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Intervention Review

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Pharmacological interventions for pruritus in adult palliative care patients

  1. Carola Xander1,*,
  2. Joerg J Meerpohl2,
  3. Daniel Galandi3,
  4. Sabine Buroh4,
  5. Guido Schwarzer5,
  6. Gerd Antes6,
  7. Gerhild Becker7

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 9 JUN 2013

Assessed as up-to-date: 1 APR 2013

DOI: 10.1002/14651858.CD008320.pub2


How to Cite

Xander C, Meerpohl JJ, Galandi D, Buroh S, Schwarzer G, Antes G, Becker G. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD008320. DOI: 10.1002/14651858.CD008320.pub2.

Author Information

  1. 1

    German Cochrane Center, Institute of Medical Biometry and Medical Informatics, Freiburg, Germany

  2. 2

    Medical Center - University of Freiburg, Cochrane Germany, Freiburg, Germany

  3. 3

    Ev. Diakoniekrankenhaus Freiburg, Medical Clinic, Freiburg, Germany

  4. 4

    University Medical Center, Library of the Surgical Clinic, Freiburg, Germany

  5. 5

    Medical Center - University of Freiburg, Center for Medical Biometry and Medical Informatics, Freiburg, Germany

  6. 6

    Medical Center – University of Freiburg, Cochrane Germany, Freiburg, Germany

  7. 7

    University Medical Center, Department of Palliative Care, Freiburg, Germany

*Carola Xander, Department of Palliative Care, University Medical Center, Robert Koch Str. 3, Freiburg, 79102, Germany. carola.xander@uniklinik-freiburg.de.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 9 JUN 2013

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Characteristics of included studies [ordered by study ID]
Ashmore 2000

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD1/UP2

Description: patients with end-stage renal disease on haemodialysis and having pruritus

Number of participants randomised: 19

Number of participants evaluable: 16

Withdrawals/dropouts: 3

Reason for dropout: non-compliance

Age (years): 28 - 77 (mean 60) for the participants completing the study

Sex (male/female): 11/8; participants completing the study: 10/6

Underlying disease/s: chronic renal failure of unknown cause (3), hypertensive nephrosclerosis (3), immunoglobulin A nephropathy (2), nephrotic syndrome (2), connective tissue disease (1), diabetic nephropathy (1), Henoch-Schönlein purpura (1), obstructive uropathy (1), systemic lupus erythematosus (1), adult polycystic kidney disease (1)

Participant pool: uni-centre

Setting: inpatient

Haemodialysis: median of 20 months (1 to 53 months)

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information

Baseline parameters:

Symptom score (measured by antihistamine escape medication):

  • Before ondansetron treatment: 21% (IQR, 8.5 to 61)
  • Before placebo treatment: 52.5% (IQR, 0 to 88.3)


Pruritus score (measured by VAS 10 cm):

  • Before ondansetron treatment: 5.3 (IQR, 3.4 to 6.3)
  • Before placebo treatment: 3.7 (IQR, 3.0 to 4.6)


InterventionsDrug (dose):

  • Intervention 1: ondansetron (8mg 3x/day)
  • Intervention 2: placebo


Additional medication: antihistamines as escape medication chlorpheniramine (9), terfenadine (4), hydroxyzine (3), iron supplements (16), erythropoietin (15), crotamiton cream (9), H2-receptor antagonist (5)

Route of administration: oral

Duration of treatment: 2 weeks (washout 1 (day 1-7) - ondansetron/placebo (8-21) - washout 2 (22-28) - crossover (29-42))

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Symptom relief (measured by antihistamine escape medication):

  • During ondansetron treatment: 8.5% (interquartile range = IQR, 0 to 33) P = 0.2
  • During placebo treatment: 5% (IQR, 0 to 31.3) P = 0.04


Pruritus relief (measured by VAS 10 cm):

  • During ondansetron treatment: 3.9 (IQR, 2.7 to 5) P = 0.2
  • During placebo treatment: 3.6 (IQR, 2.4 to 4.8) P = 0.3


Adverse events: no information

Additional outcomes:

serum calcium, phosphate, magnesium, urea, creatinine levels, bilirubin, alanine transaminase, alkaline phosphatase, haemoglobin, ferritin, parathyroid hormone

Author conclusion:

Ondansetron had no advantage over placebo in either relief of pruritus or reduction in antihistamine use. Escape medication use decreased during both placebo and ondansetron treatment.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"We randomly assigned 16 haemodialysis patients ..."

Participants were randomised to receive active drug or placebo ..."

Method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Participants were randomised (...) in a double-blind crossover study."

Unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data, (3 participants withdrawn due to protocol violation), then PP analysis; no intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasUnclear riskPartly sponsored by Glaxo Smith Kline

Bachs 1989

MethodsRCT

Comparative trial

Cross-over design

Blinding: open study


ParticipantsPruritus: CP3

Description: patients with clinical, biochemical, immunological, and histological features of primary biliary cirrhosis (PBC4) and pruritus

Number of participants randomised: 22

Number of participants evaluable:

  • Rifampicin: 21
  • Phenobarbitone: 18


Withdrawals / dropouts:

  • Rifampicin: 1
  • Phenobarbitone: 4


Reason for drop-out:

  • Rifampicin: development of anaemia and renal failure
  • Phenobarbitone: rash (3), 1 participant refused the drug


Age (years, mean): 49.7±8.4

Sex (male/female): 0/22

Underlying disease/s: PBC

Participant pool: no information

Setting: outpatient

Haemodialysis: N/a5

Baseline pruritus assessment: yes

Pruritus assessment: 4-point scale

Duration/severity of pruritus: no information

Baseline parameters:

Pruritus score (measured by a 4-point scale; 0=no itching, 3=continuous pruritus):

  • Rifampicin: 2.4±0.6
  • Phenobarbitone: 1.8±1.2


InterventionsDrug (dose):

  • Intervention 1: rifampicin (10mg/kg)
  • Intervention 2: phenobarbitone (3mg/kg


Additional medication: stopped 1 month prior the study

Route of administration: oral

Duration of treatment: 2 weeks (2 weeks rifampicin/phenobarbitone - 30 days washout - 2 weeks crossover)

Follow-up: no information


OutcomesPruritus assessment: 4-point scale

Results:

Pruritus relief (measured on a 4-point scale; 0=no itching, 3=continuous pruritus) given as mean value:

  • Rifampicin: 0.8±0.9, P < 0.001 (19 improved, 9 participants with complete resolution, 3 of which were free of itch when switching over to phenobarbitone)
  • Phenobarbitone: 1.4±0.9 (8 improved)


Adverse events:

  • Rifampicin: haemolytic anaemia and renal failure (1)
  • Phenobarbitone: skin rash after a few days of treatment (3), sedative effect


Additional outcomes:

Fasting serum concentrations of bile acids, alkaline phosphatase, and gamma-glutamyl-transpeptidase decreased with rifampicin but not with phenobarbitone.

Author conclusion:

Rifampicin is significantly more effective than phenobarbitone for relieving pruritus in participants with PBC.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The order of treatment was randomised."

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo information provided, probably no blinding

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo information provided, probably no blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; unclear if intention-to-treat analysis was used

Selective reporting (reporting bias)Low riskNo indication of selective reporting although no results on cholesterol given

Other biasLow riskNo indication

Bergasa 2006

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 16

Number of participants evaluable:

  • Gabapentin: 7
  • Placebo: 6


Number of participants enrolled: 15 - 1 withdrawal prior to randomisation

  • Gabapentin: 8
  • Placebo: 7


Withdrawals/dropouts: 3

  • Gabapentin: 1
  • Placebo: 1
  • Prior to randomisation: 1


Reason for dropout:

  • Gabapentin: vomiting
  • Placebo: persistent severe pruritus within 2 weeks
  • Prior to randomisation: participant did not want to be hospitalised


Age (years): 44-63 (median: 49)

Sex (male/female): 0/16

Underlying disease/s: PBC (9), chronic liver disease secondary to infection with hepatitis C (6), PSC6 (1)

Participant pool: uni-centre

Setting: inpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment:

  • VAS
  • Hourly scratching activity (HSA)
  • Interviews


Duration/severity of pruritus:1-12 years, except one participant for whom it was 4 months; antipruritic drugs had not provided satisfactory relief

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: gabapentin (starting dose of 300mg/d (100mg, 3x/day), increased if necessary and in the absence of side effects by 300 mg (100mg, 3x/d) every 3 days to a maximum of 2400mg/d or until pruritus relief)
  • Intervention 2: placebo


Additional medication: Antipruritic drugs were discontinued 5 days before collecting baseline data. Participants who took antihistamines to sleep were kept on those doses.

Route of administration: oral

Duration of treatment: 4 weeks

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus relief measured by VAS (10 cm):

  • Gabapentin - Patient no. 1: -0.618 (0.002) 14: -0,629 (0.033) 16: -0.844 (0.005) 2: 1.132 (0.077) 6: 2.461 (0.000) 10: 0.628 (0.098) 12: -1.745 (0.012)


  • Placebo: - Patient no. 3: 3.202 (0.000) 4: 5.282 (0.000) 7: 2.778 (0.001) 11: -0.285 (0.717) 15: 1.683 (0.034) 13: 1.229 (0.013)


Itch behaviour measured by HSA (hourly scratching activity):

  • Gabapentin: - Patient no. 1: -15.26 (0.361) 14: -122.15 (0.002) 16: 8.20 (0.382)*2: 75.29 (0.027) 6: 209.42 (0.019) 10: 35.46 (0.011) 12: technical failure pre


  • Placebo - Patient no. 3: 33.22 (0.000) 4: 42.53 (0.025) 7: 47.10 (0.000) 11: 14.05 (0.085) 15: 11.69 (0.183) 13: technical failure pre


*Based on 10 measurements. All others based on 22-24 measurements.

Negative number indicates that the treatment measurement was higher (i.e. worse) than at baseline, P values in parentheses.

Adverse events:

  • Gabapentin: (minor) fatigue (1), dizziness (1), worsening symptoms of carpal tunnel syndrome (1), dizziness on increasing dose and fluctuating rise in serum creatinine (1);(major) vomiting (1)
  • Placebo: (minor) fatigue and leukopenia (1), symptoms of carpal tunnel syndrome (1); (major) -/-


Additional outcomes:

  • At baseline: complete blood count, coagulation, comprehensive metabolic panels
  • Dermatological evaluation: None of the participants had a dermatological disease associated with pruritus.
  • Psychiatric evaluation: Hamilton depression rating scale and Structured Clinical Interview Questionnaire; the results of the psychiatric evaluations suggested that liver disease and pruritus might have contributed to the depressive symptomatology of the subject.


Author conclusion:

Gabapentin did not provide a significant therapeutic advantage over placebo; in fact, it was associated with an increase in the perception of pruritus and HSA in some participants.


NotesGabapentin was discontinued in patient no. 2, 4, 7, 8 and 16. Patient 4 and 7 took gabapentin after completing treatment with placebo. Patient 8 was dropped because of side effects. Gabapentin was discontinued in patients 2 and 16 after completing the study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"(...) randomised to receive the placebo or the active drug according to a randomisation code generated and kept at the research pharmacy."

Allocation concealment (selection bias)Low risk" ... according to a randomisation code generated and kept at the research pharmacy."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The study was a double-blind (...)."

Unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskGabapentin was discontinued in patient no. 2,4,7,8 and 16; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasUnclear riskWash out period only 5 days; co-medication with antihistamines

Borgeat 1993

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 12

Number of participants evaluable: 10

Withdrawals/dropouts: 2

Reason for exclusion: history of skin disease associated with pruritus

Age (years): 21 - 79

Sex (male/female): 4/6

Underlying disease/s: pancreatic neoplasia (3), cholangitis (2), PBC (2), hepatic metastasis (2), bile duct neoplasia (1)

Participant pool: no information

Setting: no information

Haemodialysis: N/a

Baseline pruritus assessment: no information

Pruritus assessment: verbal rating score (0 -10 cm)

Duration/severity of pruritus: no information

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: propofol (15mg/day, when pruritus was > 6 on the verbal rating score)
  • Intervention 2: placebo (15mg/day Intralipid)


Additional medication: no information

Route of administration: intravenously

Duration of treatment: 2 days (2 days propofol/placebo - 2 days crossover)

Follow-up: no information


OutcomesPruritus assessment: verbal rating score

Results:

Pruritus relief (verbal rating score: 0 -10 cm)

  • Propofol: treatment was successful in 17 of 20 doses of propofol (85%); 6 participants (60%) had 2 positive responses
  • Placebo: treatment was successful in 2 of 20 doses of propofol (10%) (P < 0.01); 6 participants (60%) had 2 negative responses


Adverse events:

  • Propofol: (minor) presence of pain on injection (3), dizziness of 10-20 seconds' duration (2)
  • Placebo: no adverse events observed


Additional outcomes: no information

Author conclusion:

Subhypnotic doses of propofol are effective for the short-term symptomatic relief of pruritus associated with liver disease.


NotesPresentation of study results is inappropriate. Study period is very short, and the sample size is very small (10 participants).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Medication was blinded and randomised by our pharmacy, which delivered a set of four coded vials per patient of either propofol or Intralipid ..."

Allocation concealment (selection bias)Unclear risk"(...) [pharmacy] delivered a set of four coded vials per patient (...)."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Medication was blinded and randomised by our pharmacy (...)"

Double-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
High riskNo information on dropouts; no information on response to placebo

Selective reporting (reporting bias)Unclear riskInclusion and exclusion criteria inadequately described; no data for hallucinations, mood changes, haemodynamic values

Other biasUnclear riskPoor additional information; small number of participants; very short study period; only two doses of propofol/placebo for each participant; assessment of compliance not stated

Breneman 1992b

MethodsRCT

Placebo controlled

Study design unclear

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 7

Number of participants evaluable: 5 (4 completed the entire 6-week trial; one additional withdrawal after 5 weeks of treatment)

Withdrawals/dropouts: 2 + 1

Reason for dropout: worsening medical status (1+1), insufficient improvement (1)

Age (years): 20 - 78

Sex (male/female): 3/4

Underlying disease/s: no information

Participant pool: no information

Setting: inpatient

Haemodialysis: at least 1 month

Baseline pruritus assessment: yes

Pruritus assessment: 4-point score

Duration/severity of pruritus: no information on duration; moderate to severe

Baseline parameters:

Pruritus score (measured by 4-point score; 1=no itching, 4=severe itching interfering with daily activities and/or sleep):

  • At least 3 or 4


InterventionsDrug (dose):

  • Intervention 1: capsaicin (0.025% 4x/day)
  • Intervention 2: placebo (4x/day)


Additional medication: no information

Route of administration: topical (cream)

Duration of treatment: 6 weeks

Follow-up: no information


OutcomesPruritus assessment: 4-point score

Results:

Pruritus relief (measured by 4-point score; 1=no itching, 4=severe itching interfering with daily activities and/or sleep):

2 evaluable participants noted complete resolution in the capsaicin-treated arm and no improvement in the vehicle-treated arm. The other 3 participants noted mild to moderate improvement in both arms.

Adverse events:

  • Capsaicin: (minor) mild burning sensation in both arms (1); (major) mild burning sensation in the capsaicin-treated arm (1)
  • Placebo: no adverse events observed


Additional outcomes: no additional outcomes given

Author conclusion:

Capsaicin 0.025% cream appears to provide significant sustained improvement in localized areas of pruritus in some participants undergoing long-term haemodialysis.


NotesStudy design is inappropriate. Participants were instructed to apply one cream solely on one arm and the cream only on the other arm; the risk that participants may have mixed up the creams is very high. Sample size was very small.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Therapies were assigned on a random basis (...)."

Method of randomisation not stated

Allocation concealment (selection bias)Unclear riskNot information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"(...) in a double-blinded fashion."

Unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2/7 participants not evaluated (1: insufficient improvement), 4/7 participants completed full trial, no intention-to-treat analysis

Selective reporting (reporting bias)High riskUnclear study design; missing participant characteristics

Other biasHigh riskVery small number of participants included; only 4 of 7 participants completed the trial. Participants were instructed to apply one cream solely on one arm and the cream from the other tube specifically on the other arm; the risk that participants may have mixed up the creams is very high.

Assessment of compliance not stated.

Cho 1997

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 22
Two subgroups: low intact PTH (parathyroid hormone) < 35 pg/ml (10) and high intact PTH > 35 pg/ml (12)

  • Group A (capsaicin - placebo): 12
  • Group B (placebo - capsaicin): 10


Number of participants evaluable: 22

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years, mean): 62±4

Sex (male/female): 14/8

Underlying disease/s:chronic glomerulonephritis (8), chronic intestinal nephritis (6), ESRD8 (3), chronic pyelonephritis (2), nephrosclerosis (2),

lupus nephritis (1)

Participant pool: no information

Setting: inpatient

Haemodialysis: average duration of 63±14 months; 3x4-4.5h/week

Baseline pruritus assessment: yes

Pruritus assessment: 4-point score

Duration/severity: no information

Baseline parameters:

Pruritus score (measured by 4-point score; 1 if no itching, 2, 3, or 4 if mild, moderate, or severe, respectively):

  • Capsaicin (iPTH < 35pg/ml): 3.7±0.2
  • Placebo (iPTH < 35pg/ml): 3.0±0.3


  • Capsaicin (iPTH > 35pg/ml): 3.5±0.2
  • Placebo (iPTH > 35pg/ml): 2.8±0.2


InterventionsDrug (dose):

  • Intervention 1: capsaicin (0.025%, 4x/day)
  • Intervention 2: placebo


Additional medication: Ongoing medications were continued without alterations in dosage; topical agents were discontinued at least 2 weeks prior the study.

Route of administration: topical (cream)

Duration of treatment: 4 weeks (4 weeks capsaicin/placebo - 2 weeks washout - 4 weeks crossover)

Follow-up: no information


OutcomesPruritus assessment: 4-point score

Results:

Pruritus relief (measured by 4-point score; 1 if no itching, 2, 3, or 4 if mild, moderate, or severe, respectively):

  • Capsaicin (iPTH < 35pg/ml): 1.6±0.2
  • Placebo (iPTH < 35pg/ml): 3.1±0.3


  • Capsaicin (iPTH > 35pg/ml): 2.1±0.2
  • Placebo (iPTH > 35pg/ml): 2.6±0.2


Capsaicin cream was significantly more effective in improving the itching score than placebo (P < 0.001). 19 of 22 had relief of the itching after active treatment, 7 of these had complete resolution and 12 obtained significant relief (P < 0.001).

Adverse events:

  • (minor) skin burning or stinging sensations or both (11), cutaneous erythema (5)


Additional outcomes:

  • Intensity of cutaneous burning and/or stinging sensations, dryness of skin, and erythema
  • Serum calcium, phosphate, and intact PTH levels


Author conclusion:

Substance P may act as a neurotransmitter in uraemic pruritus and topical capsaicin can be used in the treatment of localized pruritus.


NotesNo raw data given. Carryover-effect because there was no wash-out period between verum and placebo phases. No between-group comparisons are reported separately for the two phases of the crossover study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Treatment order was arranged from the computer-generated random numbers ..."

Allocation concealment (selection bias)Low risk"Treatment order was arranged from the computer-generated random numbers by one of the coauthors who did not participate in the observation."

Blinding of participants and personnel (performance bias)
All outcomes
Low riskTreatments with either capsaicin 0.025% cream or placebo;
Base creams "were unknown by the observers and patients"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Treatments with either capsaicin 0.025% cream or placebo base cream were unknown by the observers and patients."

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data, all 22 participants evaluated; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskNo raw data and no between-group comparisons reported for the two phases of the crossover-study

Other biasUnclear riskIndication for carry-over effect; self-assessment of pruritus by participants

De Marchi 1992

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 20

  • Group 1 (pruritus, erythropoietin - placebo): 5
  • Group 2 (pruritus, placebo - erythropoietin): 5


  • Group 3 (no pruritus, erythropoietin - placebo): 5
  • Group 4 (no pruritus, placebo - erythropoietin): 5


Number of participants evaluable: 9

Withdrawals/dropouts: 1 participant before cross-over

Reason for dropout: participant did not respond to erythropoietin

Age (years, mean) :

  • Group 1 & 2: 55±10
  • Group 3 & 4: 54±9


Sex (male/female):

  • Group 1 & 2: 7/3
  • Group 3 & 4: 6/4


Underlying disease/s: no information

Participant pool: no information

Setting: inpatient

Haemodialysis: 3 times weekly

Baseline pruritus assessment: yes

Pruritus assessment: Scoring system proposed by Duo and modified by Mettang

Duration/severity of pruritus:

  • Group 1 & 2: generalized for at least 1 year; severe enough to disturb sleep and interfere with daytime activities, unresponsive to commonly used antipruritic drugs
  • Group 3 & 4: participants with uremia but without pruritus


Baseline parameters:

Biochemical parameters (measured by blood samples):

Group 1 (pruritus, erythropoietin - placebo):

  • Erythropoietin: Histamine 20.8±4, Hemoglobin 3.86±0.18, Hematocrit 0.18±0.01
  • Placebo: Histamine 4.2±0.4, Hemoglobin 4.48±0.12, Hematocrit 0.21±0.01


Group 2 (pruritus, placebo - erythropoietin):

  • Erythropoietin: Histamine 19.5±4.1, Hemoglobin 3.98±0.18, Hematocrit 0.19±0.01
  • Placebo: Histamine 20.5±3.8, Hemoglobin 3.98±0.12, Hematocrit 0.19±0.01


Group 3 (no pruritus, erythropoietin - placebo):

  • Erythropoietin: Histamine 4.1±0.9, Hemoglobin 3.92±0.18, Hematocrit 0.19±0.1
  • Placebo: Histamine 2.6±0.4, Hemoglobin 4.45±0.12, Hematocrit 0.21±0.01


Group 4 (no pruritus, placebo - erythropoietin):

  • Placebo: Histamine 4.3±0.7, Hemoglobin 3.86±0.12, Hematocrit 0.18±0.01
  • Erythropoietin: Histamine 4.5+/0.8, Hemoglobin 3.92±0.18, Hematocrit 0.18±0.01


Pruritus score (measured by scoring system proposed by Duo, modified by Mettang, maximum score for a 24h period: 40 (14 of 40 attributed to the night time period)):

Group 1 (pruritus, erythropoietin - placebo):

  • Erythropoietin: 25.3±3
  • Placebo: 11±6


Group 2 (pruritus, placebo - erythropoietin):

  • Placebo: 27±4
  • Erythropoietin: 27±4


InterventionsDrug (dose):

  • Intervention 1: Erythropoietin (36 units/kg body weight 3 times a week)
  • Intervention 2: Placebo


Additional medication: no information

Route of administration: intravenous

Duration of treatment: 5 weeks (2 weeks baseline - 5 weeks erythropoietin/placebo - 5 weeks cross over)

Follow-up: baseline, weekly blood samples before and at the end of each 5-week study


OutcomesPruritus assessment: Scoring system proposed by Duo and modified by Mettang

Results:

Biochemical parameters (measured by blood samples):

Group 1 (pruritus, erythropoietin - placebo):

  • Erythropoietin: Histamine 4.2±0.4, Hemoglobin 4.48±0.12, Hematocrit 0.21±0.01
  • Placebo: Histamine 23.2±4.9, Hemoglobin 3.92±0.12, Hematocrit 0.19±0.01


Group 2 (pruritus, placebo - erythropoietin):

  • Placebo: Histamine 19.5±4.1, Hemoglobin 3.98±0.18, Hematocrit 0.19±0.01
  • erythropoietin: Histamine 5.8±1.4, Hemoglobin 4.48±0.18, Hematocrit 0.21±0.01


Group 3 (no pruritus, erythropoietin - placebo):

  • Erythropoietin: Histamine 2.6±0.4, Hemoglobin 4.45±0.12, Hematocrit 0.21±0.01
  • Placebo: Histamine 5.0±1.2, Hemoglobin 3.98±0.12, Hematocrit 0.18 ±0.01


Group 4 (no pruritus, placebo - erythropoietin):

  • Placebo: Histamine 4.5±0.8, Hemoglobin 3.92±0.18, Hematocrit 0.18±0.01
  • Erythropoietin: Histamine 2.5±0.2, Hemoglobin 4.42±0.18, Hematocrit 0.21±0.01


Pruritus relief (measured by scoring system proposed by Duo, modified by Mettang, maximum score for a 24h period: 40 (14 of 40 attributed to the night time period)):

Group 1 (pruritus, erythropoietin - placebo):

  • Erythropoietin 11±6
  • Placebo: 26±3


Group 2 (pruritus, placebo - erythropoietin):

  • Placebo: 27±4
  • Erythropoietin: 9±4


Significant decrease (P < 0.05) of the mean daily pruritus score in participants receiving erythropoietin (group 1) compared to placebo (group 2).

Adverse events: no information

Additional outcomes: plasma histamine levels

Author conclusion:

Erythropoietin therapy lowers plasma histamine concentrations in patients with uremia and can result in marked improvement of pruritus.


NotesRoute of administration not clearly stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The patients were randomly assigned (...)"

Allocation concealment (selection bias)Low riskCode broken only after completion

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind including outcome assessor; "a single investigator who was unaware of the treatment assignments evaluated all patients". Participants and personnel were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessor was blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOne withdrawal; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskNo conflicts of interest declared

Duncan 1984

MethodsRCT

Comparative trial

Cross-over design

Blinding: single blind


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 8

Number of participants evaluable: 8

Withdrawals/dropouts: 1 dropout in a placebo-group

Reason for dropout: nausea and cutaneous burning

Age (years): no information

Sex (male/female): no information

Underlying disease/s: primary biliary cirrhosis (7), sclerosing cholangitis (1)

Participant pool: uni-centre

Setting: outpatient

Haemodialysis: N/a

Baseline pruritus assessment: no information

Pruritus assessment: 4-point score

Duration/severity of pruritus: no information

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: cholestyramine (4g at night on Day 1 and increased if tolerated to 2x/day on Day 3; not further increased)
  • Intervention 2: terfenadine (60mg at night on Day 1and increased if tolerated to 2x/day on Day 3; increased to 3x/day on Day 5)
  • Intervention 3: chlorpheniramine (4mg at night on Day 1and increased if tolerated to 2x/day on Day 3; increased to 3x/day on Day 5)
  • Intervention 4: placebo (lactose, 200mg at night on Day 1, increased if tolerated to 2x/day on Day 3; increased to 3x/day on Day 5)


Additional medication: All antipruritic drugs were stopped at least 1 week prior to the study.

Route of administration: oral

Duration of treatment: 2 weeks each (crossover)

Follow-up: no information


OutcomesPruritus assessment: 4-point score

Results:

Pruritus relief (measured 4-point cumulative pruritus scores over 10 days):

  • Cholestyramine: mean cumulative pruritus score 12.9
  • Terfenadine: mean cumulative pruritus score 15.8
  • Chlorpheniramine: mean cumulative pruritus score 19.3
  • Placebo: mean cumulative pruritus score 20.3


Mean cumulative pruritus scores were significantly lower during treatment, with cholestyramine and terfenadine lower than placebo and chlorpheniramine. Terfenadine has a significant antipruritic effect and was well tolerated.

Adverse events:

  • Cholestyramine: diarrhoea and vomiting (4)
  • Terfenadine: emotional lability (1); cerebral side effects observed when participants were taking a dose higher than 60 mg
  • Chlorpheniramine: drowsiness (2), headache (1)
  • Placebo: nausea an cutaneous burning (1)


Additional outcomes: psychometric testing

Results showed that the participants remained stable throughout the treatment regimens.

Author conclusion:

Certain patients benefit from either cholestyramine or terfenadine. Others experienced a modest improvement with both drugs, which suggests that they may work well together. However, they should not be administered simultaneously because of the binding properties of cholestyramine.


NotesPresentation of the results is inappropriate. Some patients stopped taking one of the trial medications, but there is no data on whether they were excluded from the analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The order of administration of the drugs was randomised, different for each patient, and concealed from the assessor"

Allocation concealment (selection bias)Unclear risk"Treatment was supplied in unlabelled bottles by the hospital pharmacy."

Blinding of participants and personnel (performance bias)
All outcomes
Low riskSingle-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskLikely not blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot clear if all participants analysed; unclear if used intention-to-treat analysis; missing participant data like sex and age

Selective reporting (reporting bias)Low riskHowever spin

Other biasUnclear riskNo washout period in between the treatments; no conflicts of interest declared

Duque 2005

MethodsRCT

Vehicle-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 22

  • Tacrolimus: 12
  • Vehicle: 10


Number of participants evaluable: 20

Withdrawals/dropouts: vehicle (2)

Reason for dropout: 1 received a kidney transplant, 1 dropped out after two weeks because of lack of improvement

Age (years, mean): 59±13.2

Sex (male/female): no information

Underlying disease/s: no information

Participant pool: multicentre (2 dialysis centres)

Setting: outpatient

Haemodialysis: at least 3 months

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information on duration; frequent and severe itch that was resistant to conventional therapies, initial VAS between 3 and 10

Baseline parameters:

Pruritus score (measured by VAS 10 cm):

  • Tacrolimus: 7.7
  • Vehicle: 7.5


InterventionsDrug (dose):

  • Intervention 1: tacrolimus 0.1% (3x/week by investigator only on pruritic areas; twice daily by participant; average of four 30g tubes per participant)
  • Intervention 2: vehicle


Additional medication: stopped 2 - 4 weeks prior the study

Route of administration: topical

Duration of treatment: 4 weeks (4 weeks tacrolimus/placebo - 4 weeks crossover)

Follow up: baseline- 4 weeks: 3x/week - 2 weeks after treatment completion


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 10 cm):

  • Tacrolimus: week 4=1.8; week 6=2.1
  • Vehicle: week 4=1.6; week 6=1.4


Skin conditions (measured by 3-point Lickert scale (0=no skin signs, 3=severe excoriations, scaliness, lichenification):

  • Tacrolimus: excoriations=40% improvement; scaliness=84% improvement; lichenification=44% improvement
  • Vehicle: excoriations=66% improvement; scaliness=100% improvement; lichenification=73% improvement


Adverse events:

  • Tacrolimus: warm sensations at baseline (8), warm sensations in week 4 (6), significant burning sensation (1)
  • Vehicle: warm sensations at baseline (2), warm sensation in week 4 (3)


Additional outcomes: no information

Author conclusion:

Tacrolimus 0.01% is not more effective than the vehicle in relieving uraemic pruritus.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy was randomised; method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskTwo dropouts in the placebo group; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskPre-specified outcomes not mentioned

Other biasLow riskConflicts of interest mentioned but negative study

Ghent 1988

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CP

Description: patients with PBC

Number of participants randomised: 9

  • Group A (rifampin - placebo): 4
  • Group B (placebo - rifampin): 5


Number of participants evaluable: 9

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): 45 - 64

Sex (male/female): 1/8

Underlying disease/s: primary biliary cirrhosis

Participant pool: uni-centre

Setting: outpatient

Haemodialysis: N/a

Baseline pruritus assessment: one week baseline record of the pruritus VAS was obtained for 5 subjects prior to the study

Pruritus assessment: VAS

Duration/severity of pruritus: persistent pruritus

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: rifampin (150 mg 2x/day for serum bilirubin level >51µmol/L (3mg/dL); 150 mg 3x/day for serum bilirubin level <51µmol/L)
  • Intervention 2: placebo


Additional medication: cholestyramine (5)

Route of administration: oral

Duration of treatment: 2 weeks (2 weeks washout - 2 weeks cross-over)

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Participants' preferences:

8 out of 9 stated a preference for rifampin on blinded choice.

Adverse events: none observed

Additional outcomes: urine analysis, blood count, serum bilirubin, creatinine, alanine transaminases, aspartate transaminases, alkaline phosphatases, fasting total serum bile acids

Author conclusion:

Rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown.


NotesPresentation of study results is inappropriate.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The order of treatment was random (...)."

Method of randomisation not stated

Allocation concealment (selection bias)Low risk"The coding of the medication order was done by an independent research pharmacist."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"(...) in a double-blind manner."

Unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll completed and analysed; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication of selective reporting

Other biasUnclear riskSmall number of participants

Gunal 2004

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 25

Number of participants evaluable: 25

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): 32 - 77 (mean=55±11)

Sex (male/female): 14/11

Underlying disease/s:ESRD, diabetes (8)

Participant pool: uni-centre

Setting: inpatient

Haemodialysis: duration of 42±33 months

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: duration > 8 weeks; not relieved by antihistamines, nicergoline, moisturizers

Baseline parameters:

Pruritus score (measured by VAS 10 cm): 8.4±0.94


InterventionsDrug (dose):

  • Intervention 1: gabapentin (300mg 3x/week at the end of haemodialysis sessions)
  • Intervention 2: placebo


Additional medication: Any medication with presumed antipruritic effects was discontinued 1 week before the study.

Route of administration: oral

Duration of treatment: 4 weeks (4 weeks gabapentin/placebo - 1 week washout - 4 weeks crossover)

Follow-up: daily record of pruritus severity (VAS)


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 10cm):

  • After placebo administration: 7.6±2.6 (P = 0.098)
  • After gabapentin administration: 1.2±1.8 (P = 0.0001)


Gabapentin improves pruritus significantly.

Adverse events:

  • Gabapentin: somnolence, fatigue, dizziness (these symptoms were mild to moderate and commonly occurred after the first dose of the drug)
  • Placebo: N/a


Additional outcomes: haematocrit, serum calcium, phosphate, albumin, parathyroid hormone levels

Author conclusion:

Gabapentin is safe and effective for treating uraemic pruritus in haemodialysis patients.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy was randomised; method not stated

Allocation concealment (selection bias)Unclear riskNot information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data, all completed and analysed; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskNo exclusion criteria mentioned; only means of participant groups given; poor raw data given.

Pruritus was scored only once a day and the scores were only subjective indications of the severity of itching; number and details of adverse effects were not given.

Other biasLow riskNo conflict of interests declared

Kuiper 2010

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 38

Number of participants evaluable: 35

  • Colesevelam: 17
  • Placebo: 18


Withdrawals/dropouts: 3

Reason for dropout: 1 participant withdrew after randomisation but before treatment, 1 participant stopped the intake of naltrexone during the trial, 1 participant was unable to fill out the questionnaires

Age (years, mean):

  • Colesevelam: 50 ±13
  • Placebo: 54 ±13


Sex (male/female):

  • Colesevelam: 8/9
  • Placebo: 5/13


Underlying disease/s:

  • Colesevelam: PSC(10), PBC (4), other (3)
  • Placebo: PBC (10), PSC(4), other (4)


Participant pool: multicentre

Setting: outpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: symptoms present for a median period of 24 months; pruritus most severe in the evening and/or at night, scratch lesions present in 55% of cases

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: colesevelam (3x625mg tablets, 2x/day)
  • Intervention 2: placebo (2x/day)


Additional medication: treatment with ursodeoxycholic acid was continued and participants were allowed to continue rifampin and naltrexone at a stable dose; other antipruritic drugs were stopped 3 days prior the study.

Route of administration: oral

Duration of treatment: 21 days

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 10cm):

  • Colesevelam: (morning) 36% reached the defined 40% reduction; (evening) 50% reached the defined 40% reduction
  • Placebo: (morning) 35% reached the defined 40% reduction; (evening) 40% reached the defined 40% reduction


No significant difference between colesevelam and placebo in reducing the pruritus score by at least 40%.

Adverse events:

  • Colesevelam: (minor) mild stool changes (1)
  • Placebo: (minor) mild stool changes (4)


Additional outcomes:

  • Quality of life: no statistically significant changes


Author conclusion:

Although colesevelam significantly decreased serum bile acid levels, this trial was unable to demonstrate that it was more effective than a placebo in alleviating the severity of pruritus of cholestasis.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Participants were assigned to one of the two arms according to a standard randomization schedule (1:1) in blocks of four and were stratified by trial center."

Allocation concealment (selection bias)Low risk"Randomization was centralized with opaque serial-numbered envelopes prepared by the trial statistician."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Both participants and investigators were blinded."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Both participants and investigators were blinded."

Incomplete outcome data (attrition bias)
All outcomes
Low risk"We included and randomized 38 patients, 35 of whom were analyzed because one patient withdrew from participation after randomization and before the start of treatment, one patient stopped the intake of naltrexone during the trial period, and one patient was unable to fill out the questionnaires."

Per-protocol analysis with 35 participants

Modified intention-to-treat analysis with 36 participants (38 were included and randomised)

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskBroad information about participant characteristics; presentation of data partially unclear; assessment of compliance not stated

Kumagai 2010

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 337

  • Nalfurafine hydrochloride (5 µg): 114
  • Nalfurafine hydrochloride (2.5 µg): 112
  • Placebo: 111


Number of participants evaluable: 329

  • Nalfurafine hydrochloride (5 µg): 111
  • Nalfurafine hydrochloride (2.5 µg): 109
  • Placebo: 109


Withdrawals/dropouts:

  • Nalfurafine hydrochloride (5 µg): 3
  • Nalfurafine hydrochloride (2.5 µg): 3
  • Placebo: 0


Reason for dropout:

  • Nalfurafine hydrochloride (5 µg): 2 participants because of insomnia
  • Nalfurafine hydrochloride (2.5 µg): 2 participants because of insomnia


Number lost to follow-up:

  • Placebo: 2


Age (years, mean):

  • Nalfurafine hydrochloride (5 µg): 59.6±11.5
  • Nalfurafine hydrochloride (2.5 µg): 61±11.4
  • Placebo: 59.6±11.8


Sex (male/female):

  • Nalfurafine hydrochloride (5 µg): 93/21
  • Nalfurafine hydrochloride (2.5 µg): 85/27
  • Placebo: 89/22


Underlying disease/s: ESRD

Participant pool: multicentre (73 centres)

Setting: inpatient

Haemodialysis: 3x/week

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information on duration; pruritus resistant to currently available treatments (mean morning or evening VAS > 50 mm, daytime or night-time VAS > 20 mm on more than 5 days during the 7 day pre-observation period)

Baseline parameters:

Pruritus score (mean VAS value 100 mm in the pre-observation period):

  • Nalfurafine hydrochloride (5 µg): 65±14
  • Nalfurafine hydrochloride (2.5 µg): 69±14
  • Placebo: 65±14


InterventionsDrug (dose):

  • Intervention 1: nalfurafine hydrochloride (5 µg once daily after supper)
  • Intervention 2: nalfurafine hydrochloride (2.5 µg once daily after supper)
  • Intervention 3: placebo (once daily after supper)


Additional medication: Opioids and phototherapy were prohibited; hypnotics, antidepressants, antipsychotics, antiepileptics and anxiolytics that were likely to affect itch were administered at a consistent dosage and via normal method of administration, as were the antipruritic drugs administered for basic therapy.

Route of administration: oral

Duration of treatment: 2 weeks (2 weeks pre-observation - 2 weeks nalfurafine 5µg/2.5µg/placebo - 8 days post-observation)

Follow-up: 8 days


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 100mm):

Changes in VAS values between the latter 7 days of treatment and pre-observation period (VAS decrease)

  • Nalfurafine hydrochloride (5µg): 22, difference from placebo: 9; P = 0.0002
  • Nalfurafine hydrochloride (2.5µg): 23, difference from placebo: 10; P = 0.0001
  • Placebo: 13


On day 7 of the treatment period, VAS changes in the 5 µg group (P < 0.0001) and the 2.5-µg group (P = 0.0101) were significantly larger than VAS change in the placebo group (t-test, one-sided 2.5% significant level). The VAS changes in 2 nalfurafine groups were greater during the latter 7 days of the treatment period than those during the first 7 days of the treatment period.

Adverse events:

  • Nalfurafine hydrochloride (5 µg): nasopharyngitis (12.3%), insomnia (14.9%), somnolence (3.5%), constipation (7.9%)
  • Nalfurafine hydrochloride (2.5 µg): nasopharyngitis (8.0%), insomnia (7.1%), somnolence (4.5%), diarrhea (4.5%)
  • Placebo: nasopharyngitis (17.1%), headache (3.6%), vomiting (3.6%)


Adverse reactions:

  • Nalfurafine hydrochloride (5 µg): incidence 35.1%; insomnia (16), anorexia (1), headache (1), pruritus (1), decreased blood TSH (2), mood altered (1), elevated mood (1), feeling abnormal (1), increases in prolactin (3), decrease in free testosterone (1)
  • Nalfurafine hydrochloride (2.5 µg): incidence 25.0%; insomnia (8), sudden hearing loss (1), hypertension (1), vomiting (1), nausea (1), increased eosinophiles (1), increases in prolactin (3), decrease in free testosterone (1)
  • Placebo: incidence 16.2%; headache (1), increases in prolactin (1), decrease in free testosterone (1)


Prolactin, TSH and free testosterone returned to the levels of pre-observation period.

Additional outcomes: none provided

Author conclusion:

This study demonstrated the efficacy of nalfurafine hydrochloride for reducing pruritus in haemodialysis patients.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"(...) were randomized 1:1:1 to receive 5 µg, 2.5 µg nalfurafine or a placebo using a variable size permuted block design stratified by center."

Allocation concealment (selection bias)Low risk"a variable size permuted block design stratified by center"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; intention-to-treat-analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskBroad information about participant characteristics; power-calculation

Legroux-Crespel 2004

MethodsRCT

Comparative trial

Parallel group design

Blinding: not described


ParticipantsPruritus: CKD/UP

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 52

  • Naltrexone: 26
  • Loratadine: 26


Number of participants evaluable:approximately 42, number not clearly stated

Withdrawals/dropouts: approximately 10/ 15, number not clearly stated

Reason for dropout: adverse effects

Age (years): no information

Sex (male/female): no information

Underlying disease/s: no information

Participant pool: multicentre

Setting: inpatient

Haemodialysis: 3x/week in sessions of 4.2h; mean duration of 82 months

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: at least 1 month; substantial pruritus

Baseline parameters:

Pruritus score (measured by VAS 10 cm):

  • Naltrexone: 4.85 (results) / 6.04 (Figure 1, discussion)
  • Loratadine: 4.85


Sleep parameters (measured by VAS 10cm):

  • Naltrexone: 1.44


InterventionsDrug (dose):

  • Intervention 1: naltrexone (50 mg/day)
  • Intervention 2: loratadine (10 mg/day)


Additional medication: no information

Route of administration: oral

Duration of treatment: 2 weeks

Follow up: day 0-7-14


OutcomesPruritus assessment: VAS

Results:

Pruritus parameter/relief (measured by VAS 10 cm):

Day 7

  • Naltrexone: 4.45
  • Loratadine: 3.96


These scores were significantly different (P < 0.01) from scores on day 0 but not from scores on day 14. There was no significant difference between mean scores of participants with naltrexone and loratadine.

Sleep parameter (measured by VAS 10 cm):

  • Naltrexone: VAS 3.46


Adverse events:

  • Naltrexone (30 effects in 15 participants):(major) vertigo (4) , nausea (9) , malaise (1), cramps (2), sleeping disturbances (1), anorexia (1); (minor)  vomiting (2), abdominal distention (1), sleep disturbances (4), vertigo (1), headaches (2),somnolence (1), paraesthesia (1)


  • Loratadine (3 events in 2 participants):(major) vomiting (1), malaise (1); (minor) vomiting (1)


Additional outcomes: blood urea, creatinine, creatinine clearance, calcium, phosphate, parathyroid hormone, ASTA, ALAT7, alkaline phosphatases, bilirubin, haemoglobin

Author conclusion:

Naltrexone is effective only in a subset of patients.


NotesCompliance assessed by collecting drug boxes at the end of the study.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"This was a randomized study (drawing of lots) (...)."

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding not reported; likely not blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskLikely not blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing endpoint data for some participants

Selective reporting (reporting bias)High riskMissing raw data; conflicting data

Other biasHigh riskConflicting data given.

Only two measurements of pruritus over the study period;

most results for day 7 instead of day 14; number of participants and of withdrawals confusing; missing end-point data

Makhlough 2010

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 34

  • Group A (capsaicin - placebo): 17
  • Group B (placebo - capsaicin): 17


Number of participants evaluable: no information

Withdrawals/dropouts: no information

Reason for dropout: N/a

Age (years, mean): 57±18.6

Sex (male/female): 14/20

Underlying disease/s: hypertension (14), diabetes mellitus (12), glomerulonephritis (1), urological problems (1), unknown (1)

Participant pool: uni-centre

Setting: inpatient

Haemodialysis: mean duration of 25±15 months

Baseline pruritus assessment: yes

Pruritus assessment: score by Duo

Duration/severity of pruritus: no information on duration; pruritus non-responsive to common treatment options

Baseline parameters:

Pruritus score (measured by score by Duo):

  • Capsaicin: 15.9±6.3
  • Placebo: 15.0±6.0


InterventionsDrug (dose):

  • Intervention 1: capsaicin (0.03%)
  • Intervention 2: placebo


Additional medication: no information

Route of administration: topical

Duration of treatment: 4 weeks (2 weeks washout - 4 weeks crossover)

Follow-up: no information


OutcomesPruritus assessment: score by Duo (Total scoring of pruritus = (severity of pruritus x distribution of pruritus) + sleep disorder scoring)

Results:

Pruritus parameter/relief (measured by score by Duo):

  • Capsaicin: 15.9±6.3 to 2.5 ± 2.5 in week 4
  • Placebo: 15.0±6.0 to 7.2 ± 5.5 in week 4


Adverse events:

  • Capsaicin: (minor) skin burning moderate (10) to severe (1)
  • Placebo: none observed


Additional outcomes: parathyroid hormone, serum alkaline phosphatase level

Author conclusion:

Topical administration of capsaicin 0.03% ointment can be a new promising approach to the treatment of haemodialysis-induced pruritus.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The patients were equally divided and randomly assigned by lottery into two groups (...)"

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all participants were evaluable; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskNumber of evaluable participants not given; no raw data given

Other biasLow riskPoor additional information (e.g. dermatological, psychological evaluation); no power-calculation; assessment of compliance not stated

Mayo 2007

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus:CP

Description: patients with cholestasis

Number of participants randomised: 12

Number of participants evaluable: 12

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): no information

Sex (male/female): 2/10

Underlying disease/s: PBC (9), PSC (2), drug-induced (postnecrotic cirrhosis) (1)

Participant pool: uni-centre

Setting: outpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: at least 3 months; no information on severity

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: sertraline (dose was previously in an open-label dose-escalation trial determined to be optimal for that individual, 25 - 100 mg)
  • Intervention 2: placebo


Additional medication: concomitant ursodiol treatment was allowed if participants were on a stable dose; other antipruritic medications were stopped at least 2 weeks prior the study. 

Route of administration: oral

Duration of treatment: 6 weeks (4 weeks washout - 6 weeks cross-over)

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus parameter/relief (measured by VAS 10cm):

  • Sertraline: pruritus improved a mean of 1.86 raw points on VAS, 8 of the 12 had improvement, excoriations improved
  • Placebo: pruritus worsened 0.38 points (P = 0.009), no improvement (P = 0.0.002), excoriations didn't improve (P = 0.001)


Adverse events:

  • Sertraline (during dose-escalation trial): (minor) increase in bowel frequency (2), visual hallucinations (2), increase in fatigue (2), insomnia (3), nausea (1);(major) dizziness (1)
  • Placebo: (minor) increase in fatigue (1), insomnia (6), nausea (1)
  • Taking no drug (baseline, washout): increase in fatigue (1), insomnia (14), nausea (1)


Additional outcomes: pruritus course, duration, distribution, pruritus insomnia, tolerability, depression, study drug preference, scratching lesions

Author conclusion:

Sertraline seems to be an effective, well-tolerated treatment of pruritus due to chronic liver disease.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"(...) Part B of the study consisted of subjects randomized to double-blind treatment with either sertraline or placebo."

Method not stated

Allocation concealment (selection bias)Unclear riskNot information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blind; no information how blinding was managed and difficulty because of different doses; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts mentioned; unclear whether intention-to-treat analysis was used

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskAssessment of compliance not stated; power-calculation used

Murphy 2003

MethodsRCT

Placebo-controlled

Cross-over design   

Blinding: double


ParticipantsPruritus: CKD/UP

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 24

  • Group A (ondansetron - placebo): 14
  • Group B (placebo - ondansetron): 10


Number of participants evaluable: 17 (Group A: 10, Group B: 7)

Withdrawals/dropouts: 7

Reason for dropout:

  • Group A (ondansetron - placebo): transplantation (1), constipation (1), non-compliance (1), CVA (1)
  • Group B (placebo - ondansetron): non-compliance (2), line sepsis (1)


Age (years, median): 59

Sex (male/female): 20/4

Underlying disease/s: no information

Participant pool: multicentre

Setting: inpatient

Haemodialysis: no information

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: duration > 8 weeks; mean VAS at least 5/10 during baseline

Baseline parameters:

Pruritus score (measured by VAS 10 cm):

  • Group A (ondansetron - placebo): 6.1±1.
  • Group B (placebo - ondansetron): 6.1±1.9


InterventionsDrug (dose):

  • Intervention 1: ondansetron (8mg 3x/day)
  • Intervention 2: placebo (Lactose)


Additional medication: no information

Route of administration: oral

Duration of treatment: 2 weeks (7 days baseline - 2 weeks ondansetron/placebo - 7 days washout - 2 weeks crossover)

Follow-up: pruritus VAS 2x/day, collected weekly


OutcomesPruritus assessment: VAS

Results:

Pruritus parameter/relief (measured by VAS 10cm)

  • During ondansetron treatment: 5.2±1.9, 16.3% decrease P = 0.04
  • During placebo treatment: 4.4±2.0, 24.9% decrease P = 0.01


The change in VAS score during treatment with ondansetron and placebo were both significant.

Adverse events:

  • Ondansetron: (major) constipation leading to withdrawal (1)


  • Placebo: none provided


Additional outcomes: none provided

Author conclusion:

The results show that ondansetron is no better than placebo in controlling renal itch.


NotesNo raw data on the participants.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"On a random basis 14 patients were blindly allocated to the ondansetron-placebo sequence and 10 to the placebo-ondansetron sequence"

Method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"(...) 14 patients were blindly allocated to the ondansetron-placebo sequence and 10 to the placebo-ondansetron sequence."

Unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts and reasons for dropout addressed per protocol analysis

Selective reporting (reporting bias)Unclear riskNo information provided

Other biasLow riskPower-calculation was carried out before the study; per protocol analysis

Naini 2007

MethodsRCT

Placebo-controlled

Parallel-group design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 34

Number of participants evaluable: 34

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): 43 - 81 (mean=62±10)

Sex (male/female): 16/18

Underlying disease/s: no information

Participant pool: uni-centre

Setting: inpatient

Haemodialysis: at least twice a week for at least 3 months

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: itching > 8 weeks; unresponsive to antihistamines

Baseline parameters:

Mean pruritus score (measured by VAS 10 cm):

  • Gabapentin: 7.2±2.3 (range: 3-10)
  • Placebo: 7.2±2.3 (range: 3-10)


InterventionsDrug (dose):

  • Intervention 1: gabapentin (400mg 2x/week after HD session)
  • Intervention 2: placebo (2x/week after HD session)


Additional medication: no information

Route of administration: oral

Duration of treatment: 4 weeks

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus parameter/relief (measured by VAS 10cm):

  • Gabapentin: ca. 0.5 (decrease 6.7±2.6), P < 0.001
  • Placebo: ca. 0.5 (decrease 6.7±2.6), P < 0.001


Adverse events:

  • Gabapentin: (minor) somnolence, dizziness, nausea (subsided); (major) attacks of dizziness in one participant (subsided gradually)
  • Placebo: none provided


Additional outcomes: haemoglobin, serum parathormone, serum phosphorus, liver enzymes, alkaline phosphatase, bilirubin

Author conclusion:

Gabapentin is a safe and effective treatment for uraemic itch.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The patients were randomly allocated to receive either gabapentin 400 mg or placebo."

Method not stated

Allocation concealment (selection bias)Unclear riskNot information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blinding stated in the abstract, but not further mentioned; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo missing outcome data; no information whether intention-to-treat analysis used

Selective reporting (reporting bias)Unclear riskNumber of side effects not stated

Other biasUnclear riskNumber of participants of the verum and the placebo group not stated; no power-calculation;assessment of compliance not stated

Nasrollahi 2007

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: single


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 16

  • Group A (montelukast - placebo): 8
  • Group B (placebo - montelukast): 8


Number of participants evaluable: 14

Withdrawals/dropouts: 2

Reason for dropout:

  • Group A: 1 man faced anaemia that was diagnosed as myelodysplastic syndrome during placebo period
  • Group B: 1 diabetic woman with ischaemic heart disease died during placebo period of myocardial infarction


Age (years): 20 - 85 (mean: 65 for male patients, 63 for female patients)

Sex (male/female): 10/6

Underlying disease/s: ESRD

Participant pool: multicentre

Setting: outpatient

Haemodialysis: 3x/week

Baseline pruritus assessment: yes

Pruritus assessment: score by Duo (Duo 1987)

Duration/severity of pruritus: persistent pruritus >3 months; at least 1 course of unsuccessful treatment

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: montelukast (10mg daily)
  • Intervention 2: placebo


Additional medication: Erythropoietin, other antipruritic treatment options (14 patients were receiving antihistamines, naltrexone or doxepin) were discontinued 1 week prior the study.

Route of administration: oral

Duration of treatment: 20 days (20 days montelukast/placebo - 14 days washout - 20 days crossover)

Follow-up: no information


OutcomesPruritus assessment: score by Duo (Duo 1987)

Results:

Pruritus parameter/relief:

  • After montelukast: score reduction 35.7%; mean change in pruritus score 16.1 (9.5-22.5)
  • After placebo: score reduction 7.1%; mean change in pruritus score 7.1 (0.5-13.7)


Montelukast in comparison with placebo was more effective in the alleviation of uraemic pruritus (P = 0.002).

Adverse events:(major, leading to withdrawal) 1 man faced anaemia that was diagnosed as myelodysplastic syndrome during placebo period after receiving montelukast for 20 days; 1 diabetic woman with ischaemic heart disease died during placebo period of myocardial infarction

Additional outcomes: serum levels of calcium, phosphorus, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, urea, creatinine, parathyroid hormone, haemoglobin

Author conclusion

Montelukast is more effective than placebo in the treatment of uraemic pruritus not responding to the currently available antipruritic drugs. It can be considered as a new and rather safe and effective treatment option in uraemic patients.                       


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The study was designed as a randomized, single-blind, placebo-controlled, crossover clinical trial."

Method of randomisation not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskSingle-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts and reasons for dropout mentioned; unclear if used intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskOnly score reduction in percentages; no raw data given

Other biasLow riskNo power-calculation; no raw data given; per protocol analysis; assessment of compliance stated

O'Donohue 2005

MethodsRCT

Placebo-controlled

Parallel-group design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 19

  • Ondansetron: 9
  • Placebo: 10


Number of participants evaluable: 18

  • Ondansetron: 8
  • Placebo: 10


Withdrawals/dropouts:

  • Ondansetron:1
  • Placebo: 0


Reason for dropout: participant with cholestasis due to chronic rejection; post orthotopic liver transplantation required rescue antipruritic treatment (oral antihistamines)

Age (years): 27 - 80 (mean 55)

  • Ondansetron (mean): 55.3 ±15.9
  • Placebo (mean): 54.8 ±15.3


Sex (male/female):

  • Ondansetron: 2/7
  • Placebo: 1/9


Underlying disease/s: primary biliary sclerosis (PBC) (17), cirrhosis because of hepatitis C (1), chronic rejection after orthotopic liver transplantation for hepatitis C cirrhosis (1)

Participant pool: uni-centre

Setting: combination of inpatient and outpatient setting

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information on duration; resistant pruritus

Baseline parameters:

Pruritus score (measured by VAS 10 cm):

  • Ondansetron: 4.1 (range: 0.4-7.1)
  • Placebo: 4.7 (range:  2.7-9.3)


InterventionsDrug (dose):

  • Intervention 1: ondansetron (8mg)
  • Intervention 2: placebo


Additional medication: All antipruritic medication were withdrawn at least 3 days before entry into the study; antipruritic medication before entry into the study was comparable in both groups (cholestyramine (17), ursodeoxycholic acid (12), antihistamines (9), tamoxifen (2), cyclosporin (1), rifampicin (1)).              

Route of administration:

  • Day 1: ondansetron 8mg in 10ml 0.9% saline or 10ml saline, intravenously over 5 min; 8 hours after injection oral tablets containing either 8mg ondansetron or placebo were given
  • Day 2-5: oral tablets twice daily


Duration of treatment: 5 days (day 0: 24 h hours observation phase)

Follow-up: within 2 weeks of the last dose of study medication; adverse events documented and blood sample taken for routine hepatic and renal biochemical markers


OutcomesPruritus assessment: VAS

Results:

Pruritus parameter/relief (measured by VAS 10 cm):

  • Ondansetron: not stated, ca. 4.1
  • Placebo: not stated, ca. 3.9


There was no significant difference in reduction in the mean pruritus burden over the 5-day treatment period compared with baseline.

Scatiching activity (measured by piezo-electric vibration transducer):

  • Ondansetron: 6 % reduction
  • Placebo: 16% reduction


Adverse events:

  • Ondansetron: (minor) moderate increases from baseline in serum alkaline phosphatase and bilirubin levels (1), constipation (4)
  • Placebo: (minor) nausea (3), headache (2)


Additional outcomes: serum albumin, alkaline phosphatase, serum bilirubin, prothrombin time

Author conclusion:

Ondansetron was of no benefit in this group of pruritic patients during short-term treatment.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Each patient was consecutively allocated an individual sequential treatment number that corresponded to one of two (...)"

Allocation concealment (selection bias)Low risk"Each patient was consecutively allocated an individual sequential treatment number that corresponded to one of two, identical in appearance, medication regimes. The study pharmacist held sealed envelopes containing the codes to the treatment regimes, so that the patient and all investigators were unaware which of the regimes was being administered."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"(...) the patient and all investigators were unaware which of the regimes was being administered." Participants and personnel were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo information provided, but not likely

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts and reasons for dropout provided; unclear if used intention-to-treat-analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskVery transparent treatment regimen; exact instruction for pruritus rating; no carry-over effects

Pauli-Magnus 2000

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end-stage renal disease on haemodialysis HD (18) and peritoneal dialysis (PD) (5)

Number of participants randomised: 23

Number of participants evaluable: 16

Withdrawals/dropouts: 7

Reason for dropout:

  • During naltrexone period: major gastrointestinal side effects (3), lower limb amputation (1);
  • During placebo period:major gastrointestinal side effects (1), cerebral ischaemia (1)
  • Period unspecified: renal transplantation (1)


Age (years): 20 - 85

Sex (male/female): no information

Underlying disease/s: no information

Participant pool: multicentre

Setting: inpatient

Haemodialysis: 3x4-5h/week, Kt/V>1.2, dialysis

Peritoneal dialysis: weekly, Kt/V > 2, Hb > 10 g/l

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: duration > 6 months; substantial pruritus: persistent, treatment-resistant, impairing sleep/daytime activities,

Baseline parameters:

Pruritus score (measured by VAS 10 cm and detailed score):

  • Group A (naltrexone - placebo): VAS 5.5, detailed score 17.7
  • Group B (placebo - naltrexone): VAS 6.5, detailed score 16.8


InterventionsDrug (dose):

  • Intervention 1: naltrexone hydrochloride (50mg/day single morning dose)
  • Intervention 2: placebo


Additional medication: no information

Route of administration: oral

Duration of treatment: 4 weeks (4 weeks naltrexone/placebo - 1 week washout - 4 weeks crossover)

Follow-up: at study begin and at the end of week 1,2 and 4 of each study period


OutcomesPruritus assessment: VAS and modified Duo-Score (comprising severity and distribution of pruritus and sleep disturbance)

Results:

Decrease of pruritus in percent of initial pruritus:

  • Naltrexone: pruritus decreased by 29.2% on the VAS and by 17.6% on the detailed score
  • Placebo: pruritus decreased by 16.9% on the VAS and by 22.3% on the detailed score


The difference between the naltrexone and the placebo period was not statistically significant (P = 0.095 for the VAS and P = 0.6 for the detailed score). Naltrexone treatment assessed as ineffective due to a non-significant decrease of pruritus.

Adverse events:

  • Naltrexone: minor gastrointestinal side effects (6), major gastrointestinal side effects leading to withdrawal (3)
  • Placebo: major gastrointestinal side effects leading to withdrawal (1)


Additional outcomes: plasma haemoglobin concentrations, serum concentrations of creatinine, urea, calcium, phosphate, alkaline phosphatase, bilirubin, transaminase, parathyroid hormone

Author conclusion:

Treatment of uraemic pruritus with naltrexone is ineffective.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy was randomised; method not stated

Allocation concealment (selection bias)Unclear riskNot information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis and per protocol analysis performed

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskMissing participant characteristics; sex and underlying disease not stated; no raw data given

Assessment of compliance by collecting drug boxes at the end of each study period and taking blood samples for naltrexone measurement at randomly chosen time

Pederson 1980

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 20

Number of participants evaluable: 11

Withdrawals/dropouts:

  • Group A (charcoal - placebo): 4
  • Group B (placebo - charcoal): 5


Reason for dropout:

  • Group A (charcoal - placebo): non-compliance (4)
  • Group B (placebo - charcoal): transplanted (1), developed bleeding (1), died (1), dissatisfaction (2)


Age (years): 34 - 72 (mean 53)

Sex (male/female): 16/4

Underlying disease/s: no information

Participant pool: no information

Setting: inpatient

Haemodialysis: duration of 3.5 to 72 months

Baseline pruritus assessment: not clear if conducted

Pruritus assessment: questionnaire as suggested by Lowrie and Ingham

Duration/severity of pruritus: 1 to 72 months; no information regarding severity

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: activated charcoal (6 g/day)
  • Intervention 2: placebo (dextrose, 6 g/day)


Additional medication: no information

Route of administration: oral

Duration of treatment: 8 weeks (8 weeks charcoal/placebo - 8 weeks crossover)

Follow-up: no information


OutcomesPruritus assessment: questionnaire as suggested by Lowrie and Ingham

Results:

The data show that dialysis patients ingesting activated charcoal have a diminished perception of pruritus. This subjective response, assessed by the questionnaire, is supported by simultaneous resolution of active skin lesions in 7 of 8 participants.

Adverse events: none provided

Additional outcomes:

  • Skin lesions
  • Serum urea nitrogen, creatinine, glucose, uric acid, calcium, phosphorus, albumin, prothrombin time, alkaline phosphatase, bilirubin, triglycerides, cholesterol


Author conclusion:

Patients ingesting activated charcoal have diminished perception of pruritus.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomly assigned (...)"

Method not stated

Allocation concealment (selection bias)Unclear risk"treatments "administered orally in identical opaque capsules"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts and reasons for dropout provided; no intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskMissing participant characteristics

Other biasUnclear riskSmall sample size; high number of drop-outs; no information on whether there was a wash-out-period between the treatment periods

Peer 1996

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 15

  • Group A (naltrexone-placebo): 8
  • Group B (placebo-naltrexone): 7


Number of participants evaluable: 15

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): no information

Sex (male/female): no information

Underlying disease/s: no information

Participant pool: no information

Setting: inpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: persistent, treatment resistant pruritus

Baseline parameters:
Pruritus score (measured by VAS 10 cm):

  • Group A (naltrexone-placebo): 9.9
  • Group B (placebo-naltrexone): 9.9


Biochemical parameters:

  • Histamine: 2.32
  • ß-endorphin: 8.90


InterventionsDrug (dose):

  • Intervention 1: naltrexone (50 mg/day)
  • Intervention 2: placebo (50 mg/day)


Additional medication: All antipruritic therapy was stopped 1 week before the study; erythropoietin for at least 3 months before the study.

Route of administration: oral

Duration of treatment: 7 days (7 days naltrexone/placebo - 7 days crossover)

Follow-up: 5 participants continued treatment with the same dose of drug for 10 weeks with no pruritus. The other participants discontinued because of the high cost of naltrexone.


OutcomesPruritus assessment: VAS

Results:

Pruritus relief at the end of the naltrexone treatment (measured by VAS 10 cm):

  • Group A (naltrexone-placebo): 2.1
  • Group B (placebo-naltrexone): 1


Values were significantly different (P < 0.001) from the respective values before naltrexone. The difference between naltrexone and placebo were significant from days 2-7.

Biochemical parameters:

  • Naltrexone: histamine=1.8; ß- endorphin=7.3
  • Placebo: histamine=2.48; ß- endorphin=9.50


Naltrexone administration in patients on chronic haemodialysis relieves severe intractable pruritus with fewer side effects.

Adverse events:

  • Naltrexone:(minor) minor heart burn (2), upper abdominal discomfort (3)
  • Placebo: none provided


Additional outcomes: plasma, endorphin, histamine

Author conclusion:

The results suggest short-term efficacy with few side-effects for the amelioration of uraemic pruritus with naltrexone.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy was randomised; method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; no information on intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskNo indication

Podesta 1991a

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 14

Number of participants evaluable: 14

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): 32 - 72 (mean 43)

Sex (male/female): 1/13

Underlying disease/s: PBC Stage IV (5), PBC Stage III (4), PBC Stage II (3), PBC Stage I (2)

Participant pool: multicentre

Setting: outpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information regarding duration; 9 participants were receiving cholestyramine with a poor or no response in 6 participants

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: rifampin (300 mg 2x/day)
  • Intervention 2: placebo


Additional medication: Participants stopped treatment 15 days before the study (washout-period).

Route of administration: oral

Duration of treatment: 7 days - 7 days wash-out period - crossover treatment for 7 days

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus parameter/relief (measured by VAS 100mm):

  • Rifampin: pruritus completely disappeared=11 (79%); partial disappearance=3 (21%)
  • Placebo: partial response=2 (14%); compared to rifampin highly significant (P < 0.001)


Short-term administration of rifampin is an effective therapy for relieving pruritus in patients with primary biliary cholangitis.

Adverse events: none observed

Additional outcomes: bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, anti-mitochondrial antibody

Author conclusion:

Rifampin appears to be a safe drug in the management of the pruritus of primary biliary cirrhosis.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization made using a coin toss

Allocation concealment (selection bias)Low risk"Vials containing a one-week-supply of drug or placebo by an independent observer and randomization made with the toss of a coin"

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants used but disclosed because of treatment effects

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; no information on intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskAssessment of compliance using pill count

Pour-Reza-Gholi 2007

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 24

Number of participants evaluable: 23

Withdrawals/dropouts: 1

Reason for dropout: drowsiness

Age (years): 35 - 65 (mean=48±5.6)

Sex (male/female): 13/11

Underlying disease/s: ESRD

Participant pool: uni-centre

Setting: outpatient

Haemodialysis: 3x/week, Kt/V> 1.2

Baseline pruritus assessment: no information

Pruritus assessment: no information

Duration/severity of pruritus: no information

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: doxepin (10mg 2x/day)
  • Intervention 2: placebo


Additional medication: erythropoietin weekly (10); others did not receive erythropoietin regularly

Route of administration: oral

Duration of treatment: 1 week (1 week doxepin/placebo - 1 week washout - 1 week cross-over)

Follow-up: no information


OutcomesPruritus assessment: Subjective outcome determined by asking the participants to describe their pruritus as completely improved, relatively improved, or remained unchanged/worsened

Results:

Pruritus relief:

After doxepin:

  • Complete improvement (no more itching) in 14 participants (58.3%)
  • Relative improvement (reduction of the symptom) in 7 participants (29.2%)
  • No effect (symptom remain unchanged or worsened) in 3 participants (12.5%)


After placebo:

  • Complete improvement (no more itching) in 1 participant (8.3%)
  • Relative improvement (reduction of the symptom) in 4 participants (16.7%)
  • No effect (symptom remain unchanged or worsened) in 18 participants (75%)


Significant effectiveness of doxepin for the treatment of pruritus in ESRD patients receiving haemodialysis.

Adverse events:(minor) drowsiness (11); (major, leading to withdrawal) drowsiness (1)

Additional outcomes: serum calcium levels, serum phosphate levels, serum intact parathyroid hormone, serum aluminium, serum magnesium, blood haemoglobin

Author conclusion:

Doxepin can help improve pruritus resistant to antihistamines in end-stage renal disease patients who undergo haemodialysis.


NotesNo scales or score for rating of pruritus; subjective outcome report of participants


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"They were randomly assigned (...)"

Method not stated

Allocation concealment (selection bias)Low risk"Doxepin was placed in another capsule in order to provide placebo capsules similar in shape, size and color"

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"The patients and the physicians involving in their management were blind to the randomization."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The patients and the physicians involving in their management were blind to the randomization."

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts and reasons for dropout provided; intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskNo scales or score for rating of pruritus; subjective outcome report of participants

Silva 1994

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 29

  • Group A (thalidomide - placebo): 14
  • Group B (placebo - thalidomide): 15


Division into 3 subgroups: according to baseline scoring/ proportion of responders analysed

Number of participants evaluable: 18

  • Group A (thalidomide - placebo): 11
  • Group B (placebo - thalidomide): 7


Withdrawals/dropouts: 11

  • Group A (thalidomide - placebo): 3
  • Group B (placebo - thalidomide): 8


Reason for dropout:

  • Group A (thalidomide - placebo): inadequate completion of the form (3)
  • Group B (placebo - thalidomide): low pruritus score at baseline (3), non-adherence to treatment (1), inadequate completion of the form (4)


Age (years, mean):

  • Group A (thalidomide - placebo): 57.5 ±7.3
  • Group B (placebo - thalidomide): 50.5 ±11.2


Sex (male/female):

  • Group A (thalidomide - placebo): 12/2
  • Group B (placebo - thalidomide): 5/10


Underlying disease/s: malignant nephrosclerosis (11), chronic glomerulonephritis (5), polycystic disease (3), others (10)

Participant pool: no information

Setting: inpatient

Haemodialysis: 3x/week for over 6 months

Baseline pruritus assessment: yes

Pruritus assessment: 4-point score

Duration/severity of pruritus: no information on duration; >25% of the maximum score during baseline

Baseline parameters:

Pruitus score (measured by 4-point score; 0=absence of itching, 1=not interfering with usual tasks, 2=perturbing but not interrupting usual tasks, 3=causing interruptions of usual tasks/sleep):

  • Group A (thalidomide - placebo): 58.7 ±6.5%
  • Group B (placebo - thalidomide): 59.0 ±8.2%


InterventionsDrug (dose):

  • Intervention 1: thalidomide (100mg 1x/day in the evening)
  • Intervention 2: placebo


Additional medication: phosphate binders (17), vitamins (12), antihypertensives (10), calcitriol (10), iron (6), H2-blockers (3), EPO (2)

Route of administration: oral

Duration of treatment: 1 week (1 week baseline - 1 week thalidomide/placebo - 1 week washout - 1 week crossover)

Follow-up: pruritus score 3x/day; blood samples at beginning/end of each study period


OutcomesPruritus assessment: 4-point score

Results:

Pruitus relief (measured by 4-point score; 0=absence of itching, 1=not interfering with usual tasks, 2=perturbing but not interrupting usual tasks, 3=causing interruptions of usual tasks/sleep):

  • Group A (thalidomide - placebo): 36.6±8.2%, P = 0.008 vs. baseline
  • Group B (placebo - thalidomide): 37.8±15.3%, P = 0.04 vs. baseline


Adverse events: none observed

Additional outcomes: complete blood count, plasma levels of calcium, phosphorus, magnesium, alkaline phosphatase, blood urea nitrogen

Author conclusion:

Thalidomide can be a precious tool in the handling of uraemic pruritus unresponsive to available therapy.


NotesResponse rate higher in participants with low baseline pruritus score; differentiation between responders and non-responders


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"(...) they were randomly assigned (...)"

Method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"(...) in a double-blind fashion."

Unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts and reasons for dropout provided; not reported if intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskResidual effect identified and participants therefore excluded from crossover

Silverberg 1977

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 10

  • Cholestyramine: 5
  • Placebo: 5


Number of participants evaluable: 10

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): no information

Sex (male/female): 10/0

Underlying disease/s: no information

Participant pool: no information

Setting: inpatient

Haemodialysis: 3x3-5hours/week

Baseline pruritus assessment: yes

Pruritus assessment: 4-point score

Duration/severity of pruritus: long lasting; no information regarding severity

Baseline parameters:

Pruritus score (measured by 4-point score; 0=none, 3=great):

  • Cholestyramine: 1.9, 2.2, 2.3, 1.9, 1.9
  • Placebo: 1.9, 0.9, 2.1, 1.2, 2.2


InterventionsDrug (dose):

  • Intervention 1: cholestyramine (5g 2x/day in juice)
  • Intervention 2: placebo (methylcellulose) (2x/day)


Additional medication: no information

Route of administration: oral

Duration of treatment: 4 weeks

Follow-up: no information


OutcomesPruritus assessment: 4-point score

Results:

Pruritus parameter/relief (measured by 4-point score; 0=none, 3=great):

  • Cholestyramine: 2.0, 0.9, 1.2, 1.0, 0.3


In one case, pruritus disappeared entirely and in other 3 cases it decreased considerably. One participant who had not shown any improvement was given 5g, 4x/day and his pruritus improved within 4 days.

  • Placebo: 1.9, 0.5, 2.3, 1.2, 2.3


One participant noted an improvement.

Adverse events:

  • Cholestyramine: constipation (1), nausea 10 - 15 min after every dose (1)
  • Placebo: none provided


Additional outcomes: prothrombin time, blood urea, serum creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphate, alkaline phosphatase, albumin, cholesterol, triglyceride concentration

Author conclusion:

Cholestyramine seems to be useful in treating uraemic pruritus, although it is not known how it acts.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The 10 patients were randomly assigned to two treatments (...)."

Method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blinding stated in the abstract but not further mentioned; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts

Selective reporting (reporting bias)Unclear riskSmall number of participants; Inclusion and exclusion criteria not mentioned; only means of 21 days before treatment and means of 28 days of treatment were compared

Other biasUnclear riskMissing participant characteristics; assessment of compliance not stated

Smith 1997

MethodsRCT

Parallel group

Blinding: not stated


ParticipantsPruritus: HIV

Description: patients with HIV-1

Number of participants randomised: 40

  • Hydroxyzine HCl10: 10
  • Pentoxifylline: 10
  • Indomethacin: 10
  • Triamcinolone: 10


Number of participants evaluable: 33

  • Hydroxyzine HCl: 8
  • Pentoxifylline: 9
  • Indomethacin: 8
  • Triamcinolone: 8


Withdrawals/drop-outs: 7

  • Hydroxyzine HCl: 2
  • Pentoxifylline: 1
  • Indomethacin: 2
  • Triamcinolone: 2


Reason for drop-out:

  • Hydroxyzine HCl: side effects (2)
  • Pentoxifylline: non-compliance (1)
  • Indomethacin: non-compliance (1), side effects (1)
  • Triamcinolone: non-compliance (2)


Age (years): no information

Sex (male/female): no information

Underlying disease/s: HIV-1

Participant pool: no information

Setting: no information

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: 4-point score

Duration/severity of pruritus: no information

Baseline parameters:

Pruritus score (Baseline: measured by 4-point score; 1=periodic at night only, 4=interferes with daily activities and sleep at night): 

  • Hydroxyzine HCl: Median=3   (Median for compliant participants: 3)
  • Pentoxifylline: Median=3
  • Indomethacin: Median=3
  • Triamcinolone: Median=3


InterventionsDrug (dose):

  • Intervention 1: hydroxyzine HCl with or without doxepin HCl at night (25mg 3x/day, 25mg at bedtime)
  • Intervention 2: pentoxifylline (400 mg,  3x/day)
  • Intervention 3: indomethacin  (25 mg, 3x/day)
  • Intervention 4: triamcinolone  (0.025% lotion, 120 ml/week)


Additional medication: no information

Route of administration: oral, oral, oral, topical

Duration of treatment: no information

Follow-up:

Number lost to follow-up:

  • Pentoxifylline: 1
  • Indomethacin: 1
  • Triamcinolone: 2


OutcomesPruritus assessment: 5-point score

Results:

Pruritus relief (Endpoint: measured by 5-point score;1=periodic at night only, 4=interferes with daily activities and sleep at night):

  • Hydroxyzine HCl: Median=2  (Median for compliant participants: 2)
  • Pentoxifylline: Median=2
  • Indomethacin: Median=3
  • Triamcinolone: Median=1


Adverse events:

  • Hydroxyzine HCl:(major) tired, drowsy, sleepy (2); (minor) tired, drowsy, sleepy (6), dry mouth or eyes (5), headache (1)


  • Pentoxifylline: (minor) headache (2)
  • Indomethacin: (minor) abdominal pain (2), headache (1), indigestion (4); (major) abdominal pain (1)
  • Triamcinolone: (minor) nausea (1)


Additional outcomes: skin lesions

Author conclusion:

The systemic therapies which may modulate the pattern of immune dysregulation seen in HIV-1 disease may be beneficial in the pruritus seen in late-stage patients.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk" ... we randomly placed patients of four different forms of therapy for their pruritus"

Allocation concealment (selection bias)Unclear risk"Patients were assigned to one of three treatment groups and a control group based on entry into the study"

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo information

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskReasons for dropouts not clearly stated; per protocol analysis

Selective reporting (reporting bias)Unclear riskInclusion and exclusion criteria inadequately described

Other biasHigh riskDuration of treatment not clearly stated (overall changes in pruritus after 4-6 weeks of treatment were graded)

Missing participant characteristics; poor additional information; study design comparing 4 treatments to placebo is problematic; assessment of compliance by asking the participants the number of pills they had left and if they had received any refills if follow-up was longer than 4 weeks

Tarng 1996

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 19

  • Group A (capsaicin - placebo): 12
  • Group B (placebo - capsaicin): 7


Number of participants evaluable: 17

Withdrawals/dropouts:

  • Group A (capsaicin - placebo): 2
  • Group B (placebo - capsaicin): 0


Reason for dropout:

  • Group A (capsaicin - placebo): insufficient improvement (1), participant died because of myocardial infarction (1)
  • Group B (placebo - capsaicin): N/a


Age (years): 27 - 85

Sex (male/female): 13/6

Underlying disease/s: no information

Participant pool: uni-centre

Setting: inpatient

Haemodialysis: mean duration of 71.4 months (range 4-219); 3x4-4.5h/week

Baseline pruritus assessment: yes

Pruritus assessment: 4-point score

Duration/severity of pruritus: mean duration of 33.1±39.3 months; 5 had moderate, 12 had severe pruritus

Baseline parameters:

Pruritus score (measured by a 4-point score, 1=no itching, 4=severe itching disturbing daily life and/or sleep): 

  • Capsaicin: moderate (8), severe (9)


InterventionsDrug (dose):

  • Intervention 1: capsaicin (0.025% 4x/day)
  • Intervention 2: placebo


Additional medication: All topical agents other than moisturizers were discontinued at least 2 weeks prior the study; any ongoing medications were continued.

Route of administration: topical

Duration of treatment: 4 weeks (4 weeks capsaicin/placebo - 2 weeks washout - 4 weeks crossover)

Follow-up: 8 weeks (without treatment)


OutcomesPruritus assessment: 4-point score (self-assessment)

Results:

Pruritus parameter/relief (measured by a 4-point score, 1=no itching, 4=severe itching disturbing daily life and/or sleep):

  • Capsaicin: none (5), mild (9), moderate (1), severe (2)
  • Placebo: not provided


After 8 weeks without treatment:

  • None (4), mild (5), moderate (5), severe (3)


14 of 17 improved after active treatment and 5 of these 14 participants had complete remission and 9 obtained significant relief (P < 0.001). Capsaicin was significantly more effective than placebo. All participants were evaluated 8 weeks after the end of treatment; 5 relapsed and 9 maintained the original state (4 complete resolution and 5 improvements).

Adverse events:

  • Capsaicin: 12
  • Placebo: 4


93.7% of adverse events were related to local burning and/or stinging sensations and 6.3% to cutaneous erythema. Adverse events were mild, transient and tolerable by the participants.

Additonal outcomes:

  • Degrees of cutaneous burning and/or stinging sensations, dryness of skin, and erythema over the treated area
  • Serum albumin, calcium, inorganic phosphorus, alkaline phosphatase and intact parathyroid hormone (PTH)


Author conclusion:

Topical capsaicin with the unique pharmacological effect is demonstrated to markedly improve the pruritus of these patients.


NotesCarryover effect up to 8 weeks after end of treatment


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Treatment order is block-randomized with the use of computer-generated random numbers."

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; "to which both observers and patients were blind"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts and reasons for dropout provided; no intention to treat analysis

Selective reporting (reporting bias)Unclear riskNo separate data for phase 1 reported

Other biasUnclear riskPoor additional information; not clear whether significant difference in itch improvement is within or between group; assessment of compliance not stated

Terg 2002

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 20

  • Group A (naltrexone-placebo): 11
  • Group B (placebo-naltrexone): 9


Number of participants evaluable: 18

Withdrawals/dropouts: 2

Reason for dropout: 1 because of clinical impairment due to progression of prior hepatocarcinoma, 1 because of nausea and vomiting

Age (years):

  • Group A: 36-70 (mean=55±10)
  • Group B: 42-69 (mean=55±9)


Sex (male/female):

  • Group A:3/8
  • Group B: 0/9


Underlying disease/s: PBC (15), chronic hepatitis C (2), PSC (1), overlap syndrome (1), cryptogenic cirrhosis (1)

Participant pool: two centres

Setting: inpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: lasting 6 to 11 months; no information on severity

Baseline parameter:

Pruritus score (VAS 10cm):

  • Group A: 6.27±1.61 (daytime), 6.52±2.42 (nighttime)
  • Group B: 6.32±3.12 (daytime), 5.03±2.48 (nighttime)


InterventionsDrug (dose):

  • Intervention 1: naltrexone (25 mg/day) 2x (9:00 h and 14:00 h)
  • Intervention 2: placebo (25 mg/day) 2x (9:00 h and 14:00 h)


Additional medication: All participants were instructed to continue with their previous medication throughout the study.

Route of administration: oral

Duration of treatment: 2 weeks (2 weeks naltrexone/placebo - 1 week washout - 2 weeks crossover)

Follow-up: no information


OutcomesPruitus assessment: VAS

Results:

Pruritus relief at the end of the naltrexone treatment (VAS 10cm):

  • Group A: 3.91±2.39 P=0.01 (daytime), 3.89±2.17 P = 0.02 (nighttime)
  • Group B: 3.06±2.47 P=0.01 (daytime), 3.05±2.77 P = 0.02 (nighttime)


Changes during placebo intake (VAS 10cm):

  • Daytime VAS: 6.12±2.34 to 5.20±2.43 (P = 0.07), nighttime VAS: 5.98±2.46 to 5.25±2.49 P = 0.06


Mean daytime pruritus VAS in naltrexone treatment was significantly lower compared to mean daytime pruritus VAS in placebo treatment (3.55±2.39 vs. 5.34±2.41 P = 0.006)

Mean nighttime pruritus VAS in naltrexone treatment was significantly lower compared to mean nighttime pruritus VAS in placebo treatment (3.55±2.42 vs 5.19±2.55 P = 0.01)

Adverse events:

  • Naltrexone: dizziness (10), nausea (8), vomit (6), headache (5), abdominal cramps (5), asthenia (3), drowsiness (3), irritability (3), dry mouth (3), insomnia (2), tremor (1), tachycardia (1), anorexia (1), flushing (1), arterial hypertension (1)
  • Placebo: nausea (1), vomit (2), headache (3), abdominal cramps (1), drowsiness (2), irritability (2)


Additonal outcomes: serum bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, prothrombin time, serum albumin, platelets, red and white cell count, serum urea, creatinine, sodium, potassium, γ-glutamyltransferase

Author conclusion:

Naltrexone can be considered as an alternative option to treat pruritus of cholestasis.


NotesAdditional open trial: 2 additional months Naltrexone for participants with at least 50% pruritus decrease (9 participants included)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was generated by tables with two random numbers for each patient. These were the numbers of the bottles containing medication or placebo"

Allocation concealment (selection bias)Low risk"Information was placed in sealed, opaque, and numbered envelopes."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"This study was double-blind (...). "

Unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; no information on intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskAssessment of pruritus by counting the pills remaining in the box

Turner 1994a

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 50

  • Flumecinol: 24
  • Placebo: 26


Number of participants evaluable: 50

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): no information

Sex (male/female): 3/47

Underlying disease/s: primary biliary cirrhosis (46), alcoholic liver disease (2), autoimmune chronic active hepatitis (1), cholestatic phase of hepatitis A (1)

Participant pool: no information

Setting: outpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information

Baseline parameters:
Pruritus score (measured by VAS 100 mm):

  • Flumecinol: 46 (32-63)
  • Placebo: 38 (17-69)


Quality of life (measured by 100 mm scale): 

  • Flumecinol: 26 (16-48)
  • Placebo: 11 (4-30)


InterventionsDrug (dose):

  • Intervention 1: flumecinol (600 mg 1x/week with evening meal)
  • Intervention 2: placebo


Additional medication: Antipruritic treatment was stopped at least 1 week prior the study; if unable to stop, they continued medication at an unchanged dose. Cholestyramine was stopped in 6 of 9 actively-treated and 7 of 8 placebo participants.

Route of administration: oral

Duration of treatment: 3 weeks

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus parameters/relief (measured by VAS 100 mm):

  • Flumecinol: 27 (14 - 45); median fall: 9.4 (2 - 29); symptomatic pruritus improvement: 13/24 (54%)
  • Placebo: 25 (7 - 66); median fall: 4.2 (-6 - 13); symptomatic pruritus improvement: 10/26 (38%)


Quality of life (measured by 100 mm scale): 

  • Flumecinol: 21 (14 - 29), median fall: 3.5 (0 - 20)
  • Placebo: 7 (3 - 27), median fall: 0.1 (-1 - 4)


Adverse events: none observed

Additonal outcomes:

  • Self-assessment of pruritus improvement (yes or no)
  • Liver function tests (bilirubin, albumin, alkaline phosphatase, aspartate transaminase), serum biochemical and haematological parameters at study commencement and completion


Author conclusion:

Flumecinol at a dose of 600 mg once weekly did not result in a significant improvement.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Flumecinol 100 mg hard gelatin capsules and identical-looking placebo in randomised numbered bottles were provided by Gedeon Richter Ltd. Patients ... were sequentially enrolled and double-blindly allocated to sequentially numbered bottles."

Allocation concealment (selection bias)Low riskVide supra

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy was double-blind, " ... without the questioner or the patient knowing the treatment arm ..."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk" ... without the questioner or the patient knowing the treatment arm ..."

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; not reported if intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskPoor additional information; imbalance male/female 3/47; assessment of compliance not stated

Turner 1994b

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 19

  • Flumecinol: 10
  • Placebo: 9


Number of participants evaluable: 19

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years): no information

Sex (male/female): 0/19

Underlying disease/s: primary biliary cirrhosis (19)

Participant pool: no information

Setting: outpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information

Baseline parameters:
Pruritus relief (measured by VAS 100mm):

  • Flumecinol: 45 (37-66)  
  • Placebo: 50 (35-58)


Quality of life (measured by 100 mm scale): 

  • Flumecinol: 32 (20-54)
  • Placebo: 42 (23-50)


InterventionsDrug (dose):

  • Intervention 1: flumecinol (300 mg 1x/day)
  • Intervention 2: placebo


Additional medication: Antipruritic treatment was stopped at least 1 week prior the study; if unable to stop they continued medication at an unchanged dose.

Cholestyramine was stopped in 2 of 10 actively-treated and 1 of 9 placebo participants but 1 continued using it.

Route of administration: oral

Duration of treatment: 3 weeks

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 100 mm):

  • Flumecinol: 32 (19-39), median fall: 21.7 (12 to - 28)*
  • Placebo: 47 (35-72); median fall: 4.0 (-22 - 10)*


Quality of life (measured by 100 mm scale):

  • Flumecinol: 19 (7-64); median fall: 4.4 (-2 - 11)
  • Placebo: 44 (20-49); median fall: 3.0 (-3 - 6)


Adverse events: none observed

Additonal outcomes:

  • Self-assessment of pruritus improvement (yes or no)
  • Liver function tests (bilirubin, albumin, alkaline phosphatase, aspartate transaminase and alanine transaminase), serum biochemical and haematological parameters at study commencement and completion


Author conclusion:

Flumecinol at a dose of 300mg daily for 3 weeks significantly improved cholestatic pruritus compared with the placebo.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAfter the 7-day baseline period, participants were randomised to flumecinol 600 mg or identical placebo (vide supra).

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind

" ... without the questioner or the patient knowing the treatment arm ..."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk" ... without the questioner or the patient knowing the treatment arm ..."

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; no information on intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskPoor additional information; assessment of compliance not stated

Vessal 2010

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number total (randomised): 62 (+ 20 as negative control)

  • Cromolyn sodium: 32
  • Placebo: 30


Number of participants evaluable: 40 (+19 as negative control)

  • Cromolyn sodium: 21
  • Placebo: 19


Withdrawals/dropouts: 22 (+1 as negative control)

  • Cromolyn sodium: 11
  • Placebo: 11


Reason for dropout:

  • Cromolyn sodium: 2 died, 3 transferred, 5 noncompliant, 1 transplanted
  • Placebo: 1 died, 2 transferred, 5 noncompliant, 3 adverse events
  • Negative control group: due to transfer


Age (years, mean):

  • Cromolyn sodium: 56.9±15.49
  • Placebo: 57.47±13.6


Sex (male/female):

  • Cromolyn sodium: 12/9
  • Placebo: 8/11


Underlying disease/s: no information

Participant pool: multicentre (2 centres)

Setting: inpatient

Haemodialysis: 4-5 hours for 2-3x per week

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: pruritus that did not respond to treatment for at least six weeks

Baseline parameters:

Pruritus relief (measured by VAS 10 cm):

  • Cromolyn sodium: 8.68±1.8 (range 4-10, median 10)
  • Placebo: 8.48±2.2 (range 4-10, median 10)


InterventionsDrug (dose):

  • Intervention 1: cromolyn sodium (135 mg)
  • Intervention 2: placebo (lactose powder)


Additional medication: Antipruritic medication was discontinued 1 week prior the study.               

Route of administration: oral (capsule was dissolved in a minimal amount of water and administered half an hour before each meal)

Duration of treatment: 8 weeks

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 10 cm):

  • Cromolyn sodium: 0.9±1.8 (range 0-6, median 0), P < 0.001
  • Placebo: 5.58±3.8 (range 0-10, median 6), P = 0.004


Significant difference between the placebo and cromolyn group during the study (P < 0.001). No significant correlation between the severity of pruritus and serum tryptase level.

Adverse events:

  • Cromolyn sodium: (minor) flatulence (1)
  • Placebo: (minor) nausea (2), diarrhoea (1), nausea and diarrhoea (3)


Additonal outcomes: haemoglobin, calcium, phosphorus, albumin, ferritin, parathyroid hormone, white blood cells, serum tryptase, platelet, hematocrit

Author conclusion:

Cromomly sodium can significantly reduce the severity of pruritus in HD patients, but this effect is not due to a decrease in serum tryptase level.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomly assigned into to groups using the stratified randomization method where the prognostic factor was the gender variable."

Allocation concealment (selection bias)Low risk"Drug packages were prepared by the principal investigator ... Both the participants and the investigator that administered the interventions and assessed the outcomes were blinded to group assignment. code breaking was performed at the end of data analysis.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; participants and personnel blinded

"Both the participants and the investigator that administered the interventions and assessed the outcomes were blinded to group assignment. Code breaking was performed at the end of data analysis."

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessor blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts and reasons for dropout mentioned; per protocol analysis

"19 resp. 21 remained and data were analyzed."

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskNo indication

Villamil 2005

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholestasis

Number of participants randomised: 18

  • Lidocaine: 12
  • Placebo: 6


Number of participants evaluable: 16

  • Lidocaine: 11
  • Placebo: 5


Withdrawals/dropouts: 2

  • Lidocaine: 1
  • Placebo: 1


Reason for dropout:

  • Lidocaine: liver transplantation
  • Placebo: incomplete records


Age (years):

  • Lidocaine: 33 - 54 (mean: 45±3)
  • Placebo: 31 - 67 (mean: 48±2)


Sex (male/female):

  • lidocaine: 2/10
  • placebo: 2/4


Underlying disease/s:

  • Lidocaine: PBC (9), PSC (2), drug-induced (1)
  • Placebo: PBC (4), PSC (2)
  • Overall: PBC (13), PSC (4), drug-induced (1)


Participant pool: uni-centre

Setting: no information

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: at least 3 months;resistant to treatment

Baseline parameters: no information


InterventionsDrug (dose):

  • Intervention 1: lidocaine (100 mg)
  • Intervention 2: placebo (5 cc, saline)


Additional medication: ursodeoxycholic acid

Route of administration: intravenous (5 minutes)

Duration of treatment: 7 days

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

  • Lidocaine: significant reduction in pruritus severity when compared with placebo administration (P < 0.05)
  • Placebo: no significant changes in severity of pruritus and fatigue


Adverse events:

  • Lidocaine: (minor) mild tinnitus associated with lingual paraesthesia during infusion; subsided 2 to 5 minutes after infusion (2)
  • Placebo: not provided


Additional outcomes: total serum bilirubin, alkaline phosphatase, albumin

Author conclusion:

Lidocaine may be a therapeutic alternative in patients with treatment-resistant pruritus related to cholestatic liver disease.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomised (2:1) to receive (...)"

Method not stated

Allocation concealment (selection bias)Unclear riskNot information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskUnclear who was blinded

"Drug administration was done under strict double-blind conditions and the code was not opened until the final analysis of the results."

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessor probably blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts and reasons for dropout mentioned; not reported if intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskPresentation of study results inappropriate; neither baseline nor endpoint data given

Other biasLow riskAssessment of compliance not stated

Wikström 2005a

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end stage renal disease on haemodialysis

Number of participants randomised: 51

  • Nalfurafine: 26
  • Placebo: 25


Number of participants evaluable: 48

Withdrawals/dropouts:

  • Nalfurafine: 2
  • Placebo: 1


Reason for dropout:

  • Nalfurafine: moderate nausea and vomiting (1), reason for second participant not provided
  • Placebo: reason not provided


Age (years): no information

Sex (male/female): no information

Underlying disease/s: ESRD

Participant pool: multicentre

Setting: no information

Haemodialysis: no information

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: Severe, uncontrolled pruritus secondary to ESRD; at least 3 “worst itching” VAS measurements during run-in period of >50mm and average worst itching >25mm

Baseline parameters:

Pruritus relief (measured by VAS 100 mm):

  • Nalfurafine: 65.3 (SD 15.2)
  • Placebo: 65.3 (SD 15.0)


InterventionsDrug (dose):

  • Intervention 1: nalfurafine (5 µg 3x/week immediately after their haemodialysis session)
  • Intervention 2: placebo


Additional medication: Before the run-in period all anti-pruritic medications, except for topical neutral agents, were discontinued for at least 7 days.

Route of administration: intravenous

Duration of treatment: 4 weeks (1 week run-in period - 4 weeks nalfurafine/placebo)

Follow-up: 2 weeks after the administration of the final dose


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 100mm):

  • Nalfurafine: week 2 44.9 (SD 26.5), week 4 40.3 (SD 27.8)
  • Placebo: week 2 55.5 (SD 21.5), week 4 52.6 (SD 24.0)


Adverse events:

Nalfurafine: 17 (65%) of 26 participants

  • Headache (3)
  • Nausea (3)
  • Insomnia (2)
  • Vertigo (2)
  • Vomiting (2)
  • Severe headache (1)
  • Severe insomnia (1)
  • Vomiting and nausea leading to withdrawal (1)


Placebo: 13 (52%) of 25 participants

  • Symptoms not provided


2 (8%) participants in the nalfurafine 5 µg group and 6 (24%) participants in the placebo group reported at least one serious adverse event (SAE), but none of the SAE was considered to be drug related.

Additional outcomes: none provided

Author conclusion:

Nalfurafine was shown to be an effective and safe compound for use in this severely ill patient population.


NotesNot clear who conducted the study; not clear if and where study was published; 17 (65%) of 26 participants had adverse drug events in the nalfurafine group, but only 15 were described


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not stated

"Seventy-nine patients were randomly assigned in this study."

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSubstantial missing outcome data; number of participants included unclear

Selective reporting (reporting bias)Unclear riskConflicting data (number of participants included); combined results from study Wikström 2005b

Other biasUnclear riskMissing participant characteristics; Bergstrom effect; assessment of compliance not stated

Wikström 2005b

MethodsRCT

Placebo-controlled

Cross-over design

Blinding: double


ParticipantsPruritus: CKD/UP         

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 34

  • Group A (nalfurafine - placebo): 16
  • Group B (placebo - nalfurafine): 18


Number of participants evaluable: 31

Withdrawals/dropouts: 3

Reason for dropout: no information

Age (years): no information

Sex (male/female): no information

Underlying disease/s: ESRD

Participant pool: multicentre

Setting: no information

Haemodialysis: "routine"

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information on duration; severe, uncontrolled pruritus secondary to ESRD, at least 3 “worst itching” VAS measurements during run-in period of > 50 mm and average worst itching >25mm

Baseline parameters:

Pruritus relief (measured by VAS 100mm):

  • Group A (nalfurafine - placebo): 63.3 (SD 10.9)
  • Group B (placebo - nalfurafine): 61.9 (SD 12.6)


InterventionsDrug (dose):

  • Intervention 1: nalfurafine (5 µg 3x/week immediately after their haemodialysis session)
  • Intervention 2: placebo


Additional medication: Before the run-in period all anti-pruritic medications, except for topical neutral agents, were discontinued for at least 7 days.

Route of administration: intravenous

Duration of treatment: 2 weeks (1week run-in period - 2 weeks nalfurafine/placebo - 3 weeks washout - 2 weeks crossover)

Follow-up: no information


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 100mm):

  • Group A (nalfurafine - placebo): after period 1 (week 2), nalfurafine 41.5 (SD 20.5)
  • Group B (placebo - nalfurafine): after period 1 (week 2), placebo 48.4 (SD 19.1)


Using the meta-analysis approach it was demonstrated that nalfurafine produced a statistically significantly greater improvement in the 'worst itching' VAS as compared with placebo after 2 weeks of therapy.

Adverse events:

  • Nalfurafine: 2 (13%) of 16 participants; vertigo (1), elevations of aspartate aminotransferase and alanine transaminase (1)
  • Placebo: 2 (11%) of 18 participants; symptoms not described
  • 3 participants in the nalfurafine 5 µg group and 3 participants in the placebo group reported a serious adverse event (SAE), but none of the SAE was considered to be drug-related.


Additional outcomes: none provided

Author conclusion:

Nalfurafine was shown to be an effective and safe compound for use in this severely ill patient population.


NotesResults combined with results of study Wikström 2005a.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"(...) patients were randomly assigned 1:1 (...)."

Method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information on withdrawals

Selective reporting (reporting bias)Unclear riskCombined with results of study Wikström 2005a, conflicting information concerning number of included participants

Other biasUnclear riskMissing participant characteristics; assessment of compliance not stated

Wolfhagen 1997

MethodsRCT

Placebo-controlled

Parallel group design

Blinding: double


ParticipantsPruritus: CP

Description: patients with cholangitis

Number of participants randomised: 16

  • Naltrexone: 8
  • Placebo: 8


Number of participants evaluable: 16

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years):

  • Naltrexone: 37 - 72 (mean: 58)
  • Placebo: 43 - 74 (mean: 46)


Sex (male/female):

  • Naltrexone: 1/7
  • Placebo: 3/5


Underlying disease/s:

  • Naltrexone: PBC (8)
  • Placebo: PBC (5), PSC (2), unclassified (1)


Participant pool: uni-centre

Setting: inpatient for one day, then outpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: no information

Baseline parameters:

Pruritus relief (measured by VAS 100 mm):

  • Naltrexone: 65 (range: 52-93) in the daytime; 59 (range: 8-92) in the nighttime
  • Placebo: 48 (range:18-80) in the daytime; 47 (range: 7-80) in the nighttime


InterventionsDrug (dose):

  • Intervention 1: naltrexone (50mg)
  • Intervention 2: placebo


Additional medication: UDCA (8), anion binders (7), antihistamines (3), rifampicin (3), light therapy (2), plasmapheresis (1)

Route of administration: oral

Duration of treatment: 4 weeks

Follow-up: twice before randomisation - after 2 weeks - after 4 weeks


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 100mm):

  • Naltrexone: -54 ±10% (daytime); -44 ±11% (nighttime)
  • Placebo: -8 ±10% (daytime); -7 ±9% (nighttime)


Adverse events:

  • Naltrexone: nausea (4), dizziness (3), flushing (2), drowsiness (2), headache (1), nightmares (1), tremor (1), abdominal cramps (5), dry mouth (2), peripheral edema (1), night-sweating (1)
  • Placebo: abdominal cramps (1), dry mouth (1), irritability (1), epistaxis (1), swelling of the hands (1)


Additional outcomes:

  • Withdrawal-like symptoms, blood pressure, heart rate, liver function (bilirubin, transaminase, alkaline phosphatase), serum creatine, albumin, total bile salt, prothrombin time
  • Scratch lesions


Author conclusion:

For patients with cholestatic liver disease and itching, refractory to regular antipruritic therapy, oral naltrexone may be an effective an well-tolerated alternative.


NotesStudy describes participants as responders and non-responders.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomly assigned (using opaque envelopes) (...)."

Allocation concealment (selection bias)Low riskOpaque envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts; not reported if intention-to-treat analysis

Selective reporting (reporting bias)Low riskNo indication

Other biasLow risk"Treatment compliance, assessed by pill counts, was 100%."

Young 2009

MethodsRCT

Placebo-controlled

Paralle group design

Blinding: double


ParticipantsPruritus: CKD/UP       

Description: patients with end-stage renal disease on haemodialysis

Number of participants randomised: 28

  • 1% pramoxine HCl lotion: 14
  • Cetapil lotion: 14


Number of participants evaluable: 27

  • 1% pramoxine HCl lotion: 13
  • Cetapil lotion: 14


Withdrawals/dropouts: 1

Reason for dropout: unrelated subject death

Age (years): 18 - 70

Sex (male/female): 14/14

Underlying disease/s: ESRD

Participant pool: uni-centre

Setting: inpatient

Haemodialysis: at least 3 months

Baseline pruritus assessment: yes

Pruritus assessment: VAS

Duration/severity of pruritus: symptoms of itch in a regular pattern over 6 months; at least 2 episodes of itch > 2 minutes within 2 weeks

Baseline parameters:

  • Pruritus relief (measured by VAS 10 cm): 5.5
  • Skin conditions (measured by 3-point Linkert scale): Erythema 0.82 (0.61), Xerosis 1.54 (0.58), Lichenification1.25 (0.7)
  • Skin hydration (measured by MoistureMeter): 23.29 (23.76)
  • Quality of life (measured by Investigator Global Assessment): 4.11 (1.13)
  • Burning / stinging (measured by scale 1-3): 0.14 (0.45)


InterventionsDrug (dose):

  • Intervention 1: pramoxine HCl (1%)
  • Intervention 2: cetaphil lotion


Additional medication: no information

Route of administration: topical to all affected areas of pruritus/2x daily

Duration of treatment: 4 weeks

Follow-up: baseline - week 1- week 4


OutcomesPruritus assessment: VAS

Results:

Pruritus relief (measured by VAS 10 cm): 

  • 1% pramoxine HCl lotion) 2.3 (61%)
  • Cetapil lotion: 5.0 (12%)


Skin conditions (measured by 3-point Linkert scale):

  • 1% pramoxine HCl lotion: Erythema 0.3 (0.13), Xerosis 0.57 (0.14), Lichenification 0.45 (0.16)
  • Cetapil lotion: Erythema 0.22 (0.12), Xerosis 0.33 (0.13), Lichenification 0.3 (0.15)


Skin hydration (measured by MoistureMeter):

  • 1% pramoxine HCl lotion: 37.81 (9.37)
  • Cetapil lotion: 37.96 (9.37)


Quality of life (measured by Investigator Global assessment):

  • 1% pramoxine HCl lotion: 2.63 (0.37)
  • Cetapil lotion: 2.34 (0.36)


Burning/stinging (measured by scale 1-3):

  • 1% pramoxine HCl lotion: 0.08 (0.05)
  • Cetapil lotion: 0.00 (0.05)


Pramoxine lotion reduces pruritus to a greater degree than control lotion.

Adverse events: none observed

Additonal outcomes:

  • Erythema, xerosis, and lichenification (assessed by a 3-point-Likert scale with '0' indication no symptoms and with '3' representing severe)
  • Inidvidual pruritus history and assessment questionnaire
  • Investigator Global Assessment (IGA) of response to treatment
  • Skin hydration measurements using the MoistureMeter pico


Author conclusion:

Individuals using pramoxine 1% lotion experienced a reduction in pruritus to a greater degree than those using the control lotion. This safe, convenient and effective topical lotion may potentially benefit the large number of patients affected by pruritus associated with end-stage renal disease.


NotesMedication versus control P values: Erythema 0.7, Xerosis 0.2, Lichenification 0.5, Investigator Global Assessment 0.6, Burning/stinging 0.3, skin hydration measurement 1.0

Pramoxine itch intensity slope: -0.105

Control itch intensity slope: -0.030

Comparison P value: 0.0072


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised; method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOne participant lost because of 'unrelated subject death'; not reported if intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskInclusion and exclusion criteria inadequately described; insufficient data on pruritus VAS (no confidence interval, only graphical illustration)

Other biasUnclear riskAssessment of compliance not stated; possible carry-over effect not mentioned

Zylicz 2003

MethodsRCT

Placebo controlled

Cross-over design

Blinding: double


ParticipantsPruritus: various malignancies

Description: patients with the following conditions:

  • Solid tumours (17)
  • Hematological malignancies (4)
  • Various non-malignant or idiopathic conditions (5)
  • Drug-induced pruritus (8)
  • Paraneoplastic pruritus (7)
  • Cholestatic pruritus (3)
  • Primary skin amyloidosis due to MEN2A syndrome (1)


Number of patients is higher than total number of patients due to  simultaneously existing causes for pruritus.

Number of participants randomised: 26

  • Group A (placebo - paroxetine): 11
  • Group B (paroxetine - placebo): 13


Number of participants evaluable: 24

Withdrawals/dropouts: 2 participants in Group B during paroxetine treatment

Reason for dropout: severe nausea and vomiting

Age (years, mean):

  • Group A (placebo - paroxetine): 64.4±18.3
  • Group B (paroxetine - placebo): 64.9±11.3


Sex (male/female):

  • Group A (placebo - paroxetine): 6/5
  • Group B (paroxetine - placebo): 7/6


Underlying disease/s: solid tumours (17), hematological malignancies (4),

osteoporosis (2), Parkinson (1), skin amyloidosis due to MEN2A (1), rheumatoid arthritis (1)

Participant pool: multicentre (2 palliative care centres)

Setting: inpatient

Haemodialysis: N/a

Baseline pruritus assessment: yes

Pruritus assessment: NAS

Duration/severity of pruritus:

  • Group A (placebo - paroxetine): <3 months (2), >3 months (9); generalized (6), local (5)
  • Group B (paroxetine - placebo): < 3months (3), >3 months (10); generalized (7), local (6)


Baseline parameters:

Pruritus relief (measured by numerical analogues scale = NAS)

  • Group A (placebo - paroxetine): 6.6±1.0
  • Group B (paroxetine - placebo): 6.5±1.1


InterventionsDrug (dose):

  • Intervention 1: paroxetine (20mg)/day
  • Intervention 2: placebo


Additional medication: cisapride (in case of severe nausea)

Route of administration: oral

Duration of treatment: 1 week (1 week run in - 1 week paroxetine/placebo - 1 week crossover)

Follow-up: no information


OutcomesPruritus assessment: NAS

Results:

Pruritus relief (measured by NAS):

Paroxetine:

  • 7 day means: 5.2±0.32, P = 0.001
  • Means of last 3 days: 4.7±0.39, P = 0.223


Placebo:

  • 7 day means: 6.0±0.32
  • Means of last 3 days: 6.0±0.39


Participant satisfaction (measured by 7-point scale: 0=indifferent, -3=extremely poor, +3=excellent):

  • Paroxetine (mean): 0.41 (SE: 0.36)
  • Placebo (mean): -0.66 (SE: 0.36)


Participant’s preference:

  • Paroxetine: 14/24
  • Placebo: 5/24
  • No preference: 5


Treatment with paroxetine was significantly more effective in the treatment of severe non-dermatological pruritus than placebo. No period or carry over effect was observed. There was a significantly higher proportion of responders with paroxetine (9/24, 37.5%) than placebo (1/24, 4,2%).

Adverse events:

Group B (paroxetine - placebo): (major, leading to withdrawal) severe nausea and vomiting (2)

Paroxetine: Treatment effect

  • Nausea: 0.93±0.3
  • Vomiting: 0.08±0.12
  • Sleepiness: 1.79±0.43


Placebo: Treatment effect

  • Nausea: 0.47±0.3
  • Vomiting: 0.25±0.12
  • Sleepiness: 1.09±0.43


Additional outcomes: participant satisfaction

Author conclusion:

Paroxetine is effective in the treatment of severe pruritus of non-dermatological origin.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not stated

"The patients were randomised when the mean NAS of pruritus ..."

Allocation concealment (selection bias)Low risk"The patients were supplied with 7 capsules of placebo or paroxetine. Identical capsules were prepared for both centres in Poland and the Netherlands."

"Blinding and randomisation were in the hands of the same pharmacist as well."

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind; unclear who was blinded

"Blinding and randomisation were in the hands of the same pharmacist as well."

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data; planning of sample size; power calculation done, intention-to-treat approach for the primary endpoint done

Selective reporting (reporting bias)Low riskNo indication

Other biasLow riskAssessment of compliance not stated;no washout period but carry-over effect evaluated

Özaykan 2001

MethodsRCT

Parallel group design

Blinding: open


ParticipantsPruritus: CKD/UP

Description: patients on haemodialysis

Number of participants randomised: 20

  • Group A (ondansetron): 10
  • Group B (cyproheptadine): 10


Number of participants evaluable: 20 (Group A: 10, Group B: 10)

Withdrawals/dropouts: 0

Reason for dropout: N/a

Age (years, median):

  • Group A (ondansetron): 23 - 63 (42,90±14,33)
  • Group B (cyproheptadine): 20 - 58 (39,50±11,60)


Sex (male/female):

  • Group A (ondansetron): 4/6
  • Group B (cyproheptadine): 3/7


Underlying disease/s: no information

Participant pool: uni-centre

Setting: no information

Haemodialysis: no information

Baseline pruritus assessment: yes

Pruritus assessment: yes

Duration/severity of pruritus: > 8 weeks

Baseline parameters:

Pruritus scoring system proposed by Duo and modified by Mettang

  • Group A (ondansetron): 28±7
  • Group B (cyproheptadine): 24±7


InterventionsDrug (dose):

  • Intervention 1: ondansetron (4mg 2x/day)
  • Intervention 2: cyproheptadine (2mg/5ml 2x/day)


Additional medication: Antipruritic medication was discontinued 2 weeks prior the study.  

Route of administration: oral

Duration of treatment: 30 days


OutcomesPruritus assessment: Pruritus scoring system proposed by Duo 1987 and modified by Mettang 1990

Results:

Pruritus relief (measured by pruritus score):

  • Group A (after 4 weeks ondansetron treatment): 3±3
  • Group B (after 4 weeks cyproheptadine treatment): 11±10


Pruritus score in group A (ondansetron) was significantly lower than pruritus score in group B (cyproheptadine): U = 21.5, P < 0.05

Significant pruritus relief in group A (ondansetron): Z = -2.80; P < 0,01

Escape medication use decreased during both placebo and ondansetron treatment.

Adverse events: none observed

Additional outcomes: none provided

Author conclusion:

Ondansetron may be an effective, safe and well tolerated drug for treatment of uraemic pruritus.


NotesArticle in Turkish.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised; method not stated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo blinding

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo missing outcome data; not reported if intention-to-treat analysis

Selective reporting (reporting bias)Unclear riskOnly data for the treatment groups given; no data on single participants

Other biasLow riskNo indication

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Almasio 2000Study intervention targeted on the treatment of underlying disease

Aperis 2010Not a RCT

Aymard 1980Not a RCT

Balaskas 1998Not a RCT

Bergasa 1991Not a RCT

Bergasa 1992Not a RCT

Bergasa 1995Does not meet inclusion criteria concerning palliative care patients

Bergasa 1999Does not meet inclusion criteria concerning palliative care patients

Berman 1998Not a RCT

Bigliardi 2007Does not meet inclusion criteria concerning palliative care patients

Borgeat 1994Doubly published data

Bousquet 1989Not a RCT

Breneman 1992aNot a RCT

Castello 2011Not a RCT

Chen 2006Not a pharmacological intervention as defined in inclusion criteria, will be enclosed in an additional review

Datta 1966Not a RCT

Davis 2003Not a RCT

Easton 1978Not a RCT

Fjellner 1979Not a RCT

Ghorbani 2011Insufficient data provided

Giovanetti 1995Not a RCT

Goicoechea 1999Not a RCT

Goncalves 2010Not a RCT

Hellier 1963Not a RCT

Jones 2005Not a RCT

Jones 2007Does not meet inclusion criteria concerning palliative care patients

Juby 1994Not a RCT

Kato 2001Not a RCT

Korfitis 2008Not a RCT

Kuypers 2004Not a RCT

Lysy 2003Does not meet inclusion criteria concerning palliative care patients

Mansour-Ghanaei 2006Not a RCT

Marquez 2012Not a RCT

Metze 1999Not a RCT

Montero 2006Not a RCT

Müller 1998aDoes not meet inclusion criteria concerning palliative care patients

Müller 1998bDoes not meet inclusion criteria concerning palliative care patients

Podesta 1991bNot a RCT

Price 1998Not a RCT

Prieto 2004Not a RCT

Razeghi 2009Not a RCT

Rifai 2006Not a RCT

Sja'bani 1997Only abstract available; contact with the authors could not be established

Ständer 2009Does not meet inclusion criteria concerning palliative care patients

Szepietowski 2005Not a RCT

Tokgöz 2005Not a RCT

 
Characteristics of studies awaiting assessment [ordered by study ID]
Feily 2012

MethodsRCT

Participants60 participants with ESRD

InterventionsCromoly sodium cream 4% versus placebo

OutcomesPruritus level measured by VAS-scale

Notes

Najafabadi 2012

MethodsRCT

Participants40 participants with end-stage ESRD

InterventionsZinc sulphate (440 mg/d) versus placebo

OutcomesRelief of pruritus measured by a NRS-scale

Notes

 
Characteristics of ongoing studies [ordered by study ID]
NCT00577967

Trial name or titleGabapentin - A Solution to Uremic Pruritus? A Prospective, Randomized, Placebo-controlled, Double-blind Study

MethodsProspective, randomised, placebo-controlled, double-blind study; parallel assignment

Participants80 patients suffering from uraemic pruritus

InterventionsGabapentin

OutcomesSubjective measurement of reduction in pruritus

Starting dateOctober 2005

Contact informationHospital Authority, Hong Kong

Notes

NCT00693654

Trial name or titleA Controlled Comparative Study of the Efficacy of SARNA Sensitive Lotion for Treatment of Uremic Pruritus in Adult Hemodialysis Patients

MethodsRandomised, controlled, double-blind study, parallel assignment

Participants30 adult haemodialysis patients

InterventionsDrug 1: SARNA sensitive lotion against pruritus; Drug 2:cetaphil

OutcomesInvestigator assessment of pruritus score and response to treatment using an itch questionnaire

Starting dateNovember 2006

Contact informationAlan Fleischer, MD, Wake Forest University Health Sciences

Notes

NCT00756171

Trial name or titleColesevelam Versus Placebo in Cholestatic Pruritus (COPE)

MethodsRandomised, placebo-controlled multicentre trial, parallel assignment

Participants38 patients with pruritus due to chronic cholestatic liver disease

InterventionsColesevelam versus placebo

Outcomes40% reduction of pruritus according to visual analogue scores

Starting dateSeptember 2008

Contact informationFoundation for Liver Research, Netherlands

Notes

NCT00793156

Trial name or titleA Randomized-Withdrawal Phase 3 Study Evaluation the Safety and Efficacy of Oral Nalfurafine HCl (AC-820)in Subjects on Hemodialysis With Uremic Pruritus (Renal Itch)

MethodsMulticentre, double-blind, placebo controlled, randomised withdrawal study, cross-over assignment

Participants350 patients with moderate to severe itching associated with end-stage renal disease and haemodialysis

InterventionsDrug: Nalfurafine HCl 2.5 µg;   Drug: Nalfurafine HCl 5.0 µg;   Other: Placebo

OutcomesPrimary efficacy endpoint is the change in worst itching intensity from baseline, compared to that in the last two weeks of the double blind, placebo controlled, randomised withdrawal period. Safety/Efficacy Study

Starting dateDecember 2009

Contact informationAcologix, Inc.

Notes

NCT01114672

Trial name or titleA Study of Oral Ergocalciferol to Treat Pruritis in Hemodialysis Patients (CRN11)

MethodsRandomized prospective, Double-Blind Placebo Controlled Study

Participants50 haemodialysis patients

InterventionsDrug: 50,000 Units Ergocalciferol;   Drug: Placebo

OutcomesChange in severity of pruritus on the basis of surveys with questions about the degree and location of the patients' pruritus

Starting dateJuly 2010

Contact informationMary Schanler, Winthrop University Hospital

Notes

NCT01513161

Trial name or titleEfficacy and Safety Study of TRK-820 to Treat Conventional-treatment-resistant Pruritus in Patients Receiving Hemodialysis

MethodsMulti-center, randomised, double-blind, placebo-controlled, parallel group, fixed dose, phase III clinical trial

Participants104 haemodialysis patients

InterventionsDrug: nalfurafine hydrochloride (TRK-820);   Drug: Placebo

OutcomesChange in pruritus degree measured by VAS(Visual Analogue Scale) score

Starting dateApril 2008

Contact informationSK Chemicals Co.,Ltd.

Notes

 
Comparison 1. Naltrexone versus placebo or standard medication

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pruritus on VAS scale (CKDP/UP and CP)3Mean Difference (Fixed, 95% CI)-2.14 [-2.91, -1.37]

 2 Pruritus on VAS scale (CKDP/UP vs. CP - subgroup analysis by nature of pruritus)3Mean Difference (Fixed, 95% CI)-2.14 [-2.91, -1.37]

    2.1 CKDP/UP
1Mean Difference (Fixed, 95% CI)-1.23 [-2.67, 0.21]

    2.2 CP
2Mean Difference (Fixed, 95% CI)-2.50 [-3.41, -1.59]

 3 Pruritus on VAS scale (subgroup analysis by study design)3Mean Difference (Fixed, 95% CI)-2.14 [-2.91, -1.37]

    3.1 Parrallel group design
1Mean Difference (Fixed, 95% CI)-3.77 [-5.28, -2.25]

    3.2 Crossover design
2Mean Difference (Fixed, 95% CI)-1.58 [-2.47, -0.68]

 4 Pruritus on VAS scale (CKDP/UP and CP) - sensitivity analysis - statistical model3Mean Difference (Random, 95% CI)-2.22 [-3.62, -0.83]

 
Comparison 2. Nalfurafine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pruritus on VAS scale (CKDP/UP)2Std. Mean Difference (Fixed, 95% CI)-0.46 [-0.65, -0.28]

 2 Pruritus on VAS scale (CKDPUP) - sensitivity analysis - statistical model2Std. Mean Difference (Random, 95% CI)-0.46 [-0.64, -0.28]

 
Comparison 3. Ondansetron versus placebo or standard medication

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Ondansetron versus placebo (CKDP/UP and CP) - pruritus on VAS scale3Mean Difference (Fixed, 95% CI)0.16 [-2.38, 2.70]

 2 Ondansetron versus cyproheptadine (CKDP/UP) - pruritus on scale by Duo/Mettang1Std. Mean Difference (Fixed, 95% CI)1.01 [0.07, 1.96]

 3 Pruritus on VAS scale - subgroup analysis by nature of pruritus (CKDP/UP)2Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Pruritus on VAS scale - subgroup analysis by nature of pruritus (CP)1Mean Difference (Fixed, 95% CI)0.16 [-2.38, 2.70]

 5 Ondansetron (CP and CKDP/UP; different scales)2Std. Mean Difference (Fixed, 95% CI)0.51 [-0.14, 1.16]

    5.1 Ondansetron versus cyproheptadine (CKDP/UP)
1Std. Mean Difference (Fixed, 95% CI)1.01 [0.07, 1.96]

    5.2 Ondansetron versus placebo (CCP)
1Std. Mean Difference (Fixed, 95% CI)0.05 [-0.85, 0.96]

 6 Pruritus on VAS scale (CKDP/UP and CP) - sensitivity analysis - statistical model3Mean Difference (Random, 95% CI)0.16 [-2.38, 2.70]

 7 Pruritus on different scales (CKDP/UP and CP) - sensitivity analysis - statistical model2Std. Mean Difference (Random, 95% CI)0.52 [-0.42, 1.46]

    7.1 Ondansetron versus cyproheptadine (CKDP/UP)
1Std. Mean Difference (Random, 95% CI)1.01 [0.07, 1.96]

    7.2 Ondansetron versus placebo (CP)
1Std. Mean Difference (Random, 95% CI)0.05 [-0.85, 0.96]

 
Comparison 4. Gabapentin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Gabapenten versus placebo (CKDP/UP)2Mean Difference (Fixed, 95% CI)-5.2 [-6.70, -3.70]

 2 Gabapentin versus placebo (CKDP/UP) - sensitivity analysis - statistical model2Mean Difference (Random, 95% CI)-5.2 [-6.70, -3.70]

 
Comparison 5. Rifampin or rifampicin versus placebo or standard medication

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Rifampin/Rifampicin versus placebo/standard medication3Std. Mean Difference (Fixed, 95% CI)-3.05 [-3.34, -2.76]

 2 Rifampin/Rifampicin versus placebo/standard medication3Std. Mean Difference (Fixed, 95% CI)-1.96 [-2.72, -1.20]

    2.1 Rifampin/Rifampicin verus placebo/standard medication (study design parallel group)
1Std. Mean Difference (Fixed, 95% CI)-3.24 [-5.00, -1.48]

    2.2 Rifampin/Rifampicin verus placebo/standard medication (study design crossover)
2Std. Mean Difference (Fixed, 95% CI)-1.67 [-2.51, -0.82]

 3 Rifampin versus placebo/standard medication - sensitivity analysis - statistical model3Std. Mean Difference (Random, 95% CI)-2.28 [-3.55, -1.02]

 
Comparison 6. Topical capsaicin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Capsaicin versus placebo1Std. Mean Difference (Fixed, 95% CI)Totals not selected

 2 Capsaicin versus placebo - sensitivity analysis - statistical model1Std. Mean Difference (Random, 95% CI)Totals not selected

 
Comparison 7. Secondary outcomes: Patient satisfaction

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Patient satisfaction (Paroxetine versus placebo)1Mean Difference (Fixed, 95% CI)Totals not selected

 2 Patient satisfaction (paroxetine versus placebo) - sensitivity analysis - statistical model1Mean Difference (Random, 95% CI)0.41 [-0.30, 1.12]

 
Summary of findings for the main comparison.

Naltrexone compared with placebo for CKD-associated or cholestatic pruritus

Patient or population: participants with CKD-associated or cholestatic pruritus

Settings: inpatients and outpatients

Intervention: naltrexone

Comparison: placebo

Participants, interventions, comparatorsParticipants

(Studies)
Quality of the evidence
(GRADE)
ComparatorIntervention versus placebo

Effect estimate

Mean difference

(95% Confidence interval)

Naltrexone versus placebo

(pruritus in participants with CKDP/UP and CP)*
59
(3)
⊕⊕⊕⊝
moderate
Pruritus on VAS scale-2.14 [-2.91, -1.37]

Naltrexone versus placebo

(pruritus in participants with CKDP/UP)
23

(1)
⊕⊕⊕⊝
moderate
Pruritus on VAS scale-1.23 [-2.67, 0.21]

Naltrexone versus placebo

(pruritus in participants with CP)
16

(2)
⊕⊕⊕⊝
moderate
Pruritus on VAS scale-2.50 [-3.41, -1.59]

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.

 * CKDP/UP=chronic kidney disease-associated or uraemic pruritus, CP=cholestatic pruritus
 
Summary of findings 2.

Nalfurafine compared with placebo for CKD-associated pruritus

Patient or population: participants with CKD-associated pruritus

Settings: inpatient and outpatient

Intervention: nalfurafine

Comparison: placebo

Participants, interventions, comparatorsParticipants

(Studies)
Quality of the evidence
(GRADE)
ComparatorIntervention versus placebo

Effect estimate

Std. mean difference

(95% Confidence interval)

Nalfurafine versus placebo

(pruritus in participants with CKDP/UP)
422
(3)
⊕⊕⊕⊝
moderate
Pruritus on VAS scale-0.46 [-0.65, -0.28]

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.

 
Summary of findings 3.

Ondansetron compared with placebo or standard medication for CKD-associated or cholestatic pruritus

Patient or population: participants with CKD-associated or cholestatic pruritus

Settings: inpatient and outpatient

Intervention: ondansetron

Comparison: placebo or standard medication

Participants, interventions, comparatorsParticipants

(Studies)
Quality of the evidence
(GRADE)
ComparatorIntervention versus placebo

Effect estimate

Mean difference/SMD

(95% Confidence interval)

Ondansetron versus placebo

(pruritus in participants with CKDP/UP and CP)
79
(4)
⊕⊕⊕⊝
moderate
Pruritus on VAS scale0.16 [-2.38, 2.70]

Ondansetron versus placebo

(pruritus in participants with CKDP/UP)
40

(2)
⊕⊕⊕⊝
moderate
Pruritus on VAS scaleEffect not estimable

Ondansetron versus cyproheptadine

(pruritus in participants with CKDP)
20

(1)
⊕⊕⊕⊝
moderate
Pruritus on scale by

Duo/Mettang

(Duo 1987; Mettang 1990)
1.01 [0.07, 1.96] (SMD)

Ondansetron versus placebo

(pruritus in participants with CP)
19

(1)
⊕⊕⊕⊝
moderate
Pruritus on VAS scale0.16 [-2.38, 2.70]

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.

 
Summary of findings 4.

Gabapentin compared with placebo for CKD-associated pruritus

Patient or population: participants with CKD-associated pruritus

Settings: inpatient and outpatient

Intervention: gabapentin

Comparison: placebo

Participants, interventions, comparatorsParticipants

(Studies)
Quality of the evidence
(GRADE)
ComparatorIntervention versus placebo

Effect estimate

Mean difference

(95% Confidence interval)

Gabapenten versus placebo

(pruritus in participants with CKDP/UP)
59
(2)
⊕⊕⊕⊝
moderate
Pruritus on VAS scale-5.20 [-6.70, -3.70]

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.

 
Summary of findings 5.

Rifampin/rifampicin compared with placebo or standard medication for cholestatic pruritus

Patient or population: participants with cholestatic pruritus

Settings: outpatient

Intervention: rifampin or rifampicin

Comparison: placebo or phenobarbitone

Participants, interventions, comparatorsParticipants

(Studies)
Quality of the evidence
(GRADE)
ComparatorIntervention versus placebo

Effect estimate

Std. mean difference

(95% Confidence interval)

Rifampin/rifampicin versus placebo

(pruritus in participants with CKDP/UP)
45
(3 )
⊕⊕⊕⊝
moderate
Pruritus on different scales-3.05 [-3.34, -2.76]

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.

 
Summary of findings 6.

Capsaicin compared with placebo for CKD-associated pruritus

Patient or population: participants with CKD-associated pruritus

Settings: inpatients and outpatients

Intervention: topical capsaicin

Comparison: placebo

Participants, interventions, comparatorsParticipants

(Studies)
Quality of the evidence
(GRADE)
ComparatorIntervention versus placebo

Effect estimate

Std. mean difference

(95% Confidence interval)

Capsaicin versus placebo

(pruritus in Participnats with CKDP/UP)
34

(1)
⊕⊕⊕⊝
moderate
Pruritus on scale by Duo

(Duo 1987)
-0.80 [-1.34, -0.25]

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.

 
Summary of findings 7.

Patient satisfaction

Patient or population: palliative care patients with advanced diseases

Settings: inpatient

Intervention: paroxetine

Comparison: placebo

Participants, interventions, comparatorsParticipants

(Studies)
Quality of the evidence
(GRADE)
ComparatorIntervention versus placebo

Effect estimate

Mean difference

(95% Confidence interval)

Paroxetine versus placebo

(patient satisfaction in palliative care patients)
26

(1)
⊕⊕⊕⊝
moderate
Patient satisfaction measured on a 7-point scale0.41 [-0.30, 1.12]

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.

 
Table 1. Measurement of pruritus

Study Pruritus scaleDetermination of Score, SDDescription of scaleDescription of partial resolution





Ashmore 20000 - 10 cm VASMedian daily pruritus score0No pruritusNot available

10Maximal pruritus

Bachs 19890 - 3 scorePuritus assessment 7 days before, and daily during, treatment0No itchingNot available

1Mild intermittent pruritus which did not affect the patient's routine or disturb sleep pattern

2Moderate pruritus present most of the time but tolerable and not interfering with sleep pattern

3Continuous pruritus disturbing sleep pattern

Bergasa 20060 - 10 cm VASMean difference of VASNot statedNot available

Borgeat 19930 - 10 cm verbal rating scoreEvaluation ten minutes after administration and then every ten minutes during the first hour0No pruritusDecrease of at least 4 points

10Most severe pruritus imaginable

Breneman 1992b4-point scaleFollow-up evaluations at weeks 1, 2, 3, 4 and 61No itchingNot available

2Mild itching, occasionally noticeable

3Moderate itching, not interfering with daily life and/or sleep

4Severe itching, disturbing daily life and/or sleep

Cho 19974-point scaleMean values1NoneNot available

2Mild

3Moderate

4Severe

De Marchi 1992Scoring system proposed by Duo and modified by Mettang (Duo 1987; Mettang 1990)Mean daily pruritus scoreScoring of severity:Not available

1Pruritus without the need to scratch

2Pruritus with the need to scratch but without excoriations

3Pruritus that was unrelieved by scratching

4Pruritus accompanied by excoriations

5Total restlessness

Scoring of distribution:

1Pruritus at a single location

2Scattered pruritus

3Generalized pruritus

Scoring of frequency:  
each four short episodes (<10 min) or one long episode (>10 min) received 1 point, max. 5 points

Scoring sleep disturbance:       
each episode of awaking due to pruritus received 2 points, max. 14 points        

The highest possible score for a 24-h period: 40 (with 35% of the points attributed to the nighttime period)





Duncan 19840 - 3 scoreMean cumulative pruritus score0No pruritusNot available

1Mild

2Moderate

3Severe

Duque 20050 - 10 cm VASVAS was measured every visit for the intensity of itch in the last 24 hours0No itchNot available

10Very strong itch

Ghent 19880 - 100 mm VASSummed 7-day pruritus score on mean VAS0NonePreference of rifampin

100Severe

Gunal 20040 - 10 cm VASMeasurement once a day0No itchNot available

10Worst possible imaginable itch

Kuiper 20100 - 10 cm VASMorning and evening VAS0No pruritus40% reduction in pruritus visual analogue scale

10Severe pruritus

Kumagai 20100 - 100 mm VASMean VAS (morning and evening) were calculated for the last 7 days of the pre-observation period, the first and latter 7 days of the treatment period and the 8-day post-observation period0No itchChange from mean VAS of the last 7 days of the pre-observation period and the mean VAS value of the latter 7 days of the treatment period

100Strongest possible itch

Legroux-Crespel 20040 - 10 cm VASDaily VAS scores0Not pruritus or sleep disordersNot available

10Maximum intense of these disorders

Makhlough 2010Detailed pruritus score introduced by Duo (Duo 1987)Mean scores ± standard deviationScoring of severity:Not available

1Itching sensation without necessity of scratching

2Itching that necessitates scratching, but without excoriations

4Itching that necessitates scratching accompanied by excoriation

5Pruritus causing total restlessness

Scoring of distribution:

1Pruritus in 2 areas of the body or less

2Pruritus in more than 2 areas of the body

3Generalized pruritus

Scoring sleep disturbance        

Every waking up due to pruritus received 2 points (max. 10 points) and every scratching due to pruritus received 1 point (max. 5 points)    





Mayo 20070 - 10 cm VASDaily VAS scores were averaged0No pruritusImprovement defined as a 20% reduction

10Worst pruritus imaginable

Murphy 20030 - 10 cm VASComposite mean VAS score0No itchNot available

10Maximum itch

Naini 20070 - 10 cm VASMean pruritus score0No itchNot available

10Worst possible itch

Nasrollahi 2007Detailed pruritus score introduced by Duo (Duo 1987)Not  statedThe scores for sleep disturbances and intensity, area of pruritus were added and the final score at the beginning and at the end of the study were calculated (maximum score: 45)   Not available





O'Donohue 20050 - 10 cm VAS;

additional measurement  of scratching activity by piezo-electric vibration transducer
Mean pruritus score0No pruritus> 50% reduction

10Worst imaginable pruritus

Pauli-Magnus 20000 - 10 cm VASDecrease of pruritus in percent of initial pruritus0No pruritusNot available

10Unbearable pruritus

Pederson 1980Questionnaire as suggested by Lowrie and Ingham (Lowrie 1975)Not stated1I never itchNot available

2I itch rarely but never complain

3I itch occasionally with mild annoyance

4I itch often; it may be severe but I can be active or rest easily

5I itch often; it may be severe and interferes with rest but not activity

6I itch always; it is severe and interferes both with rest and activity

Statements were arranged in nine paired response alternatives, allowing the ranking of the itching as a severity continuum on a scale of one (no itching) to 10 (severe constant itching) 





Peer 19960 - 10 cm VASMean daily scores0No pruritusNot available

10Maximum intensity of pruritus

Podesta 1991a

 
0 - 100 cm VASMean pruritus score100Pruritus that interfered with sleep, altered daily activities, or resulted in self-inflicted skin-breakdownFull response to treatment was defined as the complete lack of pruritus and a partial response as a 50% reduction in the pruritus score

Pour-Reza-Gholi 2007Not  statedNot statedResponse to treatment was recorded as: complete improvement (no more itching) relative improvement (reduction of the symptom) no effect (symptom remained unchanged or worsened)   Not available





Silva 19940 - 3 scoreDepicted as a percent of maximum score0AbsentReduction of  at least 50%

1Pruritus at rest or during usual tasks but not interfering with its accomplishment

2Pruritus perturbing but not interrupting performance of regular tasks

3Pruritus causing interruption of tasks or sleep

Silverberg 19770 - 3 scoreMean of all daily scores0NoneNot available

1Slight

2Moderate

3Great

Smith 19971-4 scoreNot stated1Periodic at night onlyNot available

2Periodic during the day and night

3Periodic during the day, but interferes with sleep at night

4Interferes with daily activities as well as sleep at night

0-4 ScoreNot statedOverall changes in pruritus after 4-6 weeks of therapy were graded as follows:Not available

0Increased pruritus

1No decrease

2Slight but definite decrease in pruritus

3Moderate decrease in pruritus

4Complete resolution of pruritus

Tarng 19964-point scaleMean values1No itchingNot available

2Mild itching, occasionally noticeable

3Moderate itching, not interfering with daily life and/or sleep

4Severe itching, disturbing daily life and/or sleep

Terg 20020 - 10 cm VASMean values0Absence of pruritusNot available

10Were pruritus that interfered with sleep, altered daily activities or resulted in self-inflicted skin breakdown

Turner 1994a

Turner 1994b
0 - 100 mm VASMean VAS scores for the last 7 days0No itchNot available

100Severe

Vessal 20100 - 10 cm VASMean scores at different time points0Absence of pruritusNot available

10Greatest severity of symptoms

Villamil 20050 - 100 mm VASMean VAS scores for the 7 days0Absence of pruritusNot available

100Unbearable intensity

Wikström 2005a

Wikström 2005b
0 - 100 mm VAS Mean worst itching VAS from run-in to the end of week 4 (study 1) and week 2 (study 2)0No itchingNot available

100Worst itching ever

Wolfhagen 19970 - 100 mm VASMean daytime/nighttime scores0No itching50% reduction in the pruritus score

100Unbearable itching

Young 20090 - 10 cm VAS[1-(mean VAS at the end of the study)/(mean VAS at baseline)*100]Itch intensity after a mosquito biteNot available

Individual itch on its best intensity

Individual itch on its worst intensity





Zylicz 20030 -10 NASMean value of 7 days0No symptomsNot available

10Worst possible symptoms

Özaykan 2001Scoring system proposed by Duo and  modified by Mettang (Duo 1987; Mettang 1990)Mean scores at different time points0-48Period: 0 - 3Not available

Intesity: 0-10

Allocation: 0 - 10

Frequency: 0 - 10

Sleeping-time: 0 - 10

Wake-up time: 0 - 5

 
Table 2. Study interventions and numbers attached to intervention

       Substance and participantsDoseNo. of participants includedAuthorsTotal number of participants





Paroxetine: 26 participants

 

Palliative Care patients

 
Paroxetine20 mg/d26Zylicz 200326

Hydroxyzine / Pentoxifylline / Indomethacin / Triamcinolone: 10 participants per intervention

HIV-1 disease patients

 
Hydroxyzine-HCl with or without doxepin-HCl at night25 mg 3x/d // 25mg q.h.s.10Smith 199740

Pentoxifylline400 mg  3x/d10

Indomethacin25 mg 3x/d10

Triamcinolone0.025% lotion120 ml/week10

Naltrexone: 100 participants

CKD/UPNaltrexone50 mg/d15Peer 1996126

CKD/UPNaltrexone50 mg/d23Pauli-Magnus 2000

CKD/UPNaltrexone vs. Loratadine50mg/day

50mg/day
26

26
Legroux-Crespel 2004

CPNaltrexone50mg/day16Wolfhagen 1997

CPNaltrexone50mg/day20Terg 2002

Nalfurafine: 450 participants

CKD/UPNalfurafine5 µg 3x/week i.v.79Wikström 2005a450

CKD/UPNalfurafine5 µg 3x/week i.v.34Wikström 2005b

CKD/UPNalfurafine2.5µg/d or 5 µg/d337Kumagai 2010

Ondansetron: 72 participants

CKD/UPOndansetron8 mg 3x/d24Murphy 200372

CKD/UPOndansetron8 mg 3x/d19Ashmore 2000

CPOndansetron8mg 2x/d, 5 days19O'Donohue 2005

CPOndansetron/Cyproheptadine8mg /d, 30 days10/10Özaykan 2001

Sertraline: 12 participants

CPSertraline25 – 100 mg/d12Mayo 200712

Gabapentin: 75 participants

.

CKD/UP
Gabapentin300 mg 3x/week25Gunal 200475

.

CKD/UP
Gabapentin400 mg 2x/week34Naini 2007

CPGabapentin300 mg - 2400 mg/d16Bergasa 2006

Rifampin/Rifampicin: 23/22 participants

CPRifampin300 mg 2x/d14Podesta 1991a55

CPRifampin150 mg 2x/d  - 150 mg 3x/d  9Ghent 1988

CPRifampicin10 mg/kg/d22Bachs 1989

Phenobarbitone3 mg/kg/d

Doxepin: 24 participants

CKD/UPDoxepin10 mg 2x/d24Pour-Reza-Gholi 200724

Cholestyramine: 18 participants

CKD/UPCholestyramine5 g 2x/d10Silverberg 1977

CPCholestyramine4 g/day8 for 2 wks eachDuncan 198418

Terfenadine60 mg- 180 mg/d

Chlorpheniramine4 mg – 12 mg/d

Colesevelam: 38 participants

CPColesevelam1875 mg 2x/d38Kuiper 201038

Thalidomide: 29 participants

CKD/UPThalidomide100 mg/day29Silva 199429

Montelukast: 16 participants

CKD/UPMontelukast10 mg/d16Nasrollahi 200716

Flumecinol: 69 participants

CPFlumecinol low dose600 mg 1x/week50Turner 1994a69

CPFlumecinol high dose300 mg/day19Turner 1994b

Erythropoietin: 20 participants

CKD/UPErythropoietin36 units/kg body weight 3x/week i.v.20De Marchi 199220

Cromolyn Sodium: 62

CKD/UPCromoly Sodium135 mg 3x/d62Vessal 201062

Activated oral charcoal: 11 participants

CKD/UPActivated oral charcoal6 g/d20Pederson 198011

Propofol: 10 participants

CPPropofol15 mg(1.5ml)/d i.v.10Borgeat 199310

Lidocain: 18 participants

CPLidocain100 mg/d i.v.18Villamil 200518

Capsaicin: 105 participants

CKD/UPCapsaicin0.03% ointment 4x/d34Makhlough 2010105

CKD/UPCapsaicin0.025% cream 4x/d19Tarng 1996

CKD/UPCapsaicin0.025% cream 4x/d45Cho 1997

CKD/UPCapsaicin0.025% cream 4x/d7Breneman 1992b

Tacrolimus: 22 participants

CKD/UPTacrolimus0.1% ointment 2x/d22Duque 200522

Pramoxin-HCl: 28 participants

CKD/UPPramoxin-HCl1% lotion 2x/d28Young 2009

 
Table 3. Secondary outcomes

Quality of lifeMethod/scaleResults

Kuiper 2010Quality-of-life scores:

Short Form 36 and Liver Disease Symptom Index 2.0
No statistically significant changes were found. Both treatment groups were comparable before and after treatment:

Short Form 36 questionnaire in the colesevelam group before and after treatment physical functioning (P = 0.67), role physical functioning (P = 0.50), bodily pain (P = 1.00), general health (P = 0.48), vitality (P = 0.90), social functioning (P = 0.37), emotional functioning (P = 0.17), and mental health (P = 0.26).

Turner 1994aVAS:

0 = able to cope with normal activities

100 = completely incapacitated
Median improvement in quality of life assessment between flumecinol and placebo was 5.0 mm (95% CI 0.4 to 13.0, P = 0.02), in favor of flumecinol.

At entry: active=26, placebo=11

At completion: active=21, placebo=7

Median fall: active=3.5, placebo=0.1

Turner 1994bVAS:

0 = able to cope with normal activities

100 = completely incapacitated
Quality of life was not significantly improved by the higher dose of flumecinol with the difference in median improvement between the two groups being 3.5 mm (95% CI - 5.9 to 24.9 mm):

At entry: active=32, placebo=42

At completion: active=19, placebo=44

Median fall: active=4.4, placebo=3.0

Patient SatisfactionMethod/scaleResults

Zylicz 20037 point scale, where “0” means indifferent, a negative value of “-3” extremely poor, and a positive value “+3” excellentOn average, patients treated with paroxetine had higher satisfaction scores (mean = 0.41 [SE = 0.36]) as compared to patients who received placebo (mean = 0.66 [SE = 0.36]).

Treatment effect:

Placebo:  mean ±SE = -0.66±0.36

Paroxetine: mean ±SE = 0.41±0.36

Mean difference (95% CI): -1.08 (-0.19 to 1.96); P = 0.027

Period effect:

Placebo:  mean ±SE = -0.09±0.36

Paroxetine: mean ±SE = -0.16±0.36

Mean difference (95% CI): 0.08 (-0.81 to 0.96); P = 0.967

DepressionMethod/scaleResults

Bergasa 20061. Hamilton depression rating scale:  includes items intrinsic to medical conditions (i.e. fatigue, sleep) and concern about health

2. Structured Clinical Interview Questionnaire (SCID) for DSM IV, Axis I Disorders:  interview

measure for the diagnosis of depression and anxiety syndromes.
Data on the full psychiatric evaluation were available for 13 participants.

Hamilton scale: 8 participants with mild depression, 3 moderate depression, 2 no to minimal depression

When items relating to medical conditions were omitted: 7 participants mild depression, no moderate depression, and 6 no to minimal depression

SCID: 1 major depressive disorder with atypical features. The remainder of the participants were diagnosed with a mood disorder because of a general medical condition, 8 with depressive features and 4 with major depression-like episodes. The results of the psychiatric evaluations suggested that liver disease and pruritus might have contributed to the depressive symptomatology of the participant.

Mayo 200730-item Inventory of Depressive Symptomatology-Self-report (IDS-SR30)All 4 participants with moderate or severe depression improved with sertraline. One of these subjects also improved with placebo. Subjects with mild depressive symptoms did not reliably improve their IDS-SR30 score with sertraline. Two of 9 participants improved on open-label sertraline, but no subject in the crossover study with mild depressive symptoms improved. In order to determine how much of the improvement in pruritus may have been related to improvement in depressive symptoms, an analysis of covariance was performed on the serial IDS-SR30 and VAS scores obtained in the open-label dose titration. The improvement in VAS after adjusting for IDS-SR30 was still highly significant (P = 0.0002). The IDS-SR30 effect was also significant (P = 0.0011). Thus, both VAS and IDSSR30 improved with increasing doses of sertraline, but the change in IDS-SR30 did not explain all of the change in VAS.

Baseline: none (8), mild (9), moderate (2), severe (2)

Post-Sertraline: none (10), mild (2), moderate (0), severe (0)

Post-Placebo: none (7), mild (4), moderate (1), severe (0)

 
Table 4. Adverse effects according to the different studies

StudyDesignPruritus/DiseaseInterventionDosePatientsAdverse events

Paroxetine

 Zylicz 2003Randomised, double-blind, placebo-controlled

crossover study
Pruritus in palliative care patients (var.)Paroxetine

vs. placebo
20 mg/d26Paroxetine:

Major: severe nausea and vomiting

(leading to withdrawal: 2)

Minor: sleepiness

 

Hydroxyne/Pentoxyfilline/IndomethacinTriamcinolone

Smith 1997Randomised comparative trialPruritus in patients with HIV-1 disease

 
Hydroxyzine-HCl with/without doxepin-HCl25 mg 3x/d

// 25 mg q.h.s.
10Major: tiredness, drowsiness, sleepiness (2)

Minor: tiredness, drowsiness, sleepiness (6); dry mouth or eyes (5), headache (1)

Pentoxifylline400 mg  3x/d10Minor: headache (2)

Indomethacin25 mg 3x/d10Minor: abdominal pain (2), headache (1), indigestion (4); major: abdominal pain (1)

Triamcinolone0.025% lotion10Minor: nausea (1)

Naltrexone

Peer 1996Randomised, double-blind, placebo-controlled crossover studyCKD/UPNaltrexone

vs. placebo
50 mg/d15Naltrexone:

Minor: minor heart burn (2), upper abdominal discomfort (3)

Placebo: adverse events not given

Pauli-Magnus 2000Randomised, double-blind, placebo-controlled crossover studyCKD/UPNaltrexone50 mg/d23Naltrexone:

Major: gastrointestinal side effects (leading to withdrawal: 3

Minor: gastrointestinal side effects (6)

Placebo:

Major: gastrointestinal side effects (leading to withdrawal) (1)

Legroux-Crespel 2004Randomised, comparative trialCKD/UPNaltrexone

vs. Loratadine
50 mg/d

50 mg/d
52Naltrexone

(30 events in 15 patients):

Major: vertigo (4) , nausea (9) , malaise (1)) , cramps (2), sleeping disturbances (1), anorexia (1)

Minor:  vomiting (2), abdominal distention (1), sleep disturbances (4), vertigo (1), headaches (2),

somnolence (1), paraesthesia (1)

Loratadine:

(3 events in 2 patients):

Major: vomiting (1), malaise (1)

Minor: vomiting (1)

Withdrawals:

Naltrexone: 12 participants  (4 due to vertigo, 3 due to nausea, 1 due to malaise, 2 for cramps, 1 due to sleeping disturbances and 1 due to anorexia)

Loratadine: 3 participants (1 due to vomiting, 1 due to malaise, 1 without relation with loratadine)

Wolfhagen 1997Randomised, double-blind, placebo-controlled studyCPNaltrexone50 mg/d16Naltrexone: nausea (4), dizziness (3), flushing (2), drowsiness (2), headache (1), nightmares (1), tremor (1), abdominal cramps (5), dry mouth (2), peripheral edema (1), night-sweating (1)

Placebo: abdominal cramps (1), dry mouth (1), irritability (1), epistaxis (1), swelling of the hands (1)

Terg 2002Randomised, double-blind, placebo-controlled crossover studyCPNaltrexone50 mg/d20Naltrexone: dizziness (10), nausea (8), vomit (6), headache (5), abdominal cramps (5), asthenia (3), drowsiness (3), irritability (3), dry mouth (3), insomnia (2), tremor (1), tachycardia (1), anorexia (1), flushing (1), arterial hypertension (1)

Placebo: nausea (1), vomit (2), headache (3), abdominal cramps (1), drowsiness (2), irritability (2)

Ondansetron

Ashmore 2000Randomised, double-blind, placebo-controlled crossover studyCKD/UPOndansetron8 mg 3x/d16Not given

Özaykan 2001Randomised, comparative, controlled trialCKD/UPOndansetron

vs. Cyproheptadine
8 mg/d

8 mg/d
10

10
None observed

Murphy 2003Randomised, placebo-controlled double-blind crossover studyCKD/UPOndansetron8 mg 3x/d24Ondansetron:

Major (leading to withdrawal): constipation (1)

Placebo: none given

O'Donohue 2005Randomised, double-blind, placebo-controlled studyCPOndansetron8 mg 2x/d19Ondansetron:

Minor: moderate increases from baseline in serum alkaline phosphatase and bilirubin levels (1), constipation (4)

Placebo:

Minor: nausea (3), headache (2)

Nalfurafine

Wikström 2005aMeta-analysis of 2 randomised, double-blind, placebo-controlled studiesCKD/UPNalfurafine5 µg 3x/wk i.v.79Nalfurafine:

(17 of 26 patients): headache (3), nausea (3), insomnia (2), vertigo (2), vomiting (2), severe headache (1), severe insomnia (1);

Leading to withdrawal: moderate nausea and vomiting (1)

Placebo:

(13 of 25 patients had adverse drug reactions):

no description

Serious adverse event (SAE):

2 (8%) patients in the nalfurafine 5 µg group and 6 (24%) patients in the placebo group reported at least one SAE, but none were considered to be drug related

Wikström 2005bMeta-analysis of 2 RCTsCKD/UPNalfurafine5 µg 3x/wk i.v.65 (not clearly stated)Nalfurafine:

(2 of 16 patients):

vertigo (1), elevations of aspartate aminotransferase and alanine transaminase (1)

Placebo:

(2 of 18 patients had adverse drug reactions):

no description

Serious adverse event (SAE):

3 patients in the nalfurafine 5 µg group and 3 patients in the placebo group reported a SAE, but none were considered to be drug related

Kumagai 2010Randomised, double-blind, placebo-controlled studyCKD/UPNalfurafine2.5µg/d or 5 µg/d337Adverse events:

Nalfurafine (5 µg): nasopharyngitis (12.3%), insomnia (14.9%), somnolence (3.5%), constipation (7.9%)

Nalfurafine (2.5 µg): nasopharyngitis (8.0%), insomnia (7.1%), somnolence (4.5%), diarrhoea (4.5%)

Placebo: nasopharyngitis (17.1%), headache (3.6%), vomiting (3.6%)

Adverse drug reactions:

Nalfurafine (5 µg): Incidence 35.1%: insomnia (16), anorexia (1), headache (1), pruritus (1), decreased blood TSH (2), mood altered (1), elevated mood (1), feeling abnormal (1), increases in prolactin (3), decrease in free testosterone (1)

Nalfurafine (2.5 µg): Incidence 25.0%, insomnia (8), sudden hearing loss (1), hypertension (1), vomiting (1), nausea (1), increased eosinophiles (1), increases in prolactin (3), decrease in free testosterone (1)

Placebo: Incidence 16.2%, headache (1), increases in prolactin (1), decrease in free testosterone (1)

Gabapentin

Gunal 2004Randomised, double-blind, placebo-controlled crossover studyCKD/UPGabapentin300 mg 3x/wk25Gabapentin: Minor to moderate:somnolence, fatigue, dizziness (usually occuring after first dose)

Placebo: none given

Bergasa 2006Randomised, double-blind, placebo-controlled studyCPGabapentin300 - 2400 mg/d16Gabapentin:

Minor: fatigue (1), dizziness (1), worsening symptoms of carpal tunnel syndrome (1), dizziness on increasing dose and fluctuating rise in serum creatinine (1);

Major: vomiting (1)

Placebo:

Minor: fatigue and leukopenia (1), symptoms of carpal tunnel syndrome (1)

Naini 2007Randomised, double-blind, placebo-controlled studyCKD/UPGabapentin400 mg 2x/wk34Gabapentin:

Minor: somnolence, dizziness, nausea (subsided)

Major: attacks of dizziness in one patient (subsided gradually)

Placebo: none given

Erythropoietin

De Marchi 1992Randomised, double-blind, placebo-controlled crossover studyCKD/UPErythropoietin36 units/kg body weight 3x/wk i.v.20None given

Montelukast

Nasrollahi 2007Randomised, single-blind, placebo-controlled crossover studyCKD/UPMontelukast10 mg/d16Major (leading to withdrawal):

1 man faced anaemia that was diagnosed as myelodysplastic syndrome during placebo period after receiving montelukast for 20 days; 1 diabetic woman with ischaemic heart disease died during placebo period of myocardial infarction

Doxepin

Pour-Reza-Gholi 2007Randomised, double-blind, placebo-controlled crossover studyCKD/UPDoxepin20 mg/d24Minor: drowsiness (11);

Major (leading to withdrawal): drowsiness (1)

Thalidomide

Silva 1994Randomised, double-blind, placebo-controlled crossover studyCKD/UPThalidomide100 mg/d29None observed

Oral cromolyn sodium

Vessal 2010Randomised, double-blind, vehicle-controlled studyCKD/UPOral cromolyn sodium405 mg/d 62Cromolyn sodium:

Minor: flatulence (1)

Placebo:

Minor: nausea (2), diarrhoea (1), nausea and diarrhoea (3)

Activated oral charcoal

Pederson 1980Randomised, double-blind, placebo-controlled crossover studyCKD/UPActivated oral charcoal6 g/d20None given

Cholestyramine

Silverberg 1977Randomised, double-blind, placebo-controlled studyCKD/UPCholestyramine10 g/d10Cholestyramine:

constipation (1), nausea 10 - 15 min after every dose (1)

Placebo:none given

Duncan 1984Randomised, single-blind, controlled crossover trailCPCholestyramine4 g/d8Diarrhoea and vomiting (4)

Terfenadine60 mg- 180 mg/dEmotional lability (1)

Chlorpheniramine4 mg ? 12 mg/dDrowsiness (2), headache (1)

Placebolactose, 200 mg

1 - 3/d
Nausea and cutaneous burning (1)

Rifampin/Rifampicin

Ghent 1988Randomised double-blind placebo-controlled crossover studyCPRifampin300 mg/d  - 450 mg/d9None observed

Bachs 1989Randomised, placebo-controlled crossover studyCPRifampicin10 mg/kg/d22Hemolytic anaemia and renal failure (1)

Phenobarbitone3 mg/kg/dSkin rash after a few days of treatment (3), sedative effect

Podesta 1991aRandomised double-blind placebo-controlled crossover studyCPRifampin600 mg/d14None observed

Sertraline

Mayo 2007Randomised, double-blind, placebo-controlled

crossover study
CPSertraline25 -

100 mg/d
12Sertraline:

Minor (during dose-escalation trial): increase in bowel frequency (2),

visual hallucinations (2), increase in fatigue (2), insomnia (3), nausea (1);

Major: (during dose-escalation trial): dizziness (1)

beneficial effect of
increased mood stability

Placebo:

Minor: increase in fatigue (1), insomnia (6), nausea (1)

taking no drug (baseline, washout): increase in fatigue (1), insomnia (14), nausea (1)

Flumecinol

Turner 1994aRandomised double blind placebo-controlled study

 
CPFlumecinol low dose600 mg 1x/wk50None observed

Turner 1994bRandomised, double-blind, placebo-controlled studyCPFlumecinol high dose300 mg/d19None observed

Lidocaine

Villamil 2005Randomised double blind placebo-controlled study

 
CPLidocaine100 mg/d i.v.18Lidocaine:

Minor: mild tinnitus associated with lingual paraesthesia during infusion (2) (symptoms subsided 2 to 5 minutes post infusion)

Placebo: none given

Propofol

Borgeat 1993Randomised, double-blind, placebo-controlled crossover studyCPPropofol15 mg/d i.v.10Propofol:

Minor: presence of pain on injection (3), dizziness of 10-20 seconds' duration (2)

Placebo: none observed

Colesevelam

Kuiper 2010Randomised, double-blind, placebo-controlled studyCPColesevelam3750 mg/d35Colesevelam: Minor: 1 (no more than mild stool changes)

Placebo:

Minor: 4 (no more than mild stool changes)

Tacrolimus

Duque 2005Randomised, double-blind, vehicle-controlled studyCKD/UPTacrolimus0.1% ointment 2x/d22Tacrolimus:

At baseline: warm sensations (8)

In week 4:

warm sensations (6), significant burning sensation (1)

Vehicle:

At baseline: warm sensations (2)

In week 4: warm sensations (3)

Capsaicin

Makhlough 2010Randomised double-blind, placebo-controlled crossover studyCKD/UPCapsaicin0.03% ointment 4x/d34Capsaicin:

Minor: skin burning moderate (10) to severe (1)

Placebo: none observed

Tarng 1996Randomised double-blind, placebo-controlled crossover studyCKD/UPCapsaicin0.025% cream 4x/d19Capsaicin:

75% (12 of 16) adverse events occurred during treatment

Placebo:

25% (4 of 16) adverse events occurred on placebo

Adverse events:

93.7% were related to local burning and/or stinging sensations and 6.3% to cutaneous erythema; adverse events were mild, transient and tolerable by the patients

Cho 1997Randomised double-blind, placebo-controlled crossover studyCKD/UPCapsaicin0.025% cream 4x/d22Capsaicin:

Minor: skin burning or stinging sensations (or both) (11), cutaneous erythema (5);

adverse events were mild and tolerable 

Breneman 1992bRandomised, double-blind, placebo-controlled studyCKD/UPCapsaicin0.025% cream 4x/d7Capsaicin:

Minor: mild burning sensation in both arms (1)

Major: mild burning sensation in the capsaicin-treated arm (1)

Placebo: none observed

Pramoxin-HCl

Young 2009Randomised, double-blind, placebo-controlled studyCKD/UPPramoxin-HCl1% lotion 2x/d28None observed

 
Table 5. Adverse Effects according to different interventions

InterventionAdverse effects (intervention)Placebo/standard medicationAdverse effects (control)Withdrawals


Minor adverse effects observedMajor adverse effects observedMinor adverse effects observedMajor adverse effects observed

Paroxetine

(Zylicz 2003)

*No of patients: 26
  • sleepiness
  • nausea and vomiting (2)
Placebo

**No of patients: 26
--Paroxetine: 2

Placebo: -

Naltrexone

(Legroux-Crespel 2004; Pauli-Magnus 2000;Peer 1996; Wolfhagen 1997; Terg 2002)

*No of patients: 92
  • nausea (21)
  • (abdominal) cramps (12)
  • vomiting (8)
  • gastrointestinal side effects (6)
  • upper abdominal discomfort (3)
  • malaise (1)
  • headache (8)
  • somnolence (1)
  • dizziness (13)
  • drowsiness (3)
  • irritability (3)
  • tremor (2)
  • flushing (1)
  • peripheral edema (1)
  • night-sweating (1)
  • nightmares (1)
  • insomnia (2)
  • asthenia (3)
  • dry mouth (5)
  • minor heart burn (2)


  • abdominal distention (1)
  • sleep disturbances (5)
  • vertigos (5)
  • tachycardia (1)
  • paraesthesia (1)
  • anorexia (1)
  • arterial hypertension (1)
  • gastrointestinal side effects (3)
Placebo (Peer 1996; Pauli-Magnus 2000; Wolfhagen 1997; Terg 2002)

**No of patients: 66

Loratadine (Legroux-Crespel 2004)

**No of patients: 26
  • abdominal cramps (2)
  • irritability (3)
  • epistaxis (1)
  • swelling of the hands (1)
  • nausea (1)
  • vomiting (2)
  • headache (3)
  • drowsiness (2)


  • vomiting (2)


  • malaise (1)
  • gastrointestinal side effect (1)
Naltrexone: 12 (uncertain)

Placebo: 1

Ondansetron

(Ashmore 2000; Murphy 2003; O'Donohue 2005;Özaykan 2001)

*No of patients: 59
  • constipation (4)
  • moderate increases from baseline in serum alkaline phosphatase and bilirubin levels (1)
  • constipation (1)
Cyproheptadine

(Özaykan 2001)

**No of patients: 10

Placebo (Ashmore 2000; Murphy 2003; O'Donohue 2005)

**No of patients: 50
-

  • nausea (3)
  • headache (2)
-Ondansetron: 5

Placebo: 3

Nalfurafine

(Kumagai 2010; Wikström 2005a; Wikström 2005b)

*No of patients: 286
  • sleep disturbance (24)
  • headache (1)
  • nausea (4)
  • insomnia (26)
  • vomiting (3)
  • nasopharyngitis (?)
  • vertigo (3)


  • anorexia (1)
  • somnolence (?)
  • diarrhoea
  • constipation (?)
  • pruritus (1)
  • hypertension (1)
  • sudden hearing loss (1)
  • elevations of aspartate aminotransferase and alanine transaminase (1)
  • decreased blood TSH (1)
  • mood altered (1)
  • elevated mood (1)
  • feeling abnormal (1)
  • increases in prolactin (6)
  • decrease in free testosterone (2)
  • increased eosinophiles (1)
  • nausea and vomiting (1)
  • severe headache (1)
  • severe insomnia (1)
Placebo

(Kumagai 2010; Wikström 2005a;

Wikström 2005b)

**No of patients: 170


  • nasopharyngitis
  • vomiting
  • headache (1)
  • increases in prolactin (1)
  • decrease in free testosterone (1)
Nalfurafine: 11

Placebo: 3

Gabapentin

(Bergasa 2006; Gunal 2004; Naini 2007)

*No of patients: 50 (uncertain)
  • somnolence
  • dizziness
  • nausea
  • fatigue worsening symptoms of carpal tunnel syndrome (1)
  • attacks of dizziness (1)


  • vomiting
Placebo

(Bergasa 2006; Gunal 2004; Naini 2007)

**No of patients: 49 (uncertain)
  • fatigue and leukopenia (1)


  • symptoms of carpal tunnel syndrome
Gabapentin: -

Erythropoietin

(De Marchi 1992)

*No of patients: 20
Adverse effects not givenErythropoietin: 1



montelukast

(Nasrollahi 2007)

*No of patients: 16
  • anaemia (1)
Placebo

**No of patients: 16
--Montelukast: 2

Doxepin

(Pour-Reza-Gholi 2007)

*No of patients: 24
  • drowsiness (11)
  • drowsiness (1)
Placebo

**No of patients: 24
--Doxepin: 1

Thalidomide

Silva 1994)

*No of patients: 29
No adverse effects observedThalidomide: 11



Oral cromolyn sodium

(Vessal 2010)

*No of patients: 21
  • flatulence (1)
Placebo

**No of patients: 19
  • nausea (2)
  • diarrhoea (1)
  • nausea and diarrhoea (3)
23 withdrawals***

Activated oral charcoal

(Pederson 1980)

*No of patients: 20
Adverse events not given9 withdrawals***



Cholestyramine

(Duncan 1984; Silverberg 1977)

*No of patients: 13
  • constipation (1)
  • nausea (1)
  • diarrhoea and vomiting (4)
Placebo

(Silverberg 1977; Duncan 1984)

**No of patients: 13

Terfenadine

(Duncan 1984)

**No of patients: 8

Chlorphenirame (Duncan 1984)

**No of patients: 8
  • nausea and cutaneous burning (1)


  • emotional lability (1)


  • drowsiness (2)
  • headache (2)
Cholestyramine: -

Terfenadine: -

Chlorpheniramine: -

Placebo: 1

Rifampin/Rifamopicin

(Bachs 1989; Ghent 1988; Podesta 1991a)

*No of patients: 45
  • haemolytic anaemia and renal failure (1)
  • haemolytic anaemia
  • renal failure
Placebo

(Ghent 1988; Podesta 1991a)

**No of patients: 23

Phenobarbitone

(Bachs 1989)

**No of patients: 22
  • skin rash (3)
  • sedative effect


-
Rifamin/rifampicin: 1

Phenobarbitone: 4

Sertraline

(Mayo 2007)

*No of patients: 12
  • increase in bowel frequency (1)
  • fatigue (2)
  • insomnia (3)
  • visual hallucinations (2)
  • nausea (1)
  • dizziness (1)
Placebo

**No of patients
  • increase in fatigue (1)
  • insomnia (6)
  • nausea (1)
-

Flumecinol

(Turner 1994a; Turner 1994b)

*No of patients: 34
No adverse effects observed-



Lidocaine

(Villamil 2005)

*No of patients: 12
  • mild tinnitus associated with lingual paraesthesia during infusion (2)
Placebo

**No of patients: 6
--2 withdrawals***

Propofol

(Borgeat 1993)

*No of patients: 10
  • dizziness (2)
  • pain during injection (3)
Placebo

**No of patients: 10
--2 withdrawals***

Colesevelam

(Kuiper 2010)

*No of patients: 17
  • mild stool changes (1)
Placebo

**No of patients: 18
  • mild stool changes (4)
3 withdrawals***

Tacrolimus

(Duque 2005)

*No of patients: 12
  • warmth sensations (14)
  • burning sensation (1)
Vehicle

**No of patients: 10
  • warming sensation (5)
Vehicle: 2

Capsaicin

(Breneman 1992b; Cho 1997; Makhlough 2010; Tarng 1996)

*No of patients: 82 (uncertain)
  • skin burning (29)
  • stinging (?)
  • cutaneous erythema (6)
Placebo

**No of patients: 82(?)
--Capsaicin: 5

Pramoxin-HCl

(Young 2009)

*No of patients: 14
No adverse effects observed1 withdrawal***



Hydroxine HCL

(Smith 1997)

*No of patients: 10
  • headache (1)
  • try mouth or eyes (5)
  • tiredness/ drowsiness/sleepiness (6)
  • sleepiness/tiredness/drowsiness (2)
Placebo--Hydroxyzine-HCL: 2

Pentoxifylline

(Smith 1997)

*No of patients: 10
  • headache (2)
Placebo--Pentoxifylline: 1

Indomethacin

(Smith 1997)

*No of patients: 10
  • abdominal pain (2)
  • headache (1)
  • indigestion (4)
  • abdominal pain (1)
Placebo--Indomethacin: 2

Triamcinolone

(Smith 1997)

*No of patients: 10
  • nausea (1)
Placebo--Triamcinolone: 2

 * Total number of patients receiving the verum examined
** Total number of patients receiving placebo or vehicle or standard medication examined; the total numbers are not consistent with the total numbers of patients included in the studies
*** Withdrawals irrespective of adverse effects