Symptom |
Therapy |
RCT |
Dosing |
Patient population |
Duration of treatment |
Outcome |
Reported side effects |
Pruritus |
Cholestyramine |
Di Padova115 |
Cholestyramine (3 mg TID) vs placebo |
10 patients with either intra- or extra- hepatic cholestasis |
4 weeks |
Improvement in itching intensity in cholestyramine group |
No reported major/minor adverse effects |
Colesevelam |
Kuiper116 |
Colesevelam (1875 mg twice daily) vs placebo |
35 patients with cholestatic pruritus (PBC: 14, PSC: 14, Other: 7) |
3 weeks |
No difference in pruritus (VAS), quality of life (SF-36 and LDSI), or itching severity between both groups |
No reported major/minor adverse effects |
Gabapentin |
Bergasa117 |
Gabapentin (300–2400 mg daily) vs placebo |
16 women with chronic liver disease (PBC: 9, PSC: 1, HCV: 6) and chronic pruritus |
4 weeks |
Increased perception of pruritus (VAS) in gabapentin group |
Minor: Pruritus, fatigue, dizziness, worsening symptoms of carpal tunnel syndrome, vomiting |
Rifampin |
Ghent164 |
Rifampin (300–450 mg daily in divided doses) vs placebo |
Nine patients with compensated PBC and chronic pruritus |
4 weeks (randomised crossover: 2 weeks rifampin, 2 weeks placebo with washout period) |
Improved pruritus scores (VAS) during rifampin therapy |
No reported major/minor adverse effects |
Podesta165 |
Rifampin (300 mg twice daily) vs placebo |
14 patients with PBC |
2 weeks (randomised crossover: 1 week rifampin, 1 week placebo with washout period) |
Improved pruritus severity (VAS) during rifampin therapy |
No reported major/minor adverse effects |
Naltrexone |
Wolfhagen119 |
Naltrexone (50 mg daily) vs placebo |
16 patients (PBC: 13, PSC: 2, Other: 1) and chronic pruritus |
4 weeks |
Improved daytime and nighttime itching (VAS) in naltrexone group |
Minor: Opioid withdrawal-like phenomena, nausea, dizziness, flushing, drowsiness, headache, tremors, abdominal cramps |
Terg33 |
Naltrexone (50 mg daily) vs placebo |
20 patients (PBC: 15, PSC 1, Other: 4) |
1–3 months |
Improved pruritus severity (VAS) in naltrexone group |
Sertraline |
Mayo122 |
Sertraline (75–100 mg daily) vs placebo |
12 patients with cholestatic liver disease (PBC: 9, PSC: 2, Other: 1; 4 with MELD >15) and chronic pruritus |
12 weeks (randomised crossover: 6 weeks sertraline, 6 weeks placebo with washout period) |
Improved itch scores (VAS) in sertraline group |
Minor: Dizziness, loose stools |
Bezafibrate |
De Vries123 |
Bezafibrate (400 mg daily) vs placebo |
70 patients with cholestatic liver disease (PSC: 44, PBC 24, Other: 2) with itch intensity of ≥5 on VAS |
3 weeks |
Higher rates of ≥50% reduction of moderate to severe pruritus (VAS) in bezafibrate group |
Minor: Pain in the mouth, lower back pain, general malaise, intensified itch and jaundice after stop of treatment |
Muscle cramps |
Taurine |
Vidot127 |
Taurine (500–1000 mg twice daily) vs placebo |
30 patients (CTP A: 6, CTP B: 20, CTP C: 4, 43% with prior or present HE) experiencing ≥3 cramps/week |
8 weeks (randomised crossover: 4 weeks taurine, 4 weeks placebo) |
Reduced frequency, duration and intensity of muscle cramps (patient self-report, VAS) in taurine group |
No reported major/minor adverse effects |
Branched-chain amino acids (BCAA) |
Hidaka128 |
Daytime BCAA (one sachet after each meal) vs Nocturnal BCAA (one sachet after breakfast and two sachets before bedtime) |
37 patients with cirrhosis and serum albumin 3.1–3.5 g/dl (CTP A: 21, CTP B: 16) |
12 weeks |
Decreased occurrence of muscle cramps (HRQOL survey) in nocturnal group |
Minor: Bloating, itching |
Quinidine |
Lee130 |
Quinidine sulphate (400 mg daily) vs placebo |
31 patients with cirrhosis (CTP A: 23, CTP B: 7, CTP C: 1) and muscle cramps |
4 weeks |
Reduced frequency of cramps (patient self-report) in quinidine group |
Minor: diarrhoea *Not approved for use in the United States due to side effect profile |
Baclofen |
Elfert131 |
Baclofen (10–30 mg total daily dose) vs placebo |
100 patients with cirrhosis (CTP score 5–9) without HE experiencing ≥3 cramps/week |
12 weeks |
Decreased frequency, severity and duration of muscle cramps (patient self-report) in baclofen group |
Minor: Drowsiness, constipation, nausea |
Methocarbamol |
Abd-Elsalam132 |
Methocarbamol (500 mg twice daily) vs placebo |
100 patients with HCV cirrhosis (CTP A: 21, CTP B: 42, CTP C: 37) experiencing ≥3 cramps/week |
4 weeks |
Decreased frequency and duration of muscle cramps (patient self-report) in methocarbamol group |
Minor: Dry mouth, drowsiness |
Orphenadrine |
Abd-Elsalam133 |
Orphenadrine (100 mg twice daily) vs placebo |
124 patients with cirrhosis (CTP A: 61, CTP B: 24, CTP C: 39) experiencing ≥3 cramps/week |
4 weeks |
Decreased frequency and duration (patient self-report) of muscle cramps in orphenadrine group |
Minor: Dry mouth, drowsiness, nausea |
Sexual dysfunction |
Tadalafil |
Jagdish136 |
Tadalafil (10 mg daily) vs placebo |
140 men with cirrhosis (CTP < 10) and erectile dysfunction (erectile function score <25 on IIEF) |
12 weeks |
Improved erectile function (>5-point increase in erectile function score of IIEF) in the tadalafil group |
Minor: Dizziness, congestion, mild headache, bloating, peri-orbital swelling, itching |
Sleep Disturbances |
Melatonin |
De Silva144 |
Melatonin (3 mg nightly) vs placebo |
60 patients with cirrhosis (CTP A or B) with sleep disturbances, without present or prior overt HE |
2 weeks |
Improved sleep quality (PSQI) and daytime sleepiness (ESS) in the melatonin group |
Minor: Abdominal pain, headache, dizziness |
Zolpidem |
Sharma143 |
Zolpidem (5 mg nightly) vs placebo |
52 patients with cirrhosis (CTP A or B) with PSQI >5 without present or prior overt HE |
4 weeks |
Increased total sleep time, sleep efficiency, subjective sleep quality (PSQI) and improvement in parameters of sleep initiation and maintenance (polysomnography) in zolpidem group |
Minor: Excessive daytime sleepiness, constipation, dry mouth |
Hydroxyzine |
Spahr145 |
Hydroxyzine (25 mg nightly) vs placebo |
35 patients with cirrhosis with minimal HE, >3 months of sleep difficulties, and ESS score >10 |
10 days |
Improved sleep behaviour (VAS, wrist actigraphy) in hydroxyzine group |
Major: 1 patient developed acute overt hepatic encephalopathy while receiving hydroxyzine |
Fatigue |
Fluvoxamine |
ter Borg149 |
Fluvoxamine (75 mg twice daily) vs placebo |
33 patients with cholestatic liver disease (PBC: 22, PSC: 11; CTP < 6) with self-reported fatigue |
6 weeks |
No statistically significant beneficial effect of fluvoxamine on fatigue (VAS, FFSS, MFI) or quality of life (SF-36) |
Minor: Headache, nausea, insomnia, dizziness |
Modafinil |
Silveira (2017)150 |
Modafinil (100 mg daily) vs placebo |
33 patients with PBC receiving UDCA >6 months before study enrolment. Excluded: MELD >15, recurrent variceal bleeding, diuretic-refractory ascites or spontaneous HE |
12 weeks |
No significant improvement in fatigue severity (≥50% improvement in FFSS) in modafinil compared to placebo |
Minor: Headaches, diarrhoea, rash |