Abstract
Dear Editor:
Intractable pruritus due to advanced cholestatic liver disease can lead to intense physical suffering in terminally ill patients. We report the case of a 90-year-old man who had distressful pruritus due to irreversible drug induced cholestasis. His symptoms failed to respond to antihistamines, bile acid binding resins, and SSRIs but responded dramatically to the opiate receptor antagonists methylnaltrexone and naloxone. Improved symptom control allowed the patient to sleep after weeks along with significant reduction in daytime symptoms.
A 90-year-old Caucasian man with a history of type 2 diabetes and congestive heart failure due to critical aortic stenosis (aortic valve area of 0.7 cm2) was admitted with severe itching, generalized icterus, and abdominal pain. Community acquired pneumonia was treated with a course of azithromycin two weeks prior to onset of symptoms. On physical exam he was afebrile with a heart rate of 84 and blood pressure of 104/80. There was generalized marked icterus and a 4/6 ejection systolic murmur loudest in the aortic area. Routine laboratory tests complete blood count and basic metabolic panel were unremarkable. Liver function tests showed that total bilirubin was 19.9 mg/dl, direct bilirubin was 17 mg/dl, alkaline phosphatase was 343 U/L, aspartate aminotransferase was 44 U/L, and alanine aminotransferase was 58 U/L. Computed tomography scan of the abdomen showed normal sized extra hepatic bile ducts without any hepatic or pancreatic mass lesions. Tests for antinuclear antibody, antimitochondrial antibody, anti-smooth muscle antibody, and antineutrophilic cytoplasmic antibody were negative. The patient and his family declined further investigations including a liver biopsy given his age and multiple comorbidities. His goals of treatment were set at comfort measures only. Azithromycin has been rarely reported to cause chronic cholestasis,1,2 and a clinical diagnosis of irreversible drug induced cholestasis was made in light of the temporal association with antibiotic use; other causes were unlikely in the absence of supporting clinical findings. Over the subsequent weeks hyperbilirubinemia and pruritus continued to worsen. Initial attempts at treatment with antihistamines, cholestyramine, and SSRIs were ineffective. He responded transiently to a methylnaltrexone (also used to treat opioid induced constipation) challenge administered subcutaneously. Subsequently, naloxone (0.4 mg/hr) continuous infusion subcutaneously was started, to treat pruritus, with a dramatic improvement in symptoms—and significantly improving the patient's quality of life. His symptoms remained well controlled over the next few weeks. He died in the palliative care unit approximately four weeks from the diagnosis of irreversible drug induced cholestasis.
Pruritus can often be the most distressful symptom of chronic cholestatic conditions such as drug induced cholestasis, primary biliary cirrhosis, and primary sclerosing cholangitis, often leading to sleep deprivation, depression, impaired quality of life, and even suicidal ideation. Intractable pruritus that is refractory of medical management is an indication for liver transplantation. 3 In terminally ill patients where age or comorbidities preclude transplantation as a therapeutic option, symptom control assumes prime importance. The pathogenesis of pruritis in cholestasis involves the accumulation of bile acids, serotonin, endogenous opiates, and lysophosphatidic acid, which through a combination of peripheral nerve stimulation and central nervous system stimulation of μ receptors produce the sensation of itch; however, the exact mechanism continues to remain unclear. A number of therapeutic options of variable efficacy are available for the treatment of pruritus in cholestasis, including bile acid binding resins, antihistamines, rifampin, SSRIs, and opiate receptor antagonists. 3 In randomized controlled trials using opiate receptor antagonists, intravenous naloxone, oral naltrexone (also used to treat substance abuse disorders) and nalmefene achieved a statistically significant reduction in the sensation of pruritus along with a reduction in scratching behavior in patients with cholestasis.4–6 However, the use of these agents remains limited in the palliative care setting. This is partially due to concerns regarding a reversal of analgesic effects of opiates prescribed for pain. In our experience analgesia was not affected by naloxone treatment. It is likely that the small dose (0.4 mg/hr) and short half life of naloxone (1 hour to 1.5 hours) were insufficient to reverse the analgesic effect of exogenously administered opiates.
In conclusion, we report the successful use of subcutaneous naloxone for the treatment of severe pruritus due to advanced liver disease in a palliative care setting. Palliative care and hospice physicians should consider the use of opiate receptor antagonists when treating refractory pruritus in patients with end-stage liver disease. Adequate symptom control at the end of life is instrumental in improving quality of life for patients and their families.