Chronic pain affects approximately 20 million veterans as about 1 in 3 Veterans have been diagnosed with a condition related to chronic pain. There is also a significant interaction between chronic pain, post-traumatic stress disorder (PTSD), and persistent post-concussive syndromes common to the veteran population. Opioids prescribed to treat chronic pain are often less than effective and are associated with a significantly increased risk of misuse, addiction, diversion, overdose, and death. Unconventional treatment options that can effectively manage pain and avoid or reduce opioid addiction in Veterans are of significant clinical importance to VA healthcare. Given the high morbidity and mortality attributable to pain therapy, not to mention the staggering medical cost, it is vital to the VA healthcare mission to explore novel strategies to effectively treat chronic pain. Chronic pancreatitis (CP) is an inflammatory disease characterized by pancreatic inflammation, fibrosis, and abdominal pain. CP patients often suffer extreme pain that shares common underlying mechanisms compared to chronic pain caused by other reasons seen in the VA population. CP pain, therefore, provides a valuable model for the treatment of pain syndromes, and improving the management of CP pain may translate to a non- opioid treatment option for Veterans. Mesenchymal stromal cells (MSCs) are adult stem cells that can be harvested and expanded for therapy. MSC therapy represents a promising new intervention as increasing evidence demonstrates that MSC therapy can effectively target several injury pathways in a variety of fibroinflammatory diseases and can reduce pain while suppressing inflammation, something that most pharmacological interventions cannot accomplish. Data from animal models and clinical trials support the outstanding and durable effects of MSC infusion in the suppression of chronic neurological pain and inflammation associated with chronic pain. The goal of this application is to test whether an infusion of autologous bone marrow-derived MSCs (BM-MSCs) can reduce pain associated with CP and to explore the potential mechanism of MSC action. Our specific aims are: Aim 1: Determine the safety, tolerability and potential efficacy of the MSC therapy in reducing pain and disease remission in patients with painful CP. We will perform a Phase I, randomized, double-blind, placebo-controlled, single-dose study to evaluate the safety and potential efficacy of MSC therapy in CP patients with severe abdominal pain. This clinical trial will enroll 40 subjects. Aim 2: Elucidate potential mechanisms of action of MSC therapy by assaying immune cell subsets and gene expression, serum neuropeptides, and inflammatory cytokines. We will measure changes in peripheral blood mononuclear cell (PBMC) subsets, and inflammatory cytokines levels in patients receiving placebo or cell therapy to elucidate potential indicators of treatment efficiency. If successful, improving the manageme...