Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn's disease: a pilot study

Abstract

Background: There is an unmet need for safe and effective medicines to treat children with Crohn's disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells.

Aims: The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn's disease.

Methods: A pilot clinical trial was conducted in children with moderate to severe Crohn's disease. Fourteen subjects with a mean age of 12.3 years (range, 8 to 17 y) were enrolled. Children were randomized to placebo or naltrexone (0.1 mg/kg) orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and Quality of life was monitored by the Impact III survey.

Results: Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn's disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9) (P=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score ≤10) and 67% had improved with mild disease activity (decrease in PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (P=0.035).

Conclusions: Naltrexone therapy seems safe with limited toxicity when given to children with Crohn's disease and may reduce disease activity.

Trial registration: ClinicalTrials.gov NCT00715117.

FIGURE 1

Study Design. At baseline, subjects were randomized to either naltrexone or placebo therapy for 8 weeks. After 8-weeks the placebo treated subjects crossed over to treatment with naltrexone and the subjects initially randomized to active drug continued on naltrexone. For analysis, PCDAI scores obtained at the pretreatment points in each group were compared to the combined PCDAI scores after 8 weeks of naltrexone therapy (gray shaded boxes). Comparisons in PCDAI scores between Baseline and 16 weeks of naltrexone therapy were also evaluated.

FIGURE 2

A. Pediatric Crohn’s Disease Activity Index Scores (PCDAI). Mean pretreatment PCDAI scores show the patients had moderate to severe disease activity. Participants showed a significant decrease in mean PCDAI scores after 8 weeks of naltrexone but not after placebo. *** p=0.005 compared to pretreatment values. B. PCDAI scores are shown in individual subjects at Baseline and after exposure to naltrexone for either 8 or 16 weeks. Significant improvement was observed *** p=0.001.

FIGURE 3

System results from the IMPACT III quality of life survey. Results from the five categories of the IMPACT III survey are shown comparing baseline values to values after therapy with naltrexone. Systemic Crohn’s disease symptoms and social well-being both significantly improved with naltrexone therapy. Columns represent mean scores ± S.E.M.; * p = 0.035.