A Scoping Review of Craving and Opioid Use Disorder (OUD) Bethea (Annie) Kleykamp, PhD Research Associate Professor University of Rochester School of Medicine and Dentistry Communications Director ACTTION

Affiliations and Disclosures BAK was previously employed by the healthcare consulting firm PinneyAssociates. PinneyAssociates provides scientific and regulatory advice on issues related to pharmaceutical risk management, abuse liability, over-the-counter switch of prescription medications, and non-combustible tobacco products (harm minimization). Clients included the pharmaceutical and tobacco industry.

Goals of Meeting Review craving as an outcome as it relates to OUD; Identify if there are gaps in the literature as it relates to craving outcome measures; If gaps exist, identify potential secondary analyses of existing data that could address these gaps; Discuss the potential utility of the concept of craving as an outcome measure in OUD treatment trials Determine whether there is utility and sufficient need for ACTTION to work toward developing and qualifying a craving OUD outcome measure.

Background (general) History of craving and addiction/drug dependence WHO, 1954 alcohol and craving meeting WHO, 1992 (craving mechanisms) NIDA, 2009: Tiffany et al., 2012 “Beyond drug use: a systematic consideration of other outcomes in evaluations of treatments for substance use ”

Background (general) Defining craving Models of craving PubMed Definition versus other definitions An intense, urgent, or abnormal desire or longing (for food, drugs, alcohol, etc.) Models of craving Background Stimulus induced craving Lack of consensus on craving and drug use Craving as a clinical endpoint Cue-elicited versus real-world craving Definition provided by FDA in recent public meeting: Craving, or a strong desire or urge to use opioids. https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm591290.htm

Background (specific to opioids) FDA Commissioner, Dr. Scott Gottlieb: “…craving is an endpoint that the FDA has included in labeling for smoking cessation products, and the agency intends to provide assistance to develop a validated measurement of “craving” or “urge to use” illicit opioids to complement other endpoints and to determine how it supports the goal of sustained abstinence.” Public meeting on patient-focused drug development public meeting Hosted by the FDA in collaboration with NIDA.

Craving defined as strong desire or urge to use opioids. In meeting. URL for above figure from FDA , 2018 Public Meeting: https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM605959.pdf Craving defined as strong desire or urge to use opioids. In meeting.

Objectives Primary objective Secondary objective provide an overview of craving outcome measures as they relate to OUD. Secondary objective identify gaps and limitations associated with the existing literature.

Methods Scoping Review Search strategy Study selection Mapping of literature related to craving measures (predictive validity not assessed) Search strategy PubMed, Scopus, and Embase databases searched with following terms: (craving OR urge to use OR desire) AND (opioid OR opiate OR OUD) Study selection Opioid dependent or in treatment Opioids primary drug of abuse Craving primary dependent variable

PRISMA Diagram

Results Overview of Studies (n=59) Craving Outcome Measures Sample sizes: Ns = 20 - 653 Publication years: 1986 – 2018 Geographically diverse (12 countries) Most experimental or observational rather than treatment-focused (11 RCTs) Craving Outcome Measures VAS most often used measure Multi-factor measures: Desire for Drugs Questionnaire (DDQ) Heroin Craving Questionnaire (HCQ) Obsessive Compulsive Drug Use Scale (OCDUS)

Desire for Drug Questionnaire (DDQ) VAS (0-100) 4 (varies 2-13) Name Scale Type Number of Items Time frame Desire for Drug Questionnaire (DDQ) VAS (0-100) 4 (varies 2-13) Present moment/ now Heroin Craving Questionnaire (HCQ) Likert-like (7-point) 45 (full) 10 (brief) Obsessive Compulsive Drug Use Scale (OCDUS) 13 Previous week Brief Substance Craving Scale (BSCS) (5-point) 4 Past 24 hours Craving Beliefs Questionnaire (CBQ) (7 point) 20 Not specified Chinese Craving Scale (CCS) (4 point) 10 Opioid Craving Scale (OCS) VAS (0-10) 3 Present moment/now Urge to Use Scale 5 Crav-Hero Inventory (5 point) Present moment/now and past week

Results continued Real-time craving studies (e.g., Ecological Momentary Assessment; EMA) Reviews of Craving and OUD (n=2) Fareed et al., 2010 non-methadone treatments (e.g., buprenorphine, naltrexone, haloperidol) 12 studies reviewed Fareed et al., 2011 Methadone focus 16 studies reviewed Fareed, A., Vayalapalli, S., Stout, S., Casarella, J., Drexler, K., & Bailey, S. P. (2010). Effect of methadone maintenance treatment on heroin craving, a literature review. Journal of addictive diseases, 30(1), 27-38. Fareed, A., Vayalapalli, S., Casarella, J., Amar, R., & Drexler, K. (2010). Heroin anticraving medications: a systematic review. The American journal of drug and alcohol abuse, 36(6), 332-341.

Additional Considerations Scale Development Measurement and Research Methods Self-report bias Timing of measurement Cue-elicited craving Mediating or Moderating Variables

Conclusions (specific) How has craving been measured in studies of OUD? Mainly VAS, single-item measures Multi-item measures that have been psychometrically evaluated exist (DDQ, HCQ) What study designs have been utilized to measure the role of craving in OUD? Mainly experimental and observational There is no gold-standard, psychometrically evaluated measure of craving for OUD. The most frequently used measure, VAS, while high in face validity, is argued to be limited in its ability to capture the varying components of craving. The field should not continue to dedicate time and resources to developing new craving measures, as there are existing measures. Efforts should be focused on ensuring that existing measures are psychometrically sound and for creating recommendations of for the use of such measures in research and clinical settings.

Conclusions (specific) What are the limitations of studies that have examined the role of craving in OUD? Variability across studies (designs, patient populations, craving measures, study outcomes) Does craving predict behavior? What are the research gaps related to craving and OUD? Limited psychometric studies Limited number of controlled trials that met inclusion criteria As noted above, there was a large amount of variability in the type of craving measures used across studies, with most studies relying on single-item VASs to assess craving. While such scales have a high degree of face validity and are more efficient for use in research, they are often criticized for not capturing the multiple components of craving found in other more complex scales (e.g., Franken et al., 2002; Heinz et al., 2006). Relatedly, one of the measures included in several of the studies, the HCQ, is often referenced using an unpublished citation (Tiffany et al., 1993 ). In addition, two publications evaluated for the present review were systematic reviews of the literature examining OUD and craving (Fareed et al., 2010; 2011). In combination, the Fareed et al. (2010; 2011) reviews included over 20 studies for analysis; however, neither review found strong evidence connecting craving and OUD treatment outcomes which begs the question as to how important the concept of craving is for predicting opioid use behavior. Lastly, several studies examining opioid use and craving included small sample sizes (<20) and these studies were excluded from review (Bradley & Moorey, 1988; Greenwald, 2002; C. R. Schuster, M. K. Greenwald, C.-E. Johanson, & S. J. Heishman, 1995; Sideroff, Charuvastra, Jarvik, & Ouren, 1978; Wolpe, 1965).  Add to ref list Overall, there is a relatively large body of literature that has examined craving measures as they relate to OUD as reflected by the 61 papers included in the present review. However, as noted, there is a great deal of variability across studies in the type of craving outcomes used to assess OUD and most of these studies were experimental or observational in nature. Most often these measures have not been critically evaluated for their psychometric properties and there are few rigorous controlled trials that have examined the prognostic utility of such measures. Also, as mentioned as a limitation of the existing body of work, the HCQ appears to be a validated measure of opioid craving; however, there exists no peer-reviewed publication to support its use. Therefore, one possible avenue for future research would be to verify the psychometric qualities of this measure and publish its properties so as to facilitate systematic use in future research.

Conclusions (general) Is there an existing reliable and valid measure of craving that can be used to predict the impact of OUD treatments? No. Some measures have been evaluated for their psychometric properties (e.g., DDQ, HCQ), but in a limited number of studies and patient populations. An expectation for a ‘gold-standard’ measure of craving depends on research goals and practical considerations (time constraints).

Conclusions (general) Should scientists dedicate time and resources to the development of reliable & valid measure of opioid craving for use in OUD treatment studies? No and Yes. There has been a great deal of work completed on the development of opioid craving measures. This work can provide a starting point for further psychometric testing of craving measures and evaluation in treatment studies. Efforts are contingent on craving being designated an important clinical endpoint in addition to drug use behavior.

Questions and Discussion