Pruritus in Chronic Kidney Disease

Nupur N. Uppal; Antonio Corona; Steven Fishbane

Disclosures

Curr Opin Nephrol Hypertens. 2022;31(5):435-441. 

In This Article

Treatment of Pruritus

Skin Care

In most cases of pruritus there is not an easily identifiable cause that allows for well-targeted treatment. Among patients with dry skin, an emollient can be helpful. The quality of marketed moisturizers varies greatly, so care must be taken to find one that provides relief. If an underlying skin condition is identified, then it should be treated appropriately, with the help of a collaborating dermatologist if needed. Dermatologists can also assist with medium range wave ultraviolet (UV-B) light. This therapy has some demonstrable efficacy, but can be quite time consuming.[33]

Antihistamines

Historically, various medications have been tried with varying degrees of relief. Antihistamines have been widely prescribed but anecdotally, in our experience they have not been consistently effective. There are only a few published studies that demonstrate relief of pruritus with antihistamines. In fact, there are few or no published studies comparing antihistamines with placebo. There are more studies in which various agents were compared with antihistamines, with the latter agent acting as a control intervention. CKD-aP is not caused by histamine and there is no reason for these agents to be effective in this condition.

Gabapentanoids (Gabapentin and Pregabalin)

For some patients, especially those who have concomitant neuropathy, then treatment with gabapentanoids (α2δ ligands) may be considered. There is data supportive of the efficacy of these agents in the treatment of uremic pruritis.[34–36] A recent systematic review analyzed seven studies with 179 patients. Most of the studies found these agents to be efficacious, even among patients who hadn't responded to emollients or antihistamines. Hercz et al. conducted a meta-analysis and found gabapentin and pregabalin to be effective for CKD-aP. In five studies with 297 participants they found a visual analogue improvement of 4.95 cm, (95% confidence interval 5.46–4.44 lower compared with placebo).[37] A dose of 100 mg of gabapentin administered after hemodialysis is a reasonable approach. When treating with gabapentinoids, especially in hemodialysis patients, there should be monitoring for adverse effects.[38]

κ-Opioid Receptor Agonists

As discussed above, an important area of research on pruritis has been on the endogenous opioid system. Several agents have been studied and two have been approved for treatment. The first, nalfurafine, is approved in Japan for the treatment of uremic pruritus for patients on hemodialysis. It is a κ-opioid receptor (KOR) agonist with some penetration into the central nervous system.[39] An extensive evaluation of the drug was conducted by Kumagai et al.[40] The drug administered orally at 5 or 2.5 μg was compared with placebo 14 days in 337 hemodialysis patients with itch resistant to other available treatments. Both doses of nalfurafine were found to significantly reduce itch intensity. An increase in insomnia, constipation and somnolence was found for nalfurafine compared with placebo.[40]

In August, 2021, difelikefalin became the first drug approved in the United States for the treatment of pruritis for patients undergoing hemodialysis. Difelikefalin is a selective KOR agonist and is peripherally restricted with no identified off-target effects.[41] Studies have demonstrated that difelikefalin doesn't cross the blood–brain barrier, helping to avoid undesirable effects such as dysphoria or hallucinations.[41] Because the drug does not bind to mu-opioid receptors, it circumvents problems with euphoria and respiratory depression. In animal models the drug diminished scratching induced by chemical pruritogens[42] and interestingly, demonstrated clear anti-inflammatory effects.[41] This set the stage for human studies.

In phase 2 difelikefalin administered thrice weekly, postdialysis, was studied in comparison with placebo. In this trial, 175 patients with moderate-to-severe pruritus were randomized to one of three doses of difelikefalin or placebo.[43] Efficacy was assessed primarily with the widely accepted Worst Itching – Numerical Rating Scale (WI-NRS).[44] The efficacy of difelikefalin was demonstrated in all three active treatment dose levels. Improved efficacy compared with placebo was evident from week 2 onwards, and consistent through to the end of 8 weeks of study. Importantly, there was no significant difference in efficacy between the lowest dose (0.5 μg/kg) to the highest dose (1.5 μg/kg). Tolerability was generally good for difelikefalin, with the most common side effects being diarrhea, nausea, and dizziness. The most serious side effect was somnolence, which was increased compared with placebo, to the greatest extent in the highest dose difelikefalin group (1.5 μg/kg) (11.4 vs. 2.2%).[43] The excellent efficacy and better safety profile for the lowest difelikefalin dose made clear that in phase 3 using only that dose would be studied.

The pivotal phase 3, KALM 1 Study, was a placebo-controlled study conducted in 56 US centers. A total of 378 hemodialysis patients with moderate-to-severe pruritis were randomized to treatment with difelikefalin, 0.5 μg/kg after every dialysis treatment, compared with placebo. The primary endpoint, at least three-point improvement in the WI-NRS was achieved in 51% of patients on difelikefalin vs. 28% of patients on placebo (P < 0.001).[45] In addition to substantially improved itching, broader measures that included quality of life also were significantly improved with difelikefalin.[45] Patients were studied for opioid withdrawal symptoms and there were none detected comparing difelikefalin with placebo, further supporting the drug's pharmacology. The drug's tolerability was quite good, with the only significant differences between difelikefalin and placebo being diarrhea and dizziness.[45]

Taken together, the development and Food and Drug Administration approval of difelikefalin is an important advance for patients with CKD and pruritus. There are no current guidelines as to how to manage difelikefalin treatment after drug initiation. We would suggest an individualized, patient-centered approach (Figure 1). Among patients in whom the drug is started, the response needs to be assessed after the first 2 weeks of treatment, since that's when most patients experience a clear symptomatic improvement. Factors that may be contributing to itching should be repeatedly reassessed, as they may change over time. After the first 12 weeks of difelikefalin, the ongoing need for treatment can be reassessed for most patients (Figure 1). For many, holding difelikefalin at that point might be a reasonable choice. However, because pruritus so frequently follows a waxing and waning course, difelikefalin, or future/other drugs used for treatment would frequently need to be restarted for symptom relief. As an example, the effect after discontinuation of study drug was assessed in the pivotal nalfurafine study. Among patients who had been treated with nalfurafine, itching returned almost to placebo levels shortly after discontinuing the drug.[40] Similarly, in the long-term follow-up of the difelikefalin phase study, even after a year of treatment, itching rapidly returned in many patients after drug discontinuation. The implication for clinical practice is that many patients will have return of symptoms after treatment is stopped. We would suggest that prior to restarting the medication, there should be a reevaluation of possible inciting factors (Figure 1).

Other Treatments

A variety of other drugs, including menthol, capsaicin, and sertraline have been utilized to treat CKD-aP. The published literature does not provide strong support for any of these agents.

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