In this large, historical cohort study, we observed a sustained pattern of increased medication prescription among patients with severe pruritus. Antidepressant medication, systemic antihistamines, and gabapentinoids were prescribed twice as often among patients with severe CKD-aP compared to those with no or mild pruritus, likely reflecting the clinical need to manage more severe symptoms. The pattern was observed in the 3 months preceding pruritus screening as well and did not change in the course of the year. Despite the frequent use of the aforementioned medications to treat pruritus [8], the evidence supporting their use to treat CKD-aP is weak and inconsistent [4, 7, 9]. Our study findings support the notion that patients with more severe CKD-aP symptoms are often prescribed multiple off-label treatments, reflecting the challenges of managing this condition effectively. Many patients in our sample reported significant itch and related distress even if they were using various therapeutic approaches, including topical agents and systemic medications.

Several factors contribute to the limited efficacy of current interventions for CKD-aP. The multifactorial nature of pruritus in this patient population, involving complex interactions of uremic toxins, inflammation, and neurosensory mechanisms, may not be addressed with traditional pruritus medications. Additionally, the pharmacokinetic alterations and comorbidities commonly observed in patients on hemodialysis necessitate careful consideration when selecting and dosing medications [10]. The addition of selective κ-opioid receptor agonist to the available pharmacopeia may change the treatment landscape for this condition by addressing CKD-aP-specific molecular pathways [11].

In this scenario emerging therapies for pruritus need to be mentioned, too. Monoclonal antibodies that inhibit interleukin-31 (IL-31) signaling, such as nemolizumab, and dual inhibitors of interleukin-4 (IL-4) and interleukin-13 (IL-13), such as dupilumab, are approved for the treatment of pruritus in conditions like prurigo nodularis and atopic dermatitis [12,13,14]. However, these therapies do not have a specific indication for the treatment of CKD-aP and therefore cannot be recommended for this context at this time. Nemolizumab failed to show clinical efficacy in patients on hemodialysis [15]. Further research is needed for dupilumab to evaluate the safety and efficacy in patients on CKD, particularly considering the unique metabolic and pharmacokinetic challenges in this population.

Limitations of this study include the lack of prospective CKD-aP measurements which would enable one to assess the effectiveness of current pruritus medications vis-à-vis the observation of their persistent prescription pattern and the potential presence of confounding effects. For instance, a patient might be both depressed and have pruritus, with depression and pruritus being covariates. As a result, the patient may be treated for depression, but it could appear as though the medication is being prescribed for pruritus. Another limitation of this study is the lack of data on the involvement of dermatologists in prescribing medications. As the dataset primarily reflects prescriptions within the nephrology care setting, it is unclear to what extent dermatological expertise contributed to the management of CKD-aP in these patients.

Additionally, topical therapies, including corticosteroids, represent an important component of pruritus management and are commonly used as adjunctive treatments for CKD-aP. However, in our study, the use of topical medications was not systematically analyzed because of inconsistencies and unreliable annotation in the dataset. This limitation prevents a detailed evaluation of their role in CKD-aP treatment patterns. Nonetheless, their potential relevance in alleviating localized symptoms underscores the need for future research to systematically assess both topical and systemic therapies in this patient population.