Interventions for itch in people with advanced chronic kidney disease

Daniel Hercz; Simon H Jiang; Angela C Webster

doi:10.1002/14651858.CD011393.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Analysis 1.1

Comparison 1: Pharmacological interventions (oral or IV), Outcome 1: Itch

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Analysis 1.2

Comparison 1: Pharmacological interventions (oral or IV), Outcome 2: Itch (dichotomous)

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Analysis 2.1

Comparison 2: Topical interventions, Outcome 1: Itch

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Analysis 3.1

Comparison 3: Oral or IV supplements, Outcome 1: Itch

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Analysis 4.1

Comparison 4: Haemodialysis modality, Outcome 1: Itch

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Analysis 5.1

Comparison 5: Other interventions, Outcome 1: Itch

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Analysis 6.1

Comparison 6: Cross‐over studies with paired data, Outcome 1: Cholestyramine

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Summary of findings 1. Pharmacological interventions versus placebo for the relief of itch in people with advanced chronic kidney disease

Outcomes	Anticipated absolute effects^* (95% CI)		Relative Effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)
Pharmacological interventions versus placebo for the relief of itch in people with advanced chronic kidney disease
Patient or population: uraemic pruritus Settings: outpatient and multi‐centre Intervention: pharmacological treatments Comparison: placebo
Outcomes	Reduction of risk of placebo	Reduction of risk with pharmacological interventions	Relative Effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)
GABA analogue VAS(0 to 10 cm)	The mean VAS score of the placebo group ranged from 0.8 to 2 cm lower than pretreatment scores	The mean reduction in VAS score of the GABA analogue group was 4.95 cm lower (5.46 to 4.44 lower) than placebo	‐	297 (5)	⊕⊕⊕⊕ HIGH
Ondansetron VAS(0 to 10 cm)	The mean VAS score of the placebo group ranged from 0.1 to 2 cm lower than pretreatment scores	The mean reduction in VAS score of the ondansetron agonist group was 0.38 cm lower (1.04 lower to 0.27 higher) than placebo	‐	183 (3)	⊕⊕⊕⊕ HIGH
Kappa‐opioid agonist VAS(0 to 10 cm)	The mean VAS score of the placebo group ranged from 1.3 to 1.9 cm lower than pretreatment scores	The mean reduction in VAS score of the kappa‐opioid agonist group was 1.05 cm lower (1.40 to 0.70 lower) than placebo	‐	661 (5)	⊕⊕⊕⊕ HIGH
Mu‐opioid antagonist VAS(0 to 10 cm)	The mean VAS score of the placebo group ranged from 0.5 to 1 cm lower than pretreatment scores	The mean reduction in VAS score of the mu‐opioid antagonist group was 4.29 cm lower (10.24 lower to 1.66 higher) than placebo	‐	62 (2)	⊕⊕⊝⊝ LOW^1,2
Nalbuphine VAS(0 to 10 cm)	The mean VAS score of the placebo group was 3.2 cm lower than pretreatment scores	The mean reduction in VAS score of the nalbuphine group was 0.75 cm lower (1.70 lower to 0.20 higher) than placebo	‐	179 (1)	⊕⊕⊝⊝ LOW^2,3
Cromolyn VAS(0 to 10 cm)	The mean VAS score of the placebo group was 3 cm lower than pretreatment scores	The mean reduction in VAS score of the cromolyn group was 4.8 cm lower (7.03 to 2.57 lower) than placebo	‐	40 (1)	⊕⊕⊝⊝ LOW^1,2
Nicotinamide VAS(0 to 5 cm)	The mean VAS score of the placebo group was 1.7 cm lower than pretreatment scores	The mean reduction in VAS score of the nicotinamide group was 0.47 cm higher (0.32 lower to 1.26 higher) than placebo	‐	50 (1)	⊕⊕⊝⊝ LOW^1,2
EPO Duo score(0 to 40)	The mean Duo score of the placebo group was 1.5 lower than pretreatment scores	The mean reduction in Duo score of the EPO group was 14.5 lower (38.78 lower to 9.78 higher) than placebo	‐	20 (1)	⊕⊝⊝⊝ VERY LOW^1,2,3
Cholestyramine 0 to 3 severity scale	The mean itch score of the placebo group ranged from 1.3 to 0.7 lower than pretreatment scores	The mean reduction in VAS score of the cholestyramine group was 0.24 higher (0.38 lower to 0.86 higher) than placebo	‐	15 (2)	⊕⊕⊝⊝ LOW^1,4
Montelukast Duo score (0 to 81) and VAS (0 to 10 cm)	The mean Duo score and VAS of the placebo group was 7 points and 0.5 cm lower (respectively) than pretreatment scores.	TheSMD reduction of the montelukast group was 1.4 lower (1.87 to 0.92 lower) than placebo	‐	87 (2)	⊕⊕⊕⊝ MODERATE⁵
Sertraline VAS(0 to 10 cm)	The mean VAS score of the placebo group was 3.7 lower than pretreatment scores	The mean reduction in VAS score of the sertraline group was 1.8 cm lower (3.65 lower to 0.05 higher) than placebo	‐	46 (1)	⊕⊕⊝⊝ LOW^1,2
Lidocaine Itch relief	167 per 1000	800 per 1000 (221 to 1000)	4.80 (0.78 to 29.50)	16 (1)	⊕⊝⊝⊝ VERY LOW^1,2,3
Sodium thalidomide Itch relief	133 per 1000	556 per 1000 (177 to 1000)	4.17 (1.08 to 16.15)	33 (1)	⊕⊝⊝⊝ VERY LOW^1,2,3
Doxepin Itch relief	208 per 1000	875 per 1000 (396 to 1000)	4.20 (1.90 to 9.30)	48 (1)	⊕⊕⊝⊝ LOW^1,2
The reduction of risk of pharmacological versus placebo (column 3) is the additional risk reduction in addition to the benefit provided by the placebo. "Lower" indicates a reduction or negative numerical change versus baseline. CI: Confidence interval; SMD: standardised mean difference; RR: Risk Ratio; VAS: visual analogues scale
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Evidence of certainty was downgraded one level because of the reliance of the estimated effect on a small number of participants ²Evidence of certainty was downgraded one level because of the imprecise treatment estimate ³Evidence of certainty was downgraded one level because of study risks of bias ⁴Evidence of certainty was downgraded one level because heterogeneous results utilizing nonvalidated itch scoring methods ⁵Evidence of certainty was downgraded one level as homogeneity was difficult to assess (due to well validated but different itch scoring methods) and that the analysis would benefit from a greater number of participants

Summary of findings 1. Pharmacological interventions versus placebo for the relief of itch in people with advanced chronic kidney disease

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Summary of findings 2. Topical treatments versus placebo for the relief of itch in people with advanced chronic kidney disease

Outcomes	Anticipated absolute effects^* (95% CI)		No. of participants (RCTs)	Quality of the evidence (GRADE)
Topical treatments versus placebo for the relief of itch in people with advanced chronic kidney disease
Patient or population: uraemic pruritus Settings: outpatient and multi‐centre Intervention: topical treatments Comparison: placebo
Outcomes	Reduction of risk of placebo	Reduction of risk with topical treatments	No. of participants (RCTs)	Quality of the evidence (GRADE)
Capsaicin cream VAS and Duo’s score	The mean VAS and Duo score of this vehicle group was 1.7 cm and 13.4 lower (respectively) than pretreatment scores.	The SMD of the capsaicin group was 0.84 lower (1.22 to 0.45 lower) than vehicle	112 (2)	⊕⊕⊕⊝ MODERATE¹
Pramoxine lotion VAS(0 to 10 cm)	The mean VAS score of this vehicle group was 1.4 cm lower than pretreatment scores.	The mean reduction in VAS score of the pramoxine lotion group was 1.97 lower (6.06 lower to 2.12 higher) than vehicle	27 (1)	⊕⊝⊝⊝ VERY LOW^2,3,4
Calcineurin inhibitor VAS(0 to 10 cm)	The mean VAS score of this vehicle group was 7.1 cm lower than pretreatment scores.	The mean reduction in VAS score of the calcineurin inhibitor group was 1.2 higher (0.36 lower to 2.76 higher) than vehicle	80 (2)	⊕⊝⊝⊝ VERY LOW^2,3,4
Dead Sea lotion 1 to 5 severity score	The mean severity score of this vehicle group was 3 lower than pretreatment scores.	The mean reduction in severity score of the Dead Sea Lotion group was 2 lower (4.31 lower to 0.31 higher) than vehicle	41 (1)	⊕⊝⊝⊝ VERY LOW^2,3,4
Cromolyn cream VAS (0 to 5 cm)	The mean VAS score of this vehicle group was 1.4 cm lower than pretreatment scores.	The mean reduction in VAS score of the cromolyn cream group was 0.8 cm lower (1.98 lower to 0.38 higher) than vehicle	60 (1)	⊕⊕⊝⊝ LOW^2,3
Baby oil Itch Severity Scale(0 to 21)	The mean Itch Severity Scale of this vehicle group was 1 lower than pretreatment scores.	The mean reduction in Itch Severity Scale of the baby oil group was 2.36 lower (3.29 to 1.44 lower) than vehicle	125 (2)	⊕⊕⊝⊝ LOW⁵
L‐arginine salve 0 to 3 severity score	The mean severity score of this vehicle group was 3.4 lower than pretreatment scores.	The mean reduction in severity score of the L‐arginine salve group was 0.58 lower (1.86 lower to 0.7 higher) than vehicle	48 (1)	⊕⊕⊝⊝ LOW^2,3
Polyunsaturated fatty acids VAS (0 to 10 cm) Duo score	The mean VAS and Duo score of this vehicle group was 1 cm lower and 5 points higher (respectively) than pretreatment scores.	The SMD of the polyunsaturated fatty acids group was 0.91 lower (1.99 lower to 0.17 higher) than vehicle	78 (2)	⊕⊕⊝⊝ LOW^2,6
The reduction of risk of pharmacological versus placebo (column 3) is the additional risk reduction in addition to the benefit provided by the placebo. "Lower" indicates a reduction or negative numerical change versus baseline. CI: Confidence interval; SMD: standardised mean difference; VAS: visual analogue scale
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Evidence of certainty was downgraded one level as homogeneity was difficult to assess (due to well validated but different itch scoring methods) and that the analysis would benefit from a greater number of participants ²Evidence of certainty was downgraded one level because of the reliance of the estimated effect on a small number of participants ³Evidence of certainty was downgraded one level because of the imprecise treatment estimate ⁴Evidence of certainty was downgraded one level because of study risks of bias ⁵Evidence of certainty was downgraded two levels because of study risks of bias and use of a non‐validated itch scoring method. ⁶Evidence of certainty was downgraded one level because of the imprecise and small treatment estimate

Summary of findings 2. Topical treatments versus placebo for the relief of itch in people with advanced chronic kidney disease

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Summary of findings 3. Supplements, haemodialysis modalities, and other treatments for the relief of itch in people with advanced chronic kidney disease

Outcomes	Anticipated absolute effects^* (95% CI)		No. of participants (RCTs)	Quality of the evidence (GRADE)
Supplements, HD modalities, and other treatments for the relief of itch in people with advanced chronic kidney disease
Patient or population: uraemic pruritus Settings: outpatient and multi‐centre Intervention: supplements, HD modalities, and other treatments Comparison: placebo; other HD comparators
Outcomes	Reduction of risk of comparator	Reduction of risk with supplements, HD modalities, and other treatments	No. of participants (RCTs)	Quality of the evidence (GRADE)
Polyunsaturated fatty acids 0 to 5severity score	The mean severity score of this placebo group was 1.6% lower than pretreatment scores.	The mean reduction in 0 to 5 severity score of the polyunsaturated fatty acids group was 11.3% lower (9.0 to 3.6 lower) than placebo	22 (1)	⊕⊕⊝⊝ LOW^1,2
L‐carnitine VAS (0 to 6 cm)	The mean VAS score of this placebo group was 0.2 higher than pretreatment scores.	The mean reduction in VAS score of the L‐carnitine group was 0.26 lower (2.85 lower to 2.43 higher) than placebo	12 (1)	⊕⊕⊝⊝ LOW^1,2
Zinc sulfate VAS (0 to 10 cm)	The mean VAS and Duo score of this vehicle group was 4.3cm and 6.1 lower (respectively) than pretreatment scores.	The mean reduction of the zinc sulfate group was 1.77 lower (2.88 to 0.66 lower) than placebo	76 (2)	⊕⊕⊕⊝ MODERATE¹
Ergocalciferol 21 point scale	The mean score of this vehicle group was 6.1 lower than pretreatment scores.	The mean reduction in VAS score of the ergocalciferol group was 0.4 higher (2.52 lower to 3.32 higher) than placebo	50 (1)	⊕⊕⊝⊝ LOW^1,2
Turmeric Duo score (5 to 40)	The mean Duo’s score of this vehicle group was 2 lower than pretreatment scores.	The mean reduction in VAS score of the turmeric group was 6.4 lower* (7.42 to 5.38 lower) than placebo	100 (1)	⊕⊕⊕⊝ MODERATE¹
Fumaria parviflora VAS (0 to 10 cm)	The mean VAS score of this vehicle group was 2.2lower than pretreatment scores.	The mean reduction in VAS score of the Fumaria parviflora group was 3.90lower (5.04 to 2.76 lower) than placebo	63 (1)	⊕⊕⊝⊝ LOW^1,3
High flux/permeability dialysis VAS (0 to 10 cm)	The mean VAS score of this control group ranged from 0.6 cm to 5.6 cm lower than pretreatment scores.	The mean reduction in VAS score of the high flow/permeability group was 2.60 cm lower (3.22 to 1.97 lower) than placebo	202 (3)	⊕⊕⊝⊝ LOW^3,4
HD with haemoperfusion VAS (0 to 10 cm)	The mean VAS score of this control group was 0.6 cm lower than pretreatment scores.	The mean reduction in VAS score of the HD with haemoperfusion group was 2.37 cm lower (2.89 to 1.85 lower) than placebo	90 (1)	⊕⊕⊝⊝ LOW^1,3
UV‐B Duo score, VAS, and %improvement	The mean Duo score and VAS of this control group was 2.2 points and 0.3 cm lower (respectively) than pretreatment scores.	The SMD of the UV‐B group was 2.49 lower (4.62 to 0.36 lower) than placebo	86 (4)	⊕⊕⊝⊝ LOW^1,3
Thermal therapy VAS (0 to 10 cm)	The mean VAS score of this control group was 5.8 lower than pretreatment scores.	The mean reduction in VAS score of the thermal therapy group was 2.06 lower (6.98 lower to 2.84 higher) than placebo	41 (1)	⊕⊕⊝⊝ LOW^1,2
The reduction of risk of pharmacological versus placebo (column 3) is the additional risk reduction in addition to the benefit provided by the placebo. "Lower" indicates a reduction or negative numerical change versus baseline. CI: Confidence interval; RR: Risk Ratio; SMD: standardised mean difference; VAS: visual analogue scale
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Evidence of certainty was downgraded one level because of the reliance of the estimated effect on a small number of participants ²Evidence of certainty was downgraded one level because of the imprecise treatment estimate ³Evidence of certainty was downgraded one level because of study risks of bias ⁴Evidence of certainty was downgraded one level because heterogeneity between studies

Summary of findings 3. Supplements, haemodialysis modalities, and other treatments for the relief of itch in people with advanced chronic kidney disease

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Table 1. Adverse events: pharmacological interventions

Intervention	Participants (studies)	Route/dose	Intervention adverse effects (dropouts/participants)*	Control adverse effects (dropouts/participants)*
GABA analogue (pregabalin or gabapentin) versus placebo	271 (6)	Pregabalin (a) Oral: 75 mg, twice/week Gabapentin (b) Oral: 400 mg, twice/week (c) Oral: 300 mg, 3 times/week (d) Oral: 300 mg/day (e) Oral: dose not reported	Gunal 2004 (c): somnolence, dizziness, fatigue Naghibi 2007 (e): somnolence Naini 2007 (b): somnolence, dizziness, nausea Nofal 2016 (d): somnolence (9/27), dizziness (5/27) Tol 2010 (c): not reported Yue 2015 (a): somnolence (3/67), loss of balance (2/67)	Gunal 2004: not reported Naghibi 2007: not reported Naini 2007: not reported Nofal 2016: not reported Tol 2010: not reported Yue 2015: not reported
Ondansetron versus placebo	161 (3)	(a) Oral: 8 mg, 3 times/day (b) Oral: 8 mg, once/day (c) Oral: 8 mg, twice/day	Ashmore 2000 (a): not reported Murphy 2003 (b): constipation (1/14), ischaemic stroke (1/18), line sepsis (1/17) Yue 2015 (c): nausea and vomiting (2/64)	Ashmore 2000: not reported Murphy 2003: not reported Yue 2015: none
Kappa opioid agonists versus placebo	626 (4)	Nalfurafine (a) Oral: 2.5 µg once/day (b) Oral: 5 µg once/day (c) IV: 5 µg, 3 times/week (d) IV: 2.5, 5 µg with dialysis CR845 (e) IV: 0.5 to 1.5 µg/kg with dialysis	Kumagai 2010 (a, b) 2.5 µg (oral): somnolence (4.5%); insomnia (7.1%), diarrhoea (4.5%), nasopharyngitis (8.0%) 5 µg (oral): constipation (7.9%), somnolence (3.5%), insomnia (14.9%), nasopharyngitis (12.3%) Spencer 2015 (e): not reported Spencer 2017 (e) (0.5 to 1.5 µg/kg): somnolence (9/129), dizziness (12/129), headache (5/129), diarrhoea (16/129), nausea (11/129) Bhaduri 2006 (d): not reported Wikstrom 2005 (c): headache (3/26), nausea (3/26), vomiting (2/26), insomnia (2/26), vertigo (2/26)	Kumagai 2010: nasopharyngitis (17.1%), headache (3.6%), vomiting (3.6%) Spencer 2015: not reported Spencer 2017: somnolence (1/45), dizziness (2/45), headache (1/45), diarrhoea (0/45) Wikstrom 2005: 13/25 (type not reported)
Mu opioid antagonists versus placebo	31 (2)	Oral: 50 mg once/day	Pauli‐Magnus 2000: loss of appetite and nausea (9) Peer 1996: heartburn (2), abdominal discomfort (3)	Pauli‐Magnus 2000: nausea (1) Peer 1996: not reported
Nalbuphine versus placebo	373 (1)	Oral: 60 or 120 mg, twice/day	TREVITR02 2017 60 mg: serious adverse events (12.7%), adverse events leading to discontinuation (33/128) 120 mg: serious adverse events (6.7%), adverse events leading to discontinuation (27/120)	TREVITR02 2017: serious adverse events (15.4%), adverse events leading to discontinuation (7/123)
EPO versus placebo	39 (2)	(a) IV: 36 U/kg/dialysis (b) SC: 2000 IU twice/day	De Marchi 1992 (a): not reported Sja'bani 1997 (b): not reported	De Marchi 1992: not reported Sja'bani 1997: not reported
Nicotinamide versus placebo	50 (1)	Oral: 500 mg twice/day	Omidian 2013: not reported	Omidian 2013: not reported
Lidocaine versus placebo	20 (1)	IV: 200 mg	Tapia 1977: not reported	Tapia 1977: not reported
Cholestyramine	20 (2)	Oral: 5 mg, twice/day	Silverberg 1977: constipation (1/5), nausea (1/5) van Leusen 1978: not reported	Silverberg 1977: not reported van Leusen 1978: not reported
Montelukast versus placebo	89 (2)	Oral: 10 mg/day	Mahmudpour 2017: not reported Nasrollahi 2007: myelodysplastic syndrome (1/8)	Mahmudpour 2017: Not reported Nasrollahi 2007: myocardial infarction (1/8)
Sertraline versus placebo	50 (1)	Oral: 50 mg twice/day	Pakfetrat 2018: not reported	Pakfetrat 2018: not reported
Sodium thiosulfate versus placebo	45 (1)	IV: 12.5 mg/dialysis session	Mohamed 2012: not reported	Mohamed 2012: not reported
Doxepin versus placebo	24 (1)	Oral: 10 mg, twice/day	Pour‐Reza‐Gholi 2007: drowsiness (12/24)	Pour‐Reza‐Gholi 2007: not reported
Thalidomide versus placebo	29 (1)	Oral: 100 mg/day	Silva 1994: not reported	Silva 1994: not reported
Cimetidine versus placebo	13 (1)	Oral: 600 mg/day	Aubia 1980: not reported	Aubia 1980: not reported
Cromolyn versus placebo	62 (1)	Oral: 135 mg, 3 times/day	Vessal 2010: flatulence (1/32)	Vessal 2010: nausea (5/30), diarrhoea (4/30)
Gabapentin versus pregabalin	50 (1)	Oral gabapentin (300 mg, once/day) versus oral pregabalin (75 mg, once/day)	Solak 2012 Gabapentin: not reported Pregabalin: not reported	‐‐
GADA versus ondansetron	131 (1)	Oral pregabalin (75 mg twice/week) versus oral ondansetron (8 mg/day)	Yue 2015 Pregabalin: somnolence (3/67), loss of balance (2/67) Ondansetron: not reported	‐‐
GABA analogue versus doxepin	90 (1)	Oral pregabalin (50 mg every other night) versus oral doxepin (10 mg/night)	Foroutan 2017 Pregabalin: intolerable adverse events (3/46), somnolence (6/37), oedema (3/37), drowsiness (3/27), imbalance (1/37), numbness (1/37) Doxepin: intolerable adverse events (1/44), nervousness (1/35)	‐‐
GABA analogue versus antihistamine	212 (4)	(a) Oral gabapentin (100 mg/day) versus oral ketotifen (1 mg, twice/day) (b) Oral gabapentin (300 mg, 3 times/week) versus oral dexchlorpheniramine (6 mg, 3 times/week) (c) Oral gabapentin (300 mg/day) versus oral loratadine (10 mg/day) (d) Oral gabapentin (100 to 200 mg/day) versus oral hydroxyzine (10 mg/day) (e) Oral gabapentin (100 mg/day) versus oral hydroxyzine (10 mg/day)	Amirkhanlou 2016 (a) Gabapentin: drowsiness (4/26), dizziness (1/26) Ketotifen: drowsiness (4/26), dizziness (1/26) Gobo‐Oliveira 2018 (b) Gabapentin: total (11/30), drowsiness (17%) Dexchlorpheniramine: total (8/30), drowsiness (1/30) Marin 2013 (c) Gabapentin: somnolence (8/30) Loratadine: none reported Noshad 2011 (d) Gabapentin: complications (7/20) Hydroxyzine: complications (10/20) Suwanpidokkul 2007 (e) Gabapentin: (9/18) Loratadine: (4/16)	‐‐
Mu opioid antagonists versus antihistamine	52 (1)	Oral naltrexone (50 mg/day) versus oral loratadine (10 mg/day)	Legroux‐Crespel 2004 Naltrexone (26): vomiting (2), nausea (9), anorexia (1), abdominal distention (1), malaise (1), cramps (2), sleep disturbances (5), vertigo (5), headache (2), somnolence (1), paraesthesia (1), withdrawn (10) Loratadine (26): vomiting (2), malaise (1), withdrawn from study (2)	‐‐
Ondansetron versus antihistamine	20 (1)	(a) Ondansetron tablet (8 mg/day) versus cyproheptadine syrup (8 mg/day) (b) "3 doses ondansetron 8mg" versus "diphenhydramine 25mg" (c) Oral ondansetron (8 mg, 3 times/day) versus oral loratadine (10 mg twice/day)	Ozaykan 2001 (a): not reported Subach 2001 (b): not reported Mirnezami 2013 (c): not reported	‐‐
*when reported GABA ‐ gamma‐aminobutyric acid

Table 1. Adverse events: pharmacological interventions

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Table 2. Adverse events: topical interventions

Intervention	Participants (studies)	Route/dose	Intervention adverse effects (dropouts/participants)*	Control adverse effects (dropouts/participants)*
Cromolyn cream versus placebo	60 (1)	4% cream	Feily 2012: burning sensation (6/30)	Feily 2012: none
Capsaicin cream versus placebo	91 (4)	(a) 0.025%, 4 times/day (b) 0.03%, 4 times/day	Breneman 1992 (a): burning and stinging sensation (5), decrease in xerosis (3), dryness (2) Cho 1997 (a): not reported Makhlough 2010 (b): skin burning Tarng 1996 (a): local burning and/or stinging sensations	Breneman 1992: not reported Cho 1997: not reported Makhlough 2010: none Tarng 1996: local burning and/or stinging sensations
Pramoxine lotion versus placebo	28 (1)	1.0% twice/day	Young 2009: none	Young 2009: none
Baby oil versus placebo	92 (1)	Chilled and unchilled 15 min application at least once/day	Lin 2012: not reported	Lin 2012: not reported
Dead Sea lotion versus placebo	50 (1)	Entire body, twice/day	Boaz 2009: total adverse events (2/25)	Boaz 2009: total adverse events (3/25)
Sericin cream versus placebo	50 (1)	1 g, twice/day	Aramwit 2012a: not reported	Aramwit 2012a: not reported
L‐arginine salve versus placebo	24 (1)	25 µg/2.5 cm² twice/day	Durant‐Finn 2008: not reported	Durant‐Finn 2008: not reported
Calcineurin inhibitors versus placebo	80 (2)	TAC: 0.1% twice/day Pimecrolimus: 1.0% twice/day	Duque 2005: warmth sensation (6/12) Ghorbani 2012a: burning sensation which disappeared by the end of 8 weeks	Duque 2005: warmth sensation (3/8) Ghorbani 2012a: none
Sweet almond oil versus no intervention	44 (1)	100 mg/day	Afrasiabifar 2017: not reported	Afrasiabifar 2017: not reported
Gamma‐linoleic acid versus placebo	17 (1)	2.2%, 30 mL/day	Chen 2006e: allergic reaction (1/8)	Chen 2006e: none
Calcineurin inhibitors versus cromolyn	60 (1)	Pimecrolimus: 2% twice/day Cromolyn: 4%, twice/day	Ghorbani Birgani 2011: unknown	Ghorbani Birgani 2011: unknown
Avena sativa versus diluted vinegar versus hydroxyzine	23 (1)	Avena sativa: variable dose, twice/day Dilute vinegar: 30 mL twice/day Oral hydroxyzine: 10 mg/day	Nakhaee 2015: not reported	‐‐
Sarna versus eurax	30 (1)	Sarna: 0.5% each of camphor, menthol, and phenol "as required" for 7 days Eurax: 10% crotamiton "as required" for 7 days	Tan 1990 Sarna: none Eurax: rash (1)	‐‐
*when reported

Table 2. Adverse events: topical interventions

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Table 3. Adverse events: oral and IV supplements

Intervention	Participants (studies)	Dose/route	Intervention adverse effects (dropouts/participants)*	Placebo adverse effects (dropouts/participants)*
Polyunsaturated fatty acids versus placebo	89 (4)	Fish oil (a) Oral: 6 g/day (b) Oral: 3 g/day Omega‐3 fatty acids (c) Oral: 3 g/day	Begum 2004 (a): not reported Ghanei 2012 (c): not reported Mojgan 2017 (b): not reported Peck 1996 (a): not reported	Begum 2004: not reported Ghanei 2012: not reported Mojgan 2017: not reported Peck 1996: not reported
L‐carnitine versus placebo	17 (1)	IV: 10 mg/kg, once/day	Mettang 1997: not reported	Mettang 1997: not reported
Zinc sulfate versus placebo	80 (2)	(a) Oral: 220 mg/day (b) Oral: 200 mg twice/day	Mapar 2015 (a): none Najafabadi 2012 (b): none “attributable to zinc sulfate”	Mapar 2015: vomiting (1/20) Najafabadi 2012: not reported
Ergocalciferol versus placebo	50 (1)	Oral: 50,000 IU/week	Shirazian 2013: none	Shirazian 2013: not reported
Turmeric (curcumin) versus placebo	100 (1)	Oral: 500 mg (22.1 mg), 3 times/day	Pakfetrat 2014: none	Pakfetrat 2014: not reported
Fumaria parviflora versus placebo	79 (1)	Oral: 1000 mg, 3 times/day	Akrami 2017: Gastric pain (4/39), rash (1/39)	Akrami 2017: abdominal pain (1/40), constipation (1/40)
Senna versus placebo	60 (1)	Oral: dose and frequency not reported	Fallahzadeh 2015: not reported	Fallahzadeh 2015: not reported
Evening primrose oil	16 (1)	Oral: 2 capsules/day (containing 360 mg of linoleic acid, 50 mg oleic acid and 45 mg of gamma‐linoleic acid)	Yoshimoto‐Furuie 1999: none	Yoshimoto‐Furuie 1999: none
Activated charcoal versus placebo	20 (1)	Oral: 6 g/day	Pederson 1980: not reported	Pederson 1980: not reported
Charcoal versus aluminium hydroxide	30 (1)	Charcoal: 6 g, 3 times/day Aluminium hydroxide: 30 mL, 3 times/day	Shariati 2010: not reported	‐‐
*when reported

Table 3. Adverse events: oral and IV supplements

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Table 4. Adverse events: dialysis modality

Intervention	Participants (studies)	Dose/route	Intervention adverse effects (dropouts/participants)*	Control adverse effects (dropouts/participants)*
High flux/ high permeability/high flow HD	252 (4)	(a) High‐flow HD (b) High‐permeability HD (c) High‐flux HD	Aliasgharpour 2018 (a): not reported Chen 2009 (b): not reported Hui 2011 (c): not reported Jiang 2016 (c): not reported	Aliasgharpour 2018: not reported Chen 2009: not reported Hui 2011: not reported Jiang 2016: not reported
HD with haemoperfusion	90 (1)	Haemoperfusion HA130‐RHA HA330‐RHA	Li 2017a: not reported	Li 2017a: not reported
Haemoperfusion plus HD versus haemoperfusion plus HDF	40 (1)	Haemoperfusion plus HD Haemoperfusion plus HDF	Zhang 2016a Haemoperfusion plus HD: not reported Haemoperfusion plus HDF: not reported	‐‐
Magnesium‐free HD versus standard HD	17 (1)	Standard HD: 0.85 mmol/L magnesium solution for 2 weeks	Carmichael 1988: not reported	Carmichael 1988: not reported
Calcium dialysate HD	4 (1)	Calcium concentration 1.0 mmol/L 1.25 mmol/L 1.75 mmol/L	Kyriazis 2000: not reported	Kyriazis 2000: not reported
Cool versus normal dialysate	60 (1)	Cool dialysate: 35.5^oC, 3 times/week Normal dialysate: 37^oC, 3 time/week	Rad 2017: not reported	Rad 2017: not reported
*when reported

Table 4. Adverse events: dialysis modality

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Table 5. Adverse events: other interventions

Intervention	Participants (studies)	Dose/route	Intervention adverse effects (dropouts/participants)*	Control adverse effects (dropouts/participants)*
UV‐B exposure	75 (4)	(a) 0.19 nJ/cm²/sec, 3 times/week (b) Minimal erythema dose, twice/week (c) 4.4 watts/m², twice/week (d) 200 mJ/cm², 3 times/week	Blachley 1985 (a): not reported Chan 1995 (b): not reported Gilchrest 1977 (c): sunburn (3/10), tanning (5/10) Gilchrest 1979 (c): mild sunburn and tanning Ko 2011 (d): erythema (2/11)	Blachley 1985: not reported Chan 1995: not reported Gilchrest 1977: not reported Gilchrest 1979: not reported Ko 2011: not reported
UV‐A exposure	11 (1)	UV‐A (exposure): 40 min exposure (10, 180 cm 85W UV‐A lamps) 3 times/week	Taylor 1983: not reported	Taylor 1983: not reported
Thermal therapy	41 (1)	40^oC thermal therapy, twice/week	Hsu 2009: not reported	Hsu 2009: not reported
UV‐B exposure versus cetirizine	30 (1)	UV‐B Whole body: 200 to 1038 mJ/cm² every 3rd day for 15 sessions Cetirizine Oral: 10 mg/day for the same duration	Sherjeena 2017: not reported	‐‐
*when reported

Table 5. Adverse events: other interventions

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Comparison 1. Pharmacological interventions (oral or IV)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Itch Show forest plot	30		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1.1 GABA analogues	5	297	Std. Mean Difference (IV, Random, 95% CI)	‐2.14 [‐2.43, ‐1.85]
1.1.2 GABA analogues versus antihistamine	5	220	Std. Mean Difference (IV, Random, 95% CI)	‐0.44 [‐0.75, ‐0.14]
1.1.3 Ondansetron	3	183	Std. Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.49, 0.15]
1.1.4 Kappa‐opioid agonist	4	661	Std. Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.60, ‐0.27]
1.1.5 Mu‐opioid antagonist	2	62	Std. Mean Difference (IV, Random, 95% CI)	‐4.10 [‐11.05, 2.85]
1.1.6 Nalbuphine	1	179	Std. Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.54, 0.10]
1.1.7 Cromolyn	1	40	Std. Mean Difference (IV, Random, 95% CI)	‐1.31 [‐2.00, ‐0.62]
1.1.8 Nicotinamide	1	50	Std. Mean Difference (IV, Random, 95% CI)	0.32 [‐0.23, 0.88]
1.1.9 EPO	1	20	Std. Mean Difference (IV, Random, 95% CI)	‐0.50 [‐1.39, 0.39]
1.1.10 Cholestyramine	2	20	Std. Mean Difference (IV, Random, 95% CI)	0.00 [‐0.89, 0.89]
1.1.11 Montelukast	2	87	Std. Mean Difference (IV, Random, 95% CI)	‐1.40 [‐1.87, ‐0.92]
1.1.12 Sertraline	1	46	Std. Mean Difference (IV, Random, 95% CI)	‐0.56 [‐1.15, 0.03]
1.1.13 Lidocaine	1	16	Std. Mean Difference (IV, Random, 95% CI)	‐0.81 [‐1.87, 0.25]
1.1.14 Gabapentin versus pregabalin	1	40	Std. Mean Difference (IV, Random, 95% CI)	0.01 [‐0.61, 0.63]
1.1.15 GABA analogues versus doxepin	1	72	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.33, ‐0.36]
1.2 Itch (dichotomous) Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.2.1 Lidocaine	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.2.2 Thalidomide	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.2.3 Doxepin	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 1. Pharmacological interventions (oral or IV)

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Comparison 2. Topical interventions

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Itch Show forest plot	10		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1.1 Capsaicin cream	2	112	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.22, ‐0.45]
2.1.2 Pramoxine cream	1	27	Std. Mean Difference (IV, Random, 95% CI)	‐0.35 [‐1.11, 0.41]
2.1.3 Calcineurin Inhibitor cream	1	60	Std. Mean Difference (IV, Random, 95% CI)	0.39 [‐0.13, 0.90]
2.1.4 Dead Sea lotion	1	41	Std. Mean Difference (IV, Random, 95% CI)	‐0.52 [‐1.14, 0.10]
2.1.5 Cromolyn cream	1	60	Std. Mean Difference (IV, Random, 95% CI)	‐0.34 [‐0.85, 0.17]
2.1.6 Baby oil	1	93	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.32, ‐0.43]
2.1.7 L‐arginine salve	1	48	Std. Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.82, 0.32]
2.1.8 Polyunsaturated fatty acids	2	78	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.99, 0.17]

Comparison 2. Topical interventions

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Comparison 3. Oral or IV supplements

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Itch Show forest plot	7		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1.1 Polyunsaturated fatty acids	1	22	Mean Difference (IV, Random, 95% CI)	‐11.30 [‐19.01, ‐3.59]
3.1.2 L‐carnitine (IV)	1	12	Mean Difference (IV, Random, 95% CI)	‐0.26 [‐2.85, 2.33]
3.1.3 Zinc sulfate	2	76	Mean Difference (IV, Random, 95% CI)	‐1.77 [‐2.88, ‐0.66]
3.1.4 Ergocalciferol	1	50	Mean Difference (IV, Random, 95% CI)	0.40 [‐2.48, 3.28]
3.1.5 Turmeric	1	100	Mean Difference (IV, Random, 95% CI)	‐6.40 [‐7.42, ‐5.38]
3.1.6 Fumaria parviflora	1	63	Mean Difference (IV, Random, 95% CI)	‐3.90 [‐5.04, ‐2.76]

Comparison 3. Oral or IV supplements

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Comparison 4. Haemodialysis modality

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Itch Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1.1 High flux or permeability HD	3	202	Mean Difference (IV, Random, 95% CI)	‐2.62 [‐3.72, ‐1.52]
4.1.2 NMR haemoperfusion	1	90	Mean Difference (IV, Random, 95% CI)	‐2.37 [‐2.89, ‐1.85]

Comparison 4. Haemodialysis modality

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Comparison 5. Other interventions

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Itch Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1.1 UV‐B	4	86	Mean Difference (IV, Random, 95% CI)	‐4.06 [‐8.40, 0.28]
5.1.2 Thermal therapy	1	49	Mean Difference (IV, Random, 95% CI)	‐2.06 [‐6.54, 2.42]

Comparison 5. Other interventions

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Comparison 6. Cross‐over studies with paired data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Cholestyramine Show forest plot	2		Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.86, 0.38]

Comparison 6. Cross‐over studies with paired data

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