Jennifer M. Wray

The clinical significance of drug craving.

Although drug craving has received considerable research attention over the past several decades, to date there has been no systematic review of the general clinical significance of craving. This paper presents an overview of measurement issues of particular relevance to a consideration of use of craving in clinical settings. The paper then considers the relevance of craving across a broad array of clinical domains, including diagnosis, prognostic utility, craving as an outcome measure, and the potential value of craving as a direct target of intervention. The paper is both descriptive and prescriptive, informed by the current state of the science on craving with recommendations for the definition of craving, assessment practices, future research, and clinical applications. We conclude that craving has considerable utility for diagnosis and as a clinical outcome, and that findings from future research will likely expand the clinical potential of the craving construct in the domains of prognosis and craving as a treatment target.

A Systematic Review of the Relationships Between Craving and Smoking Cessation

INTRODUCTION Craving is often portrayed as a defining feature of addiction, but the role of craving in the addictive process is controversial. Particularly contentious is the extent to which drug craving predicts subsequent relapse. METHODS This review synthesizes findings from 62 smoking cessation studies published through December 2011. Eligible studies measured craving for cigarettes in treatment-seeking smokers and related this to subsequent smoking status. The relationships of general craving and cue-specific craving with treatment outcome were examined separately. Further, analyses that related general craving to smoking status were divided into those that used craving data collected before the quit attempt, after the quit attempt, and those that used change in craving over time as a predictor. RESULTS Results across studies revealed a total of 198 indices of association with 94 (47%) of these being significant. In general, the findings indicated (a) there were only a few cases of significant associations between craving collected as part of cue-reactivity studies and treatment outcome, (b) postquit craving was a stronger predictor of treatment outcome than prequit craving, and (c) several moderators likely influence the relationship between craving and cessation outcome. CONCLUSIONS The overall results suggest that craving is not a necessary condition of relapse. In addition, inconsistent relationships between craving and treatment outcome call into question the value of craving as a target of treatment and underscore limitations in the prognostic utility of craving.

Gender differences in responses to cues presented in the natural environment of cigarette smokers.

INTRODUCTION Although the evidence is mixed, female smokers appear to have more difficulty quitting smoking than male smokers. Craving, stress, and negative affect have been hypothesized as potential factors underlying gender differences in quit rates. METHODS In the current study, the cue-reactivity paradigm was used to assess craving, stress, and negative affect in response to cues presented in the natural environment of cigarette smokers using ecological momentary assessment. Seventy-six daily smokers (42% female) responded to photographs (smoking, stress, and neutral) presented 4 times per day on an iPhone over the course of 2 weeks. RESULTS Both smoking and stress cues elicited stronger cigarette craving and stress responses compared to neutral cues. Compared with males, females reported higher levels of post-stress cue craving, stress, and negative affect, but response to smoking cues did not differ by gender. DISCUSSION Findings from this project were largely consistent with results from laboratory-based research and extend previous work by measuring response to cues in the natural environment of cigarette smokers. This study extends previous cue reactivity ecological momentary assessment research by using a new platform and by measuring response to stress cues outside of the laboratory. Findings from this project highlight the importance of addressing coping in response to stress cues in clinical settings, especially when working with female smokers.

Impact of varenicline on cue-specific craving assessed in the natural environment among treatment-seeking smokers

RationaleVarenicline is believed to work, in part, by reducing craving responses to smoking cues and by reducing general levels of craving; however, these hypotheses have never been evaluated with craving assessed in the natural environments of treatment-seeking smokers.ObjectivesEcological momentary assessment procedures were used to assess the impact of varenicline on cue-specific and general craving in treatment-seeking smokers prior to quitting.MethodsFor 5 weeks prior to quitting, 60 smokers carried personal digital assistants that assessed their response to smoking or neutral cues. During week 1 (baseline), participants did not receive medication; during weeks 2–4 (drug manipulation), participants were randomized to receive varenicline or placebo; during week 5 (standard therapy), all participants received varenicline. Craving was assessed before each cue; cue-specific craving and attention to cue were assessed after each cue.ResultsDuring all phases, smoking cues elicited greater craving than neutral cues; the magnitude of this effect declined after the first week. General craving declined across each phase of the study. Relative to the placebo condition, varenicline was associated with a greater decline in general craving over the drug manipulation phase. Varenicline did not significantly attenuate cue-specific craving during any phase of the study.ConclusionsSmoking cues delivered in the natural environment elicited strong craving responses in treatment-seeking smokers, but cue-specific craving was not affected by varenicline administered prior to the quit attempt. These findings suggest that the clinical efficacy of varenicline is not mediated by changes in cue-specific craving during the pre-quit period of treatment-seeking smokers.

The magnitude and reliability of cue-specific craving in nondependent smokers.

BACKGROUND Cue-reactivity is a robust phenomenon in regular cigarette smokers (Carter and Tiffany, 1999), but it has not been widely investigated in nondependent smokers. Further, most research on cue-specific craving assesses response to cues in a single experimental session. As such, investigations of cue-specific craving have primarily measured state-like but not trait-like responses to smoking stimuli. METHODS This study measured general and cue-specific craving in nondependent smokers and assessed the within-session and cross-session reliability of these two facets of craving. Participants (n=154) attended five laboratory sessions over the course of three months and completed multiple cue-reactivity trials (using smoking and neutral in vivo and photographic stimuli) during each study visit. RESULTS Results indicated that smoking cues elicited significantly stronger craving than neutral cues across study sessions, and that craving ratings following smoking cues decreased across subsequent sessions. Within-session and cross-session reliability was extremely high. CONCLUSIONS Overall, findings indicate that nondependent smokers experience reactivity to smoking cues, and that this response is quite reliable within and across sessions. Further, the magnitude of cue-specific craving was comparable to what has been observed in heavy, dependent smokers.

Effects of experimental negative affect manipulations on ad libitum smoking: a meta-analysis.

AIMS To quantify the effect of negative affect (NA), when manipulated experimentally, upon smoking as measured within laboratory paradigms. Quantitative meta-analyses tested the effects of NA versus neutral conditions on (1) latency to smoke and (2) number of puffs taken. METHODS Twelve experimental studies tested the influence of NA induction, relative to a neutral control condition (n = 1190; range = 24-235). Those providing relevant data contributed to separate random-effects meta-analyses to examine the effects of NA on two primary smoking measures: (1) latency to smoke (nine studies) and (2) number of puffs taken during ad libitum smoking (11 studies). Hedges g was calculated for all studies through the use of post-NA cue responses relative to post-neutral cue responses. This effect size estimate is similar to Cohens d, but corrects for small sample size bias. RESULTS NA reliably decreased latency to smoke (g = -0.14; CI = -0.23 to -0.04; P = 0.007) and increased number of puffs taken (g = 0.14; CI = 0.02 to 0.25; P = 0.02). There was considerable variability across studies for both outcomes (I(2)  = 51 and 65% for latency and consumption, respectively). Potential publication bias was indicated for both outcomes, and adjusted effect sizes were smaller and no longer statistically significant. CONCLUSIONS In experimental laboratory studies of smokers, negative affect appears to reduce latency to smoking and increase number of puffs taken, but this could be due to publication bias.

Response Time to Craving-Item Ratings as an Implicit Measure of Craving-Related Processes

Drug craving is typically measured through explicit ratings of craving levels. We examined response time to craving ratings as an implicit measure of craving processes in cigarette smokers. Response time and interitem variability were investigated as potential indices of certainty in craving ratings. Cigarette smokers, categorized as tobacco dependent or nondependent, completed multiple cue-reactivity sessions with smoking and neutral cues. After each cue presentation, craving level and response time were assessed. Significant inverted-U relationships emerged between craving level and both response time and interitem variability across conditions, sessions, and groups. Faster response times and less interitem variability emerged after neutral cues relative to smoking cues for nondependent smokers and after smoking cues relative to neutral cues for dependent smokers. Response time provided incremental validity beyond craving level in predicting dependence. Results support use of response time as an implicit measure of craving processes and further distinguish craving experiences between dependent and nondependent smokers.

Diagnostic Utility of Craving in Predicting Nicotine Dependence: Impact of Craving Content and Item Stability

INTRODUCTION Craving is useful in the diagnosis of drug dependence, but it is unclear how various items used to assess craving might influence the diagnostic performance of craving measures. This study determined the diagnostic performance of individual items and item subgroups of the 32-item Questionnaire on Smoking Urges (QSU) as a function of item wording, level of craving intensity, and item stability. METHODS Nondaily and daily smokers (n = 222) completed the QSU on 6 separate occasions, and item responses were averaged across the administrations. Nicotine dependence was assessed with the Wisconsin Inventory of Smoking Dependence Motives. The discriminative performance of the QSU items was evaluated with receiver-operating characteristic curves and area under the curve statistics. RESULTS Although each of the QSU items and selected subgroups of items significantly discriminated dependent from nondependent smokers, certain item subgroups outperformed others. There was no difference in discriminative performance between use of the specific terms urge and crave or between items assessing intention to smoke relative to those assessing desire to smoke, but there were significant differences in the two major factors represented on the QSU and in craving items reflecting more intense relative to less intense craving. Stability of the item scores was strongly related to the discriminative performance of craving. CONCLUSIONS Items indexing stable, high-intensity aspects of craving that reflect the negative reinforcing effects of smoking will likely be most useful for diagnostic purposes. Future directions and implications are discussed.

Selection criteria limit generalizability of smoking pharmacotherapy studies differentially across clinical trials and laboratory studies: A systematic review on varenicline

BACKGROUND The selection criteria used in clinical trials for smoking cessation and in laboratory studies that seek to understand mechanisms responsible for treatment outcomes may limit their generalizability to one another and to the general population. METHODS We reviewed studies on varenicline versus placebo and compared eligibility criteria and participant characteristics of clinical trials (N=23) and laboratory studies (N=22) across study type and to nationally representative survey data on adult, daily USA smokers (2014 National Health Interview Survey; 2014 National Survey on Drug Use and Health). RESULTS Relative to laboratory studies, clinical trials more commonly reported excluding smokers who were unmotivated to quit and for specific medical conditions (e.g., cardiovascular disease, COPD), although both study types frequently reported excluding for general medical or psychiatric reasons. Laboratory versus clinical samples smoked less, had lower nicotine dependence, were younger, and more homogeneous with respect to smoking level and nicotine dependence. Application of common eligibility criteria to national survey data resulted in considerable elimination of the daily-smoking population for both clinical trials (≥47%) and laboratory studies (≥39%). Relative to the target population, studies in this review recruited participants who smoked considerably more and had a later smoking onset age, and were under-representative of Caucasians. CONCLUSIONS Results suggest that selection criteria of varenicline studies limit generalizability in meaningful ways, and differences in criteria across study type may undermine efforts at translational research. Recommendations for improvements in participant selection and reporting standards are discussed.

Menstrual Cycle Phase Effects in the Gender Dimorphic Stress Cue Reactivity of Smokers

INTRODUCTION We previously reported that female smokers evidence greater subjective craving and stress/emotional reactivity to personalized stress cues than males. The present study employed the same dataset to assess whether females in the follicular versus luteal phase of the menstrual cycle accounted for the gender differences. METHODS Two objective criteria, onset of menses and luteinizing hormone surge (evaluated via home testing kits), were used to determine whether female smokers were in either the follicular (n = 22) or the luteal (n = 15) phase of their menstrual cycle, respectively. The females and a sample of male smokers (n = 53) were then administered a laboratory-based cue reactivity paradigm that involved assessment of craving, stress, and emotional reactivity in response to counterbalanced presentations of both a personalized stress script and neutral/relaxed script. RESULTS While there were no significant differences between females in the follicular versus luteal phase on any outcome measure, females in the luteal menstrual phase reported greater craving than males whereas females in the follicular phase reported greater stress and arousal than males and perceived the stress cues as more emotionally aversive than males. CONCLUSIONS This preliminary investigation suggests that gender differences in craving versus affective responding to stress cues may, in part, be explained variation by menstrual cycle phase. Study limitations and implications of the findings for future research and treatment are briefly discussed.