A Scoping Review of Craving and Opioid Use Disorder (OUD)

1. 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

2. 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.

3. 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.

4. 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 ”

5. Background (general) • Defining 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

6. 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.

7. 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.

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

9. Methods • Scoping Review • 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

10. PRISMA Diagram

11. Results • Overview of Studies (n=59) • 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)

13. 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

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

15. 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

16. 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

17. 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).

18. 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.

19. Questions and Discussion