SAN DIEGO – The oral opioid nalbuphine was safe and significantly reduced itching intensity in hemodialysis patients with uremic pruritus, a randomized, placebo-controlled trial showed.
“Uremic pruritus is a common problem in dialysis patients,” Dr. Vandana S. Mathur said during a press briefing at a meeting sponsored by the American Society of Nephrology. “A recent study in over 73,000 patients found that 60% of them experience pruritus, and 30% of them experience moderate to severe pruritus. Uremic pruritus is associated with worsening quality of life, sleep, mood, social functioning, higher use of IV antibiotics, higher erythropoiesis-stimulating agent and iron doses, and higher mortality.”
Dr. Vandana S. Mathur
Endogenous opioids are important in the pathogenesis of itch, including itch related to systemic disease, noted Dr. Mathur, a nephrologist and clinical and regulatory drug development consultant based in Woodside, Calif.
“Mu receptors mediate mast cell degranulation and have direct central and peripheral pruritogenic effects, while kappa receptors mediate opposing, antipruritic effects,” she said. “Hemodialysis patients have an increased ratio of beta-endorphin to dynorphin A, and the ratio is associated with increased itch intensity.”
Extended-release nalbuphine is a mu receptor antagonist and a kappa receptor agonist being developed by Trevi Therapeutics. “This dual mechanism of action suggests that it may be effective in the treatment of uremic pruritus,” Dr. Mathur said.
The researchers enrolled 373 hemodialysis patients at 46 sites who had moderate or severe uremic pruritus in a phase II/III study. The primary objectives were to evaluate the drug’s effects on itching intensity as assessed by the Worst Itching Numerical Rating Scale (NRS), as well as safety and tolerability. The patients were randomized 1:1:1 to nalbuphine 60 mg b.i.d., nalbuphine 120 mg b.i.d., or placebo b.i.d. for 8 weeks.
Patients’ mean age was 55 years, and 57% were male. They had been on hemodialysis for nearly 5 years and had experienced pruritus for an average of 3.2 years.
The mean NRS in the 120-mg nalbuphine group declined by 3.5 (from 6.9) on the 10-point scale, which represented a 49% decrease in symptoms and was statistically significant from the least squares mean NRS observed in the placebo group (P = .017), Dr. Mathur reported.
The mean NRS in the 60-mg nalbuphine group declined by 3.1 (from 6.9), which was not statistically different from the least squares mean NRS in the placebo group (P = .432).
“The effect of 120-mg nalbuphine b.i.d. was evident within 1 week following titration and was durable for the full 8-week treatment period,” Dr. Mathur said.
The most common adverse events resulting in discontinuation were nausea, vomiting, somnolence, dizziness, and hallucination, with the incidence rate of these events quickly approaching that of placebo after the first week of titration.
The study’s secondary endpoints of itch-related quality of life and sleep were not significantly improved, “but directional trends supported the primary endpoint findings,” she said.
Trevi Therapeutics supported the study. Dr. Mathur disclosed that she is a consultant for the company.