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.     

Update on the treatment of the pruritus of cholestasis

The pruritus of cholestasis is a difficult clinical problem to manage. It can be severe and interfere with sleep. Clinical behavioral studies have confirmed that the pruritus is mediated at least in part by endogenous opioids. Other neurotransmitter systems may be involved in the mediation of pruritus. Work continues to identify the mechanisms that mediate the pruritus and to develop specific drugs to treat this often maddening symptom.     

Pathogenesis and treatment of pruritus in patients with cholestasis

The pathogenesis of initiating the pruritus in patients with cholestasis is still not completely understood. One hypothesis is, that the cause for initiating the pruritus in patients with cholestasis is the activation of nerves in the skin. The activating substances are unknown, probably they are substances who accumulate in patients with cholestasis. Therefore one of the conventional approaches to treat pruritus is to remove pruritogenic substances from the body. Examples of this approach include the administration of anion exchange resins as cholestyramine or the administration of hepatic enzyme-inducing drugs such as rifampicin or phenobarbital. None of these drugs has been conclusively shown to be efficacious. A new hypothesis is the association of pruritus with altered central neurotransmission. Altered opioid concentrations probably play a central role in the pathogenesis of pruritus. This hypothesis is corroborate by the possibility of treating pruritus in patients with cholestasis with opiate antagonists such as naloxone or nalmefene. The treatment with ondansetron may also have effects on the pruritus of patients with cholestasis. A completely new treatment strategy is the application of dronabinol (r-9-tetrahydrocannabinol).     

Role of intravenous naloxone in severe pruritus of acute cholestasis

Pruritus is a well-known manifestation of various cholestatic disorders. Increased opioidergic tone is one of the mechanisms for this. This prospective, uncontrolled study was done to determine the efficacy of intravenous naloxone in pruritus of acute cholestasis. Twenty-two patients with severe pruritus (based on visual analogue scale [VAS] score of 0–100 and associated symptoms) were treated with intravenous naloxone (0.4 mg every 8 hours) for at least 48 hours. Viral hepatitis E was found to be the most common etiology for cholestatic pruritus (n=12). Eighteen patients (81.8%) patients had significant reduction in VAS after 48 hours of starting naloxone; these patients also showed reduction in alkaline phosphatase and gamma glutamyl transpeptidase. There was no side-effect or ‘breakthrough’ phenomenon noted in any patient over next 6 weeks. Naloxone is safe and efficacious in symptomatic improvement in cholestatic pruritus.     

An approach to the management of the poisoned patient

Our systematic approach to the evaluation and treatment of the acutely poisoned patient involves establishing an accurate diagnosis and prognosis that often may be based on quantitation of the blood concentration of the toxic substance. The major feature of this approach is the proper selection of treatment(s) for the poisoned patient, ie, decontamination and supportive care and, in some cases, antidotal therapy and/or active removal of the toxic substance. Invasive, expensive methods of active removal (eg, hemodialysis or hemoperfusion) are generally recommended only if specific criteria are satisfied. Noninvasive, inexpensive methods of active removal (eg, manipulation of urinary pH or the oral administration of multiple doses of activated charcoal) may have significant utility in the treatment of poisoned patients not requiring invasive methods. This systematic approach to the poisoned patient should lead to an effective use of treatment modalities with minimal risks and optimal clinical results.     

Evolving concepts of the pathogenesis and treatment of the pruritus of cholestasis.

The site of the pathogenic events responsible for initiating the pruritus of cholestasis has been assumed to be the skin. This assumption cannot be excluded but is not supported by convincing data. Empirical therapies such as anion exchange resins and rifampicin often appear to be partially efficacious. Recent evidence suggests that altered neurotransmission in the brain may contribute to this form of pruritus. In particular, the hypothesis that increased central opioidergic tone is involved is supported by three observations: opiate agonists induce opioid receptor-mediated scratching activity of central origin, central opioidergic tone is increased in cholestasis and opiate antagonists reduce scratching activity in cholestatic patients. Apparent subjective ameliorations of pruritus following intravenous administration of ondansetron to cholestatic patients suggest that altered serotoninergic neurotransmission may also contribute to this form of pruritus.     

Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy

ObjectiveIntrahepatic cholestasis of pregnancy is a temporary, pregnancy-specific disease that resolves with delivery, characterized by itching (pruritus), as well as high transaminase and serum bile acid levels in the third trimester of pregnancy. Due to the effects of Autotaxin on the physiology of pregnancy, we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy.Patients and methodsSixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study. Fasting serum bile acid, pruritus intensity, serum parameters, gestational week of the patients at the time of diagnosis were recorded, and birth week and birth weight were monitored. Autotaxin serum level was measured enzymatically.ResultsThe mean serum bile acid level (n = 69; 38.74 ± 35.92 μmol/L) in patients with intrahepatic cholestasis of pregnancy (n = 69) was detected to be higher than healthy pregnant women (n = 20; 5.05 ± 1.88 μmol/L) (p < 0.001). Weak correlation was detected between serum bile acid level and itch intensity (p = 0.014, r = 0.295), while no relation was detected between Autotaxin and itch intensity (p = 0.446, r = 0.09). Although mean Autotaxin (intrahepatic cholestasis of pregnancy: 678.10 ± 424.42 pg/mL, control: 535.16 ± 256.47 pg/mL) levels were high in patients with intrahepatic cholestasis of pregnancy, it was not statistically significant (p = 0.157).ConclusionIn our study, we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women. These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy.     

A controlled trial of naloxone infusions for the pruritus of chronic cholestasis.

To test the hypothesis that opioid agonist activity contributes to the pruritus of cholestasis, a placebo-controlled single-blinded trial of naloxone, an opioid antagonist, was conducted in eight patients with primary biliary cirrhosis. After discontinuation of all conventional antipruritic medications, one or two continuous (24-hour) IV infusions of naloxone (0.2 micrograms.kg-1.min-1) and placebo solution were administered consecutively in an order that was not predetermined. Pruritus was assessed subjectively by means of four hourly recordings of a visual analogue score. In addition, objective measurements of scratching activity that were independent of gross body movements were continuously recorded using an apparatus specifically designed to measure the frequencies associated with this activity. No side effects associated with naloxone infusions were observed. Only scratching activity data obtained for the same periods of day and night during both naloxone and placebo infusions were compared. Naloxone infusions were consistently associated with a decrease in values of the scratching activity index. In addition, in 50% of the patients the infusions were associated with a decrease in visual analogue score. The mean decrease in scratching activity ranged from 29% to 96% (mean, 50%; P less than 0.001). These findings imply that increased opioid agonist activity contributes to scratching activity in cholestatic patients.     

An evidence-based approach to the management of pulmonary arterial hypertension

PURPOSE OF REVIEW: Evidence-based therapies and guidelines for pulmonary arterial hypertension are critiqued. RECENT FINDINGS: Morbidity and mortality in pulmonary arterial hypertension reflects failure of right ventricular compensation for increased afterload caused by obstructive pulmonary arterial remodeling. This predominantly reflects excessive proliferation/impaired apoptosis of smooth muscle and endothelial cells, rather than vasoconstriction. To exclude confounding effects of cardiac output and left ventricular end-diastolic pressure, the diagnosis of pulmonary arterial hypertension should require a pulmonary vascular resistance >3 Wood-units, not simply a mean pulmonary arterial pressure >25 mmHg. A 'positive' response (20% fall in pulmonary arterial pressure/pulmonary vascular resistance PAP/PVR) to acute, selective, pulmonary vasodilators (e.g. inhaled nitric oxide), occurs in 20% of patients, portends a favorable prognosis and justifies a trial of calcium channel blockers. Randomized controlled trials support treatment of NYHA class III pulmonary arterial hypertension with oral endothelin antagonists or phosphodiesterase-5 inhibitors. Prostacyclin analogues (inhaled/subcutaneous) are useful adjunctive therapies. Intravenous epoprostenol remains the therapeutic mainstay for class IV PAH. Emerging antiproliferative-proapoptotic therapies that merit investigator-initiated clinical trials include: statins, Imatinib, NONO-ates, anti-survivin, potassium channel modulation, and dichloroacetate. SUMMARY: The diagnostic criteria for pulmonary arterial hypertension should be revised to include PVR. Sildenafil's efficacy and price recommend it as a first-line oral therapy. New pulmonary arterial hypertension-regression therapies and therapeutic combinations offer the potential for cure of pulmonary arterial hypertension.