Pruritus is a common symptom experienced by many patients in palliative and hospice care which can dramatically affect a patient’s comfort and quality of life even though it is not the most prevalent symptom such as pain or dyspnea. While the complete pathology of all causes of pruritus is not yet completely understood, the itching sensation is best relieved by properly treating the underlying etiology if it is known.1
Pruritus has been associated with both malignant disease as well as nonmalignant chronic diseases such as renal, thyroid, and hepatic disease. A Cochrane Review found that about one third of all patients with end stage renal disease not on hemodialysis and 70%-80% of patients receiving hemodialysis experience significant pruritus. The same review found that nearly 100% of patients with biliary cirrhosis had a cholestatic pruritus.1 According to the guidelines from the American Association for the Study of Liver Diseases, cholestatic pruritus is often times the initial symptom in half of the patients with biliary cirrhosis.1,2
There exist many therapies that could be used to treat pruritus in general such as antihistamines like hydroxyzine, opioid receptor antagonists similar to naloxone, direct serotonergic agents such as ondansetron, selective serotonin reuptake inhibitors (SSRI’s) such as paroxetine and sertraline, antiepileptics such as gabapentin, and the antibiotic rifampicin. Most of these agents have different mechanisms against pruritus which may be more or less effective given certain patient factors. The American Association for the Study of Liver Diseases guidelines for primary biliary cirrhosis recommend several agents for the treatment of cholestatic pruritus:1,2
Bile Acid Sequestrants: The first line therapy recommendation is to use a bile acid sequestrant agent. Bile acid sequestrants are approved for the treatment of dyslipidemias by functioning as a resin that traps cholesterol and other acids from bile in the GI tract which can allow passing of these substances out through the GI tract instead of being systemically reabsorbed. It is believed that forcing the elimination of these bile acids will also relieve cholestatic pruritus. The bile acid sequestrant of choice is cholestyramine dosed at 4 grams per dose with a maximum dose of 16 grams daily. [The other currently available bile acid sequestrants, colesevelam, and colestipol, have not been studied and currently contain no recommendations for the treatment of pruritis.2] Complications of bile acid sequestrant therapy include gastrointestinal disturbances (constipation, loose stool, cramping, excessive flatus, etc.) and the prevention of drug absorption in the GI tract since acidic drugs will also be trapped by the resin.1,2 It is recommended to separate the administration of a bile acid sequestrant from other medications by 2-4 hours.
Antidepressants: It is believed that serotoninergic activity contributes to signal transduction of pruritus. Several antidepressants have been tested including paroxetine, doxepin, and sertraline. Sertraline 75 mg to 100 mg is the preferred therapy for cholestatic pruritus according to the guidelines by the American Association for the Study of Liver Disease.2 General pruritus relief has been noticed with paroxetine 5 mg to 10 mg at night for multiple etiologies including hepatic and renal disease.1 Doxepin appears to be effective at doses of 25 mg daily, however tricyclic antidepressants tend to have anticholinergic activity which can cause adverse effects in older patients and should be avoided unless necessary.1,3 Relief of pruritus by antidepressants is usually seen in 24 to 48 hours, much sooner than the antidepressant effects of these agents.1 Ondansetron has been studied as a direct acting serotonergic agent, however it has only shown mild to no benefit in clinical trials.1,2
Rifampicin: Rifampicin is an antibiotic and hepatic enzyme inducer shown in several trials and meta-analyses to relieve hepatic pruritus. Recommended dose is 150-300 mg twice daily depending on serum bilirubin (300 mg for bilirubin less than 3 mg/dL and 150 mg for bilirubin 3 mg/dL or higher). Complications of therapy include drug induced hepatotoxicity or renal impairment and hepatic ennzyme induction which could decrease the efficacy of other medication therapies.1,2 Due to the risks for hepatotoxicity and nephrotoxicity, liver and renal function tests will need to be continually monitored suggesting that therapy with rifampicin should be held in reserve for when benefit outweighs risk in end-of-life care.
Opioid Antagonists: While there is strong evidence for the use of the opioid antagonists naloxone or naltrexone, these therapies are usually inappropriate in hospice care since these agents will counter the analgesic activity of other opioids used in the treatment of chronic pain and could also induce opiate withdrawal.1,2 In addition, naltrexone has a rare potential for causing hepatotoxicity which will require monitoring liver function. The recommended dose of naltrexone is 50 mg by mouth daily, however naltrexone is hepatically eliminated and will accumulate in decompensated and end-stage liver disease requiring that the dose of naltrexone be decreased.2 Due to the monitoring burden and the risk of counteracting chronic opiate activity, it is recommended only to use naltrexone when the patient is not taking opioid analgesics and benefit outweighs risk of decreasing liver function.
Antihistamines: The mechanism of antihistaminergic compounds is reliant on non-specific antipruritic effects with little treatment to the direct etiology of hepatic pruritus.2 Complications that occur are the risk of confusion, sedation, exacerbation of dementias, and increase in fall potential for patients that are still ambulatory from the anticholinergic activity of the antihistamine agents similar to diphenhydramine and hydroxyzine.3 It is recommended to use these only when other systemic therapies have failed or are inappropriate.
Phenobarbital: Phenobarbital was once utilized as a therapy for hepatic pruritus, however its use is limited in modern practice due to risks of severe sedation and hepatic enzyme induction.2,3
There is a large variety of medication therapies that can be used to treat pruritus from a hepatic etiology. Topical therapies such as the counter-irritants capsacin or menthol have some limited efficacy1 but the application area may become so large in advanced disease that their use becomes impractical. While conventional therapies of systemic antihistamines may be moderately effective, they have the potential for undesirable adverse events and may be less effective or efficient than an etiology specific agent. Cholestyramine or sertraline may not be the first agent that comes to mind when a patient complains of an itch, however these less conventional therapies have become a mainstay for the treatment of pruritus in advanced hepatic disease. In addition, the use of these alternate therapies broadens the spectrum of drugs that could be used for multiple pharmacological effects and can afford a patient specific drug selection.
Submitted by: James R. Thomas, PharmD., BS Hospice Clinical Pharmacist and Pharmacy Resident at Delta Care Rx
1. Xander, C., Meerpohl, J. J., Galandi, D., Buroh, S., Schwarzer, G., Antes, G., & Becker, G. (2013). Pharmacological interventions for pruritus in adult palliative care patients. The Cochrane Database of Systematic Reviews, 6(6), CD008320. doi:10.1002/14651858.CD008320.pub2
2. Lindor, K. D., Gershwin, M. E., Poupon, R., Kaplan, M., Bergasa, N. V., & Heathcote, E. J. (2009). Primary biliary cirrhosis. Hepatology. doi:10.1002/hep.22906