Overview of pruritus in palliative care

INTRODUCTION — Pruritus (itch) is the unpleasant sensation that provokes an urge to scratch. Fortunately, pruritus is relatively uncommon in the palliative care population, and when present, may be short-lived or go unreported. However, in a minority of patients, pruritus may be severe or persistent, resulting in significant distress and poor quality of life [1,2].

The palliative care population includes a diverse group of patients with disparate advanced diseases, and the overall prevalence of significant pruritus in this population has not been well studied but may be as high as 35 percent in hospitalized palliative care patients [3].

This topic will present information on the management of common causes of pruritus in palliative care patients. Further discussion of pruritus in the general population, and in patients with uremia and cholestasis, is provided separately. (See "Pruritus: Therapies for localized pruritus" and "Pruritus: Etiology and patient evaluation" and "Chronic kidney disease-associated pruritus" and "Pruritus associated with cholestasis".)

Classification and pathophysiology — The International Forum for the Study of Itch proposes a two-tier classification system for pruritus based on whether the etiology is known or not [4]. When the etiology is known, pruritus is further divided into dermatologic, systemic, neurologic, psychogenic, and mixed categories. (See "Pruritus: Etiology and patient evaluation", section on 'Classification'.)

Although the neurologic pathways that lead to itch are not fully understood, it is generally accepted that transmission of signals along unmyelinated, histamine-sensitive, and non-histamine-sensitive peripheral C nerve fibers is involved. These fibers represent a minority (up to 5 percent) of C nerve fibers in the body and are distinct from the C nerve fibers that transmit pain. They are characterized by a slow conduction velocity and extensive terminal branching. Histamine-sensitive fibers have an important role in the transmission of acute itch and itch in urticaria, while non-histamine sensitive nerve fibers have a significant role in itch transmission of most types of chronic itch, possibly accounting for the poor response of many types of chronic itch to oral antihistamines.

Both scratching and rubbing the skin inhibit the sensation of pruritus by stimulating inhibitory local circuits in the spinal cord and brain; scratching also stimulates pain receptors, which inhibits the sensation of itch. The inhibitory interneurons can be activated by both peripheral and central stimuli, and they release endogenous opiates. Additionally, central sensitization for itching may occur in patients with chronic pruritus such that noxious stimuli are perceived as itch rather than pain. (See "Pruritus: Etiology and patient evaluation", section on 'Pathogenesis'.)

COMMON ETIOLOGIES IN PALLIATIVE CARE — Pruritus in the palliative care population is often multifactorial, and the main causes are related to chronic kidney failure, cholestatic liver disease, hematologic or lymphoproliferative disorders, other forms of malignancy, immunotherapy in cancer patients, and drugs (especially opioids) (table 1). Additionally, dry skin is frequently present, especially in older adults, and can exacerbate all causes of pruritus.

Uremic pruritus — Pruritus is a frequent symptom in patients with advanced or end-stage kidney disease [5]. It is usually generalized and may be intermittent or continuous. Pruritus is mainly associated with chronic rather than acute kidney failure, occurring most frequently in patients who are on maintenance dialysis (40 to 50 percent of patients) [6,7]. It may accompany either primary or secondary kidney disease, such as that due to heart failure. (See "Chronic kidney disease-associated pruritus", section on 'Epidemiology'.)

The pathogenesis of uremic pruritus is multifactorial and includes skin atrophy and dryness due to secondary hyperparathyroidism, accumulation of pruritogenic metabolites, and abnormal mast cell proliferation in skin. Dry skin is present in 66 to 93 percent of patients with uremic pruritus. (See "Chronic kidney disease-associated pruritus", section on 'Pathophysiology'.)

Cholestasis — The most common cholestatic liver disorders in palliative care populations are malignancy-related and are characterized by diminished delivery of bile into the intestine. Tumors that may produce extrahepatic and/or intrahepatic biliary obstruction include liver tumors (primary or metastatic), gallbladder cancers, and tumors obstructing the common bile ducts (eg, extrahepatic cholangiocarcinomas, pancreatic cancer). Approximately 45 percent of patients with malignant biliary obstruction report pruritus [8]. A presumptive diagnosis of cholestasis-associated pruritus can be made in a patient with cholestasis who complains of itching. (See "Pruritus associated with cholestasis", section on 'Associated conditions'.)

The pathogenesis of pruritus in cholestasis in unknown, but both peripheral and central mechanisms appear to be involved. Several hypotheses have been proposed, including bile acid accumulation, increased endogenous opioids [9,10], and elevations in lysophosphatidic acid levels. While bile acids are potential mediators of pruritus, no direct correlation has been demonstrated between pruritus and the severity of the underlying liver disease or circulating bile acid levels. (See "Pruritus associated with cholestasis", section on 'Pathogenesis'.)

Malignancy — Several forms of malignancy may cause pruritus, including conditions not associated with cholestasis. The most common hematologic and nonhematologic malignant disorders associated with pruritus include Hodgkin lymphoma, non-Hodgkin lymphoma, myeloproliferative syndromes such as polycythemia vera, mycosis fungoides, the leukemias, and histamine-producing gastric carcinoid tumors. (See "Pruritus: Etiology and patient evaluation", section on 'Malignancy'.)

Pruritus related to malignancy often represents a paraneoplastic syndrome. Less common causes include cutaneous metastases [11], lymphocytic infiltration, or the compressive effect of a tumor, such as with a tumor nerve entrapment syndrome (eg, spinal tumors causing brachioradial pruritus). (See "Pruritus: Etiology and patient evaluation", section on 'Brachioradial pruritus'.)

In general, the prevalence of pruritus is higher in hematologic malignancies than in solid tumors [12]. For example, several hematologic disorders, such as cutaneous T-cell lymphoma (CTCL), Hodgkin lymphoma, multiple myeloma, and leukemia, are associated with pruritus which may be caused by cutaneous disease infiltration, a paraneoplastic process, or both. Pruritus is one of the hallmarks of mycosis fungoides and its leukemic variant Sézary syndrome, with the prevalence and severity increasing in advanced stages [13]. Generalized pruritus is present in over 80 percent of patients with Sézary syndrome, approximately 50 percent with polycythemia vera, 30 percent with Hodgkin lymphoma, 10 percent with non-Hodgkin lymphoma, and 5 percent with leukemia [14-16]. With advancing disease, pruritus is often severe, diffuse, and accompanied by a burning sensation similar to neuropathic pain. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Pruritus'.)

Specific syndromes include:

●Paraneoplastic pruritus – The Special Interest Group of the International Forum for the Study of Itch defines paraneoplastic pruritus as "a systemic reaction to the presence of a solid tumor or a hematologic malignancy neither induced by the local presence of cancer cells nor by tumor therapy" [14]. In this setting, pruritus is usually generalized, may precede the diagnosis of the malignancy by months to years, and tends to increase in severity with advanced stages of illness [17,18].

The pathophysiology of paraneoplastic pruritus is not well understood, but it appears to involve an immunologic reaction to tumor-specific antigens. Several data suggest that high and unbalanced production of cytokines results in histamine-independent itching. Other studies suggest a role of interleukin 31 (IL-31) as an important mediator of pruritus in CTCL [19,20]. In subjects with polycythemia vera, aquagenic pruritus has been shown to be associated with increased skin infiltration and mast cell degranulation [21], and it is more pronounced in patients showing the JAK2 617V mutation. (See "Clinical manifestations and diagnosis of polycythemia vera", section on 'JAK2 mutations'.)

●Localized pruritus – Localized pruritus at specific sites has been observed in solid tumors, such as in the scrotum (prostate cancer), perianal region (colorectal and anal cancers), vulva (cervical cancer), and nostril (brain tumors infiltrating the floor of the fourth ventricle). Cutaneous metastases, particularly breast cancer, may occasionally present with rash, pain, and/or pruritus [22,23].

●Treatment-related pruritus – Pruritus in cancer patients may also be due to cancer treatments, such as molecularly targeted therapies (eg, epidermal growth factor receptor [EGFR] inhibitors, tyrosine kinase inhibitors, BRAF inhibitors, MEK inhibitors, immune checkpoint inhibitors), and opioids, which are frequently prescribed for pain management in cancer patients (table 2). (See 'Drug-related' below.)

HIV/AIDS — Pruritus is a common symptom in patients with human immunodeficiency virus (HIV) infection, with a prevalence between 31 to 45 percent. (See "Pruritus: Etiology and patient evaluation", section on 'Infections'.)

Pruritus due to HIV can be present with or without obvious skin lesions (eg, pruritic papular eruptions and folliculitis). In addition, drug eruptions, skin infections and infestations (eg, scabies, pediculosis corporis and pubis), and dry skin are other causes of pruritus in this patient population. HIV patients with peripheral neuropathy may also complain of localized pruritus.

A small subset of HIV patients have severe refractory pruritus, often associated with recurrent crops of discrete, erythematous, urticarial follicular papules and rare pustules with hypereosinophilia, thought to be due to hyperactivation of humoral immunity and characterized by a higher HIV viral load than in patients without this condition [24]. (See "HIV-associated eosinophilic folliculitis".)

Drug-related — Opioids are likely to be a common cause of drug-related pruritus in this population. In addition, some antibiotics (such as penicillins, trimethoprim-sulfamethoxazole), statin drugs, and nonsteroidal antiinflammatory drugs have been associated with pruritus without an associated skin eruption (table 2). Some antineoplastic agents, both conventional cytotoxic drugs and molecularly targeted therapies, such as immune checkpoint inhibitors, EGFR inhibitors (including tyrosine kinase inhibitors), BRAF inhibitors, and MEK inhibitors, can also cause pruritus, even in the absence of a cutaneous abnormality. (See "Pruritus: Etiology and patient evaluation", section on 'Drug reactions' and "Toxicities associated with immune checkpoint inhibitors", section on 'Dermatologic and mucosal toxicity'.)

The mechanisms through which medications induce pruritus vary and may include drug-induced dry skin (eg, with cetuximab and other EGFR inhibitors) or phototoxicity (eg, with doxycycline). (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy" and "Cutaneous adverse effects of conventional chemotherapy agents".)

Opioids — Opioid therapy is the cornerstone of management of moderate to severe pain in palliative care, especially in patients with cancer, and is administered through oral, transdermal, subcutaneous, neuraxial, and intravenous routes.

Neuraxial opioids — Pruritus is a frequent phenomenon with neuraxial opioids in the postoperative or postpartum settings, occurring in 30 to 100 percent of patients [25-31]. Pruritus usually begins shortly after analgesia, with the incidence, duration, and pruritic severity depending on the type and dose of the opioid and whether a local anesthetic was concomitantly administered, which decreases both the incidence and the severity of pruritus.

Intrathecal morphine administration has been associated with a high incidence of pruritus (70 to 85 percent) [28,32,33]. Lipid-soluble opioids, such as fentanyl and sufentanil, invoke pruritus of a shorter duration than intrathecal morphine. (See "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Pruritus'.)

However, patients receiving intrathecal opioid administration for longer duration such as for chronic pain have been shown to have the same low rate of pruritus at four weeks as those taking oral opioids [34]. Further, in the single large trial of chronic intrathecal opioids versus systemic opioids, pruritus was less common with intrathecal therapy [34].

Systemic opioids — Pruritus is about as common in patients treated with systemic opioids as in those treated with neuraxial opioids. Persistent or troublesome pruritus occurs only in approximately 1 percent of patients overall [35,36]. However, mild or transient episodes of pruritus are reported in up to 10 percent of patients on chronic systemic opioids, higher with intravenous than oral opioids. When present, pruritus is usually generalized and not associated with a rash.

Pruritus may be more common with naturally occurring opioids, such as codeine and morphine, as compared with semisynthetic (eg, hydrocodone and oxycodone) and synthetic opioids (eg, methadone and fentanyl), although data are conflicting [37-40].

Mechanism — The mechanism of opioid-induced pruritus (OIP) is uncertain [41]. Many mechanisms have been postulated that involve peripheral-acting (including histamine release from mast cells) and/or central-acting pathways, but no single mechanism can explain all instances of OIP:

●OIP may be mediated through central mu-opioid receptors [42-51]. A central role for mu-opioid receptors is supported by the fact that mu-opioid receptor antagonists have a primary role in preventing or treating OIP caused by neuraxial opioid administration, at least in the perioperative setting. (See 'Opioid-induced pruritus' below and "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Pruritus'.)

●OIP arising from central mechanisms may also be mediated through 5 hydroxytryptamine subtype 3 (5-HT3) receptors and may be potentially improved through the use of 5-HT3 antagonists such as ondansetron [52-55].

●On the other hand, both peripheral and central mechanisms appear to play a role in pruritus associated with systemically administered opioids:

•Opioid peripheral effects can include cutaneous vascular (wheal and flare) responses, which, depending on the opioid, involve histamine release from mast cells, a direct opioid receptor effect on the vasculature, or both [49,56,57]. Opioids such as morphine, meperidine, and fentanyl invoke both pruritus and vascular responses; while naloxone, a mu-opioid receptor antagonist, completely blocked fentanyl effects, it did so only partially for morphine and meperidine [56]. Further, while antihistamines had no effect on fentanyl cutaneous reaction, they exhibited partial blocking effects for the cutaneous vascular response with morphine and meperidine.

•In other experiments, morphine and codeine (but not fentanyl, oxymorphone, or tramadol) have been shown to directly release histamine from skin mast cells in a nonimmunologic manner [49,50,56,58-60].

These data suggest that effects of fentanyl, oxymorphone, and tramadol on pruritus with or without wheal and flare response are histamine independent and involve mu-opioid receptors, while the effect of other opioids, such as morphine, codeine, and meperidine, involve both mu-opioid receptor and histamine-related mechanisms [49,56,57]. Although more research is warranted, studies suggest that attempts to antagonize the pruritic or cutaneous vascular effects of systemically administered opioids that are known to release histamine with antihistamines alone will only have partial effects. (See 'Systemic drugs for patients with persistent or generalized pruritus' below.)

Management of OIP is discussed below. (See 'Opioid-induced pruritus' below.)

MANAGEMENT — Due to the different causes and underlying mechanisms of pruritus in palliative care patients, there is no universally effective antipruritic strategy. An individualized stepwise approach that incorporates symptom severity, clinical circumstances and goals of care, the presumed etiology of the pruritus, and response to initial therapies is recommended.

Our approach is to begin with general skin care and topical therapies, due to the lower propensity of side effects, especially when pruritus is intermittent, mild, and/or localized. (See 'Skin care measures for all patients' below and 'Topical therapies' below.)

For patients with persistent or generalized pruritus, or those in whom topical therapies are not effective, we use systemic pharmacologic agents. (See 'Systemic drugs for patients with persistent or generalized pruritus' below.)

When known, the presumptive etiology can guide the choice of initial therapy. (See 'Recommendations for specific clinical syndromes' below.)

Skin care measures for all patients — General skin care measures are recommended for all patients, regardless of the cause of pruritus. Dry skin can accompany and exacerbate all causes of pruritus; therefore, measures to regularly lubricate the skin with nonfragrant topical emollients, especially after bathing, are important. Patients should be educated on wearing nonirritating and loose clothing, avoiding skin irritants such as perfumes, and maintaining a cool, humidified environment. (See "Pruritus: Therapies for generalized pruritus", section on 'Elimination of aggravating factors'.)

Topical therapies

Treatments for most patients — A number of topical agents, such as cooling agents, anesthetics, substance P and calcineurin inhibitors, corticosteroids, and antihistamines have been used for symptomatic improvement of itch, with varying degrees of success. There are no comparative data, and one class of topical therapy cannot be recommended over any other for specific patients. These treatments are described briefly below and are discussed in detail separately. (See "Pruritus: Therapies for localized pruritus", section on 'Topical therapies'.)

●For localized areas of itching with no evidence of inflammation, the initial approach in the palliative care population includes the use of topical cooling agents (either 1% menthol or 0.5 to 2% camphor), which substitute the sensation of a cooling effect for itching and are well tolerated. They can be used with or without topical anesthetics.

Available topical anesthetic agents include lidocaine, prilocaine and pramoxine. Examples of common over-the-counter preparations include lidocaine cream (2.5%), lidocaine patch (5%), lidocaine-menthol cream, lidocaine-menthol patch, mixture of lidocaine 2.5% and prilocaine 2.5% cream (EMLA), and pramoxine 1% lotion. Application of large quantities of lidocaine or EMLA should be avoided because systemic absorption may occur. Methemoglobinemia is a potential consequence of EMLA use in young children. (See "Clinical use of topical anesthetics in children" and "Pruritus: Therapies for localized pruritus", section on 'Topical anesthetics'.)

Pramoxine 1% lotion, applied twice a day to the affected area, was shown to be superior to placebo in reduction of pruritus symptoms (61 versus 12 percent) in a four-week randomized trial of 28 patients with uremic pruritus [61]. (See 'Uremia' below.)

Patients with inflammation

●Topical corticosteroids are effective for treatment of inflammatory skin disease, which often results in the concomitant relief of the associated pruritus. These agents are not indicated for pruritus without evidence of skin inflammation. (See "Pruritus: Therapies for localized pruritus", section on 'Topical anti-inflammatory agents'.)

Other topical treatments

●Topical antihistamines are generally avoided in this patient population due to concern for systemic absorption. Doxepin (5%) cream has been used for atopic dermatitis, but there are insufficient data for use of other antihistamines, including topical diphenhydramine. Topical diphenhydramine toxicity has been well described due in part to its erratic absorption [62]. Potential adverse effects of topical doxepin include drowsiness and dry mouth from systemic absorption, as well as contact dermatitis and stinging or burning at the site of application. Its use should therefore be limited to very localized areas of pruritus involving less than 10 percent of the body surface, and to no more than a few days, with a maximum topical dose of 3 g per application up to three times daily. (See "Pruritus: Therapies for localized pruritus", section on 'Topical antihistamines'.)

●The role of other topical therapies such as capsaicin (8-methyl-N-vanillyl-6 nonenamide) and calcineurin inhibitors is unclear. Capsaicin is a substance derived from chili peppers that has been used for the treatment of chronic pain and pruritus [63]. It acts by activating the transient receptor potential vanilloid 1 (TRPV1) ion channel on C fibers, which stimulates neurons to release substance P, eventually depleting it. Initial application of capsaicin (0.025 to 0.1%) ointment causes a burning sensation that may last for up to 30 minutes, which limits its use for localized pruritus and contributes to poor compliance. A topical anaesthetic applied prior to capsaicin may help. A systematic review of randomized trials found insufficient evidence for efficacy in patients with pruritus [64]. (See "Pruritus: Therapies for localized pruritus", section on 'Topical capsaicin'.)

●Topical calcineurin inhibitors, including tacrolimus (0.03 and 0.1% ointments) and pimecrolimus (1% cream), may be useful for itch associated with various inflammatory skin disorders, such as atopic dermatitis, anogenital pruritus, chronic hand dermatitis, and nonsclerotic chronic graft-versus-host disease. As with capsaicin, the mechanism of action may also involve initial release of substance P, and they may also be associated with an initial burning sensation. (See "Pruritus: Therapies for localized pruritus", section on 'Topical anti-inflammatory agents' and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Overview'.)

Systemic drugs for patients with persistent or generalized pruritus — Several pharmacologic therapies are used in palliative care patients with pruritus. Antihistamines (H1 receptor antagonists) are not routinely recommended, as most of the causes of pruritus in palliative care do not involve histamine release. However, the sedating effect of antihistamines might have a beneficial effect in patients who are unable to sleep due to pruritus symptoms.

If effective, all systemic drugs tend to work quickly. For most patients with pruritus, we would usually start with one drug class and, if there is no relief within a day, we would move on to a different class. Specific treatments for conditions common in palliative care patients are presented below. (See 'Recommendations for specific clinical syndromes' below.)

Efficacy in palliative care patients — Data to support efficacy of these agents in the general patient population are reviewed elsewhere. (See "Pruritus: Therapies for generalized pruritus".)

In a 2023 review of 91 studies assessing the effects of 51 different interventions for pruritus of multiple origins in participants with advanced disease, the strongest evidence of benefit was for gamma-aminobutyric acid (GABA) analogues compared with placebo in patients with uremic pruritus (five trials), and lesser benefit from treatment with kappa-opioid receptor agonists compared with placebo (six trials) [65]. In addition, seven studies compared gabapentin with antihistamines, showing superiority of gabapentin in most cases. Evidence was uncertain or low regarding treatments for cholestatic pruritus, and no therapies for pruritus associated with malignancy were found to be effective.

Recommendations for specific clinical syndromes

Cholestasis — For patients with malignant extrahepatic biliary obstruction, bile duct stenting should be considered if the clinical situation is appropriate and consistent with the goals of care. The most common initial pharmacologic therapies include bile acid sequestrants, rifampicin, and opioid antagonists. These and other pharmacologic treatments for pruritus due to cholestasis are discussed in detail elsewhere. (See "Pruritus associated with cholestasis", section on 'Management'.)

Uremia — All patients with pruritus due to uremia should be treated with emollients and other topical analgesics. For treatment of uremic pruritus that is refractory to optimized dialysis, topical treatments, and general skin care measures, we use oral gabapentin. Further discussion is provided elsewhere. (See "Kidney palliative care: Principles, benefits, and core components", section on 'Pruritus'.)

Hematologic diseases, tumor infiltration, paraneoplastic pruritus — A number of drugs, such as H1 antihistamines, corticosteroids, antidepressants, gabapentinoids, opioid antagonists, and neurokinin 1 (NK1) receptor antagonists have been used to control pruritus in this patient population, as reported in small uncontrolled studies or case reports. There are no comparative trials, and the choice of initial therapy is empiric. As in other conditions associated with pruritus, H1 antihistamines are usually ineffective in paraneoplastic pruritus, but they have beneficial sedating effects when nocturnal itching is present. Examples include hydroxyzine at doses of 10 to 25 mg at night.

●Selective serotonin reuptake inhibitors or gabapentinoid drugs are usually considered first, and may be used on combination if needed. Moderate and usually rapid-onset (within days) antipruritic effects have been suggested in some studies with paroxetine (5 to 20 mg/day), sertraline (25 to 50 mg) and fluvoxamine (25 to 100 mg/day) [66,67]. In several case reports, mirtazapine (15 to 30 mg/day) has also demonstrated antipruritic effects [11,68-70].

●The gabapentinoids gabapentin (300 mg, up to 3600 mg maximum daily divided in up to three doses) and pregabalin (75 mg, up to 600 mg/day divided in up to three doses) may also be effective as antipruritic therapies [71-73]. The mechanism of action is likely a combination of central inhibition of pruritus perception, decreased excitability of spinal and supraspinal neurons, and inhibition of serotonergic circuits. Gabapentin in combination with mirtazapine was found to be helpful in relieving pruritus in patients with CTCL [70].

●Glucocorticoids, such as prednisone (30 to 40 mg) tapered off over three weeks has been reported to be helpful in treating pruritus in lymphoma patients not responsive to above therapies. Steroids have been shown to reduce IL-31 expression in malignant T cells, which is correlated with reduced itch in CTCL patients [20].

●Other agents to consider in patients with refractory pruritus include thalidomide, naltrexone, butorphanol, and aprepitant. Thalidomide (50 to 100 mg), an immunomodulatory agent, has been shown in case reports to improve refractory pruritus in patients with mycosis fungoides and Hodgkin lymphoma [74,75]. Although the exact mechanism by which thalidomide exhibits its antipruritic effects is not understood, immunomodulatory effects result in destruction of lymphoma cells or a decrease in the production of pruritogenic mediators [76].

●In case reports, the opioid receptor antagonist naltrexone (25 to 100 mg/day orally) was shown to mitigate pruritus symptoms in patients with aquagenic pruritus, non-Hodgkin lymphoma, and mycosis fungoides [77-79]. Butorphanol is a kappa-opioid agonist and mu-opioid antagonist that has demonstrated antipruritic effects in one patient with non-Hodgkin lymphoma when given intranasally at dose of 1 mg/day [80,81].

●Aprepitant is a NK1 receptor antagonist that is approved for prevention and treatment of chemotherapy-induced nausea and vomiting. In case reports, aprepitant given orally once daily (dose of 80 mg) or for three consecutive days every two weeks (125 mg on day 1 and 80 mg on days 2 and 3) provided benefit for relief of pruritus [82,83]. However the cost, may be prohibitive.

Opioid-induced pruritus — Treatment of opioid-induced pruritus (OIP), especially pruritus related to spinal administration of opioids, remains a challenge. Due to the prevalence of pruritus with neuraxial opioids administered in the perioperative setting, prevention is the key, using the lowest effective doses of opioids and prophylactic antipruritic therapy starting simultaneously with the neuraxial opioid. The options for prophylactic treatment include small doses of opioid antagonists, 5 hydroxytryptamine subtype 3 (5-HT3) receptor antagonists, propofol, anticonvulsants, and glucocorticoids. This subject is discussed in detail elsewhere. (See "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Pruritus'.)

First-line treatment options for symptomatic pruritus from a systemically administered opioid include rotation to a different opioid and antipruritic therapies. For patients with pruritus related to oral or intravenous morphine, a trial of an oral antihistamine is reasonable, such as hydroxyzine 10 to 25 mg two to three times daily, monitoring for excessive sedation; another option is rotation to a different opioid with negligible to absent histamine-releasing properties (eg, fentanyl, oxymorphone, or oxycodone). (See 'Mechanism' above.)

For pruritus related to fentanyl or oxymorphone, depending on the severity of symptoms, pharmacologic treatment or opioid rotation may be considered. Nonpharmacologic treatments, such as cool compresses or moisturizers, may be beneficial for certain patients.

For most patients receiving systemic opioids, prophylactic antipruritic agents are not recommended. However, use of an opioid antagonist or a mixed opioid receptor agonist/antagonist may be considered in select cases, such as with use of epidural or intrathecal opioids:

●Opioid antagonists such as naloxone and naltrexone may be useful [84], but they can be associated with reversal of analgesic effects at higher doses. For naloxone, studies suggest that the most useful dose range is 0.25 to 1 mcg/kg. As naloxone has a short half-life of approximately one hour, continuous intravenous infusion is necessary. Doses should not exceed 2 mcg/kg/hour due to the risk of reversal of analgesic effects. Naltrexone, an analogue of naloxone, has a longer half-life of four to five hours and has the advantage of being available in an oral formulation. For OIP prophylaxis, doses of 6 and 9 mg given once or twice daily have been shown to be effective but may decrease analgesic efficacy in a dose-dependent manner [85,86].

●Nalbuphine, a mixed opioid receptor agonist/antagonist, may be more useful than the pure opioid antagonists as it is not associated with reversal of analgesic effects. It can be administered spinally and via subcutaneous or intravenous routes. In a systematic review of 10 randomized controlled trials [87], low-dose nalbuphine treatment (2.5 or 5 mg intravenously) provided greater efficacy in treating OIP compared with placebo or other agents, such as diphenhydramine, naloxone, and propofol, without affecting analgesia or sedation. Although most of the studies were in patients undergoing neuraxial analgesia, 3 of the 10 trials included patients receiving intravenous patient-controlled analgesia.

Pruritus of unknown cause — For patients with pruritus of unknown cause who have not responded to topical therapy, reasonable options for first-line therapy serotonin-modulating drugs such as mirtazapine, sertraline, or paroxetine [88]. Patients with concomitant sleep or appetite issues (common in palliative care patients) may benefit with mirtazapine 7.5 to 30 mg at bedtime. At these doses, mirtazapine has also been found useful in pruritus due to malignancy, cholestasis, and uremia. Sertraline at 25 to 100 mg or paroxetine at 5 to 20 mg are other alternatives that can be considered first or if there is no relief with mirtazapine, and they have also been found useful in pruritus associated with cholestasis, uremia, or opioids. While 5‑HT3 receptor antagonists such as ondansetron have been shown to be useful in other pruritus conditions (opioids, uremia, and cholestasis) we do not recommend use as first-line therapy due to the expense and adverse effects of headaches and constipation. Gabapentin usually starting at 300 mg at bedtime may be considered alone as first-line therapy or in addition to the selective serotonin reuptake inhibitors.

Glucocorticoids such as prednisone 30 mg/day or dexamethasone 4 to 8 mg/day may be considered if pruritus is acute, severe, and remains refractory. If effective, these drugs tend to work quickly and ideally should be tapered off within two to three weeks. Longer duration may be associated with undesired side effects including hyperglycemia, gastric ulcers, and adrenocorticotropic hormone (ACTH) suppression. If discontinuation is not possible, the lowest effective dose should be continued with added gastrointestinal protection.

Phototherapy — For refractory cases, phototherapy using ultraviolet B light has been shown to be most useful in pruritus associated with uremia [89], but it may also benefit pruritus associated with cholestasis and malignant skin infiltrations. (See "Pruritus: Therapies for generalized pruritus", section on 'Other therapies' and "Pruritus: Therapies for generalized pruritus", section on 'Phototherapy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)

SUMMARY AND RECOMMENDATIONS

●The main causes of pruritus in the palliative care population are chronic renal failure, liver disease, hematologic or lymphoproliferative disorders, malignancy, and drugs (especially opioids) (table 1). Xerosis (dry skin) is frequently present in older adults and can accompany or exacerbate all causes of pruritus. (See 'Common etiologies in palliative care' above.)

●Treatment involves an individualized stepwise approach that depends upon the severity of symptoms, the patient's clinical circumstances and goals of care, and the response to initial therapies. Although systematic evaluation and treatment directed at eradicating the primary cause of the pruritus may be recommended (eg, stenting for biliary obstruction), this is not a feasible option for the vast majority of palliative care patients, and therapy is directed at reducing itch regardless of etiology. (See 'Management' above.)

●General skin care measures are recommended for all patients, regardless of the cause of the pruritus. Dry skin can exacerbate all causes of pruritus; therefore, measures to regularly lubricate the skin with nonfragrant topical emollients, especially after bathing, are important. (See 'Skin care measures for all patients' above.)

●Topical therapies are generally preferred as initial treatment due to a lower propensity for side effects, especially when pruritus is mild, intermittent, or localized. Systemic drugs may be recommended for persistent and/or generalized pruritus, or when topical therapies are not effective for localized pruritus. If therapy is initiated, ongoing evaluation of the benefit versus the burden and side effects of the ongoing treatment is needed. (See 'Topical therapies' above.)

●Histamine release does not play a meaningful role in the pruritus typically observed in palliative patients; therefore, oral antihistamines are not usually beneficial. (See 'Systemic drugs for patients with persistent or generalized pruritus' above.)

●For patients with malignant extrahepatic biliary obstruction, bile duct stenting is reasonable in the setting of biliary obstruction if it is consistent with the goals of care. Further treatments are discussed elsewhere. (See 'Cholestasis' above and "Pruritus associated with cholestasis", section on 'Management'.)

●For treatment of uremic pruritus that is refractory to optimized dialysis, topical treatments and general skin care measures, we use oral gabapentin. This and other treatments are discussed in detail elsewhere. (See 'Uremia' above and "Kidney palliative care: Principles, benefits, and core components", section on 'Pruritus'.)

●Treatment of opioid-induced pruritus (OIP) is challenging. Due to the high prevalence of pruritus with neuraxial opioids, simultaneous prophylactic therapy is a reasonable approach for most patients. For patients with OIP who are receiving systemic opioids, oral antihistamines (for patients receiving systemic morphine) and switching to an alternative opioid are the preferred approaches. (See 'Opioid-induced pruritus' above.)

●For patients with malignant skin infiltrations, hematologic diseases associated with pruritus, and paraneoplastic pruritus, a number of diverse groups of drugs, such as H1 antihistamines, corticosteroids, antidepressants, anticonvulsants, opioid antagonists, and neurokinin 1 (NK1) receptor antagonists, have been used to control pruritus. There are no comparative trials, and the choice of initial therapy is empiric. (See 'Hematologic diseases, tumor infiltration, paraneoplastic pruritus' above.)

●If effective, all systemic drugs tend to work quickly. For most patients with pruritus, we would usually start with one drug class, and if there is no relief within a day, we would move on to a different class.

●For refractory cases, phototherapy using ultraviolet B light is most useful in pruritus associated with uremia, but it may also benefit pruritus associated with cholestasis and malignant skin infiltrations. The treatment sessions are usually three times per week, and this may not be practical in terminally ill patients, depending on the clinical circumstances and goals of care. (See 'Phototherapy' above.)