Cholestatic Pruritus in Palliative Care

Pruritus is a common and distressing symptom in patients receiving palliative care. The itch-scratch cycle can compromise skin integrity, increasing the risk of infection. People with advanced, life-limiting illness often already have fragile skin. This can be due to a range of factors such as reduced blood flow, nutritional deficiencies, medications, immobility, and age-related changes.

There are many potential causes of itch in this population, including:

• Dry skin;
• Uraemia related to advanced kidney disease;
• Cancer;
• Opioid analgesics; and
• Comorbid conditions unrelated to the life-limiting illness.

Itch may also be related to cholestasis due to biliary obstruction, intrahepatic disease, or adverse drug effects.

The pathogenesis of pruritus in cholestasis is not entirely understood. It is thought that impaired bile flow leads to the accumulation of pruritogenic substances. These substances may then interact with sensory nerve fibres in the skin, producing the sensation of itch. Substances that may be acting as pruritogens include bile acids, endogenous opioids, and lysophosphatidic acid (LPA).

Cholestatic itch can be treated with biliary drainage. However, this may not be appropriate for all patients with a life-limiting illness. Where systemic drug treatment is required, the Therapeutic Guidelines recommend the following therapies:

• Rifampicin 150mg orally at night (maximum of 600mg daily); or
• Sertraline 50mg daily (maximum of 100mg daily).

These first-line agents are interesting as they are not traditionally thought of as anti-itch medications. Their use in this setting would be considered off-label.

Rifampicin

Rifampicin is an antibiotic that is typically reserved for the treatment of infections due to mycobacteria or methicillin-resistant Staphylococcus aureus (MRSA) and for the prevention of meningitis and epiglottitis. However, it may also be effective in relieving itch in cholestatic pruritus.

One of the proposed mechanisms for this involves the phospholipid, LPA. This molecule is involved in many physiologic and pathologic processes, some of which can lead to the production of pruritogenic interleukins. While LPA is primarily produced intracellularly for the purposes of cell membrane synthesis, it is its extracellular production that is thought to be important in pruritus. When LPA is produced extracellularly, autotaxin is the rate-limiting enzyme involved. Therefore, inhibition of autotaxin could relieve pruritus by reducing the production of LPA.

Rifampicin is a potent agonist of the pregnane X receptor (PXR). Activation of this receptor has been shown to reduce autotaxin expression on hepatocytes. Other theories on the action of rifampicin relate to changes in the intestinal microbiome which may influence the reabsorption of pruritogens.

A Cochrane review found that rifampicin may relieve cholestatic pruritus in palliative care patients, although the certainty of evidence is very low. Rifampicin was associated with a significant reduction in pruritus compared to placebo, with a mean difference of −42.00 (95% confidence interval: −87.31 to 3.31).

Rifampicin therapy does carry a risk of hepatitis. Therefore, caution is required when used in patients with cholestatic conditions. Serum aminotransferases should be monitored at regular intervals.

Sertraline

Sertraline is a selective serotonin reuptake inhibitor (SSRI) that may be used off-label for the management of cholestatic pruritus. Its mechanism of action in pruritus may be related to the role that serotonin plays in nociception and perception of pruritus. As sertraline inhibits the reuptake of serotonin, it may modify itch signalling.

In a study by Ataei et al., the efficacy of sertraline and rifampicin were compared in patients with cholestatic pruritus. Patients were randomised to receive either sertraline 100mg daily or rifampicin 300mg daily. A similar reduction in pruritus scores was seen in each group (-46% for sertraline vs -43% for rifampicin). However, sertraline was considered safer than rifampicin regarding hepatobiliary enzyme levels. This study had some limitations, including the small sample size and the single-blind design.

Sertraline is generally well tolerated. More commonly experienced adverse effects include nausea, diarrhoea, insomnia, and dizziness.

Colestyramine

Pruritus due to partial biliary obstruction is a registered indication for colestyramine. However, it is not currently recommended by the Therapeutic Guidelines in the palliative care setting. This is due to limited evidence to support its use in this population as well as poor tolerance.

Colestyramine is a bile acid sequestrant. It combines with bile acids in the intestine to form insoluble complexes that are excreted in the faeces. Preventing the reabsorption of bile acids results in a continuous, but incomplete, removal of bile acids from the enterohepatic circulation.

Colestyramine is presented as powder that must be mixed with water, juice or highly fluid food before administration. The usual dose for the relief of itch is 4g (one sachet) once or twice daily.

Constipation is the most commonly reported adverse event. This is often mild and easily managed, although severe cases have occurred. In rare cases, this may be accompanied by faecal impaction or haemorrhoids. Other common adverse effects include abdominal pain, dyspepsia, nausea, and anorexia

Colestyramine can reduce the absorption of other orally administered drugs. To avoid this issue, other oral medicines should be taken at least one hour before or four hours after colestyramine.

General measures

General skincare measures are important and may avoid the need for systemic drug therapy. The following measures are recommended for all patients with pruritus and are particularly valuable for patients with dry skin:

• Generous use of emollients twice a day, particularly after bathing
  • Options include aqueous cream, glycerine 10% in sorbolene, and paraffin ointment (liquid paraffin 50% + white soft paraffin 50%)
• Bathe using warm water and gently pat skin dry
• Avoid soap and shampoos
  • Soap substitutes can be used, e.g. aqueous cream, or soap-free washes
  • Dispersible oils may be preferred if the skin is very dry
• Avoid scratching, keep fingernail and toenails short, consider use of cotton gloves and socks at night.