Patients with chronic pancreatitis who received glucagon-like peptide-1 receptor agonists had lower rates of opioid use and invasive pancreatic interventions than matched patients who did not receive the medications, researchers reported in a large real-world cohort study.
“Chronic pancreatitis pain is difficult to manage, and many patients eventually need long-term opioids or invasive interventions,” first author Arkadeep Dhali, MBBS, MPH, a gastroenterology fellow at Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England, told GI & Hepatology News. “Our study found that GLP-1 receptor agonists, in selected patients with chronic pancreatitis, may be associated with lower rates of new opioid prescriptions, opioid use disorder, and pancreatic interventions. This gives us a real-world signal that deserves further prospective testing.”
Reporting in Gastro Hep Advances, Dr. Dhali and colleagues used data from the TriNetX US Collaborative Network to compare outcomes among adults with chronic pancreatitis who received dulaglutide, semaglutide, or tirzepatide with those of similar patients who did not receive a glucagon-like peptide-1 receptor agonist. After matching patients for demographic and clinical characteristics, the analysis included 21,250 patients, evenly divided between the two groups. The average age was 60 years, and 54% were women.
During up to three years of follow-up, patients who received a GLP-1 receptor agonist were less likely to require opioids or undergo pancreatic procedures than those who did not receive the drugs.
The difference was most evident for opioid use. Among patients without prior chronic opioid therapy, 4% of GLP-1 receptor agonist users started long-term opioid treatment during follow-up, compared with 7% of controls. Treatment with a GLP-1 receptor agonist was associated with a 41% lower likelihood of initiating chronic opioids.
Among patients without previous chronic opioid use, 4% of GLP-1 RA users initiated chronic opioid therapy compared with 7% of matched controls. Kaplan-Meier analysis showed that patients receiving GLP-1 RAs had a 41% lower likelihood of starting chronic opioids during follow-up. The probability of remaining free from chronic opioid prescriptions at three years was 94% among GLP-1 RA users vs 90% among controls.
The benefit extended beyond opioid prescribing. Opioid use disorder was diagnosed in 2% of patients receiving a GLP-1 receptor agonist, compared with 4% of matched controls. Treatment was associated with a 42% lower likelihood of developing the disorder during the study period, and 97% remained free of opioid use disorder at three years vs 95% of controls.
The study also found fewer invasive interventions among patients receiving a GLP-1 receptor agonist. Fewer than 1% of patients in either group underwent celiac plexus block or neurolysis, but treated patients were nearly 50% less likely to require one of these procedures.
The same pattern was seen for endoscopic pancreatic procedures. Interventions such as stent placement or exchange, balloon dilation, sphincterotomy, and stone removal were required in 2% of GLP-1 receptor agonist users and 5% of controls, a 53% lower likelihood among treated patients. The three-year probability of avoiding an endoscopic procedure was 97% vs. 94%.
Major pancreatic surgery was also less common among patients receiving a GLP-1 receptor agonist. Procedures such as distal pancreatectomy, Puestow procedure, and pancreaticoduodenectomy were performed in 1% of treated patients, compared with 2% of controls. Overall, treatment was associated with a 56% lower likelihood of undergoing major pancreatic surgery during follow-up.
Although the study was not designed to explain why the association occurred, the authors noted that previous research has linked GLP-1 signaling to reduced inflammation, changes in pain processing, and effects on addiction-related brain pathways. Experimental studies have also suggested a role in pancreatic fibrosis through effects on pancreatic stellate cells.
The authors noted limitations of the study, including its retrospective design and reliance on electronic health record data and diagnostic coding. Information on disease severity, pancreatitis etiology, genetic risk factors, medication adherence, treatment duration, and dosing was unavailable. Residual confounding and selection bias also remain possible despite propensity score matching. In addition, the database could not determine why GLP-1 RA therapy was prescribed, and procedural rates may have varied across institutions.
The study received no external funding and the authors reported no relevant conflicts of interest.
Expert Insight
GI & Hepatology News invited first author Arkadeep Dhali, MBBS, MPH, a gastroenterology fellow at Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England, to elaborate on the study results.
Did any of the study findings stand out as unexpected?
Dr. Dhali: The most striking finding was the consistency of the association across very different outcomes. We expected to look mainly at opioid-related outcomes, but GLP-1 RA use was also associated with lower rates of other complex interventions like celiac plexus block, endoscopic pancreatic intervention, and major pancreatic surgery. The reduction in endoscopic interventions and surgery was particularly interesting because it raises the possibility that the effect may extend beyond symptom control alone. But as I suggested, we need further prospective studies to evaluate that hypothesis.
What are the practical implications of these findings for clinicians?
Dr. Dhali: I would be cautious here. This is an observational retrospective study, so it should not immediately change guidelines or lead to GLP-1 RAs being prescribed solely for chronic pancreatitis pain. However, for patients with chronic pancreatitis who also have diabetes or obesity, these findings may encourage clinicians to think about GLP-1 RAs as part of broader multidisciplinary care, especially where opioid-sparing strategies are important.
What are the next steps for research in this area?
Dr. Dhali: The main gap is that we need prospective validation. Electronic health record data cannot fully capture pain severity, imaging changes, medication adherence, dose, duration of treatment, or the exact reason GLP-1 RA therapy was started. The next step should be prospective studies, ideally randomized trials, with detailed pain scores, opioid use data, imaging, and careful characterization of chronic pancreatitis severity and etiology.
What else would you like clinicians to take away from this work?
Dr. Dhali: I think the most important point is that this is a hypothesis-generating study, not a definitive treatment recommendation. But it identifies a clinically relevant and potentially actionable signal in a large real-world setting. Given the lack of effective opioid-sparing options in chronic pancreatitis, we believe this is a signal worth taking forward carefully.