Low-Dose Naltrexone in Crohn’s Disease: A Prematurely Terminated Randomized Trial Showing Reduced Fatigue Without Clinical or Endoscopic Benefit

BACKGROUND: Crohn's disease (CD) is often refractory to standard therapies, and patients are sometimes reluctant to initiate immunosuppressive therapy, prompting interest in novel treatments such as low-dose naltrexone (LDN). AIMS: To evaluate the efficacy of LDN for induction of remission in patients with mild-to-moderate active CD. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial in 7 hospitals in the Netherlands. Adults with active CD (defined by mucosal ulcers on endoscopy and Simple endoscopic score for CD 3-15) were randomized 1:1 to LDN 4.5 mg once daily or placebo for 12 weeks. The primary endpoint was endoscopic remission at week 12. Secondary endpoints included clinical and endoscopic response, safety and patient-reported outcome measures. The trial was stopped early due to futility. RESULTS: Forty-one patients were randomized. After 12 weeks, endoscopic remission occurred in 1 (5.6%) vs. 3 (18.8%) patients for LDN and placebo (p=0.233), respectively. Clinical remission occurred in 22.2% (LDN) vs. 70.0% (placebo) (p=0.037). No serious adverse events were reported. For the FACIT-Fatigue questionnaire, the median difference after 12 weeks was 2.5 (IQR 0-7) for LDN vs. -3 (IQR -7-2) for placebo (p=0.012). Additionally, patient-reported outcomes showed no significant difference between LDN and placebo. CONCLUSIONS: LDN was not effective for inducing remission in CD and showed no benefit over placebo. Despite not being an effective treatment for clinical and endoscopic outcomes, it may enhance better quality of life by reducing fatigue symptoms. Future studies are needed to clarify its potential benefit on fatigue in patients with inflammatory bowel disease.