Natural history of pruritus in primary biliary cirrhosis.

The natural history of pruritus in primary biliary cirrhosis (PBC) remains poorly defined. The aim of this investigation was to evaluate outcomes of pruritus in clinical trials for ursodeoxycholic acid (UDCA). In a UDCA-placebo trial begun in 1988 (n = 180), a 55% prevalence rate for pruritus was observed. Serum alkaline phosphatase level and Mayo risk score were independent risk factors for pruritus (P < 0.0001). Among placebo-treated patients (n = 91), the annual risks for development or improvement/resolution of pruritus were 27% and 23%, respectively. For UDCA-treated patients (n = 89), a trend toward improvement in pruritus was observed after 1 year compared to placebo (30% vs. 23%, P = 0.08) but not at 2 or 3 years. In a 3-dose UDCA trial begun in 1995 (n = 155), the overall prevalence of pruritus was significantly lower at 37% when compared to UDCA-placebo participants (P < 0.001). Baseline serum alkaline phosphatase level and Mayo risk score were again independent risk factors for pruritus (P < 0.0001). Among 13 (3.9%) patients with refractory pruritus, symptom resolution (n = 5) or improvement (n = 8) was associated with the use of oral rifampin (300 or 600 mg daily). Two patients treated with rifampin developed biochemical evidence for hepatotoxicity necessitating drug withdrawal. Although less prevalent among recently diagnosed individuals, more than one third of PBC patients develop pruritus. No significant risk reduction in developing pruritus with UDCA therapy was observed compared to placebo-treated patients. The long-term administration of rifampin for refractory pruritus is associated with occasional hepatotoxicity.     

Treatment of pruritus of primary biliary cirrhosis with rifampin

Pruritus can be a debilitating symptom in patients with chronic cholestasis. Based on previous reports of its efficacy, we evaluated the impact of rifampin on the pruritus associated with primary biliary cirrhosis. Fourteen patients were included in a randomized, crossover study. After a 15-day washout period, subjects were followed for three weeks. During the first and third week, patients received 600 mg of rifampin or placebo; no treatment was administered during the second week. Pruritus was subjectively scored on a scale from 0 to 100. With rifampin, pruritus disappeared in 11 patients and partially improved in three; with placebo, only two had a partial response (P<0.001). Six patients with a prior poor or no response to cholestyramine improved with rifampin. No changes in biochemical tests or side effects were observed during this period. We conclude that short-term administration of rifampin relieves pruritus in primary biliary cirrhosis. When administered over a period of eight months in an open study, the relief of pruritus was maintained, while one individual developed an allergic reaction. Rifampin appears to be a safe drug in the management of the pruritus of primary biliary cirrhosis.     

Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.     

Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis,a crossover,double blind,placebo-controlled study

BACKGROUND/AIMS: To assess the efficacy and safety of naltrexone for the short and long term treatment of pruritus of cholestasis. METHODS: Twenty patients with pruritus and cholestasis were included. A baseline pruritus score was obtained over 1 week. Patients were then randomized to receive 50 mg/day of naltrexone or placebo for 2 weeks. Subsequently, a 1-week washout period ensued and patients were crossed over to the other therapy for 2 additional weeks. Pruritus was assessed daily with a visual analogue scale (VAS) from 0 to 10. Patients whose pruritus decreased >50% of basal with naltrexone received naltrexone 50 mg/day for 2 additional months. RESULTS: Mean basal VAS was similar in both groups. VAS showed greater and more significant changes with naltrexone than with placebo (P<0.0003). In nine out of 20 patients (45%) receiving naltrexone, pruritus decreased >50% compared to basal value, including five whose pruritus disappeared completely. No significant changes were observed in serum biochemistry. Most of the adverse events that occurred during the first 48 h of naltrexone therapy were consistent with opioid withdrawal-like phenomena and spontaneously disappeared 2 days after starting treatment. CONCLUSIONS: Naltrexone can be considered as an alternative option to treat pruritus of cholestasis. In the current study, side effects were transient and did not require specific medication.     

Rifampin relieves pruritus in children with cholestatic liver disease

Chronic cholestatic liver disease in children frequently results in severe intractable pruritus. Current forms of therapy, including cholestyramine, are usually ineffective. Therefore, a 6-wk, double-blind, crossover study was designed to test the ability of rifampin to relieve pruritus in children with chronic cholestasis. Rifampin proved effective in alleviating pruritus in all five children tested compared with a placebo-treated group. After the 6-wk study period, rifampin was continued for 6 mo, and its effectiveness was maintained. No complications resulted from rifampin use. This study and a similar study in older patients with primary biliary cirrhosis suggest that a highly effective form of therapy is available for treatment of severe pruritus in patients with chronic cholestasis. These patients must be carefully selected and frequently monitored.     

Ondansetron and pruritus in chronic liver disease: a controlled study

BACKGROUND/AIMS: Increased central opioidergic neurotransmission, mediated by endogenous opioid peptide agonists, contributes to the pruritus of cholestasis. There are interrelationships between the opioid and serotonin neurotransmitter systems. The serotonin 5-HT3 receptor subtype antagonist, ondansetron, has been reported to ameliorate centrally-mediated pruritus induced by exogenously administered opiates. This study was designed to determine whether long-term oral administration of ondansetron is efficacious in ameliorating pruritus complicating chronic liver disease. METHODOLOGY: Seventeen patients with severe pruritus complicating established chronic liver disease were randomized to receive, double-blind, ondansetron (8 mg) or a placebo orally; each was administered thrice daily for a 4-week period. Endpoints were subjective scores of pruritus and objective 24-hour measurements of scratching activity. Analysable data were generated in 13 of the patients. RESULTS: Ondansetron therapy was associated with ameliorations of pruritus that appeared to be clinically significant in 5 patients (38%); in these 5 patients the mean decrease in a subjective score of pruritus was 27% of the scale of the score. However, these apparent ameliorations were not associated with robust decreases in scratching activity. For the whole group of 13 patients mean scratching activity during ondansetron therapy was not significantly less than that during treatment with placebo (p = 0.19). The total time that patients were not scratching was similar during treatment with ondansetron and placebo (p = 0.57). CONCLUSIONS: The findings suggest that serotoninergic neurotransmission, in neurons bearing receptors of the 5-HT3 subtype, plays no more than a minor role in the mediation of pruritus complicating chronic liver disease. The lack of an association between the results of applying subjective scores of pruritus and scratching activity emphasizes the need to include an objective quantitative efficacy endpoint in the design of trials of new therapies for pruritus.     

Failure of rifampin to relieve pruritus in chronic liver disease

We investigated the effect of rifampin on pruritus in 12 patients with chronic liver disease: non-A, non-B hepatitis (n = 3), alcoholic cirrhosis (n = 4), primary biliary cirrhosis (n = 4), and primary sclerosing cholangitis (n = 1). The study was a crossover, randomized, double-blind trial where placebo and drug were given daily in identical capsules (300 mg) for 2 weeks each, with a 1 week washout before and after each cycle. Mean duration of pruritus was 1.6 years (range of 4 months-5 years). Blood tests were done weekly and patients used a visual analogue scale (VAS) from 0 to 100 to mark their level of itchiness daily. Only transaminases were significantly lower while the patients were on rifampin. VAS scores were minimally affected by either rifampin or placebo. At the end of the trial, four patients said they were less itchy on rifampin and three preferred placebo. Of these seven patients, small falls in VAS scores occurred in two patients on rifampin and two on placebo; there was no change in the remaining three. There was little change in serum bile salt levels during the trial. No patient became jaundiced and deepening of jaundice did not occur in the four patients with initially elevated bilirubin. We conclude that a daily 300 mg dose of rifampin was not effective in relieving pruritus in a variety of chronic liver diseases.     

A Pilot Study of Etanercept in the Treatment of Primary Sclerosing Cholangitis

There is no effective medical treatment for primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease that usually progresses to cirrhosis and liver failure. The aim of this study was to determine the safety and efficacy of etanercept, an inhibitor of tumor necrosis factor, in the treatment of PSC. Ten patients with clinically active PSC were studied. All had elevated serum alkaline phosphatase levels, cholangiograms that were diagnostic of PSC, and liver histology consistent with PSC. Five patients had elevated serum bilirubin levels, five had pruritus, eight had failed to respond to ursodiol and/or methotrexate, and six had rapidly recurring dominant bile duct strictures. Patients were to receive etanercept, 25 mg subcutaneously twice weekly, for 6 months if there were no side effects and for 1 year if there was evidence of efficacy after 6 months. Biochemical tests of liver function did not improve in any patient. Mean serum bilirubin levels increased significantly, from 2.0 to 3.6 mg/dl (P = 0.026). Two of the five patients with pruritus had resolution of pruritus during treatment with etanercept, recurrence when etanercept was stopped, and resolution when it was restarted, although there was little change in liver enzymes or bilirubin levels. There was no decrease in the rate of stricture formation and there were no side effects. Etanercept, at the dosage used, was well tolerated but not effective in the treatment of PSC. It may be helpful in treating pruritus due to cholestasis.     

Oral rifampin for eradication of Staphylococcus aureus carriage from healthy and sick populations: a systematic review of the evidence from comparative trials

BACKGROUND: Rifampin has been used for the eradication of Staphylococcus aureus (S. aureus) colonization in various populations of healthy and sick people. METHODS: We performed a systematic review of the evidence from randomized and nonrandomized controlled trials that compared the effectiveness and safety of a rifampin-based regimen with another regimen in eradicating S. aureus colonization from healthy and sick people. RESULTS: Nine comparative trials (6 of which were randomized controlled trials) were included in our analysis. S. aureus was eradicated more commonly in patients receiving rifampin-containing regimens compared to monotherapy with other systemic agents (ciprofloxacin, cloxacillin, minocycline, or vancomycin), both during early and late (>1 month after therapy) post treatment evaluations (odds ratio [OR] 46.2, 95% confidence interval [CI] 14.4-148, and OR 8.8, 95% CI 3.4-22.5 respectively, 4 studies included). There was no statistically significant difference between rifampin monotherapy and combinations of rifampin with other topical (bacitracin) or systemic (cloxacillin and minocycline) antibiotics in eradicating S. aureus both in early and late evaluations (OR 1.5, 95% CI 0.5-4.4, and OR 1.6, 95% CI 0.7-3.7, respectively, 3 studies included). Eradication of methicillin-resistant S. aureus (MRSA) varied according to the type and duration of the rifampin-containing regimen. It ranged from 25% for the combination of rifampin with trimethoprim/sulfamethoxazole for 5 days to 100% for the combination of oral rifampin and minocycline for 14 days. Discontinuation of rifampin due to drug-related toxicity was necessary in 2% of 282 studied patients. Development of resistance of S. aureus to rifampin during and after treatment with a regimen containing rifampin ranged from 0% to 40% (7 studies) and overall 17% of the 236 patients for whom relevant data was reported. CONCLUSION: The available evidence suggests that oral rifampin is an effective agent for the eradication of S. aureus carriage. However, development of antimicrobial resistance during and after treatment with rifampin occurs in a considerable proportion of patients; using rifampin in combination with another antimicrobial agent may decrease this resistance.     

The efficacy and safety of bile Acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus

OBJECTIVES: The objective of this review was to evaluate the efficacy and safety of rifampin, opioid antagonists, or bile acid binding agents in the treatment of cholestasis-related pruritus (CAP) from available randomized controlled trial evidence. METHODS: In addition to a comprehensive gray literature search, the Cochrane Library, MEDLINE, EMBASE, PubMed, and Web of Science were searched. Only full-text RCTs in participants (>75% adult) with CAP on at least one of the three medications were included. The primary outcome was change in pruritus score, recorded as a continuous or dichotomous outcome. Two independent reviewers performed trial selection and quality assessment. RESULTS: From 487 citations, 12 RCTs were included. Rifampin (standardized mean difference [SMD]-1.62, 95% CI -3.05 to -0.18) and opioid antagonists (SMD -0.68, 95% CI -1.19 to -0.17) significantly reduced CAP. The two cholestyramine studies were too heterogeneous to pool. Although cholestyramine (P= 0.35) and rifampin (P= 0.96) were not associated with greater side effects compared with placebo, opioid antagonists were (number needed to harm = 2.6, 95% CI 1.4-25). CONCLUSIONS: The available RCTs are small, few in number, and use varying scales for measuring pruritus. Although both opioid antagonists and rifampin demonstrated a reduction in pruritus, there were insufficient data to judge the efficacy of cholestyramine. Opioid antagonists were associated with transient side effects in a significant proportion of patients. A longer well-designed randomized controlled trial is needed to confirm the efficacy of bile acid binding agents and accurately assess adverse events.     

Cetirizine-induce cholestasis

Cetirizine, a human metabolite of hydroxyzine, is a selective H1-receptor antagonist currently approved for the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, and chronic urticaria. In U.S. clinical trials, transient reversible hepatic transaminase elevations were observed in <2% of patients during cetirizine therapy. We report a case of cetirizine-induced cholestasis in a 28-year-old man with no previous hepatobiliary disease after a 2-year period of taking cetirizine on a daily basis. The treatment of this patient included the use of ursodeoxycholic acid, as well as hydroxyzine, for symptomatic relief of pruritus. In light of the patient's clinical and biochemical improvement while using hydroxyzine, it appears that the hepatic metabolism of hydroxyzine to metabolites, including cetirizine, is not involved in the pathogenesis of this particular case of drug-induced hepatotoxicity. Cetirizine should be considered as a potential cause of drug-induced cholestasis.     

Successfully treated intractable pruritus with rifampin in a case of benign recurrent intrahepatic cholestasis

A 56-year-old gentleman with benign recurrent intrahepatic cholestasis (BRIC) suffered from recurrent episodes of pruritus for over 40 years. The treatment prescribed, namely cholestyramine, was minimally effective. However, rifampin 150 mg b.i.d promptly and completely relieved his severe pruritus. The diagnosis of BRIC, being a rare condition, may go unrecognized. The severity of the lifelong episodes of intermittent cholestasis with pruritus in BRIC may be extremely distressing to the affected patient. Administration of rifampin during the acute episode of severe pruritus led to a marked improvement in his quality of life.     

Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity

CONTEXT: American Thoracic Society guidelines recommend a 9-month course of therapy with isoniazid for treatment of persons with latent tuberculosis infection who are at high risk for reactivation of disease. Major liver injury has been reported with the alternative regimen, a 2-month course of pyrazinamide and rifampin. OBJECTIVE: To evaluate the rate of completion and incidence of hepatotoxicity of a short regimen of pyrazinamide and rifampin for latent tuberculosis as compared with standard isoniazid therapy before and after instituting an intensive monitoring program. Design, setting, and participants: Prospective cohort study of 224 patients in a community setting between 1999 and 2001. INTERVENTIONS: Daily pyrazinamide and rifampin for 2 months or daily isoniazid for 6 months. MAIN OUTCOME MEASURES: Treatment completion, hepatotoxicity (fourfold increase of alanine transaminase [ALT]), severe hepatotoxicity (40-fold increase in ALT). RESULTS: Treatment was completed by 71% (78 of 110 patients) in the pyrazinamide/rifampin group and by 59% (67 of 114 patients) in the isoniazid group (p = 0.07). Hepatotoxicity (ALT > 160 U/L) was documented in 13% (14 of 110 patients) in the pyrazinamide/rifampin group and in 4% (5 of 114 patients) in the isoniazid group (p = 0.03). Severe hepatotoxicity (ALT > 1,600 U/L) occurred in 2 of 43 patients (5%) receiving pyrazinamide/rifampin prior to instituting intensive monitoring. Once more intensive monitoring of liver enzymes was implemented, severe hepatotoxicity occurred in none of 67 patients. CONCLUSION: The risk of hepatitis in patients receiving pyrazinamide/rifampin for prevention of latent tuberculosis is increased threefold as compared to patients receiving isoniazid. When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance (p = 0.15).     

Cholestasis from ticlopidine: two clinical cases

The development of cholestasis during treatment with ticlopidine is an uncommon event in view of the large number of patients to whom this drug is prescribed. We describe the cases of 2 patients who had been treated with ticlopidine for 4 weeks and 2 months respectively. The first patient developed cholestasis with jaundice and pruritus while the second presented with biochemical cholestasis but no jaundice. When treatment with ticlopidine was withdrawn, in the first case pruritus disappeared and jaundice improved. In both cases the liver function tests returned to normal. Both patients were treated with ursodeoxycholic acid which might have an anticholestatic effect in case of hepatotoxicity induced by ticlopidine.     

Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study

Parenteral S-adenosylmethionine proved to be effective in reversing intrahepatic cholestasis in pregnant women. Based on these findings, a prospective multicenter, double-blind, placebo-controlled trial was planned to assess whether oral S-adenosylmethionine is effective in cholestatic patients with chronic liver disease. Accordingly, 220 inpatients (26% chronic active hepatitis, 68% cirrhosis, 6% primary biliary cirrhosis) with stable (1 month or more) at least twofold increases in serum total and conjugated bilirubin and alkaline phosphatase volunteered for the trial. Serum markers of cholestasis significantly (P less than 0.01) decreased after oral S-adenosylmethionine administration (1600 mg/day), and their values were significantly (P less than 0.01) lower than the corresponding values in the placebo group. S-adenosylmethionine significantly (P less than 0.01) improved subjective symptoms such as pruritus, fatigue, and feeling of being unwell, whereas placebo was ineffective. Two patients in the S-adenosylmethionine group and 9 controls (P less than 0.05) withdrew from the trial for reduced compliance because of inefficacy of treatment. Oral S-adenosylmethionine was tolerated to the same extent as placebo. In conclusion, short-term administration of oral S-adenosylmethionine is more effective than placebo in improving clinical and laboratory measures of intrahepatic cholestasis and offers a new therapeutic modality for the symptomatic management of this syndrome.     

Pilot study of bright-light therapy reflected toward the eyes for the pruritus of chronic liver disease

OBJECTIVE: It is proposed that the pruritus of cholestasis is, in part, centrally mediated by endogenous opioid peptides. The expression of these peptides and their receptors on neurons displays a circadian rhythm, as does the scratching activity in patients with cholestasis and pruritus. Because light has regulatory effects on circadian rhythms via retinothalamic pathways, we hypothesized that bright-light therapy (BLT) reflected toward the eyes might alter the pruritus of cholestasis. To test this hypothesis, we studied the effect of BLT on this form of pruritus. METHODS: Eight patients with chronic liver disease of different etiologies and pruritus were studied in an open-label, pilot study of 8-wk duration. BLT (10,000 lux) was administered for up to 60 min twice a day. Pruritus was assessed subjectively by a visual analog scale from which a visual analog score (VAS) was derived, and objectively, by a scratching activity monitoring system that recorded hourly scratching activity (HSA). RESULTS: In seven of the eight patients studied, the mean HSA was lower during BLT. BLT was associated with a mean decrease in HSA of 32.2% (p = 0.123). The mean VAS for pruritus was lower in six patients during BLT; the mean VAS score derived from the eight patients studied decreased by 42% (p = 0.05) during treatment. CONCLUSIONS: The results of this short-term study suggest that the pruritus of cholestasis is responsive to bright light reflected toward the eyes and that in some patients, BLT may ameliorate this form of pruritus.     

Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial

Pruritus is defined as the second order of nociception, the first being pain; thus, there is a rationale to study gabapentin, a drug that increases the threshold to experience nociception. The aim of this double-blind, randomized, placebo-controlled trial was to study the effect of gabapentin on the perception of pruritus and its behavioral manifestation, scratching, in cholestasis. The participants were 16 women with chronic liver disease and chronic pruritus. Hourly scratching activity (HSA) was continuously recorded for up to 48 hours at baseline and on treatment for at least 4 weeks in an inpatient setting. The perception of pruritus was assessed by interviews and by a visual analog score (VAS) of pruritus recorded every hour while patients were awake. Patients were randomized to the study drug (gabapentin or placebo) at a starting dose of 300 mg orally per day in divided doses to a maximum of 2,400 mg or until relief from pruritus. Gabapentin was associated with an increase in mean HSA, in contrast to the placebo, which was associated with a decrease. The mean VAS decreased significantly among those taking the placebo and in some patients on gabapentin. In conclusion, gabapentin did not provide a significant therapeutic advantage over the placebo; in fact, it was associated with an increase in the perception of pruritus and in HSA in some patients.     

Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts

RATIONALE: Treatment of latent tuberculosis (TB) infection with weekly rifapentine and isoniazid is a potentially effective alternative to current therapies. OBJECTIVES: To compare the efficacy of weekly rifapentine/isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil. METHODS: Contacts of patients with TB were randomized to rifapentine 900 mg/isoniazid 900 mg once weekly for 12 wk or rifampin 450-600 mg/pyrazinamide 750-1,500 mg daily for 8 wk and followed for at least 2 yr. MEASUREMENTS: TB rates, adverse events, and adherence to therapy. MAIN RESULTS: A total of 399 household contacts were enrolled, 206 in the rifapentine/isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/isoniazid (p<0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, -1.6 to 3.7%). CONCLUSIONS: Rifapentine/isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection.     

S-adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo-controlled study with negative results

S-Adenosyl-L-methionine has been reported to induce beneficial effects in intrahepatic cholestasis of pregnancy. Because cholestasis of pregnancy has a high prevalence in Chile and a deleterious effect on fetal prognosis, we decided to verify the efficacy of S-adenosyl-L-methionine in this disease. Eighteen patients with pruritus that appeared during pregnancy and with elevated serum levels of bile salts (68.1 +/- 15.9 mumol/L; mean +/- S.E.M.) and ALT (226 +/- 50 KU/L) were enrolled in a prospective double-blind study comparing the effects of the drug with a placebo. S-Adenosyl-L-methionine, 900 mg, or placebo was administered in daily intravenous infusions for 20 days. Every 5 days liver function tests were done and pruritus was assessed using a preestablished score. No significant differences in pruritus or in serum levels of bile salts, ALT, bilirubin and alkaline phosphatases were seen during or after treatment between patients who received S-adenosyl-L-methionine (n = 9) or placebo (n = 9). No relevant adverse reactions were detected. Most patients had cesarean sections because of reasons unrelated to the therapeutic trial. All newborns had Apgar scores greater than 7 and normal postnatal development. Our patients had moderately severe to severe cholestasis of pregnancy as indicated by the onset of pruritus before wk 32 of pregnancy. Seven of nine multiparous patients had a past history of recurrent cholestasis of pregnancy. In this study, the administration of S-adenosyl-L-methionine during 20 days did not improve intrahepatic cholestasis of pregnancy.     

Treatment of the pruritus of cholestasis

Opinion statement The etiology of the pruritus of cholestasis is unknown. It is inferred that the pruritogen( s) is produced in the liver, excreted in bile, and as a result of cholestasis it accumulates in plasma. It may follow, logically, that the removal of the substance(s) that mediate pruritus leads to its resolution. The problem with this approach, however, is that the substance(s) is unknown; thus, it is not possible to reduce its serum levels specifically. Oral cholestyramine, a resin that is not absorbed, is associated with increased fecal excretion of certain substances, including cholesterol and bile acids. Many patients respond to treatment with cholestyramine with a relief of pruritus, which unfortunately may be temporary, but is well tolerated in general and it seems reasonable to prescribe it as an initial therapy. When pruritus is not relieved by resins, the use of opiate antagonists (eg, naloxone and naltrexone) is supported by data from controlled clinical trials. Butorphanol is an agonist at the kappa opioid receptor and an antagonist at the mu opioid receptor with minimal or absent abuse potential. The use of butorphanol spray in selective patients may be a therapeutic alternative. In uncontrolled observations dronabinol, an agonist at the cannabinoid B1 receptor, and sertraline, a serotonin reuptake inhibitor, have been reported to be associated with the relief of pruritus. The cannabinoidergic and serotoninergic systems participate in the mediation of nociception; therefore, there appears to be a rationale for the use of these drugs to treat pruritus. Data from controlled clinical trials on the use of dronabinol and sertraline, however, are not available at present.