A recent article in AJKD by Simonsen et al (Open Access) describes a systematic review of treatment options for uremic pruritis, a debilitating condition in patients with end-stage renal disease (ESRD) and an identified priority for renal research by patients. The pathogenesis of this generalized itch is poorly understood and likely multi-factorial, leading to challenges in choosing specific treatments. Many postulated treatments such as capsaicin, neuro-modulatory agents, phototherapy, and mast cell stabilizers are poorly studied, and study heterogeneity precluded a formal meta-analysis.
Simonsen et al included 44 trials with a total of 2,293 patients in their systematic review; subjects were predominantly on hemodialysis (HD). The best evidence came from studies of gabapentin and pregabalin, which largely showed statistically significant improvements in pruritus scores compared to placebo, at the expense of drowsiness. Mast cell stabilizers (agents such as cromolyn, zinc sulphate, and nicotinamide) were less well-studied and often demonstrated no effect, although cromolyn sodium showed a benefit versus placebo in 2 small studies. Trials of many other systemic agents were reviewed, which frequently showed benefit in single small studies. These included cholestyramine (bile acid binder), naltrexone (opioid antagonist), thalidomide, montelukast (leukotriene inhibitor), and nalfurafine, a novel selective κ-opioid receptor agonist. Topical agents, such as capsaicin cream and tacrolimus, were also included as were some trials of herbal remedies, although no firm conclusions could be made regarding these treatments due to poor quality evidence.
Trials of HD prescription modifications were also heterogeneous. High-flux HD demonstrated benefit versus low-flux HD but also showed benefit when compared to hemodiafiltration. This is certainly counterintuitive if the postulated mechanism at play is enhanced middle molecule clearance. Another trial somewhat bizarrely compared the efficacy of hemodiafiltration against hemodialysis with both groups also receiving hemoperfusion, highlighting the variable nature of the interventions. Similarly, trials looking at phototherapy did not show a robust benefit although the studies were heterogeneous. The interventions included UVA, UVB (as narrow band or broad band), and far-infrared ray, compared to each other or placebo.
Overall, the findings of this study highlight the uncertainty regarding treatment of uremic pruritus. Apart from the benefit evident with gabapentin, and perhaps pregabalin, the available treatments are largely untested. The published studies are low quality and carry a high risk of bias, preventing us from drawing firm conclusions on their merits. While Simonsen et al correctly conclude that “large, methodologically rigorous, parallel arm RCTs are urgently needed,” given the low priority that industry likely views this problem, it’s hard to see that happening.
Pragmatic randomized controlled trial, anybody?