Widely-prescribed prodrug opioids (e.g., hydrocodone) require conversion by liver enzyme CYP-2D6 to exert their analgesic effects. The most commonly prescribed antidepressant, selective serotonin reuptake inhibitors (SSRIs), inhibits CYP-2D6 activity and therefore may reduce the effectiveness of prodrug opioids. We used a machine learning approach to identify patients prescribed a combination of SSRIs and prodrug opioids postoperatively and to examine the effect of this combination on postoperative pain control. Using EHR data from an academic medical center, we identified patients receiving surgery over a 9-year period. We developed and validated natural language processing (NLP) algorithms to extract depression-related information (diagnosis, SSRI use, symptoms) from structured and unstructured data elements. The primary outcome was the difference between preoperative pain score and postoperative pain at discharge, 3-week and 8-week time points. We developed computational models to predict the increase or decrease in the postoperative pain across the 3 time points by using the patient’s EHR data (e.g. medications, vitals, demographics) captured before surgery. We evaluate the generalizability of the model using 10-fold cross-validation method where the holdout test method is repeated 10 times and mean area-under-the-curve (AUC) is considered as evaluation metrics for the prediction performance. We identified 4,306 surgical patients with symptoms of depression. A total of 14.1% were prescribed both an SSRI and a prodrug opioid, 29.4% were prescribed an SSRI and a non-prodrug opioid, 18.6% were prescribed a prodrug opioid but were not on SSRIs, and 37.5% were prescribed a non-prodrug opioid but were not on SSRIs. Our NLP algorithm identified depression with a F1 score of 0.95 against manual annotation of 300 randomly sampled clinical notes. On average, patients receiving prodrug opioids had lower average pain scores (p<0.05), with the exception of the SSRI+ group at 3-weeks postoperative follow-up. However, SSRI+/Prodrug+ had significantly worse pain control at discharge, 3 and 8-week follow-up (p 0.05). The machine learning algorithm accurately predicted the increase or decrease of the discharge, 3-week and 8-week follow-up pain scores when compared to the pre-operative pain score using 10-fold cross validation (mean area under the receiver operating characteristic curve 0.87, 0.81, and 0.69, respectively). Preoperative pain, surgery type, and opioid tolerance were the strongest predictors of postoperative pain control. We provide the first direct clinical evidence that the known ability of SSRIs to inhibit prodrug opioid effectiveness is associated with worse pain control among depressed patients. Current prescribing patterns indicate that prescribers may not account for this interaction when choosing an opioid. The study results imply that prescribers might instead choose direct acting opioids (e.g. oxycodone or morphine) in depressed patients on SSRIs.