of smoke chemistry in determining the absorption and effects of smoke constituents, especially harm producing or pharmacologically active compounds. Independent scientific research has suggested that the nicotine dosing characteristics, hence the addiction potential of cigarettes, may be determined in part by the amount of free-base nicotine in cigarette smoke and its effects on the location, route, and speed of absorption in the body and on the sensory perception effects of the inhaled smoke. Tobacco industry documents describe the use of a number of methods internally for measuring free-base nicotine delivery. These include the common use of cigarette “smoke pH” as a means to estimate the fraction of free-base nicotine in the particulate matter (PM) in cigarette smoke, as well as efforts to measure free-base nicotine directly. Although these methods do not provide accurate absolute measures of free-base nicotine in smoke, consistencies observed in the findings across the various manufacturers indicate: (1) real relative differences in the acid/base chemistry of the smoke from different brands of cigarettes; (2) a connection between differences in free-base levels and brand-dependent differences in sensory perception and smoke “impact”; and (3) levels of free-base nicotine that are greater than have typically been publicly discussed by the industry. Furthermore, the results of these methods are generally consistent with those of a recent study from the Centers for Disease Control and Prevention which directly measured the free-base fraction of nicotine across a range of cigarette types. Consideration of the likely fundamental importance of free-base nicotine levels in cigarette smoke, together with the efforts discussed in the tobacco industry documents to measure such levels, indicates that the public health community would benefit from additional research to assess directly the delivery of free-base nicotine in cigarette smoke across brands. This may be especially useful for those products (“light”, “ultralight”, “reduced carcinogen”, etc) that have been promoted, either explicitly or implicitly, as “harm reducing”.

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.