In 2016, the Centers for Disease Control and Prevention (CDC) issued guidelines for ?all prescribers to avoid co-prescribing of benzodiazepine (benzo) and opioids?. Other guidelines also advise against benzos for anxiety because safer substitutes exist (serotonin?norepinephrine reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]). Since the 2016 CDC guideline, use of gabapentinoids as an opioid substitute has risen. While recent data showed a decline in opioid prescribing rates after publication of the CDC guideline, a knowledge gap exists in terms of the rates, effectiveness and safety of opioid/benzo substitute prescribing and co-prescribing, especially in populations at high risk of drug toxicity: persons living with disabilities, the elderly and Medicare enrollees in home health care. We now propose to address this gap in knowledge by comprehensively evaluating the toxicity and effectiveness of opioid and benzo substitutes, alone or in combination, compared to opioids and benzos. We anticipate the emergence of previously unrecognized toxicities from drug substitution and co-prescribing.
Our Specific Aims are: 1. Assess temporal change in prescribing rates of opioids, opioid substitutes, benzos and benzo substitutes and their co-prescribing among commercially insured and Medicare patients, and the role of provider, patient, federal and state policy on drug substitution and co-prescribing. 2. Examine toxicities (e.g., falls, fractures, emergency room visits) related to substitutes for opioids and benzos, and how toxicities vary with different combinations of drug substitution and co-prescribing, using longitudinal data analytic methods as well as data mining methods for previously unrecognized toxicities. 3. Examine changes in physical function and measures of pain and anxiety in Medicare enrollees prescribed substitutes for both opioids and benzos, and how these outcomes vary with different combinations of drug substitution and co-prescribing among Medicare enrollees in home health care. We will use 20% national Medicare data to identify the elderly and the disabled Medicare populations, and the Clinformatics Data Mart to identify commercially insured populations. Our overall hypotheses is that the substitute drugs, alone or in combination, have considerably lower rates of serious toxicity than do opioids and benzos, with similar effectiveness in many clinical situations. If this is the case, its demonstration by our proposed research should result in acceleration in the shift away from opioids and benzos to safer alternatives.

Public Health Relevance

In 2016, the Centers for Disease Control and Prevention issued guidelines for ?all prescribers to avoid co- prescribing of benzodiazepine and opioids and other guidelines also advised against benzos for anxiety because safer substitutes exist. Neither opioid nor benzo substitutes (gabapentinoids, Z-drugs and SSRIs) alone or in combination have been studied. We will use both 20% national Medicare data and a large commercial health insurance database to study the effectiveness and safety of the substitutes, whether the substitutes improve pain and function, and whether they have fewer toxicities.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Su, Shelley
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Med Br Galveston
Public Health & Prev Medicine
Schools of Medicine
United States
Zip Code
Raji, Mukaila A; Kuo, Yong-Fang; Adhikari, Deepak et al. (2018) Decline in opioid prescribing after federal rescheduling of hydrocodone products. Pharmacoepidemiol Drug Saf 27:513-519
Kuo, Yong-Fang; Raji, Mukaila A; Liaw, Victor et al. (2018) Opioid Prescriptions in Older Medicare Beneficiaries After the 2014 Federal Rescheduling of Hydrocodone Products. J Am Geriatr Soc 66:945-953
Raji, Mukaila A; Kuo, Yong-Fang; Chen, Nai-Wei et al. (2017) Impact of Laws Regulating Pain Clinics on Opioid Prescribing and Opioid-Related Toxicity Among Texas Medicare Part D Beneficiaries. J Pharm Technol 33:60-65
Connolly 3rd, Joseph; Javed, Zulqarnain; Raji, Mukaila A et al. (2017) Predictors of Long-term Opioid Use Following Lumbar Fusion Surgery. Spine (Phila Pa 1976) 42:1405-1411