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Naltrexone Therapy Improves Activity and Promotes Mucosal Healing in Active Crohn’S Disease: a Placebo-Controlled Trial
Jill P. Smith¹, Sandra I. Bingaman¹, Francesca Ruggiero², David T. Mauger³, Aparna Mukherjee¹, Christopher O. McGovern¹, Ian S. Zagon⁴
1. GI and Hepatology, Medicine, Pennsylvania State University, Hershey, PA, United States, 2. Pathology, Pennsylvania State University, Hershey, PA, United States, 3. Public Health Sciences, Pennsylvania State University, Hershey, PA, United States, 4. Neural & Behavioral Sciences, Pennsylvania State University, Hershey, PA, United States

Background: Accumulating evidence supports a role for endogenous opioid peptides in the development or perpetuation of inflammation. It is hypothesized that the endogenous opioid system plays a role in inflammatory bowel disease, and disruption of the opioid-opioid receptor interaction will reverse inflammation and promote mucosal healing. Methods: A randomized placebo-controlled double blinded study was designed to test the efficacy and safety of an opioid antagonist, naltrexone, in adults with active Crohn’s disease. Patients with confirmed Crohn’s disease and a Crohn’s Disease Activity Index score (CDAI) of at least 220 were randomized to naltrexone (4.5 mg daily) or placebo by mouth daily for 12-weeks. Subsequently, those who had received placebo were treated with naltrexone and those randomized to naltrexone continued on naltrexone for an additional 12 weeks to assess safety and maintenance of response for extended duration. Colonoscopies with biopsies were performed at baseline, weeks-12, and 24 to determine endoscopic and histologic scores by persons blinded to the treatments. The primary outcomes included the CDAI, endoscopic, and histologic inflammatory scores. Other outcomes included quality of life (QOL) according to the IBDQ and SF-36 surveys, and laboratory tests for safety. Results: Forty patients were enrolled and randomized into the study. Baseline CDAI scores (346±16.4) indicated moderate to severe disease. CDAI scores decreased significantly from baseline (p<0.001) in those treated with naltrexone, but not in placebo treated controls. Eighty-two percent of the naltrexone-treated subjects had at least a 70-point drop in the CDAI score indicative of a response and 45% achieved clinical remission (CDAI < 150). Endoscopy and histology inflammatory scores improved in naltrexone treated subjects (p=0.0019) with evidence of decreased mucosal inflammation, and restored crypt architecture. No endoscopic or histological change was found in placebo treated controls. No significant changes were noted in laboratory parameters or QOL surveys. Patients in the placebo group reported increased fatigue compared to naltrexone treated subjects (p=0.04) and two naltrexone-treated subjects had transient mild elevation in liver transaminases which resolved without interruption of therapy. Conclusion: Naltrexone induces mucosal healing and decreases CDAI scores in subjects with moderate to severe Crohn’s disease with minimal side effects recorded. Strategies to alter the endogenous opioid system provide promise for a novel treatment of inflammatory bowel disease in the future. (Supported by BMRP IBD-0180R and NIH DK073614).