The broad objective guiding this research study is to conduct analyses that will provide critical insights to clinicians and decision makers to optimize knee osteoarthritis (OA) pain management while reducing opioid use in persons with OA and major comorbidities, including mental health disorders and morbid obesity. The study proposes to use a validated computer simulation model of knee OA (OAPol) to narrow the gap between evidence and practice by assessing the value of three major therapeutic strategies in managing pain in knee OA patients with comorbidities: 1) tailored pain management according to pain phenotypes to optimize pharmacologic regimens; 2) weight management in morbidly obese persons to improve outcomes of OA-focused treatments; and 3) PA programs as non-pharmacologic pain reduction regimens.