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Objective Some crush-resistant tablet formulations (CRTs) reduce prescription opioid abuse by nonoral routes of administration (ROAs), especially insufflation and injection, while oral abuse increases. Oral abuse involving product manipulation vs swallowing whole for CRTs and comparators was examined. Methods Abuse by oral modes of administration (e.g. swallowing whole, chewing, dissolving in the mouth), was examined using the ASI-MV, a computerized, clinical interview for adults in substance abuse treatment from January 2009 to March 2015. CRTs (reformulated oxycodone extended-release [ER], reformulated oxymorphone ER, and tapentadol ER) were compared with non-CRT versions, morphine ER, and oxycodone immediate-release single entity. Analyses employed descriptive statistics and logistic regression. Results Among 364,329 unique assessments, 18,135 patients reported oral abuse of the CRTs and comparators examined. CRTs had a higher prevalence of oral abuse involving product manipulation than comparators (P  < 0.0001) among all abusers of product. Oral abuse involving product manipulation for CRTs was greater among the subset of patients reporting oral abuse and significantly higher than comparators (P  < 0.003). CRTs were significantly less likely than comparators to be swallowed whole (P  < 0.0001) and significantly more likely to be chewed (P  < 0.003). CRTs were more likely to be dissolved in the mouth than most comparators. Conclusions Results suggest the need for abuse-deterrent formulations designed to reduce abuse by oral administration with product manipulation, such as chewing. Advances in this area may reduce the overall abuse of prescription opioids and interrupt the progression from abuse by swallowing whole to oral administration involving product manipulation and other ROAs. [ABSTRACT FROM AUTHOR]