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4 Methods for Investigating Addictive Potential
Pages 149-190

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From page 149...
... with regard to the public health standard concerns, in part, an evaluation of the product with regard to its tendency to promote the following: • Initiation and continuation of its regular use • Switching to its use and cessation of the consumption of more harmful tobacco products (e.g., aid in cessation of use of conventional cigarettes) • Dual use (use of the MRTP concurrent with continued use of an existing harmful form of tobacco use such as smoking conventional cigarettes)
From page 150...
... can be gauged through animal research; however, in the present situation, animal research on reinforcement value does not appear optimal. First, animal research is especially warranted when the product poses significant immediate health risks.
From page 151...
... Doses may reflect what is considered a meaningful dose in terms of real-world use, they may be based upon brief ad libitum use, or they may be established via dose banding methods. Ideally, an MRTP would be sufficiently reinforcing so as to attract smokers away from conventional cigarettes but not encourage the widespread dependent use of the product by individuals who were previously nonusers or who would have quit smoking.
From page 152...
... Relative Reinforcement Value in Regular Smokers One question of key importance is the extent to which an MRTP is reinforcing among current heavy smokers. This would be relevant to the extent to which the product would be used heavily enough by smokers to serve as a cessation aid or a long-term substitute with regard to smoking conventional cigarettes.
From page 153...
... Adolescents who have experimented with smoking might constitute a particularly high-risk population with high public health significance. Finally, the use of ex-smokers would suggest the potential reinforcement value of MRTP use in this population, which has demonstrated sensitiv ity to nicotine reinforcement.
From page 154...
... It is important that subjects have similar expectations about the experiment and what it entails (e.g., the nature of the tested products) unless manipulation of expectations is an explicit element of the study design (because expectations can significantly affect response to a tobacco product [Perkins et al., 2010]
From page 155...
... . In particular, acute blood nicotine absorption profiles in response to both single and repeated use of products is a relevant component in assessing the addictive potential of MRTPs.
From page 156...
... However, as discussed elsewhere, it seems that use of both conventional cigarettes (when smokers or ex-smokers are used as subjects) and NRT would be informative, because these represent products with very high versus modest reinforcement value.
From page 157...
... Timing and Exposure Parameters Experiments aimed at characterizing reinforcement value could present MRTPs and other products in diverse ways. The mode of presentation should be dictated by the experimental paradigm used, as well as the research question.
From page 158...
... or with unusual con trolled dosing procedures, it may be desirable to allow the subjects some practice with the procedure so learning or familiarization effects are not confounded with changes in reinforcement value that develop with drug use experience.
From page 159...
... However, the apparent differences among some tobacco products (snus versus conventional cigarettes or e-cigarettes) may compromise the ability to achieve true placebo con trol or blinding.
From page 160...
... This is important in part because pharmacodynamics may greatly affect reinforcement value and abuse potential (Dewit et al., 1993; Mumford et al., 1995)
From page 161...
... on the other hand, then instrumental responses for the agent or product would constitute a key indication of reinforcement potency. In an acute laboratory setting subjects could work for products across several different contexts: under differing levels of tobacco withdrawal, with different response requirements, and using different instrumental paradigms (progressive ratio schedules for individual products, concurrent schedules for the MRTP versus conventional cigarettes and/or money; and with varying response requirements to generate demand curves)
From page 162...
... Such data would be relevant to the question of whether the MRTP might substitute for conventional tobacco products in such populations. Finally, while human drug discrimination paradigms can be highly informative in the evaluation of new products (Carter and Griffiths, 2009)
From page 163...
... . Demand elasticity refers to the extent to which work for a substance (e.g., an MRTP or conventional tobacco product)
From page 164...
... and to reduce motivation to smoke conventional cigarettes because of preloading with the MRTP. Important in all of these paradigms is the modeling of change over repeated exposure occasions because this could reflect development of increased reinforcement value owing to tolerance to aversive effects or dependence development.
From page 165...
... how its use affects the initiation of use of conventional tobacco products and relapse back to use of such products (e.g., resumption of smoking conventional cigarettes after an extended period of abstinence)
From page 166...
... If the major question is how MRTP availability affects future use of conventional tobacco products, the design should contrast a condition where some subjects are randomly assigned to use the MRTP and others a placebo or a comparison product (Robinson et al., 2000)
From page 167...
... . Other criteria could also be forwarded, such as withdrawal from an MRTP should not be as severe as that arising from withdrawal from conventional tobacco products.
From page 168...
... Primary outcomes should be few in number and explicit. It seems that a primary outcome should be percentage of smokers of conventional cigarettes (or another conventional tobacco product, depending on the goal of the study)
From page 169...
... Checklist Item Page No. Title and abstract 1a Identification as a randomized trial in the title 1b Structured summary of trial design, methods, results, and conclusions (for specific guidance, see CONSORT for abstracts)
From page 170...
... , describing any steps taken to conceal the sequence until interventions were assigned Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 11b If relevant, description of the similarity of interventions Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses
From page 171...
... included in each analysis and whether the analysis was by original assigned groups Outcomes and estimation 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) 17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing prespecified from exploratory Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms)
From page 172...
... Discussion Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses Generalizability 21 Generalizability (external validity, applicability) of the trial findings Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Other information Registration 23 Registration number and name of trial registry Protocol 24 Where the full trial protocol can be accessed, if available Funding 25 Sources of funding and other support (such as supply of drugs)
From page 173...
... Therefore, chronic smokers of conventional cigarettes (the most harmful conventional tobacco product) are an important target population for an RCT.
From page 174...
... Finally, while it might seem difficult to attract smokers into a clinical trial who do not wish to quit, in fact, many such smokers are willing to participate in order to try a new product that might be safer than conventional tobacco or that might allow them to reduce their smoking (Carpenter et al., 2004)
From page 175...
... In terms of tobacco dependence assessment, the Fagerstrom Test for Nicotine Dependence or one of the new multifactorial dependence assessments (the Nicotine Dependence Syndrome Scale [Shiffman and Sayette, 2005; Shiffman et al., 2004] or the Wisconsin Inventory of Smoking Dependence Motives [Smith et al., 2010]
From page 176...
... . In particular, acute blood nico tine absorption profiles in response to both single and repeated use of products is a meaningful component in assessing the addictive potential of MRTPs.
From page 177...
... Baseline measures should be taken of all those variables that are to be used as outcomes, moderators, covariates, or to characterize the sample, such as smoking rate, use of all tobacco products, biochemical measures of heaviness of tobacco use, nicotine dependence, socioeconomic and educational status, withdrawal symptoms, affect, mental health history, physical health status and perceived health status, medication use, aversive events (e.g., due to nicotine toxicity) , smoking history (e.g., age of first smoking/daily smoking, longest prior abstinence from a quit attempt, prior use of quitting aids)
From page 178...
... data not only on conventional tobacco and MRTP use, but also on such secondary outcomes as MRTP attitudes and liking, motivation to quit, tobacco dependence, changes in important environmental variables (e.g., smokers in the home) , and MRTP use in subjects' social networks (if study is postmarketing)
From page 179...
... , where many individuals may not even use the MRTP or attempt to quit using a conventional tobacco product, how does MRTP availability affect outcomes? If it is deemed important to determine the effectiveness of the product in a formal, structured quit attempt relative to cessation aids such as NRTs, then it should be offered with considerable support for its use.
From page 180...
... . For instance, not only is it of interest to determine if the MRTP affects future use of conventional tobacco, but also it is important to obtain additional information on the health risks that might attend chronic and unsupervised use, or the extent to which MRTP use affects tobacco withdrawal symptoms.
From page 181...
... Explicit permission for a subject to skip a follow-up contact with the understanding that s/he may resume participation at some future point in time These methods should be adopted in an effort to reduce attrition and boost ascertainment rates. With such methods it may be possible to track clinical trial participants over several years.
From page 182...
... and use with measures of use of conventional tobacco products (e.g., cigarette
From page 183...
... Nicotine dependence with regard to use of both the MRTP as well as conventional tobacco products 6. Changes in perception of conventional tobacco products and of the MRTP as a function of MRTP use over time (e.g., liking, addictiveness, safety)
From page 184...
... ; however, note that the MRTP need not necessarily be "better" or even equivalent to the NRT in order to exert a public health benefit. An MRTP that is inferior to NRTs (more toxicants, less effective at boosting cessation of smoking conventional cigarettes)
From page 185...
... 1997. A double-blind randomized trial of nicotine nasal spray as an aid in smoking cessation.
From page 186...
... 2009. Clinical trials methods for evaluation of potential reduced exposure products.
From page 187...
... J Hedley, and Hong Kong Council on Smok ing and Health Smoking Cessation Health Centre Steering Group.
From page 188...
... 2010. Refining the tobacco dependence pheno type using the Wisconsin Inventory of Smoking Dependence Motives: II.
From page 189...
... 2009. A randomized placebo-controlled clinical trial of 5 smoking cessation pharmaco therapies.
From page 190...
... 1992. Randomised controlled trial of nasal nicotine spray in smoking cessation.


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