Pharmacological interventions for pruritus in adult palliative care patients.

BACKGROUND: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). 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 a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. 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reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data.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 and created 13 summary of findings tables. MAIN RESULTS: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine). AUTHORS CONCLUSIONS: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. 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.

Pharmacological interventions for pruritus in adult palliative care patients.

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.

Pharmacological interventions for pruritus in adult palliative care patients.

BACKGROUND: Pruritus is not the most prevalent but one of the most puzzling symptoms in palliative care patients. It can cause considerable discomfort and has a major impact on patients' quality of life. In the field of palliative care, pruritus is a symptom occurring in patients with disparate underlying diseases and based on different pathologic mechanisms but ending in the same phenomenon. The pathogenesis of pruritus is complex and not fully elucidated. Thus, it is still very difficult to treat pruritus effectively. Evidence-based treatment approaches are needed. OBJECTIVES: The objective was to evaluate the efficacy of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: A systematic literature search up to January 2012 was performed and it was updated in August 2012. The following databases were searched: The Cochrane Library (CENTRAL, DARE, CDSR) (2012, issue 8 of 12); MEDLINE (1950 to August 2012); EMBASE (1980 to August 2012) and three other databases. In addition, we searched trials registries and checked the reference lists of all relevant studies, key textbooks, reviews, and websites, and contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of different pharmacological treatments on preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed identified titles and abstracts. Three independent review authors performed assessment of all potentially relevant studies, data extraction, assessment of risk of bias and methodological quality. Results were summarised descriptively according to the different pharmacological interventions and the type of underlying pruritus. Where possible, results were presented in meta-analyses. MAIN RESULTS: In total, 38 reports comprising 40 studies and 1286 participants were included in the review. Altogether, 30 different treatments for pruritus in four different patient groups were included.The findings of this review indicated that the treatment of pruritus for palliative care patients is challenging and requires an individualistic approach. Results showed that effective therapeutic choices have to be guided by the pathophysiology of the pruritus. Various forms of pruritus occur, especially in the field of palliative care, and sometimes the origin of the pruritus is difficult to determine. Therefore, identifying the underlying cause of pruritus is of prime importance in order to develop tailored treatment plans, even if in palliative care the treatment is focused towards the symptom and not necessarily the underlying disease.Results show that in palliative care patients with pruritus of different natures, treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, may be beneficial. For patients suffering from pruritus associated with HIV infection, indomethacin was described as the most effective drug, although the evidence was weak. For patients suffering from chronic kidney disease-associated pruritus, gabapentin may be an option. An alternative treatment for this patient group seems to be the κ-opioid receptor agonist nalfurafine, which has shown significant amelioration of pruritus and acceptable adverse effects. As they have exhibited a low incidence of adverse effects, rifampicin and flumecinol may be recommended for patients with cholestatic pruritus. The opioid antagonist naltrexone has been shown to offer a therapeutic alternative for patients suffering from uraemic or cholestatic pruritus. However, these drugs are often inappropriate in the palliative population because of the risk of reducing analgesia when giving high doses of naltrexone. AUTHORS' CONCLUSIONS: The findings of this review indicate that the number of systemic and topical drugs used for the different subforms of pruritus is increasing. Different interventions have been shown to be effective in the treatment of pruritus of different origins. Nevertheless, an optimal therapy for pruritus is constrained due to the limited understanding of crucial itch mediators and receptors in the various subforms of itch. Ideal antipruritic therapies are still lacking, especially for palliative care patients.This systematic review also indicates that there is insufficient evidence to give any concrete recommendations regarding treatment of pruritus in palliative care patients. Due to the very small sample sizes and poor methodological quality of the majority of studies that were included, the results of this review need to be interpreted with caution. Furthermore, the generalizability is questionable. Additional studies, and particularly carefully designed treatment trials, are needed to provide valid evidence for adequate treatment of pruritus in palliative care patients.

Reevaluation of statistically significant meta-analyses in advanced cancer patients using the Hartung-Knapp method and prediction intervals-A methodological study.

Using the Hartung-Knapp method and 95% prediction intervals (PIs) in random-effects meta-analyses is recommended by experts but rarely applied. Therefore, we aimed to reevaluate statistically significant meta-analyses using the Hartung-Knapp method and 95% PIs. In this methodological study, three databases were searched from January 2010 to July 2019. We included systematic reviews reporting a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients using either a fixed-effect or random-effects model. We investigated the impact of switching from fixed-effect to random-effects meta-analysis and of using the recommended Hartung-Knapp method in random-effects meta-analyses. Furthermore, we calculated 95% PIs for all included meta-analyses. We identified 6234 hits, of which 261 statistically significant meta-analyses were included. Our recalculations of these 261 meta-analyses produced statistically significant results in 132 of 138 fixed-effect and 114 of 123 random-effects meta-analyses. When switching to a random-effects model, 19 of 132 fixed-effect meta-analyses (14.4%) were no longer statistically significant. Using the Hartung-Knapp method in random-effects meta-analyses resulted in 34 of 114 nonsignificant meta-analyses (29.8%). In the full sample (N = 261), the null effect was included by the 95% PI in 195 (74.7%) and the opposite effect (e.g., hazard ratio 0.5, opposite effect 2) in 98 meta-analyses (37.5%). Using the Hartung-Knapp method and PIs substantially influenced the interpretation of many published, statistically significant meta-analyses. We strongly encourage researchers to check if using the Hartung-Knapp method and reporting 95% PIs is appropriate in random-effects meta-analyses.

Methodological quality was critically low in 9/10 systematic reviews in advanced cancer patients-A methodological study.

OBJECTIVE: To assess the methodological quality and the consideration of heterogeneity in systematic reviews (SRs). STUDY DESIGN AND SETTING: We conducted a methodological study (CRD42019134904) and searched three databases from January 2010 to July 2019. Interventional SRs with a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients were included. A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) 2 was used to evaluate the SRs' methodological quality. The consideration of heterogeneity was categorized in clinical or/and methodological heterogeneity and not explored. RESULTS: From 6234 identified references, 261 SRs were included. Most SRs had a critically low quality (230, 88.1%). The majority of them (209, 80.1%) was classified as critically low because of non-registration (222, 85.1%) combined with the non-reporting of excluded full-texts and missing justifications for exclusion (218, 83.5%). Heterogeneity in trial results was not explored at all in 51 (19.5%) SRs whereas clinical heterogeneity was considered in 117 (44.8%), methodological heterogeneity in 13 (5.0%), and both clinical and methodological heterogeneity in 80 (30.7%) SRs. CONCLUSION: The consideration of these findings in trainings for review authors and peer reviewers could improve the awareness of quality criteria and the quality of future SRs. TRIAL REGISTRATION: PROSPERO-ID: CRD42019134904.

BMI and Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer: A Study and Meta-Analysis.

INTRODUCTION: There is only limited data from clinical practice on the relevance of body mass index (BMI) on pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC). PATIENTS AND METHODS: The impact of BMI on pCR and survival outcome was examined in 324 patients with primary non-metastatic BC. An additional meta-analysis was performed on the current data and relevant previously published studies in clinical practice. RESULTS: Multivariable regression analysis identified lymph vascular invasion (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.01-0.18; P = .0000), grading 3 (OR, 3.12; 95% CI, 1.59-6.12; P = .0009), and HER2/neu status (OR, 4.76; 95% CI, 1.86-12.18; P = .011) as independent factors for pCR after NAC. There was no association between pCR and continuous or categorical BMI. Various additional subgroup analyses of molecular BC subtypes (triple-negative, luminal-like, HER2-luminal, HER2-like) and BMI also showed no association. These findings were confirmed by the meta-analysis. Except for one subgroup analysis in which overweight and obese patients were combined as one group, no association between BMI and pCR as well as survival outcome was found. CONCLUSIONS: BMI was not established as a relevant clinical factor. Only lymph vascular invasion, grading 3, luminal-like, and HER2/like BC subtype showed predictive and prognostic impact in patients with BC receiving NAC.

Cell-assisted lipotransfer.

BACKGROUND: Because of their easy accessibility and versatile biological properties, mesenchymal stem cells taken from fatty tissue (adipose-derived stem cells, ADSC) are attractive for various potential clinical uses. For example, ADSC can be added to fatty tissue before transplantation in the hope of improving the outcome of autologous lipotransfer: the modified procedure is called cell-assisted lipotransfer. The clinical use and commercial promotion of this novel stem-cell treatment (and others) are spreading rapidly, even though there is not yet any clear clinical evidence for its safety and efficacy. METHODS: In cooperation with the German Cochrane Center, we systematically searched the literature according to the PRISMA criteria. Eight major medical databases were searched. The retrieved publications were examined by two independent reviewers and assessed using objective criteria. RESULTS: After screening of the 3161 retrieved publications by title, abstract, and (where appropriate) full text, 78 were still considered relevant. 13 of these were reports of clinical studies; only 3 of the 13 met criteria for grade II or III evidence. The studies that were analyzed involved a total of 286 cell-assisted lipotransfer procedures with a longest follow-up time of 42 months. Oncological safety was not demonstrated. CONCLUSION: The studies published to date have not shown that cell-assisted lipotransfer is generally superior to conventional autologous lipotransfer. They dealt with safety aspects inappropriately or not at all. The case of cell-assisted lipotransfer illustrates the indispensability of high-quality clinical evidence before the introduction of novel stem-cell-based treatments.