OBJECTIVES: Difelikefalin, a selective kappa opioid receptor agonist, is approved in 41 countries worldwide to treat moderate to severe CKD-associated pruritus (CKD-aP) in patients on hemodialysis. Pruritus is a known side effect of mu opioid receptor agonistic drugs, but it is unknown if their concomitant use influences the antipruritic effects or safety of difelikefalin.

METHODS: Phase-3 open-label study CLIN3105 supported the safety and efficacy of Difelikefalin in hemodialysis patients with CKD-aP. Prior to each dialysis session, patients were asked to assess worst itch intensity in the past 24 hours using the Worst Itching Intensity Numeric Scale (WI-NRS), ranging from 0 (no itch) to 10 (worst itch imaginable). Analysis was performed using the weekly mean of the WI-NRS measured at baseline and after 12 weeks of treatment.

This exploratory post-hoc analysis assesses the effectiveness and safety of difelikefalin, dependent upon exposure to concomitant opioid medication.

RESULTS: Out of 222 participants, 69 (31%) were taking concomitant opioid medications. The percentages of patients taking concomitant opioids and achieving WI-NRS improvements of ≥3point, ≥4point and complete response (defined as ≥75% of daily scores 0 or 1) at week 12 were 77.0%, 63.9% and 26.1%, respectively. In patients not taking concomitant opioid medications the percentages were comparable, 72.2%, 57.1%, and 25.5%, respectively.

The percentages of treatment emergent adverse events (TEAEs) and severe TEAEs was higher in patients with concomitant opioid medication compared to those without: 73.9% versus 60.1% and 14.5% versus 5.9%, respectively. Yet, the share of TEAEs leading to study drug discontinuation was numerically higher in patients not taking concomitant opioids (5.8% versus 6.5%).

CONCLUSIONS: This exploratory analysis did not find any influence of concomitant opioid medications on the effectiveness of difelikefalin. The higher rate of TEAEs in patients receiving difelikefalin in combination with opioids makes careful assessment of continued use of opioid medications advisable.