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Background: Oncologists and palliative specialists prescribe opioids for millions of cancer patients despite limited research on effective screening and mitigation strategies to reduce risk of opioid-related harm in that population. Objective: To evaluate the efficacy of a novel opioid risk stratification process for predicting significant aberrant behaviors (SABs) related to prescribed opioid medications. Design and Setting/Subjects: This is a prospective, longitudinal study of 319 consecutive patients referred to an outpatient palliative care clinic between 2010 and 2012, a period during which prescription opioid-related deaths began to increase in the United States. Measures: Patients completed a psychodiagnostic/substance use risk assessment with a licensed clinical psychologist or social worker at the initial palliative clinic visit. Patients were assigned to Low-, Moderate-, or High-Risk groups based on predetermined stratification criteria and were managed via an opioid harm reduction approach. The primary dependent measure was the presence of at least one SAB after the initial visit. Results: Eighteen percent of patients (n = 56) demonstrated at least one major aberrant behavior. Odds of future aberrant behavior was 15 times greater in the High-Risk versus the Low-Risk category. Five risk factors significantly enhanced our risk model: age 18 to 45 years, job instability, history of bipolar diagnosis, history of substance abuse, and theft. Conclusion: Our risk stratification process provides a useful model for predicting those at greatest risk of future aberrant behaviors and most in need of comanagement. We recommend additional studies to test our proposed streamlined risk stratification tool. [ABSTRACT FROM AUTHOR]