Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn’s Disease: A Randomized Placebo-Controlled Trial

Abstract

Background Endogenous opioid peptides have been shown to play a role in the development and/or perpetuation of inflammation. We hypothesize that the endogenous opioid system is involved in inflammatory bowel disease, and antagonism of the opioid–opioid receptor will lead to reversal of inflammation. Aims A randomized double-blind placebo-controlled study was designed to test the efficacy and safety of an opioid antagonist for 12 weeks in adults with active Crohn’s disease. Methods Forty subjects with active Crohn’s disease were enrolled in the study. Randomized patients received daily oral administration of 4.5-mg naltrexone or placebo. Providers and patients were masked to treatment assignment. The primary outcome was the proportion of subjects in each arm with a 70-point decline in Crohn’s Disease Activity Index score (CDAI). The secondary outcome included mucosal healing based upon colonoscopy appearance and histology. Results Eighty-eight percent of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (p = 0.009). After 12 weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn’s disease endoscopy index severity score (CDEIS) from baseline compared to 28% response in placebo-treated controls (p = 0.008), and 33% achieved remission with a CDEIS score <6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo. Conclusions Naltrexone improves clinical and inflammatory activity of subjects with moderate to severe Crohn’s disease compared to placebo-treated controls. Strategies to alter the endogenous opioid system provide promise for the treatment of Crohn’s disease.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target

“…For the assessment of remission using the CDEIS, a score of <3 indicates endoscopic remission, a score of ≥3 indicates active disease, and a decrease in CDEIS by >5 demonstrates response ( 16,(42)(43)(44) (CEBM 2a). Using relative (rather than absolute) changes in SES-CD and CDEIS scores, such as a decrease from baseline of at least 50%, has been shown to have predictive value for clinical outcomes ( 45 ) (CEBM 2b).…”

Do opioid receptors play a role in the pathogenesis of the inflammatory response in acute pancreatitis?

“…Although opioid receptors alone do not cause inflammation, there is no doubt that they can stimulate lymphocytes and macrophages as well as cytokines production. Indeed, opioid receptors blockade actually reduces inflammation in chemically induced colitis 13 . In fact, naltrexone, an opioid antagonist, is able to block acute endotoxic shock by inhibiting TNFα production 14 .…”

Targeted overexpression of OGFr in epithelium of transgenic mice suppresses cell proliferation and impairs full-thickness wound closure

“…For example, imiquimod and resiquimod, as well as the opioid antagonist naltrexone, have been reported to upregulate OGFr and depress cell proliferation. Indeed, clinical trials using OGF alone have shown that treatment with this peptide has a marked antineoplastic effect by extending survival, without toxicity, in patients with pancreatic cancer (24,26), as well as mucosal healing in Crohn's patients with LDN (25,27).…”