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Patients undergoing hemodialysis or peritoneal dialysis often experience pruritus which is associated with morbidity and mortality. One proposed treatment approach is to target the opioid pathway using either µ-opioid antagonists or κ-opioid agonists.
To review the efficacy of targeting the opioid pathway for pruritus among dialysis patients (uremic pruritus).
Systematic review and meta-analysis.
The systematic review included randomized controlled and randomized crossover trials identified in the MEDLINE, EMBASE, and Cochrane databases (1990 to June 2014) evaluating the efficacy of µ-opioid antagonists or κ-opioid agonists in the treatment of uremic pruritus.
Adult (≥18 years) chronic dialysis patients.
The primary outcome being evaluated was reduction in itch severity measured on a patient-reported visual analog scale (VAS).
Five studies out of 3587 screened articles met the inclusion criteria. Three studies evaluated the efficacy of naltrexone, a µ-opioid antagonist, and 2 studies evaluated the efficacy of nalfurafine, a κ-opioid agonist. Duration of included studies was short, ranging from 2 to 9 weeks.
Due to the heterogeneity in reporting of outcomes, data from the studies evaluating naltrexone could not be pooled. Pooled analysis, using a random effects model, found that use of nalfurafine resulted in a 9.50 mm (95% confidence interval [CI], 6.27-12.74, P < .001) greater reduction of itch severity (measured on a 100-mm VAS) than placebo in the treatment of uremic pruritus.
Nalfurafine holds some promise with respect to the treatment of uremic pruritus among dialysis patients. However, more long-term randomized controlled trials evaluating the efficacy of therapies targeting the opioid pathway for uremic pruritus are required.
Les patients sous hémodialyse ou traités par dialyse péritonéale éprouvent souvent du prurit et ce dernier est associé au taux de morbidité et de mortalité. Une approche proposée pour le traitement de cette affection est de cibler la voie métabolique des opioïdes par l’administration d’opioïdes-μ antagonistes ou d’opioïdes-κ agonistes.
On a voulu examiner l’efficacité d’un traitement ayant pour cible la voie métabolique des opioïdes dans le soulagement du prurit urémique chez les patients sous dialyse.
L’étude a consisté en une méta-analyse et une revue systématique des bases de données de MEDLINE, EMBASE et Cochrane. On y a répertorié tous les essais randomisés contrôlés ainsi que les essais croisés randomisés qui évaluaient l’efficacité des opioïdes-μ antagonistes ou des opioïdes-κ agonistes dans le traitement du prurit urémique.
L’étude a porté sur des adultes sous dialyse chronique.
Le principal paramètre évalué était la réduction de la sévérité des démangeaisons que l’on a mesurée sur une échelle visuelle analogue d’après un compte rendu du patient.
Seulement cinq études, parmi les 3587 articles passés en revue, satisfaisaient le critère d’exclusion. Trois études avaient évalué l’efficacité de la naltrexone, un opioïde-μ antagoniste, et deux autres avaient évalué l’efficacité de la nalfurafine, un opioïde-κ agoniste. La durée des études retenues était relativement courte, soit de deux à neuf semaines.
Les données concernant la naltrexone n’ont pu être regroupées en raison d’un manque d’homogénéité dans la façon de présenter les résultats. L’analyse par regroupement, effectuée à l’aide d’un modèle à effets aléatoires, a permis d’observer que l’administration de nalfurafine a entrainé une diminution de la sévérité des démangeaisons (mesurée sur une échelle visuelle analogue de 100 mm) de 9,50 mm (IC à 95% entre 6,27 et 12,74; P < 0,001) de plus qu’un placebo lors du à traitement du prurit urémique.
La nalfurafine offre de bonnes perspectives pour le traitement du prurit urémique chez les patients sous dialyse. Par contre, un plus grand nombre d’essais randomisés contrôlés, évaluant à long terme l’efficacité des thérapies ciblant la voie métabolique des opioïdes pour le traitement du prurit urémique, sont souhaités.
Uremic pruritus is a debilitating condition affecting dialysis patients. Individual studies have evaluated the effectiveness of opioid-pathway modifiers of uremic pruritus, but pooled effects have not been evaluated.
This study enhances our understanding of the efficacy of a µ-opioid antagonist (naltrexone) and κ-opioid agonist (nalfurafine) in the management of uremic pruritus. This study also identifies an important area of research that needs more randomized controlled trials to be conducted.
Patients with chronic kidney disease often experience persistent itch termed “uremic pruritus.”1,2 Uremic pruritus (chronic persistent itch that is an associated complication of kidney disease) is a common symptom of patients undergoing hemodialysis and peritoneal dialysis.1,2
The prevalence of uremic pruritus among dialysis has been reported as being close to 50% to 90% in some studies.3-7 Consequences of uremic pruritus are not insignificant; studies have reported that uremic pruritus is associated with an impaired quality of life, depressed mood, and disturbed sleep.2,5-7 Furthermore, the degree of quality-of-life impairment and sleep disturbance increases with itch severity.2,5,6 One study also found that moderate-to-extreme pruritus was associated with a 17% higher mortality risk among hemodialysis patients.6
The pathophysiological mechanism underlying uremic pruritus is not well understood.1,8 Furthermore, multiple complex mechanisms may play a role in causing pruritus associated with end-stage renal disease.1,3,4,8 One proposed mechanism involves endogenous opioid peptides and the opioid system.1,3,4,8 Activation of the µ-opioid system has been suggested to induce pruritus; this is supported by reports of morphine, an agonist of the µ-opioid system, triggering itch.1,4,8,9 In addition, studies also suggest that activation of the κ-opioid system modulates pruritus by reducing itch.1,3,4,8 Moreover, studies utilizing mouse models report that antagonism of µ-opioid receptors and activation of κ-opioid receptors inhibit substance P-induced itch.9,10
Interventions targeting the opioid itch pathway have the potential to reduce itch severity in patients experiencing uremic pruritus. To our knowledge, a systematic review evaluating the efficacy of such interventions has not been carried out. To study this, we conducted a systematic review and meta-analysis of randomized controlled trials involving drugs that target µ- and κ-opioid receptors for the treatment of uremic pruritus in dialysis patients.
We initially searched for studies in the following electronic databases: MEDLINE, EMBASE, and the Cochrane Library (all years to June 2014). We developed our search strategy with the assistance of a medical librarian including keywords and controlled subject language for 2 concepts and then combined the sets of terms. The first category pertained to the symptom of interest and included the terms such as “pruritus,” “itch,” and “scratch.” The second category pertained to the disease state of interest and included the terms such as “chronic kidney disease,” “chronic kidney failure,” “uremic,” and “end stage renal disease.” Terms related to the interventions were not included to avoid narrowing our search results and potentially excluding citations that would have warranted screening. Search results from each database were combined, and duplicate citations were removed. The full search strategy for Medline is available as a supplemental file (Supplement 1); we did not limit searches by language of publication and we included conference proceedings.
We included randomized controlled or randomized crossover trials comparing either a µ-opioid antagonist or κ-opioid agonist to placebo or another drug among dialysis patients 18 years or older. Our primary outcome of interest was pruritus severity measured using a 10-point, 10-cm or 100-mm visual analog scale (VAS), or numerical rating system. We did not limit the inclusion of any studies on the basis of treatment duration.
Exclusion criteria were as follows:
Two reviewers (D.J. and D.U.) independently screened citations generated from the first search by applying selection criteria. Articles meeting criteria or for which there was uncertainty were selected for inclusion after both reviewers assessed the full text of the article. Any disagreement pertaining to the final inclusion of a study was resolved by consensus or via input from a third reviewer (K.K.T.).
Characteristics and outcome data for included studies were recorded in a standardized spreadsheet by D.J. and checked by D.U.; any discrepancies were resolved by consensus. Study characteristics extracted included study design, geographic jurisdiction, participant characteristics, inclusion and exclusion criteria, intervention characteristics, primary outcome data, and secondary outcome data such as the intervention’s impact on itch duration and sleep. We attempted to contact all authors of included studies with missing or unclear data.
Two reviewers (D.J. and D.U.) independently assessed included studies using the Cochrane Risk of Bias tool.11 Risk of bias across 6 domains (random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting), as outlined in the Cochrane Handbook, were given a rating of high, uncertain, or low.11 The formatting of our article was consistent with the guidelines set out by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.12
When there was sufficient homogeneous data available, we pooled the weighted mean differences in pruritus severity reduction with a generic inverse-variance approach and random effects model.13 We compared the mean difference in pruritus severity reduction over 2 weeks between patients receiving a κ-opioid agonist versus placebo. We appropriately calculated standard errors (SEs) from reported 95% confidence interval (CI) data as described in the Cochrane Handbook14 and rescaled individual trial outcomes on the VAS itch score to 0 to 100 points for consistent presentation. In addition, we used methods described in the Cochrane Handbook to combine mean differences from 2 intervention groups that investigated the same therapy at different doses14; this was done to avoid double counting the placebo comparison group. We describe the percentage variability in effect estimates (I2) to quantify heterogeneity across pooled data.13 We used the Review Manager 5.3 software package to conduct quantitative analyses.15 Furthermore, we also conducted a narrative synthesis of all included studies and described the overall quality of evidence available. The need for ethics approval was waived by our local research ethics board (The Nova Scotia Health Authority Research Ethics Board).
We identified 3587 independent citations in our electronic search strategy; 3057 were excluded after the title screen (kappa = 0.48), and an additional 525 were excluded after the abstract screen (no disagreement between reviewers). Overall, 3582 were excluded based on a title and abstract screen (Figure 1); reasons for exclusion were as follows: Study was not a randomized controlled or randomized crossover trial (n = 193), study did not involve the intervention being reviewed (n = 2136), study did not examine pruritus or pruritus severity (n = 184), or the population of interest (n = 1067). Two abstracts were excluded because, despite contacting publishers and organizers of conference proceedings, we were unable to access them.16,17 Five articles were selected for full text review, and none were excluded during this phase.18-22
Three studies19-21 utilized naltrexone (µ-opioid antagonist) and 2 studies18,22 utilized nalfurafine (κ-opioid agonist) as the intervention (Table 1). Of the 3 studies that utilized naltrexone, 220,21 compared with placebo and 119 compared with loratadine. Both studies of nalfurafine compared our treatment of interest with a placebo group. Two studies20,21 were randomized crossover trials, and the remaining 3 studies18,19,22 were 2-arm randomized controlled trials. Four studies reported locations where the trials were conducted (Japan,18 France,19 Germany,20 Sweden,22 and Poland22).
All studies18-22 had a low risk of the random sequence generation component of selection bias (Figure 2). One study18 had a low risk of the allocation concealment component of selection bias, 4 studies18,20-22 had a low risk of performance and detection bias, and 3 studies18,21,22 had a low risk of attrition bias. Selective reporting bias could not be determined for any of the studies.18-22
Studies utilizing naltrexone as the intervention were not synthesized using meta-analysis because of the heterogeneity resulting from inadequate reporting of outcome data. Two studies19,21 (Tables 1 and and2)2) reported that administration of 50 mg of daily naltrexone reduced pruritus score measured on a 10 cm VAS. Legroux-Crespel et al19 identified a reduction in mean pruritus score (rescaled on a 100-point scale) from 48.50 mm at baseline to 45.40 mm on day 7 (P < .01); however, there were no significant differences in scores between patients receiving naltrexone or loratadine. In the crossover study by Peer et al,21 a decrease in rescaled VAS scores was observed at day 7—99.00 mm (interquartile range [IQR], 98.50-99.50 mm]) to 21.00 mm (IQR, 15.00-21.50 mm)—in the group that received naltrexone as first treatment. A decrease in rescaled VAS scores (99.00 mm [IQR, 93.00-100.00 mm] to 10.00 mm [IQR, 4.00-11.50 mm]) was also observed at day 7 post naltrexone treatment in the group that first received placebo.21 In contrast, Pauli-Magnus et al20 reported no significant decline in mean pruritus score measured on a rescaled 100-point VAS with the administration of 50 mg of daily naltrexone for 4 weeks (Tables 1 and and2;2; change in mean pruritus score from 55 [95% CI, 42-68] to 41 [95% CI, 26-56]).20
The 2 included studies18,22 that evaluated nalfurafine reported a significantly greater reduction in mean pruritus score measured on a 100-mm VAS over 2 weeks compared with control. After pooling the data of both studies (n = 422), as shown in Figure 3, the pooled difference in mean pruritus score reduction over 2 weeks was 9.50 mm (95% CI, 6.27-12.74) between nalfurafine treatment and placebo (P < .001). No significant heterogeneity among the pooled results was identified (I2 of 0%).
Kumagai et al18 reported a mean pruritus score reduction difference of 10 mm (95% CI, 4-14) between the intervention group receiving nalfurafine 2.5 µg daily and the placebo group. The same study also reported a mean pruritus score reduction difference over 2 weeks of 9 mm (95% CI, 4-14) between the intervention group receiving nalfurafine 5 µg daily and the placebo group.18 Wikstrom et al22 reported a weighted mean pruritus score reduction difference over 2 weeks of 9.53 mm (95% CI, 1.42-17.64) between the intervention receiving nalfurafine 5 µg thrice weekly and placebo.
Only 2 studies20,22 reported relevant secondary outcomes (Tables 1 and and2).2). Pauli-Magnus et al20 reported a detailed score that was a composite of reported itch severity/distribution and frequency of pruritus-related sleep disturbance. No significant reduction in the detailed score (from 17.7 [95% CI, 12.9-22.5] to 14.2 [95% CI, 8.9-19.6]) was reported after 4 weeks of naltrexone.20 Wikstrom et al22 identified an increase in the number of nights with sound sleep from 1.7 to 4.3 nights/week (at week 2) in the group receiving nalfurafine hydrochloride. The study also reported an increase in the number of days with nondisturbing itch from 0.6 to 2.8 days/week (at week 2).22
Four studies18,19,21,22 reported incidence of adverse events or reactions (Table 3). Kumagai et al18 reported event rates (in the intervention groups receiving nalfurafine hydrochloride 2.5 and 5 µg) of 25% and 35% versus 16% in the placebo group.18 Common adverse drug reactions included insomnia, somnolence, and constipation.18 The incidence of adverse drug events in the study by Wikstrom et al22 was 45% in those receiving nalfurafine and 34% in the placebo group, but types of events were not included. Event incidence rates in studies of naltrexone were 33%21 and 58%.19 Reported events included vomiting, nausea, anorexia, abdominal distention, malaise, cramps, sleep disturbance, vertigos, headaches, somnolence, paresthesia, heartburn, and upper abdominal discomfort.
Our systematic review and meta-analysis aimed to evaluate the efficacy of µ-opioid antagonists and κ-opioid agonists in the treatment of uremic pruritus experienced by patients undergoing dialysis. We found that nalfurafine led to a significantly greater reduction in pruritus severity over 2 weeks compared with placebo. Although 2 out of 3 studies reported a significant reduction in pruritus severity using naltrexone, data could not be pooled due to heterogeneity of data, intervention and outcome.
How might these findings inform practice? Although it is difficult to recommend the use of the µ-opioid antagonist naltrexone for management of uremic pruritus based on limited data, our meta-analysis suggests that nalfurafine is a potential treatment for uremic pruritus. Acknowledging that uremic pruritus is a debilitating symptom with multiple negative consequences,2,5-7 identifying therapies that may provide benefit is crucial. However, despite the signal for benefit, there are also important limitations of the current body of literature surrounding nalfurafine. Studies have only been of short duration (2 weeks), and the majority of the weight in our pooled analysis is derived from 1 study.18,22 Inconsistency with adverse event reporting makes it difficult to determine whether the benefits outweigh the risks and side effects of therapy. A lack of homogeneity prevented the evaluation of changes in mood, sleep, or quality of life with treatment. Finally, it is difficult to put a reduction in itch severity of 9.50 mm more than placebo for those receiving nalfurafine treatment in clinical context. Although a minimal clinically important difference (MCID) has not been definitively established for pruritus, Reich and colleagues23 have suggested that it may be 3 points (2.6-3.5 cm) if pruritus is improved. As the pooled reduction was less than the suggested MCID, our results should be interpreted cautiously. Therefore, although there is promise with this treatment, it is difficult to recommend it for long-term therapy of uremic pruritus based on the available data. Rather, more extensive, longer term evaluations of the relative efficacy of nalfurafine are required.
The need for longer follow-up is further highlighted by the results of observational studies. In an open label, single arm, prospective study of 145 patients, nalfurafine hydrochloride (5 µg orally daily) was administered over 52 weeks.24 There was a significant reduction in mean pruritus score on the 100-mm VAS from 75.2 mm (95% CI, 73.5-76.9) to 30.9 mm (95% CI, 26.6-35.1) by week 52, and statistically significant improvements in nighttime symptom severity.24 However, the incidence of adverse drug reactions (including insomnia and constipation) was 48.8%.24 Moreover, anemia was a common adverse drug reaction that was reported to occur between weeks 3 and 52.24 Nevertheless, it appears as though reductions in pruritus severity may be sustained with continued use of nalfurafine, acknowledging the side effects that may accompany treatment. It is unclear (outside of inferences from treatment discontinuation) whether patients are able to better tolerate side effects if concurrently experiencing marked benefits. Once again, confirmation in a longer term randomized controlled trial would be an important consideration, as would evaluation of a combined endpoint that incorporates side effects with relative benefits of pruritus reduction. Furthermore, the recently demonstrated efficacy of nalbuphine hydrochloride extended release (HCL ER), a mixed µ-antagonist/κ-agonist, may add further support to the potential benefit of opioid-pathway modifiers for uremic pruritus.25
This meta-analysis highlights the relative deficiency of literature surrounding optimal opioid-pathway modifying management strategies for uremic pruritus. This deficiency is made more apparent when considering patient perspectives. A recent survey (conducted by the Canadian Kidney Knowledge Translation and Generation Network) identified that management of dialysis-associated itch was a priority area for patients and their care providers.26 Additional evaluation of pharmacological therapies1,27 (including topical treatments) and nonpharmacological treatments of uremic pruritus1,27 should be considered. As well, because none of the studies were conducted in North America and included very few peritoneal dialysis patients, threats to external validity in future studies could be mitigated by involving peritoneal dialysis patients and extending trials to North American centers.
A major strength of our study is that a comprehensive search strategy was utilized to identify randomized controlled and randomized crossover trials that evaluated naltrexone and nalfurafine treatment for uremic pruritus. Our study also pooled data and established short-term efficacy of nalfurafine. Furthermore, we were able to identify important considerations for future research projects that aim to evaluate nalfurafine or naltrexone for the treatment of uremic pruritus.
There are limitations to this study. In terms of bias, although most studies demonstrated a low risk of selection bias and blinding of participants further strengthened the results, we were not able to evaluate bias for selective reporting within the included studies. Furthermore, because of the small number of eligible studies, we were not able to assess for publication bias. We were unable to compare different opioid pathways (in terms of efficacy in reducing pruritus) due to data heterogeneity and the limited total number of studies. Furthermore, while we did manage to evaluate efficacy in itch reduction for nalfurafine, we were not able to comprehensively evaluate the effect of the studied treatments on quality of life, an important secondary outcome.
Although nalfurafine is a promising treatment for uremic pruritus, additional long-term randomized controlled trials are needed to establish its efficacy. Future studies of therapies for uremic pruritus should additionally evaluate the impact of nalfurafine on factors such as sleep quality, adverse events, and quality of life.
List of Abbreviations: VAS, visual analog scale.
Ethics Approval: Waived by Nova Scotia Health Authority Research Ethics Board
Consent for Publication: Not applicable.
Availability of Data and Supporting Materials: The search strategy is attached in a supplemental file.
Authors’ Note: The results presented in this article have not been published previously in whole or part, except in abstract format.
Author Contributions: All Authors contributed to the design of this study. DJ and DU performed the initial article review. Any disagreements were resolved with consensus review by KKT. Data analysis was performed with assistance from JH. DJ drafted the original article. All authors provided manuscript revisions for scientific content. All authors approved the final version of the manuscript for publication.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Karthik Tennankore has received unrestricted grant funding for quality improvement projects from Amgen, Canada.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Deep Jaiswal received a Dalhousie Medical Research Foundation E.J. Gordon Studentship through the Research in Medicine program at Dalhousie University as part of funding for this project.