Response of patients with hemodialysis-associated pruritus to new treatment algorithm with nalfurafine hydrochloride: a retrospective survey-based study

Pruritus develops in 60–80 % of hemodialysis patients [2–4] as a result of abnormalities originating from renal failure and hemodialysis itself, skin abnormalities, and abnormalities in the regulation of itch sensation by the central nervous system (Fig. 6). The complex interplay of these multiple factors in hemodialysis patients can result in pruritus that often fails to respond sufficiently to existing treatments, including antihistamines, anti-allergy drugs, and steroids [10–13].

The first type of abnormality, those resulting from renal failure or hemodialysis itself, is thought to involve the accumulation of uremic substances, elevation of serum calcium and phosphorus levels, secondary hyperparathyroidism, influences from substances that initiate pruritus (e.g., histamine and substance P), and the activation of complement and interleukins by hemodialysis membranes. The second type, skin abnormalities, includes dry skin and growth of nerve fibers (C fibers) into the epidermis as a result of dryness. Dryness itself may be caused by multiple factors, including lower stratum corneum moisture, decreased sweating, and reduced sebaceous gland secretion.

In the third type of abnormality, abnormal itch sensation regulation by the central nervous system, the possible role of endogenous opioids has recently received increased attention. A previous report indicated that hemodialysis patients with intense pruritus had a higher ratio of endogenous ?-opioid peptide to endogenous ?-opioid peptide in the serum, suggesting that ?-opioids induced pruritus while ?-opioids suppressed the condition [14]. Nalfurafine, a selective ?-opioid receptor agonist, was introduced in 2009 to address central nervous system-mediated therapy-resistant pruritus. Our institution introduced the use of nalfurafine as part of a new treatment algorithm for pruritus in hemodialysis patients after conducting a review of our existing treatment protocol.

We surveyed hemodialysis patients twice, once before the review of our pruritus treatment strategy, and again approximately 4 years after implementation of the new algorithm. Because of the possible psychological impact of switching from existing therapies for pruritus to new treatment methods and the reliance on patient self-assessment regarding pruritus severity, the second survey was administered approximately 4 years following review of our previous treatment strategy. The validity of selecting this time period has not been verified.

Our pre-algorithm survey results, which revealed a high prevalence of pruritus and low satisfaction with treatment among hemodialysis patients, are in agreement with those of a large-scale survey conducted by Yamada et al. that included 858 patients [2]. That study reported that 54.8 % of patients were satisfied or very satisfied with their pruritus treatment, while 45.2 % were neutral, dissatisfied, or very dissatisfied with treatment. In the present study, the prevalence of pruritus decreased and patient satisfaction with treatment increased after implementation of the new treatment protocol. Furthermore, the daytime Shiratori severity scores decreased significantly. The nighttime Shiratori severity scores also decreased, although the change was not statistically significant. Prior to changes in our pruritus treatment strategy, 31.2 % of patients reported moderate to severe daytime pruritus according to the Shiratori criteria and 12.1 % reported severe nighttime pruritus; mean Shiratori severity scores were 2.05?±?1.20 during the day and 1.26 ± 1.10 at night. Thus, before changes in our treatment strategy, pruritus tended to be less severe at night than during the day. This difference helps to explain why changes in our treatment strategy did not result in significant differences in nighttime pruritus. However, the percentage of patients who reported insomnia resulting from pruritus did decrease significantly.

Implementation of the new treatment algorithm resulted in decreased use of oral antihistamines, topical antihistamines, topical steroids, other topical drugs, and anti-allergy injections. In the past, antihistamines and anti-allergy drugs were often prescribed even for patients without dermatological conditions, in the absence of valid pruritus treatments. After reviewing our pruritus treatment strategy and the efficacy of these drugs, the use of antihistamines and anti-allergy drugs was restricted to patients who were diagnosed with dermatological diseases requiring these therapies. This change probably explains the decrease in the use of existing drugs (Fig. 1).

Between the first survey in 2009 and the second in 2013, 58 of the surveyed hemodialysis patients died. The data from these patients was not included in our analyses, which raises the concern that our data are valid only for hemodialysis patients with a relatively good prognosis. However, analysis of our initial survey data revealed that the prevalence of pruritus and the mean daytime Shiratori score were significantly lower (p?=?0.003 and p?=?0.027, respectively) and the prevalence of moderate or severe pruritus, mean VAS scores, and mean nocturnal Shiratori scores were lower (although not significantly so) among these excluded patients. Therefore, it is unlikely that the severity of pruritus at the time of the 2009 questionnaire was higher among the excluded patients than among those included. We therefore consider it unlikely that exclusion of the 58 deceased patients from analysis resulted in overestimation of the efficacy of this new treatment algorithm.

The efficacy of 52 weeks of treatment with nalfurafine was demonstrated in a pre-marketing long-term dosing study [7]. At our facility, nalfurafine treatment for 104 weeks in 13 patients with therapy-resistant pruritus resulted in a significant reduction in VAS values during the treatment period [15]. These results indicate that continuous treatment with nalfurafine alleviates pruritus over a long period in hemodialysis patients. In a previous study of patients treated with nalfurafine, the authors found that 6 out of 7 patients were able to discontinue existing oral drug therapy and to reduce the dose of topical steroids, switch to a less potent topical steroid, or discontinue topical steroids altogether [16]. Yamada et al. reported that 42.3 % of patients treated with nalfurafine experienced alleviation of nighttime pruritus and sleep disorders [2]. Inui et al. reported that treatment with nalfurafine for 4 weeks resulted in a significant reduction in the mean VAS values and in State-Trait Anxiety Inventory scores for state anxiety [17]. Thus, nalfurafine has been shown to be useful for improving state anxiety in hemodialysis patients [18].

One possible explanation for the low satisfaction of hemodialysis patients with pruritus treatment is that in many patients, pruritus involves a complex interplay among multiple factors, which can cause therapeutic resistance. In the present study, nalfurafine suppressed existing therapy-resistant pruritus and enabled dose reduction or discontinuation of ineffective therapies, suggesting that nalfurafine can significantly contribute to improved QOL by alleviating sleep disorders and anxiety. We therefore conclude that including oral nalfurafine in the treatment of therapy-resistant pruritus at our facility has been very important clinically.

To implement this treatment algorithm, a team-based approach to patient care is essential. At our facility, team-based treatment has been performed in the following way. Nurses provide guidance to patients regarding skin care and daily life, pharmacists supply information regarding the correct use of medications, clinical engineers carry out meticulous management of various data obtained from usual medical care, and physicians make final assessments regarding treatment response. It is not possible to treat pruritus with medications alone. The team-based approach, which involves health-care professionals, the patient, and the patient’s family, is important so that patients with pruritus can be sufficiently monitored and encouraged to continue the use of supplemental agents such as daily moisturizer. This type of team-based approach is expected to improve pruritus awareness among health-care professionals and patients and to improve patient outcomes.

This study had several limitations. First, there was no control group. Therefore, it is difficult to certify that the new treatment algorithm was the most important factor in alleviating pruritus. Second, we did not investigate the change in patient QOL, although we did investigate changes in pruritus-induced insomnia and patient satisfaction with treatment. It remains uncertain whether the new treatment algorithm improves patient QOL. Third, the second survey was administered approximately 4 years after the review of our previous treatment strategy, to avoid effects from the psychological impact of switching treatment methods. The validity of selecting this time period has not been verified. Finally, it was not possible to identify the cause of pruritus in individual patients because hemodialysis-associated pruritus involves the complex interplay among multiple factors.