Pharmacological interventions for pruritus in adult palliative care patients Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract 

Background 

This is an update of the original Cochrane review published in 2013 (Issue 6). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is one of the most puzzling symptoms. It can cause considerable discomfort and affects patients' quality of life.

Objectives 

To assess the effects of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients.

Search methods 

For this update, we searched CENTRAL (the Cochrane Library), and MEDLINE (OVID) up to 9 June 2016 and Embase (OVID) up to 7 June 2016. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data.

Selection criteria 

We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients.

Data collection and analysis 

Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta‐analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 10 'Summary of findings' tables.

Main results 

In total, we included 50 studies and 1916 participants in the review. We added 10 studies with 627 participants for this update. Altogether, we included 39 different treatments for pruritus in four different patient groups.

The overall risk of bias profile was heterogeneous and ranged from high to low risk. However, 48 studies (96%) had a high risk of bias due to low sample size (i.e. fewer than 50 participants per treatment arm). Using GRADE criteria, we downgraded our judgement on the quality of evidence to moderate in seven and to low in three comparisons for our primary outcome (pruritus), mainly due to imprecision and risk of bias.

In palliative care participants with pruritus of different nature, the treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, reduced pruritus by 0.78 points (numerical analogue scale from 0 to 10; 95% confidence interval (CI) −1.19 to −0.37; one RCT, N = 48, quality of evidence: moderate) compared to placebo.

For participants suffering from uraemic pruritus (UP), gabapentin was more effective than placebo (visual analogue scale (VAS): 0 to 10), mean difference (MD) −5.91, 95% CI −6.87 to −4.96; two RCTs, N = 118, quality of evidence: moderate). The κ‐opioid receptor agonist nalfurafine showed amelioration of UP (VAS 0 to 10, MD −0.95, 95% CI −1.32 to −0.58; three RCTs, N = 422, quality of evidence: moderate) and only few adverse events. Moreover, cromolyn sodium relieved UP participants from pruritus by 2.94 points on the VAS (0 to 10) (95% CI −4.04 to −1.83; two RCTs, N = 100, quality of evidence: moderate) compared to placebo.

In participants with cholestatic pruritus (CP), data favoured rifampin (VAS: 0 to 100, MD −24.64, 95% CI −31.08 to −18.21; two RCTs, N = 42, quality of evidence: low) and flumecinol (RR > 1 favours treatment group; RR 1.89, 95% CI 1.05 to 3.39; two RCTs, N = 69, quality of evidence: low) and showed a low incidence of adverse events in comparison with placebo. The opioid antagonist naltrexone reduced pruritus for participants with CP (VAS: 0 to 10, MD −2.26, 95% CI −3.19 to −1.33; two RCTs, N = 52, quality of evidence: moderate) compared to placebo. However, effects in participants with UP were inconclusive (percentage difference −12.30%, 95% CI −25.82% to 1.22%, one RCT, N = 32). Furthermore, large doses of opioid antagonists (e.g. naltrexone) could be inappropriate in palliative care patients because of the risk of reducing analgesia.

For participants with HIV‐associated pruritus, it is uncertain whether drug treatment with hydroxyzine hydrochloride, pentoxifylline, triamcinolone or indomethacin reduces pruritus because the evidence was of very low quality (e.g. small sample size, lack of blinding).

Authors' conclusions 

Different interventions tended to be effective for CP and UP. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta‐analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

Author(s)

Waldemar Siemens, Carola Xander, Joerg J Meerpohl, Sabine Buroh, Gerd Antes, Guido Schwarzer, Gerhild Becker

Abstract

Plain language summary 

Drugs for itching in adult palliative care patients 

Background 

Pruritus is the medical term for itching. This symptom can be a problem in palliative care settings where treatments for cancer or severe kidney disease are given at the same time. In this updated review, we searched for high quality clinical trials of drugs for preventing or treating itch in palliative care.

Key findings and quality of evidence 

In June 2016, we found 50 studies that tested 39 different drugs in 1916 people with itch. An ideal antipruritic (anti‐itch) therapy is currently lacking. However, there was enough evidence to point out some possibly useful treatments for particular causes of the itch. These included gabapentin, nalfurafine and cromolyn sodium for itch associated with chronic kidney disease, and rifampicin and flumecinol for itch associated with liver problems. Paroxetine may be useful for palliative care patients whatever the cause of the itching, although evidence was only available from one study. Overall, most of the drugs caused few and mild side effects. Naltrexone showed by far the most side effects. Overall the evidence ranged from very low to moderate quality.

Further research 

Research in palliative care is challenging and often limited to a restricted period of time at the end of life. More high‐quality studies on preventing and treating itch (pruritus) are needed.

Author(s)

Waldemar Siemens, Carola Xander, Joerg J Meerpohl, Sabine Buroh, Gerd Antes, Guido Schwarzer, Gerhild Becker

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions.

For people with pruritus and advanced disease 

An ideal or general antipruritic therapy for patients with advanced disease is currently lacking. However, we identified some possibly useful treatments for particular patients. Gabapentin (and maybe pregabalin), nalfurafine and cromolyn sodium may be useful for itch associated with UP, and rifampicin and flumecinol could be effective for itch associated with liver problems. Paroxetine showed promise in palliative care patients, although evidence was only available from one study. Overall, most of the drugs were associated with few and mild adverse events. Naltrexone showed the most adverse events.

For clinicians 

The varying pathogenesis of pruritus in different disorders means that a universally accepted therapy is difficult to establish. Therapy for pruritus is challenging and requires an individualistic approach. Therefore, identifying the underlying cause of pruritus is still of prime importance in order to develop tailored treatment plans. Especially in palliative care, patients with pruritus may have more than one origin for their pruritus. The fact that itch affects the skin, immune system, and the peripheral and central nervous system means that complex and combinatory pathways are likely to be more effective than a single‐line approach.

Palliative care participants with pruritus of different origin 

For participants in palliative care settings who mainly suffered from pruritus related to neoplasms, paroxetine tended to be effective (quality of evidence: moderate).

Participants with advanced diseases suffering from UP or CP 

The opioid antagonist naltrexone offered a therapeutic alternative for participants suffering from UP or CP. However, these drugs are sometimes inappropriate in the palliative care population that suffers from pain because of the risk of loss of analgesia at higher doses of naltrexone (Higginson 1997; Potter 2003; Walsh 2000).

For patients suffering from UP, gabapentin, nalfurafine, cromolyn sodium (oral rather than topical) and capsaicin could be effective for pruritus relief (quality of evidence: moderate), and in CP participants with advanced disease, rifampicin and flumecinol (low quality of evidence) may be beneficial.

Ondansetron tended to have only very small or no effect for treatment of UP or CP, and the results for cholestyramine, thalidomide, lidocaine and sertraline are very limited due to the small sample sizes.

Participants with HIV‐associated pruritus 

For patients suffering from pruritus associated with HIV infection, we could not draw any distinct conclusions, as the evidence was very low quality. Indomethacin was described as the most effective drug, but the results cannot be generalised.

For policy‐makers 

Two factors could be taken into account for policy‐making. First, many drugs presented here were used off‐label. The off‐label use of drugs is a typical and well‐known phenomenon in palliative care. Second, treatments for pruritus are not necessarily bound to the pharmaceutical law (e.g. omega‐3 fatty acid). This influences time and costs of RCTs.

For funders 

Funders could consider supporting high‐quality RCTs with 50 or more participants per treatment arm. Most of the investigated drugs showed a positive tendency in reducing pruritus, but these results need to be confirmed in further RCTs (e.g. gabapentin, cromolyn sodium; see also below).

Implications for research 

General 

This update revealed that omega‐3 fatty acids and turmeric could be effective in participants with UP (Ghanei 2012; Pakfetrat 2014). These results have to be confirmed in future RCTs.

Gabapentin may have the largest effect of the investigated drugs (Gunal 2004; Naini 2007). However, these results are only valid for UP patients. The conflicting results for CP participants should be clarified in a future RCT with an adequate sample size (at least 50 participants per treatment arm) (Anand 2013). Furthermore, it is necessary to reproduce those large effects for the UP population in a powered and sound RCT.

A future goal is a wide range of topical and systemic therapies that target the various receptors and neural pathways that mediate different types of itch and lead to improved management of all kinds of pruritus.

As already mentioned, opioid antagonists (e.g. naltrexone) are often inappropriate in the palliative care population because of the risk of loss of analgesia at higher doses of naltrexone. Methylnaltrexone, a peripherally acting μ‐opioid receptor antagonist, was approved by the Food and Drug Administration (FDA) in 2008 for the treatment of opioid‐induced constipation in patients with advanced illness. Notably, methylnaltrexone does not cross the blood‐brain barrier, offering the advantage of peripheral action only and thus has significantly fewer adverse events, including addiction. Researching the efficacy of methylnaltrexone in larger, high‐quality studies, especially in the field of palliative care, would be of particular interest. In addition, given the possible role of the opioidergic system in pruritus, the role of the μ‐opioid receptor antagonist naltrexone in a topical 1% form in the treatment of severe pruritus might be of interest for palliative care patients and could also be researched in a future RCT (Bigliardi 2007).

Design 

In the future, larger studies would help delineate the efficacy of the available and proposed antipruritics. Studies in the field of palliative care are especially lacking, and the evidence for interventions targeting palliative care patients is low. Therefore, well‐designed treatment studies, where possible placebo‐controlled and randomised, are needed to further verify the effectiveness of many antipruritic agents currently in use. Ideally, these RCTs should at least include 50 participants per treatment arm (depends also on sample size calculation).

Measurement (endpoints) 

Most authors used a simple 10 cm or 100 mm VAS to assess pruritus. The VAS should be the minimum standard for assessing pruritus (e.g. in addition to the Duo scale, satisfaction and quality of life). Another advantage of the VAS is that the results can be easily pooled and interpreted in meta‐analyses.

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