Multiple challenges exist for patients with diseases in the gastrointestinal tract who experience uncontrolled pain and malabsorption of orally delivered medications. For example, patients with intestinal failure and short bowel syndrome have significant variability of medication absorption and therefore require larger doses or unconventional analgesic drug delivery. In addition, pathophysiological changes occur pre- and post-gastrointestinal surgical interventions that affect drug transit time, mucosal integrity, dependent digestive enzymes or acids presence, and specific area of absorption in the bowel. Therefore, clinicians must review the pharmacology of medications for patients with limited bowel function. This presentation aims to review the physiological impact of intestinal failure and short gut syndrome on drug delivery and the available evidence of alternative routes of administration and methods of improving drug absorption in pain management.