OBJECTIVE: Chronic pain can worsen PTSD symptomatology and may increase the risk of the prescription of multiple central nervous system (CNS)-active medications. The objective is to determine the impact of chronic pain on the number of CNS medications, including psychiatric medications, as well as the amount of medication changes. METHODS: Veterans Affairs (VA) administrative data were used to identify VA-served Veterans with PTSD (N = 637,428) who had chronic pain (50.3%) and did not have chronic pain (49.7%) in 2020. The outcomes included the number of changes in psychiatric medications and the number of currently prescribed CNS-active mediations during a one-year observation period. RESULTS: The number of changes in psychiatric medications was significantly higher for those with chronic pain (mean (M) = 1.8) versus those without chronic pain (M = 1.6) (Z = 38.4, p < 0.001). The mean number of concurrent CNS-active medications were significantly higher for those with chronic pain (M = 2.7) versus those without chronic pain (M = 2.0) (Z = 179.7, p < 0.001). These differences persisted after adjustment for confounding factors using negative binomial regression. CONCLUSIONS: Veterans with comorbid chronic pain and PTSD are at increased risk for a higher number of medication changes and for receiving CNS-active polytherapy.