A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus

Abstract

Background: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at μ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a μ-opioid antagonist and κ-opioid agonist. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. Results: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. Conclusions: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

Dermatologic manifestations in end stage renal disease

“…Nalbuphine, another novel therapy for pruritus, is a k‐opioid and μ‐opioid receptor antagonist. A multicenter, randomized, double blind, placebo‐controlled trial of 373 hemodialysis patients with moderate or severe uremic pruritus found that nalbuphine significantly reduced itching intensity among hemodialysis patients . In two studies naltrexone, a μ‐opioid receptor antagonist, yielded mixed results.…”

“…A multicenter, randomized, double blind, placebo-controlled trial of 373 hemodialysis patients with moderate or severe uremic pruritus found that nalbuphine significantly reduced itching intensity among hemodialysis patients. 42 In two studies naltrexone, a μ-opioid receptor antagonist, yielded mixed results. One study showed statistically significant benefit over placebo 43 while the other did not.…”

What are new treatment concepts in systemic itch?

“…In an open‐label study in 15 patients with CKDaP nalbuphine hydrochloride at doses of 180 or 240 mg twice daily exerted a reduction of itch intensity on a VAS from 4.0 to 1.2 and 0.8, respectively . A large randomized, placebo‐controlled trial in 371 patients on haemodialysis with moderate or severe CKDaP reported on a mild, but statistically significant NRS reduction in the 120 mg nalbuphine group of 3.5 compared to 2.8 in the placebo group after 8 weeks of therapy . In summary, the currently investigated κ‐opioid receptor agonists presented limited anti‐pruritic effects in RCTs.…”

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors

“…Nalbuphine (NAL) has been recognized as a moderate‐efficacy partial agonist or antagonist of the μ‐opioid receptor and as a high‐efficacy partial agonist of the κ‐opioid receptor with its low affinity for either the δ‐opioid receptor or the σ receptor (Al‐Hasani & Bruchas, ; Barry & Zuo, ; Bodnar, ; Raghav, Jain, Dhawan, Roy, & Kumar, ). It can relieve moderate to severe pain and itching, the mechanisms are thought to be its binding to opioid receptors (Bodnar, ; Chen et al, ; Davis, Fernandez, Regel, & McPherson, ; Mathur et al, ; Pereira & Stander, ; Reszke & Szepietowski, ; Tubog, Harenberg, Buszta, & Hestand, ; Withey, Paronis, & Bergman, ). Alternatively, it can be used to balance anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia (Bindra, Kumar, & Jindal, ; Kim, Kim, Lee, Chung, & Hong, ).…”

“…. It can relieve moderate to severe pain and itching, the mechanisms are thought to be its binding to opioid receptors (Bodnar, 2017;Chen et al, 2014;Davis, Fernandez, Regel, & McPherson, 2018;Mathur et al, 2017;Pereira & Stander, 2018;Reszke & Szepietowski, 2018;Tubog, Harenberg, Buszta, & Hestand, 2018;Withey, Paronis, & Bergman, 2018). Alternatively, it can be used to balance anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia (Bindra, Kumar, & Jindal, 2018;Kim, Kim, Lee, Chung, & Hong, 2011).…”