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REVIEW ARTICLE
Year : 2016  |  Volume : 4  |  Issue : 1  |  Page : 17-23

Review of management of pruritus in palliative care


1 Department of Palliative Medicine, Comprehensive Cancer Centre, King Fahad Medical City, Riyadh; Centre for Postgraduate Studies in Family Medicine, Ministry of Health, Riyadh, Saudi Arabia
2 Department of Palliative Medicine, Comprehensive Cancer Centre, King Fahad Medical City, Riyadh, Saudi Arabia

Date of Web Publication13-Jan-2016

Correspondence Address:
Dr. Sami Ayed Alshammary
Department of Palliative Medicine, King Fahad Medical City, Riyadh
Saudi Arabia
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DOI: 10.4103/1658-600X.173844

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  Abstract 

Pruritus or itch is an uncommon symptom observed in palliative care, even more uncommon in cancer patients. However, if a patient experiences pruritus, the 'itch-scratch' cycle can damage the skin integrity and can increase the susceptibility of patients to infection owing to their frail immune system. The outcome can be very distressing, dramatically impacting the quality-of-life of the patient. Moreover, since severe pruritus seen in patients with advanced disease can be associated with failure of different organ systems, pruritus must be assessed based on the underlying organ systems and the pathophysiology involved. Regardless of the cause of pruritus, general skin care is important. Depending on the origin of pruritus, specific approach and medications must be considered. Caution must be taken during management of pruritus since most cancer patients take pain medications that interact with some antipruritic medications. In addition to the complex and unclear nature of cutaneous and central pathogenesis of pruritus, treatment of pruritus is challenging.

Keywords: Clinical manifestation, itch, pain, palliative care, pathophysiology, pruritus


How to cite this article:
Alshammary SA, Duraisamy BP, Alsuhail A. Review of management of pruritus in palliative care. J Health Spec 2016;4:17-23

How to cite this URL:
Alshammary SA, Duraisamy BP, Alsuhail A. Review of management of pruritus in palliative care. J Health Spec [serial online] 2016 [cited 2019 Aug 25];4:17-23. Available from: http://www.thejhs.org/text.asp?2016/4/1/17/173844


  Introduction Top


Pruritus or itch is a sensation of the skin or mucous membranes with free nerve endings, which causes the desire to scratch the affected area and consequently causing breaks in the skin, inflammation, infection and/or bleeding.[1],[2]

Pruritus is a rare symptom observed in palliative care of cancer patients, projected to have a frequency rate of 6% for general palliative care setting and between 5% and 24% occurrence for patients with 'incurable' cancer diagnoses. Manifestation of pruritus in patients during palliation can be one major factor that contributes to difficulties in the daily activities of the patients. In addition to the mood disorders, social unacceptability and lack of sleep alter the patients quality-of-life (QOL) detrimentally. Pruritus is not simply a skin disorder but rather a systemic problem from multiple causes. Moreover, depending on the cause(s) of pruritus, the best fit approach for certain clinical manifestations might not necessarily work for the others and vice versa.[1],[2]

This article presents the different pathophysiological processes and clinical manifestations of pruritus in palliative care patients, and it further describes the different therapeutic options of pruritus.


  Pathophysiology of Pruritus Top


Pruritus has a complex and unclear nature of cutaneous and central pathogenesis. It is important to be aware of the risk factors and causes of pruritus, and the best available means of effective therapy. Pathophysiologically, pruritus can be classified as prurioreceptive (within the skin), neuropathic (damage to the afferent pathway), neurogenic, (cerebrally induced) and psychogenic pruritus (related to psychiatric disorder).[1],[2] It is difficult to isolate these categories from each other entirely; therefore, may presumably overlap one another to some extent.

Prurioreceptive pruritus

This occurs when the itch is initiated within the skin (e.g., inflammation of the skin, adverse insect bite reactions), which opens up the neuronal pathway in the free nerve endings of the skin that is similar to the response of the body to pain. This is then received by the brain through the transmission by the dedicated unmyelinated C fibres along the dorsal horn and relayed to the contralateral spinothalamic tract, where it is identified as an itch. It in turn blocks the perception of the feeling of irritation by stimulating the Aδ sensory fibres through scratching, which is directed by our motor reflexes.[1],[2] This is known as the Melzak-Wall 'gate theory'. Though both pain and itch have the same chemical messengers that excite theses C fibres, a subset of these fibres responds specifically to pruritus-inducing stimuli and peripheral mediators, and these include histamine, serotonin, prostaglandin, acetylcholine, cytokines, opioids and neuropeptides.

Neuropathic pruritus

It happens along the neurological pathway where the damage to the nervous system is known to have occurred. It is frequently associated with symptoms of tingling and numbness.[1],[2] This type of itch is usually seen after shingles, post-stroke, burn injury and nostalgia paraesthetica (an area of itching, usually at the back), often treated with non-narcotic analgesics and capsaicin.

Neurogenic pruritus

It is brought about and mediated by the opioid and serotonin receptors, and for that reason, it is unresponsive to antihistamines. It fundamentally affects the central inhibitory circuits.[1],[2] It can be commonly observed in patients with chronic liver and kidney disease and in response to opioid neuropeptides. Narcotic and non-narcotic analgesics are used for the treatment.

Psychogenic pruritus

It is commonly linked to psychiatric disorders [1],[2] such as depression and delusional parasitosis. It is in response to altered norepinephrine and serotonin in the brain, which is also associated with chronic stress. The choices of treatment medications for this are antidepressants and antipsychotics.


  Causes of Pruritus Top


Similar to pathogenesis, the disease processes causing pruritus are also of different kinds, such as cholestasis, uraemia, opioid-induced, malignancies, infection and drug-induced (reaction) pruritus.

Cholestasis

This is the most prevalent source of pruritus, occurring in 20 - 25% of the patients with end-stage liver disease. Cholestasis occurs in 100% of the patients with primary biliary cirrhosis. It not only relies on the accumulation of bile acids but it is also believed to be associated with breakdown of endogenous opioids; hence, the use of opioid antagonist medications will also be advantageous. The pathogenesis of cholestasis is still unknown, but one supposed mechanism is in the increased release of serotonin hormones, in which serotonin modulators can be prescribed. On the other hand, histamines may also be related but to a lesser extent; therefore, the use of antihistamine in most cases is ineffective.[1],[2]

Uraemia

Also known as renal itch, uraemia affects patients with chronic renal failure. This can happen to both dialysed and non-dialysed patients with no significant difference in the probability of occurrence, even with the absence of primary skin disease and/or psychological dysfunction. Manifestation of uraemic pruritus can be continuous or intermittent. In end-stage renal disease (ESRD), the extent of pruritus reaches up to 55 - 80%.[3]

Malignancy

Pruritus in malignancies can be attributed to multiple factors, i.e., cancer-causing cells that produce the itching sensation, side-effect of cancer medication, medications used in pain management (i.e. opioids) and complications from the malignancy such as renal failure and cholestasis.[1] Malignancy can be categorised as either solid tumours or haematologic disorders.

Pruritus in solid tumours is believed to signify disease progression. However, it could be due to an immunologic reaction to the tumour-specific antigens though the pathophysiology is not fully clear. Itch can be localised or generalised as perianal itch in colorectal cancer, vulvar itch in cervical cancer or scrotal itch in prostate cancer. It can also be caused by biliary obstruction, for example, in pancreatic cancers, in which biliary drainage by stenting is a very potent therapy.[1],[2]

Haematologic disorders such as leukaemia and lymphoma also present with itching; more frequently experienced than in solid tumours due to the direct infiltration of the skin in chronic myeloid leukaemia, lymphoma and polycythaemia vera. Pruritus is associated in about 30% of the patients with Hodgkin disease. About 30 - 50% of the patients with polycythaemia vera experience itching after taking a shower.[1],[2]

Opioid-induced pruritus

It is normally encountered with spinal administration of opioids with 20 - 90% incidence as compared to systemic opioids (<1%). The specific mechanism of the opioid-induction is still unknown. It is centrally mediated through μ-opioid receptors and prevented by κ-opioid receptors.[2],[4]

Infection

Infection is another probable cause of itching. Genital pruritus can be associated to genital infections such as sexually transmitted disease and acquired immunodeficiency syndrome (AIDS) that are triggered by human immunodeficiency virus (HIV). Varicella-zoster virus, which is responsible for chicken pox, can cause rash, blisters and itching.

Drug-induced (reaction) pruritus

Apart from the above-mentioned clinical conditions that can cause itching, drug administration can result in acute or chronic itching, as reaction, depending on the body's response. One of the common medications that have adverse pruritus effect are the highly active antiretroviral therapy drugs, which are used for the treatment of AIDS. Some antibiotics can cause urticarial rashes and systemic reactions as well.[4]


  Management of Pruritus Top


Regardless of the origin of pruritus, general skin measures play a big role in preventing and managing pruritus. Although it is not completely effective, in some cases, topical creams and ointments are helpful for patients who experience both acute and chronic itching as well as dry skin. Moisturisers (containing glycerol acetate, urea, petroleum, mineral oil and glyceryl stearate), corticosteroids, Vitamin D analogues, topical anaesthetics, capsaicin and menthol are some of the widely used topical treatments for pruritus.[5] Regular application of these emollients helps keep the skin moist and lubricated. Topical anaesthetics such as 2.5% lidocaine cream can be applied to the localised area of itch to anaesthetise nerve endings. Applying menthol or phenol to affected areas can also help by substituting itch with a cooling sensation. Moreover, applying agents such as capsaicin that block pruritus mediators can relieve itching. In the presence of inflammations, corticosteroids might be of help.[5] Bathing with lukewarm water and unscented soap are helpful in patients experiencing dry and bad skin reaction. [Table 1] enumerates the different general measures and different topical remedies for the management of pruritus.[1],[2],[4]
Table 1: General measures and topical remedies of pruritus management

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Systemic medications for the management of pruritus include antihistamines, opioid antagonists, serotonin modulators, antiepileptics, rifampicin, cholestyramine, thalidomide, nalfurafine, leukotriene antagonists, charcoal and oral cromolyn sodium, [Table 2].
Table 2: Pharmacologic treatments for pruritus

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Antihistamines

Also known as H1 receptor antagonists, antihistamines such as hydroxyzine and diphenhydramine act by blocking the histamines that are produced during itching. In addition, antihistamines have a sedating effect that can assist sleep, but on the other hand, may also result in some adverse anticholinergic effects such as dry mouth, nausea and headache. Due to these unwanted side-effects, low-sedating antihistamines such as loratadine and cetirizine are commonly used. However, because majority of the causes of pruritus in palliative care is not from histamines, administration of antihistamines is considered ineffective for pruritus management in palliative care. Since histamine is not a contributing factor in uraemia, this drug is ineffective in management of uraemic pruritus as well. Moreover, since histamine is involved in cholestatic pruritus only to a lesser extent, it is ineffective in cholestasis as well.[1],[2]

Opioid antagonists

Opioid-induced pruritus (OIP) is an adverse side-effect of therapeutic use of opioid medications. Pure opioid antagonists such as naltrexone and naloxone have been used for the management of OIP, as μ-opioid receptor antagonists are central mediators of pruritus.[1],[2],[4] Studies have shown that intake of pure opioid antagonists at a dosage of 50 mg/day, by patients not requiring opioids for pain control, to be particularly effective in the treatment of uraemic and cholestatic pruritus.[6],[7],[8],[9] However, these drugs are often unsuitable for the palliative patient population since most of these patients are using opioids for pain management. Opioid antagonists could reverse analgesia or lead to withdrawal symptoms. For OIP secondary to systemic opioids, the initial approach is to switch to a different opioid. Spinal opioids are frequently given with bupivacaine that reduces itch as well.[2]

Serotonin modulators

Serotonin reuptake inhibitors, referred to more simply as serotonin modulators, help in pruritus management by blocking reuptake of serotonin into presynaptic vesicles, hence significantly increasing the concentration of serotonin in the central nervous system. Different case reports have acknowledged the antipruritic role of centrally released serotonin. Below are the most common serotonin modulators used:

  • Ondansetron (Zofran) is a serotonin 5-HT3 receptor antagonist, which is used for managing pruritus associated with uraemia, opioids and cholestasis. Compared to other antipruritic medicines, it is rather expensive and can result in constipation, in which palliative patients are often distressed.[1],[2] In addition to these disadvantages, ondansetron reported no advantage over placebo, concluding no significant effectiveness for the management of pruritus [10]
  • Mirtazapine is primarily used to treat depression and post-traumatic stress disorder. However, with its 5-HT2, 5-HT3 and H1 receptor antagonist properties, it can also be used for the management of uraemic, cholestatic and malignant pruritus. Treatment usually begins with a 15 mg dose nightly, but a lower dose of 7.5 mg to begin is also effective. It can have some sedating effect and can cause weight gain [11]
  • Paroxetine is a serotonin reuptake inhibitor, and it can be administered to patients having pruritus associated with cholestasis, uraemia and opioids. Furthermore, paroxetine shows evidence of efficacy with management of pruritus secondary to malignant disease. Preferably, patients must start with small doses of 5 - 10 mg nightly to have fewer side-effects. Effects can usually be observed within 24 - 48 h [1],[2],[12]
  • Sertraline, an antidepressant of the serotonin reuptake inhibitors class, is considered the first-line treatment for cholestatic pruritus. Usage of sertraline shows effectiveness at the 25 mg dosage and tolerance level of patients to this medicine is high. A retrospective study shows that low-dose sertraline is effective for the management of antihistamine-refractory pruritus in patients with ESRD.[13]


Antiepileptic

Gabapentin and pregabalin which are commonly used as anticonvulsant or antiepileptic drugs have the capabilities of managing symptoms of pruritus by blocking neuropathic pathway. Gabapentin is approved by US Food and Drug Authority for the treatment of partial seizures and post-herpetic neuralgia. When used, patients tolerate it well, and there is no need for routine clinical laboratory monitoring. It does not have drug interactions due to its pharmacokinetics.[14] It is proven to be effective for the management of uraemic pruritus with low-dose administration of 300 - 400 mg after dialysis 3 times a week,[15],[16] but not for cholestatic pruritus.[17] Pregabalin, which is another anticonvulsant medicine, presented equal effectiveness as gabapentin based on a study wherein a randomised trial on 17 patients were given 75 mg of pregabalin and 300 mg of gabapentin after dialysis. Patients showed comparable level of tolerance toward the two medications.[18]

Rifampicin

Rifamipicin inhibits the uptake of bile acids by hepatocytes, and evidence suggests that it is second line of treatment for cholestatic pruritus, although the usage of this medication is unsatisfactory for most patients due to gastrointestinal side-effects such as constipation.[19],[20],[21] Rifamipicin is also consumed as an ansamycin antibiotic at the dosage of 300 - 600 mg/day, which exhibits antibacterial properties. A study has shown significant changes during a 14-day treatment period.[21]

Cholestyramine

Cholestyramine is more commonly known as a safe cholesterol-lowering agent being a bile acid sequestrant. Although cholestyramine has shown a level of efficacy for the management of cholestatic pruritus to some extent;[22],[23] because there is no correlation between the level of bile acids and the degree of pruritus, usage of cholestyramine is often ineffective. This drug is not effective for uraemic pruritus in addition to the adverse side-effects such as acidosis. Because of its low-cost, it is recommended to try this medication first before considering more expensive treatments. The usual administration of cholestyramine is 4 mg or 5 mg BID.

Thalidomide

As an immunomodulatory drug, thalidomide is the main treatment for multiple myelomas and leprosy complications. A common side-effect of this drug is sedation. A study has shown 81% mean reduction in pruritus scores of 29 haemodialysis case patients experiencing uraemic pruritus after administration of thalidomide at bedtime for 7 days.[24]

Nalfurafine (κ-opioid receptor antagonist)

From a κ-opioid receptor antagonist, nalfurafine just as thalidomide is used and found effective for the treatment of uraemic pruritus for haemodialysis patients.[25],[26] The activation of κ-opioid receptors is known to control the signals activated through micro-opioid receptors, hence reducing pruritus in patients undergoing haemodialysis. The most common side-effect is insomnia.

Montelukast

This CysLT1 leukotriene receptor antagonist is commonly used for maintenance treatment of asthma and to relieve symptoms of seasonal allergies. With administration of 10 mg/day, montelukast suggests effectiveness for the management of uraemic pruritus.[27]

Evening primrose oil

Evening primrose oil is rich in essential fatty acids such as γ–linolenic acid that aids the body in reducing inflammation and is found effective for the treatment of uraemic pruritus.[28]

Oral activated charcoal (6 g/d)

Although charcoal's mechanism of action in pruritus is unknown, a study had shown effectiveness of activated powdered charcoal in patients with uraemic pruritus when administered with 6 g/day dosage. Few advantages are safety, low-cost and effective.[29]

Oral cromolyn sodium (135 mg TID)

This acts by inhibiting the release of histamine and leukotrienes from the mast cell. A study had shown its effectiveness in the management of haemodialysis patients with uraemic pruritus with the administration of cromolyn sodium.[30]

Indomethacin

Patients with HIV can develop pruritus from different factors, i.e., xerosis, drug and photo eruptions, follicular and papular eruptions, and infections by a variety of organisms. A study compared four different regimes of treatment for pruritus caused by infection and showed that indomethacin provided relief more consistently and more effectively to the patients.[31]

Nonpharmacologic approaches

Aside from the above-mentioned medications, a number of non-pharmacologic approaches of treatment are available for patients experiencing severe pruritus. Surgery is also of benefit for gastric and pancreatic tumours to relieve the obstruction. On the other hand, stenting for bile duct obstruction can be considered in pancreatic cancer patients.[4] These procedures are particularly important in avoiding adverse side-effects from certain drugs. Ultraviolet B therapy, although exact mechanism is unknown, can be attempted for the management of cholestatic and uraemic pruritus and malignant skin infiltrations. It is done 3 times a week, but for patients who are toward their end of life, this is considered an impractical approach.[1],[2]


  Conclusion Top


Pathogenesis of pruritus is complex and to some extent is uncertain, and hence trying to understand its behaviour is challenging. Through different clinical trials, some medications and non-pharmacological procedures are found to be effective in the management strategy of certain types of pruritus. The suitability of medication mainly depends on the mechanism of action involved in the pruritus and of the medication itself; essentially the two should have reversing actions. If pruritus is not managed accordingly, this can adversely affect the QOL of the patients. General skin measures play a big role in preventing and managing pruritus.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2]


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