Interventions for itch in people with advanced chronic kidney disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Our objectives are to determine:
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the benefits and harms (both absolute and relative) of all topical and systemic interventions for the treatment of uraemic itch, either alone or in combination, when compared with placebo or standard care; and
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if the effects of these interventions vary depending on co‐interventions, dose strength or frequency, stage of kidney disease or method of dialysis used (where applicable).
Background
Description of the condition
Itch is a common symptom in people with end‐stage kidney disease and affects 42% to 57% of people on dialysis (Mistik 2006; Patel 2007; Pisoni 2006; Zucker 2003). Itch (uraemic pruritus) has significant adverse effects on mortality (Narita 2006) and quality of life due to discomfort, disordered sleep, anxiety and depression (Pisoni 2006). Despite its high prevalence, mechanisms driving uraemic itch remain poorly understood; two common theories implicate hyperactive and disordered immune (Mettang 2002) or opioid systems (Peer 1996). However, roles have also been proposed for hyperparathyroidism (Hampers 1968; Massry 1968), abnormal serum chemistry (Carmichael 1988), mast cell hyperactivity (Kaku 1990), and dialysis technique (Kato 2001; Tan 1991).
Description of the intervention
Given uncertainty in the pathophysiology of uraemic itch, a diverse range of interventions including topical, symptomatic treatments to systemic treatments that are aimed at putative underlying mechanisms have been hypothesised and investigated.
How the intervention might work
Recent studies have recognised spinal mu‐receptor (µ‐receptor) agonist as the mechanism of opioid‐associated itch (Liu 2011); supporting the theory that uraemic itch could represent hyperactivity of µ‐receptors. A case report describing successful treatment of uraemic itch using naloxone (Andersen 1984), a µ‐receptor antagonist, appeared to support this concept, and lead to several trials being conducted to investigate this effect (Pauli‐Magnus 2000; Peer 1996).
Mu‐agonist is typically associated with analgesia, and kappa‐agonist with dysphoria and mu‐antagonism (Pan 1998). It has also been suggested that excessive µ‐receptor or inadequate kappa‐receptor activity, with systemic imbalance rather than isolated µ‐receptor hyperactivity, may stimulate itch (Kumagai 2010). Kappa‐receptor agonist therefore may also be a therapeutic target (Kumagai 2010; Wikström 2005).
Dysregulated immune system has also been implicated in the development of uraemic itch. The observation that sun exposure could relieve undifferentiated itch led to trials of ultraviolet radiation in uraemic itch (Gilchrest 1977; Ko 2011). Early positive results were eventually attributed to the effect of ultraviolet B radiation in altering T‐helper subsets (Garssen 1999). These conclusions led to several controlled and non‐controlled trials of immuno‐modulators that could suppress T‐cell responses, such as tacrolimus, pimecrolimus, and thalidomide.
Increased mast cell numbers have been observed in the skin of people with chronic kidney disease (CKD) (Dimković 1992; Matsumoto 1985) leading to speculation that this excess was associated with increased mast cell and histamine activity (Stockenhuber 1987). Antagonising histamine or inhibiting mast cell degranulation block this pathway. Another purported mechanism of excessive mast cell degranulation is by relative zinc deficiency. By supplementing zinc, mast cell degranulation and histamine release may be prevented.
B₂‐microglobulin and mid‐sized molecules have also been proposed as being implicated in the development of uraemic itch (Robinson‐Bostom 2000). In response, it has been suggested that increasing dialytic efficiency or using high‐permeability membranes may clear the itch effect of these toxins (Chen 2009).
Several other interventions have been suggested to target symptom pathways. Capscasin has been demonstrated to deplete substance P, a principal neurotransmitter regulating passage of noxious stimuli (Burks 1985) to block transmission of itch sensation. Acupuncture and acupoint therapies have unclear mechanisms of action, and trialled based on reported analgesic actions (Che‐Yi 2005).
Several agents have also been trialled empirically with no clear mechanism identified. In the past, gabapentin anecdotally appeared to ameliorate itch when used concurrently for painful diabetic neuropathy (Naini 2007), as did erythropoietin during treatment of anaemia (De Marchi 1991). Ondansetron and cholestyramine have been trialled based on reported benefit with cholestatic itch. Mineral‐rich creams have also been investigated empirically.
Further investigation of these empirical agents has been fruitful. In recent years, there has been quality evidence that gabapentin can be effective in the treatment severe itch associated with CKD (Rayner 2013).
Why it is important to do this review
Itch affects many people with CKD, and most people undergoing haemodialysis report itch symptoms. Around 20% of all those on haemodialysis report significant sleep disturbances (Narita 2006). Typically, trials investigating itch treatments are single‐centre studies with small numbers of participants and frequently report conflicting results.
The most recent meta‐analysis of these studies was conducted more than 20 years ago (Tan 1991). Tan 1991 concluded that there were insufficient data to recommend any one treatment, and further studies were needed. A related meta‐analysis focused on treatment of itch among people receiving palliative care not specific to CKD (Xander 2013). Therefore, it is important that an up to date systematic assessment of the existing evidence be conducted to summarise the effect of current interventions.
This review will analyse randomised controlled trials (RCTs) conducted in people with advanced CKD that compared any topical or systemic intervention with placebo or usual care in the management of uraemic itch.
Objectives
Our objectives are to determine:
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the benefits and harms (both absolute and relative) of all topical and systemic interventions for the treatment of uraemic itch, either alone or in combination, when compared with placebo or standard care; and
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if the effects of these interventions vary depending on co‐interventions, dose strength or frequency, stage of kidney disease or method of dialysis used (where applicable).
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at evaluating interventions involving uraemic itch.
Types of participants
Inclusion criteria
Patients with advanced CKD defined as CKD stages 4, 5, or 5D will be included. In the era predating adoption of CKD definition (2002), studies will be restricted to patients on dialysis.
Exclusion criteria
Patients CKD stages 1, 2 and 3 will be excluded. In studies before 2002, patients with CKD not on dialysis will be excluded.
Types of interventions
Any intervention, administered by any method (oral, intravenous, topical, or otherwise), in any frequency and at any dose strength will be included. Among people undergoing dialysis, the intervention may be administered on dialysis or non‐dialysis days. Complementary interventions (such as acupuncture) will be omitted because they are not easily comparable or categorisable with other interventions.
Participants in study control arms should have received no intervention, placebo, a different dose strength or frequency from the experimental intervention, or any other intervention not administered to experimental arm participants.
We will analyse:
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Intervention versus placebo
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Intervention A versus intervention B
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Co‐intervention A versus co‐intervention B.
To simplify interpretation, each intervention type will be assigned a GRADE evidence profile in a summary of findings table (Guyatt 2011).
Types of outcome measures
Outcome measures will be assessed at the end of the treatment period or up to two weeks post treatment, or as reported by investigators.
Primary outcomes
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Post treatment itch
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Measured by visual analogue scale (VAS), Duo score or any other validated score for itch
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Other recognised numerical or categorical itch measurement scores.
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Secondary outcomes
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Quality of life as measured by any validated quality of life scale
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Mortality
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Length of treatment in hospital or outpatient clinic
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Length of time to itch relief
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Incidence of adverse reactions
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Sleep disturbances
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Dermatological reactions
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Other adverse effects.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co‐ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.
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Monthly searches of the Cochrane Central Register of Controlled Trials CENTRAL
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Weekly searches of MEDLINE OVID SP
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Handsearching of renal‐related journals and the proceedings of major renal conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected renal journals
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Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
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Reference lists of review articles, relevant studies and clinical practice guidelines.
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Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. Titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however, studies and reviews that might include relevant data or information on trials will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy our inclusion criteria.
Data extraction and management
Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.
Assessment of risk of bias in included studies
The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).
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Was there adequate sequence generation (selection bias)?
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Was allocation adequately concealed (selection bias)?
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Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
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Participants and personnel
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Outcome assessors
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Were incomplete outcome data adequately addressed (attrition bias)?
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Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
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Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (e.g. any itch versus no itch) results will be expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (e.g. Duo score or VAS), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.
Any validated tool for the quantification of itch may be used. These include, but are not limited to VAS and the Duo scoring system, which are the most commonly reported measurement tools for itch. VAS is scored on a 10 point scale and the Duo scoring system is based on severity, distribution and sleep disturbance to a maximum score of 45. Duo scores will be expressed as SMD.
Unit of analysis issues
The unit of focus will be the quantities and qualities affecting a single person. For example, itch episodes per person will be preferable to total number of itch episodes affecting an unspecified number of people or time frame.
Dealing with missing data
Any further information required from the original author will be requested by written correspondence (e.g. emailing or writing to corresponding author/s) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat, as‐treated and per‐protocol population will be carefully performed. Attrition rates, for example drop‐outs, losses to follow‐up and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) will be critically appraised (Higgins 2011).
Assessment of heterogeneity
Heterogeneity will be analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).
Data synthesis
Data will be pooled using the random‐effects model but the fixed‐effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions, and study quality). Heterogeneity among participants could be related to age, geography, and stage of CKD. Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy (such as increased tolerance after prolonged use of anti‐itch agents). Adverse effects will be tabulated and assessed using descriptive techniques, because they are likely to differ among agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared with no treatment or another agent.
Sensitivity analysis
We will perform sensitivity analyses to explore the influence of the following factors on effect size.
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Repeating the analysis excluding unpublished studies
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Repeating the analysis taking account of risk of bias, as specified
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Repeating the analysis excluding any very long or large studies to establish how much they dominate the results
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Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.
