Managing Pruritus in Advanced Chronic Disease

Abstract

Even though pruritus affects a significant number of people with chronic disease, it is rarely adequately treated. Drug therapies often rely on antihistamines, which have not shown to be beneficial in systemic pruritus. Hydroxyzine is frequently used to treat pruritus associated with kidney failure. Since Canada’s sole manufacturer of hydroxyzine is no longer making this product, this is an ideal time to review the mechanisms of itch in advanced organ failure and the specific therapies that give relief. Although there is literature describing itch in patients with cancer, this article is limited to pathogenesis and treatment of systemic itch secondary to chronic, noncancer diseases. We summarize recent systematic reviews, although the studies included in these reviews are often small, and mostly cohort studies.

Key points:

Chronic diseases, such as diabetes, kidney failure, and chronic liver disease, are associated with systemic pruritus.

Severe systemic pruritis has a significant impact on quality of life, causing exacerbation of other symptoms (insomnia and pain) as well as new symptoms (mood disorder, social isolation).

Antihistamines should not be routinely used for systemic pruritus.

Treatment options include treating the underlying disorder along with discontinuing medications that are contributing to itch as well as drugs acting on opioid receptors, neuropathic agents such as gabapentin, and antidepressants.

Introduction

Chronic systemic pruritus affects a significant number of people with chronic disease, yet it is infrequently diagnosed and often not adequately treated. The constant presence of unrelenting itch can devastate a person’s quality of life. Pruritus typically affects people with advanced disease, but in persons with multiple comorbidities or significant symptom burden, it can debilitate much earlier.

Drug therapies have relied on antihistamines, which are not effective in systemic pruritus.¹ Hydroxyzine, commonly used in uremic pruritus, will no longer be available in Canada, forcing clinicians to move to new and more effective therapies. We provide this evidence-based narrative style, umbrella review, to aid clinicians treating those with pruritus secondary to organ pathology and diabetes. Although guidelines on management of pruritus exist, this article is focused on organ failure and diabetes.

Methodology

We conducted a targeted literature search of MEDLINE, PubMed, and Cochrane database from inception to January 2024. Search terms included “chronic itch,” “chronic pruritus,” “systemic itch/pruritus,” “uremic itch/pruritus,” “cholestatic itch/pruritus,” “itch/pruritus in heart failure,” “itch/pruritus in diabetes,” “symptoms with kidney disease, liver disease, heart failure and diabetes,” and “pruritis/itch and quality of life.” We limited the search to articles in English. Our search focused on clinical guides, systematic reviews, and meta-analyses. We included original and review articles that showed at least some effectiveness, even if sample sizes were small or the study was not as robust as a randomized controlled trial (RCT) and excluded studies that lacked relevance (Supplementary Tabel S1).

How Common is Itch?

Itch is more common in older adults because of medical comorbidities, dry skin, and pathology of the nervous system.² Pruritus is common in advanced chronic kidney disease (CKD) affecting up to 65% of patients. Of those, 37% have moderate symptoms and 7% have severe issues. Up to 17% do not report itch due to not being aware of its link to renal failure, believing it is part of aging, and prioritizing other health care needs over itch.³ In chronic liver disease (CLD), the prevalence of itching is as high as 70%, depending on the underlying disorder.⁴ In advanced heart failure (HF), older studies have reported an incidence of 10%–40% but it has not been well studied.⁵ Diabetics have an increased prevalence of itching, likely related to comorbidities and polyneuropathy.

Underlying Mechanism of Itch

The 1630 definition of pruritus as an unpleasant sensation that results in an urge to scratch remains valid today. Not until the mid-20th century did clinicians realize itch could be a “sensory neurosis of the skin” that could occur with or without lesions. Throughout history, therapies have ranged from travel to a different climate, blood-letting, to ionizing radiation, all with little improvement.⁶

There are four main causes of chronic itch: 1) dermatologic, or primary skin disorders, 2) neuropathic, 3) psychogenic, and 4) systemic (chronic renal, hepatic, and cardiac failure). In systemic pruritus, coexisting dermatological disorders, or comorbidities (e.g., cancer), and drugs, can complicate the diagnosis and should always be considered in the diagnosis.

In dermatologic itch, where mast cells and other immune cells release histamine, histaminergic C fibers in the skin are triggered, resulting in neurogenic inflammation and the classical allergic skin reactions. These types of itch respond well to antihistamines.⁷

Chronic or systemic pruritus, results from the stimulation of nonhistaminergic C fibers. Nonhistaminergic receptors make up 80%–90% of itch fibers, and transmit their signals through numerous receptors in the dorsal horn. Secondary afferent nerves transmit the signal to the thalamus and beyond to multiple areas of the cortex that process the sensation of itch and initiate the scratch response. Itch is intrinsically inhibited by a central inhibitory pathway from the cortex to thalamus to dorsal horn, peripheral cold receptors, and kappa-opioid receptors.⁵

The process of peripheral and central sensitization in systemic itch is similar to that of chronic pain, which has implications for understanding the resulting symptoms and changes in the neural system, as well as for therapies. Neurogenic inflammation, neuronal plasticity, and sensitization of nerve fibers result in dysregulation of neuroimmune circuits and persistent itch as described in detail by a recent review.⁸

Impact of Systemic Itch

Itch ranges from a momentary sensation to an unrelenting severe preoccupation that disrupts sleep, affects mood, and lowers quality of life. Unrelenting pruritus affects sleep cycle, mood, anxiety, and leads to social withdrawal. Sleep disturbance results in increased intensity of other symptoms, including pain, anxiety, and depression, with suicidal ideation reported in 18.5% of patients with chronic itch.⁹

In CKD patients with systemic pruritus, 45% of patients report impaired sleep and in those on dialysis, severe pruritus contributes to missed sessions and cessation of dialysis.¹⁰

Persons with chronic pruritus have a lower health-related quality of life than patients with a history of stroke, and its constant presence can be as debilitating as chronic pain.¹¹ Because of its impact on daily life and its collateral impact on other physical, psychological, and existential symptoms, itch needs to be diagnosed and treated aggressively, throughout the trajectory of the illness.

Assessment of Itch

Determining the underlying cause of pruritus is important because it influences the treatment choices. In systemic pruritus, coexisting dermatological disorders, comorbidities (such as cancer), drugs, and in some cases, a combination of etiologies can exist. This needs to be factored in when making treatment decisions.

It is important to treat the underlying disease first, where possible, and discontinue medications that contribute to the disorder or itch.

Incorporating routine surveillance for itch during clinical encounters will ensure it is not missed. Commonly used itch assessment tools include the visual Analog scale and the 5-D Itch tool.^12,13 Simple tools such as the revised Edmonton Symptom Assessment System for renal patients can help patients quantify the symptom of itch on a 0–10 numerical scale¹⁴ along with other symptoms that can be associated with chronic itch.

Treatment Options for Systemic Pruritus in Organ Failure

Table 1 presents the pruritogens, the possible mechanisms and potential therapies in systemic pruritus.

Table 1.

Mechanisms and Treatments of Systemic Pruritus

Disease	Assessment	Mechanism	Potential drug therapy	Notes
Chronic kidney disease	Is the dialysis regime optimized (for patients on dialysis)? What does the skin look like? Is there evidence of urticaria? Is there visible skin dryness? Are there other comorbidities?	Skin changes with atrophy of sebaceous glands leading to xerosis Imbalance of endogenous opioid system Uremic neuropathy Abnormal metabolism Immunopathology	Emollients/moisturizers Gabapentin 100–300 mg daily/pregabalin 25–50 mg daily (observe closely for accumulation). Sertraline 50–100 mg/paroxetine 5–10 mg daily Consider naltrexone 50 mg/montelukast 10 mg/Aprepitant 80 mg daily/sodium thiosulfate 12.5 g 2–4 weekly/topical capsaicin (if localized itch)	Nalfurafine shown to improve itch in RCTs but only available in Japan Naltrexone not effective in RCT but can consider it if other options have been ineffective
Chronic liver disease	What are the options for treating the underlying disorder? What does the skin look like? Is there evidence of urticaria? Is there visible skin dryness? Are there other comorbidities? Have bile sequestrants been optimized?	Cholestasis leading to elevated bile acids Imbalance of endogenous opioid system Elevated neuropeptides and other pruritogens	Emollients/moisturizers Rifampicin 300–600 mg daily Naltrexone 50 mg daily Sertraline 50–100 mg/paroxetine 5–10 mg daily Mirtazapine 7.5–15 mg daily (can increase further if tolerated) Topical capsaicin (if localized itch)	Rifampicin has been shown to improve itch in 77% of patients RCTs have not shown benefit with gabapentin
Heart failure	Is the patient on drugs that may be causing itch (ACEIs, ARBs, B-blockers, amiodarone, statins, Ca channel blockers, hydrochlorothiazide, heparin)? What does the skin look like? Is there evidence of urticaria? Is there visible skin dryness? Are there other comorbidities?	Drugs used to treat heart failure Comorbidities—liver dysfunction, renal impairment Peripheral edema Abnormal metabolism Immunopathology	Loop diuretics may be beneficial Emollients/moisturizers Sertraline 50–100 mg/paroxetine 5–10 mg daily Gabapentin 100–300 mg daily/pregabalin 25–50 mg daily Mirtazapine 7.5–15 mg daily (can increase further if tolerated) Topical capsaicin (if localized itch)	No studies of drugs used for itch specific to heart failure It may not be possible to discontinue all drugs
Diabetes	Is the diabetes adequately controlled? What does the skin look like? Is there evidence of urticaria? Is there visible skin dryness? Are there other comorbidities?	Poorly controlled disease Skin changes leading to xerosis Polyneuropathy Neurogenic inflammation	Emollients/moisturizers Metformin may be beneficial Gabapentin 100–300 mg/pregabalin 25–50 mg daily Sertraline 50–100 mg/paroxetine 5–10mg daily Topical capsaicin (if localized itch)	Clinically relevant neuropathy seen in almost 50% pf patients, associated with longer duration of disease

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.

Of the limited studies that exist in this area, most are studies in patients with CKD, some are in patients with CLD.

Potential treatments are limited by side effects, challenges with metabolism and clearance, with smaller doses prescribed off label. In hemodialysis patients, renally cleared drugs can accumulate predialysis, leading to side effects more problematic than the pruritus, as well as reduced efficacy during and immediately following dialysis for drugs that are then dialyzed out.

Good general care of the aging skin, in addition to general measures such as cooling and emollients can also help. Patients with CKD and diabetes often have dry skin and changes in skin pH due to atrophy of the sebaceous glands and thickening of the basement membrane. Moisturizers have been shown to improve itch in patients with CKD.^4,9 Treatment of pruritus in the elderly starts with ensuring use of moisturizers and emollients to address the underlying skin changes contributing. If this does not prove effective, targeting itch aggravated by organ disease is as outlined in Table 1.

Treatment of other symptoms caused by itch, such as insomnia, depression, anxiety is essential. Mirtazapine, which has serotonin and norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor (SSRI) effect, may be helpful in management of insomnia while also reducing sensation of pruritus. Studies in patients with underlying cancer and pruritus show mirtazapine can help, probably by blocking elevated excitatory neuropeptides (serotonin, norepinephrine) implicated in itch and activating descending inhibitory systems, although there are no RCTs supporting their use.¹⁵ Methadone, used as an N-methyl-D-aspartate receptor antagonist, may provide relief for patients with chronic pain and systemic itch.⁷

Chronic Kidney Disease

Many cohort studies around the world show that updated dialysis methods are associated with reduced pruritus.¹⁶ Improvement may be due to better removal of inflammatory cytokines.

Observational studies and RCTs have shown reduction in pruritus with gabapentin and pregabalin.¹⁷ In addition, 2020 Cochrane Database review determined that of all researched treatments for uremic pruritus, gabapentin and pregabalin were the most studied and show the greatest reduction in itch scores. Further RCTs, even large RCTs, are unlikely to significantly change this finding.¹⁸ Doses are often much smaller, limited by potential for accumulation, and side effects of sedation, drowsiness, dizziness, and fatigue. Increased itch during and after dialysis may require a complex and creative dose regime.⁷

The main opioid receptors are µ-opioid receptors (MOR), κ-opioid receptors (KOR), and δ-opioid receptors, and they play a role in pruritus. MOR activation can induce itch, whereas KOR activation can inhibit itch. Although less robust compared with gabapentin and pregabalin,¹⁶ difelikefalin and nalfurafine are KOR agonists that have been shown to improve itch in patients with CKD in multicenter RCT and phase 3 clinical trials.¹⁹ While it has been approved for use, the Canadian Drug and Health Technology Agency has not recommended approval for reimbursement for difelikefalin in treating uremic pruritus citing high placebo response and challenges determining treatment effect from the medication itself. Nalfurafine is widely available in Japan and though available in Canada, it is not covered by existing federal and provincial drug plans, and therefore costly, limiting its use. Naltrexone, a nonselective opioid antagonist, has shown variable benefit in small trials.^20,21 In addition, naltrexone may precipitate symptoms of withdrawal and worsening of pain in those on chronic opioid therapy for palliative symptom management.

If pregabalin or gabapentin proves ineffective and there is no access to KOR agonists, consider the following options: UV-B therapy, widely used for atopic dermatitis and psoriatic pruritus, has demonstrated effectiveness in uremic pruritus.²² Although the results were borderline in a parallel study in 50 hemodialysis pts (sertraline vs. placebo), SSRIs through their effect on descending inhibitory pathways may be worth trying.¹⁶ An RCT of montelukast, a leukotriene inhibitor, for use in uremic pruritus showed statistically significant reduction in severity compared with placebo for refractory symptoms.²³

Chronic Liver Disease

Treatments should be aimed at improving the underlying disorder first and may differ depending on the primary disorder.

Ursodeoxycholic acid (UDCA) increases the hepatic clearance of bile acids. A meta-analysis of seven RCTs showed many patients will respond.²⁴ Bezafibrate is a peroxisome proliferator-activated receptor agonist that has shown to improve pruritus in patients with primary biliary cirrhosis and primary sclerosing cholangitis. It may also improve fatigue. Cholestyramine is a bile acid sequestrant that binds bile in the gastrointestinal tract, preventing its reuptake. Two small RCTs demonstrated benefit in cholestatic itch,¹⁶ although its use is often limited by its side effects of constipation, nausea, and abdominal pain in addition to a terrible taste. Rifampicin increases excretion of pruritogens and has an antimicrobial effect on gut mucosa and has been shown to improve pruritus in a meta-analysis comparing placebo or alternatives, but a small RCT in patients with mixed liver diseases did not show benefit.²⁵ Naltrexone can improve itch in liver disease by suppressing MOR. It has been shown to be effective in three RCTs.²⁶ SSRIs such as sertraline and paroxetine, starting with low doses may be helpful when rifampicin and UDCA are not helping, although there are no RCTs in liver patients.²⁷ There are also case reports of tricyclic antidepressants relieving itch in cholestatic itch.¹⁶

Heart Failure

Evidence for itch and its management in HF is significantly lacking. Patients with HF often have coexisting liver dysfunction, diabetes, and CKD. In a small study of hospitalized patients with acute HF, bilirubin was found to be elevated in patients with HF and itch;⁶ therefore, cholestasis may play a role in causing itch in some patients with HF, although underlying mechanisms are still largely unknown.

Many drugs used in the treatment of HF are associated with pruritus, such as angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Conversely, loop diuretics may help by acting on the inhibitory itch pathways.

Diabetes

Approximately 35% of patients with type II diabetes and 20% of patients with type I diabetes complain of itch. There appears to be at least some correlation with poorly controlled disease and dermatologic as well as systemic mechanisms at play.²⁸ Neuroinflammation appears to be a significant cause of chronic itch in diabetes.²⁹ Gabapentin and pregabalin and SSRIs such as sertraline and paroxetine may be beneficial, although none have been specifically studied in patients with diabetes.

Off-Label and Emerging Therapies

Aprepitant, most commonly used for management of nausea, can reduce systemic itch through blocking neurokinin-1 receptors at multiple sites, resulting in reduced production of several mediators, including histamine, leukotriene, and prostaglandins.³⁰ Maralixibat inhibits the enterohepatic circulation of bile acids by blocking the reabsorption of bile acids through apical sodium-dependent bile acid transporters. It is approved for use in a rare genetic disorder that causes significant build-up of bile and phase 2 clinical trials showed significant improvement in pruritus.²⁹ Topical treatments could be used as adjuvant therapy in localized areas if they prove to be refractory to systemic treatments. Pramoxine, gamma linolenic acid moisturizing creams, and capsaicin have all shown some benefit in reducing pruritus. Capsaicin reduces pruritus by depleting the sensory nerve Substance P reserves and reducing neuroinflammation, although the use may be limited by burning discomfort in the first two weeks of application.¹⁰ Reducing the concentration of the capsaicin and increasing it as tolerated can mitigate this. Limited data suggest that topical cannabinoids may offer benefit in reduction of uremic pruritus.³¹ Trials are limited in size and quality. Other topical interventions under investigation include topical calcineurin inhibitors such as tacrolimus for localized symptoms and compounds of ketamine–amitriptyline–lidocaine, likely through multiple mechanisms.³²

Conclusion

Pruritus in chronic disease is common, has significant effects on quality of life, yet treatment options remain limited. Despite this, it is important to screen for it, especially in patients with CKD, CLD, diabetes, and HF. As our knowledge of underlying mechanisms of pruritus improves, new treatment options should emerge.

Footnotes

Author Disclosure Statement

Dr. Kaya is the current pastpresident of the Canadian Society of Palliative Care Physicians (CSPCP), Drs. McDonald and Gallagher are Directors-at-Large for the CSPCP.

Funding Information

This article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Supplementary Material

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Supplementary Material

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