This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Pruritus is a hallmark feature of cholestatic liver diseases and is estimated to occur in 20%-50% of patients with jaundice and 70%-80% of patients with primary biliary cirrhosis (PBC). Pruritus significantly affects quality of life and can lead to chronic sleep deprivation. Currently used therapies are often ineffective and/or poorly tolerated. Only a few have been examined in the setting of controlled trials. Practice guidelines issued by the American Association for the Study of Liver Diseases state that the first line of therapy for cholestatic pruritus is bile acid binding resins such as cholestyramine. Bile acid binding resins can be partially effective in up to 85% of patients, but compliance tends to be poor because the preparation is unpalatable. In addition, these resins avidly bind to and prevent absorption of almost all other medications, severely restricting the medical management of the patients. The second line of therapy is rifampicin, which has been shown to be modestly effective in several small trials. The major problem with rifampicin is that it leads to increases in serum bilirubin levels. Serum bilirubin is the single most important predictor of survival in patients with PBC, and thus rifampicin therapy impairs the physician's ability to follow the patient's course. In addition, there have been reports of rifampicin-induced hepatitis, which could pose a serious problem in patients with already limited liver function. The third line therapies are all considered experimental because they either have unproved efficacy and/or severely limiting side effects. They include: opioid receptor blockers, which are unpleasant because they result in an opioid withdrawal-like syndrome in PBC patients; phenobarbitol and propofol, which are heavily sedating; anti-histamines, which are not very effective and also worsen the xerostomia of sicca syndrome that is present in 80% of patients with PBC and many patients with hepatitis C (HCV); s-adenosylmethionine (SAMe, a dietary supplement), phototherapy; anti-convulsants, ondansetron, and plasmapheresis. Intractable cholestatic pruritus is considered a valid indication for liver transplantation in the absence of overt hepatocellular failure, an effective but drastic and costly measure. In rare cases, patients have opted for suicide in order to avoid the constant distress of unmanageable pruritus.The broad, long-term objective of this project is to improve the health and quality of life of patients with systemic diseases that cause pruritus. The hypothesis of this project, which is based on our previous observation that some patients with PBC have experienced resolution of their pruritus when given sertraline, is that sertraline therapy will improve the symptom of cholestatic pruritus. This particular study is intended to serve as a feasibility and dose-finding pilot trial to determine the tolerability and effective dose of sertraline as a treatment for cholestatic pruritus. It is anticipated that this pilot trial will be followed by a larger, double-blind, randomized, placebo-controlled trial to definitively evaluate the efficacy sertraline therapy for pruritus.
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