INTRODUCTION — Generalized pruritus can be defined as pruritus that is widespread and not limited to a specific body area. Generalized pruritus can occur in association with multiple conditions, such as dermatologic disorders, liver or kidney dysfunction, malignancy, systemic rheumatic disease, infections, or drug reactions. Pruritus may also occur in the absence of an identifiable etiology. (See "Pruritus: Etiology and patient evaluation", section on 'Potential causes'.)
Generalized pruritus negatively affects quality of life. The condition can result in skin injury, sleep deprivation, and psychologic distress. Successful treatment often requires a multifaceted approach, consisting of treatment of underlying conditions, elimination of aggravating factors, and medical therapy. (See "Pruritus: Therapies for localized pruritus", section on 'General approach' and 'Antipruritic therapies' below.)
The management of generalized pruritus will be reviewed here. General principles for the diagnosis and treatment of pruritus and the management of localized pruritus are reviewed separately.
In-depth discussions of specific presentations of pruritus are provided separately.
●(See "Uremic pruritus".)
GENERAL APPROACH — The cause of generalized pruritus influences the approach to treatment. In general, management consists of:
●Treatment of the underlying disorder (when feasible)
●Elimination of aggravating factors (see 'Elimination of aggravating factors' below)
Treatment of underlying cause — Successful treatment of the underlying cause of pruritus may result in resolution . Thus, identification and treatment of the cause of pruritus is advised, whenever feasible. (See "Pruritus: Etiology and patient evaluation".)
Occasionally, the cause of pruritus cannot be identified. (See "Pruritus: Etiology and patient evaluation", section on 'Chronic pruritus of unknown origin' and 'Chronic pruritus of unknown origin' below.)
Elimination of aggravating factors — The elimination of aggravating factors for pruritus is an important component of symptom management. Interventions that may be beneficial include:
●Skin moisturization – Dry skin can cause or exacerbate pruritus; thus, all patients with generalized symptoms should be educated on proper skin care. For example, gentle cleansers should be used during bathing, and patients should apply emollients to the skin daily. (See 'Xerosis (dry skin)' below.)
●Cool environment – Symptoms of pruritus may be exacerbated by exposure to heat. Lightweight clothing, air-conditioned environments, and the use of lukewarm (rather than hot) water during showers or baths may reduce symptoms. Lotions that provide a cooling sensation on the skin can provide additional relief. (See "Pruritus: Therapies for localized pruritus", section on 'Cooling lotions'.)
●Avoidance of skin irritants – Direct contact with substances that may irritate the skin, such as wool clothing and household cleansing products, should be avoided.
●Stress reduction – Stress and other psychogenic factors may induce or aggravate chronic itch [2-5], and stress reduction may help to reduce symptoms. In addition, psychologic support, education on pruritus, and behavioral interventions that minimize symptoms may help patients to cope . Holistic approaches, such as meditation, acupuncture, and yoga, may be useful as adjunctive therapies [7,8]. (See "Acupuncture" and "Overview of yoga".)
●Physical interventions – Scratching may increase symptoms of pruritus, resulting in a perpetual itch-scratch cycle. Occlusion of localized areas of pruritus with Unna boots or other occlusive dressings (eg, hydrocolloid dressings) may help to break this cycle . Keeping fingernails trimmed to a short length may also help to minimize skin damage induced from scratching. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Unna boot'.)
Selection of therapy — Antipruritic therapies are helpful for the management of pruritus, particularly when elimination of the underlying cause is not feasible or does not result in immediate resolution of symptoms. Although topical antipruritic therapies can be useful adjunctive interventions, satisfactory suppression of generalized pruritus often requires systemic therapy or phototherapy (table 1A-B).
The cause of generalized pruritus determines the most appropriate approach to treatment. (See 'Specific forms of generalized pruritus' below.)
Initial therapy often consists of a combination of topical therapy (eg, cooling lotions) and nighttime use of sedating antihistamines, as these treatments are widely available and generally well tolerated. Antihistamines also play a key role in the treatment of histamine-mediated pruritus (eg, pruritus related to urticaria or mastocytosis). (See 'Topical therapies' below and 'Role of antihistamines' below.)
Antidepressants and anticonvulsants are often incorporated when initial interventions are insufficient. Opioid receptor antagonists and opioid receptor agonists are primarily reserved for severe or refractory pruritus. Failure or intolerance of these therapies may lead to trials of other agents. (See 'Antidepressants' below and 'Anticonvulsants' below and 'Opioid receptor antagonists' below and 'Opioid receptor agonists' below and 'Other agents' below.)
Phototherapy is an alternative to systemic therapy that can be useful for pruritus related to ultraviolet light-responsive dermatoses, such as psoriasis . Phototherapy may also be beneficial in the absence of primary skin disease, such as for pruritus related to prurigo nodularis and uremic pruritus. (See 'Phototherapy' below.)
Common initial therapies — Topical therapies and oral antihistamines are common initial treatments. (See 'Other therapies' below.)
Topical therapies — Topical agents often used for localized pruritus may be helpful as adjuncts to systemic therapy. Application of cooling lotions containing menthol and camphor can provide temporary relief. Other topical therapies used for localized pruritus may also be beneficial for the treatment of focal body areas. (See "Pruritus: Therapies for localized pruritus", section on 'Topical therapies'.)
Role of antihistamines — Various oral antihistamines have been used for the treatment of pruritus:
●Indications – H1 antihistamines are often the first systemic therapies attempted in patients with widespread pruritus due to the relative safety, wide availability, and affordability of these agents. However, with the exception of disorders in which histamine is known to play an important role in pruritus (eg, urticaria and mastocytosis), data on the efficacy of systemic antihistamines for pruritus are limited [1,11]. (See "New-onset urticaria", section on 'Treatment' and "Cutaneous mastocytosis: Treatment, monitoring, and prognosis", section on 'Antihistamines'.)
A sedation-induced decrease in the perception of pruritus is considered the major benefit of antihistamine therapy in the treatment of other disorders. This approach, which involves use of sedating H1 antihistamines such as hydroxyzine and diphenhydramine, may be particularly useful for patients who experience nocturnal exacerbations of pruritus . (See "Treatment of atopic dermatitis (eczema)", section on 'Oral antihistamines' and "Exanthematous (maculopapular) drug eruption", section on 'Symptomatic treatment'.)
●Rationale for use – Oral H1 antihistamines function through the blockage of H1 receptors on afferent C nerve fibers and may also inhibit the release of pruritic mediators from mast cells when administered at high doses . (See "New-onset urticaria".)
●Administration – Sedating antihistamines, such as hydroxyzine and diphenhydramine, are often given at night because drowsiness is common, and sedation during the day is generally unwanted and may be hazardous, particularly in older adult patients. A typical adult dose is 25 to 50 mg of hydroxyzine or diphenhydramine before bed. Other potential adverse effects include xerostomia and, at high doses, respiratory depression. (See "Hydroxyzine: Drug information".)
Other therapies — Oral antidepressants, anticonvulsants, phototherapy, opioid receptor antagonists, opioid receptor agonists, and other agents may improve pruritus (table 1B). (See 'Selection of therapy' above.)
Antidepressants — Oral antidepressants, such as mirtazapine and selective serotonin reuptake inhibitors (eg, fluvoxamine, paroxetine, sertraline), and tricyclic antidepressants (eg, doxepin) may be useful for the treatment of chronic pruritus :
●Indications – Overall, there is the greatest amount of literature support for antidepressant benefit in chronic pruritus related to malignancies, cholestasis, and chronic kidney disease . Additional randomized trials will be helpful for clarifying indications for antidepressant therapy.
●Rationale for use – Benefit from oral antidepressants is postulated to result from the effects of these drugs on serotonin and histamine levels.
However, randomized trials are few, and most data on the efficacy of these agents come from open-label studies, case reports, and case series . As an example, in a randomized trial of 110 patients treated with intrathecal morphine, prophylactic mirtazapine was associated with a reduced incidence of pruritus after morphine therapy . In addition, in an open-label study in which 72 patients with severe, chronic pruritus were treated with paroxetine or fluvoxamine, 68 percent of patients had a mild, good, or very good response to treatment .
In a randomized, cross-over trial that included 24 patients on hemodialysis given either doxepin (20 mg per day) or placebo for one week and switched to the converse agent for a second week, complete resolution of pruritus was achieved in 14 patients (58 percent) during doxepin therapy compared with only 2 patients (8 percent) in the placebo group .
●Administration – Typical dose ranges for adults are reviewed in a table (table 1B). Antipruritic benefit may be evident within the first few days of treatment for mirtazapine; in contrast, other benefit from other antidepressants may not occur for several weeks. Adverse effects are reviewed in detail separately (table 2). (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Mirtazapine' and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Side effects'.)
●Indications – Gabapentin and pregabalin may be particularly useful in forms of neuropathic pruritus related to nerve entrapment disorders, such as brachioradial pruritus and notalgia paresthetica . (See "Pruritus: Therapies for localized pruritus", section on 'Peripheral neuropathic itch'.)
●Rationale for use – Anticonvulsants such as gabapentin and pregabalin are structural analogs of the neurotransmitter gamma-aminobutyric acid (GABA). The mechanism through which these agents improve pruritus is unknown.
●Administration – Dosing of gabapentin and pregabalin for pruritus in adults is provided in a table (table 1B). Doses are titrated upward based upon response and tolerability. Once an effective dose is reached, improvement is usually evident immediately. Dose adjustments are necessary for patients with renal insufficiency. Dizziness and sedation are common adverse effects. (See "Gabapentin: Drug information" and "Pregabalin: Drug information".)
Phototherapy — Phototherapy with ultraviolet radiation is an option for the treatment of pruritus :
●Indications – Although phototherapy has been most extensively used for skin lesion resolution in inflammatory dermatoses, such as psoriasis, it may also improve pruritus in the absence of a primary skin disease, such as in cases of prurigo nodularis [20-22], uremia [23-25], polycythemia vera [26,27], psychogenic excoriations , and notalgia paresthetica . Advantages of phototherapy include the ability to use it in patients with contraindications to systemic agents, such as some older adult patients taking multiple medications .
●Rationale for use – The mechanism through which ultraviolet light reduces pruritus is unknown but may involve effects on epidermal opioid systems, epidermal cytokines, cutaneous mast cells, or epidermal nerve fibers [12,25].
●Administration – Multiple forms of phototherapy have been used for pruritus, including broadband ultraviolet B (UVB), narrowband ultraviolet B (NBUVB), psoralen plus ultraviolet A (PUVA), and ultraviolet A1 (UVA1). The efficacies of specific types of phototherapy vary among different disorders and individual patients [19,31,32]. In our experience, at least two months of treatment is often necessary for improvement. (See "UVB therapy (broadband and narrowband)" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "UVA1 phototherapy".)
Potential side effects include skin burning or blistering and a potential increase in risk for skin cancer.
Opioid receptor antagonists — The mu-opioid receptor antagonists, such as naltrexone, nalmefene, and naloxone, appear to be effective against some forms of pruritus [33,34]. Methylnaltrexone is a peripherally acting opioid receptor antagonist that may have benefit in the management of pruritus [35,36]. However, further studies are necessary to determine the efficacy of this drug:
●Indications – In randomized trials, opioid receptor antagonists have been beneficial for the treatment of pruritus secondary to cholestasis, chronic urticaria, atopic dermatitis, and epidural morphine administration [33,34,37]. In addition, cases in which opioid receptor antagonists were used successfully for the treatment of prurigo nodularis, mycosis fungoides, aquagenic pruritus, and other pruritic disorders have been reported .
Use of opioid receptor antagonists for cholestatic pruritus and uremic pruritus is reviewed in detail separately. (See "Pruritus associated with cholestasis", section on 'Opioid antagonists' and "Uremic pruritus", section on 'Specific opioid agonists and antagonists'.)
●Rationale for use – Activation of mu-opioid receptors in the central nervous system may contribute to itch through suppression of the inhibitory effect of pain-transmitting neurons on pruriceptive neurons [12,38].
●Administration – Dosing for naltrexone for adults typically ranges from 12.5 to 50 mg per day. Use of naltrexone and other opioid receptor antagonists in cholestatic pruritus and uremic pruritus is reviewed separately. (See "Pruritus associated with cholestasis" and "Uremic pruritus".)
Precipitation of opioid withdrawal is a common adverse effect. Patients develop symptoms such as agitation, nausea, vomiting, and anxiety. Other adverse effects of opioid receptor antagonists are reviewed in detail separately. (See "Naltrexone: Drug information" and "Naloxone: Drug information".)
Opioid receptor agonists — Examples of kappa-opioid receptor agonists used for pruritus include butorphanol, nalbuphine, nalfurafine, and difelikefalin. Nalfurafine is not available in the United States but is available in Japan. Difelikefalin has demonstrated efficacy for uremic pruritus (see "Uremic pruritus", section on 'Specific opioid agonists and antagonists'):
●Indications – Opioid receptor agonists play a role in the treatment of uremic pruritus. These agents have also been used for the treatment of other forms of intractable pruritus [39,40].
Use of opioid receptor agonists in patients with uremic pruritus is reviewed in detail separately. (See "Uremic pruritus", section on 'Specific opioid agonists and antagonists'.)
●Rationale for use – Activation of kappa-opioid receptors in the central nervous system may inhibit itch .
Nalbuphine, a kappa-opioid agonist and partial mu-opioid agonist, has been shown to reduce pruritus induced by mu-opioid agonist medications, including epidural morphine . Nalbuphine is under investigation for efficacy for prurigo nodularis.
In a phase 3, placebo-controlled trial involving 337 patients with pruritus related to chronic kidney disease, oral nalfurafine reduced itch . A randomized, phase 3 trial supports benefit of difelikefalin for uremic pruritus . (See "Uremic pruritus", section on 'Specific opioid agonists and antagonists'.)
In a case series of five patients with intractable pruritus due to inflammatory skin disease or systemic disorders, intranasal butorphanol was associated with rapid and marked improvement . Most patients responded to a dose of 1 mg per day. Other case series suggest benefit of butorphanol for cholestatic itch and intractable itch [40,44].
●Administration – Butorphanol can be administered intranasally; typical doses for pruritus in adults range from 1 to 4 mg per day. Common adverse effects include drowsiness, dizziness, insomnia, nausea, vomiting, and nasal congestion. Use of other opioid receptor agonists for uremic pruritus is reviewed separately. (See "Uremic pruritus", section on 'Specific opioid agonists and antagonists'.)
Other agents — Additional drugs that have been used for refractory pruritus include aprepitant and thalidomide. Immunomodulatory agents, including immunosuppressants and biologic agents, may also be of benefit for specific forms of pruritus.
Aprepitant — Improvement in refractory pruritus has been reported in patients treated with aprepitant, a neurokinin receptor 1 antagonist [45-51]. The efficacy of this drug may be related to inhibition of the binding of substance P (a mediator of pruritus) to the neurokinin receptor. Additional studies are necessary to determine the role of aprepitant in the management of patients with pruritus.
Thalidomide — Thalidomide, an agent occasionally used for the treatment of various refractory autoimmune and inflammatory skin diseases, may be useful for the treatment of refractory, chronic pruritus. Efficacy may occur through a variety of mechanisms; thalidomide has central depressant, anti-inflammatory, immunomodulatory, and neuromodulatory properties . Benefit for pruritus has been reported in patients with a variety of disorders associated with chronic pruritus, most commonly prurigo nodularis . (See "Prurigo nodularis", section on 'Systemic therapies'.)
Thalidomide is associated with side effects, including sedation, peripheral neuropathy, thromboembolism, skin eruptions, and dizziness. The drug is teratogenic and should not be administered to pregnant patients. In the United States, participation in a Risk Evaluation and Mitigation Strategy (REMS) program is necessary to obtain thalidomide.
Immunomodulating agents — In patients with inflammatory skin diseases, such as atopic dermatitis or psoriasis, systemic therapy for skin disease with immunosuppressants or biologic agents may lead to improvement in skin manifestations and associated pruritus.
Th17-related cytokines have emerged as novel targets for treatment of itch in psoriasis. Secukinumab, ixekizumab, and brodalumab are human monoclonal antibodies targeting interleukin (IL) 17A used for the treatment of moderate to severe psoriasis. Randomized trials support the efficacy of these agents for improving itch in patients with moderate to severe plaque psoriasis [53-55].
Dupilumab, an IL-4 and IL-13 inhibitor for atopic dermatitis, improves atopic itch rapidly and has been associated with improvement of pruritus in other conditions in case series, such as prurigo nodularis, hand eczema, bullous pemphigoid, chronic spontaneous urticaria, and anogenital itch [56,57]. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)
Medical marijuana — In a case report, medical marijuana therapy was associated with improvement and eventual resolution of pruritus in a patient with pruritus associated with lichen amyloidosis secondary to primary sclerosing cholangitis . The patient experienced mild sedation as a side effect.
SPECIFIC FORMS OF GENERALIZED PRURITUS
Dermatologic disorders — As with localized pruritus, widespread pruritus related to extensive skin disease often improves with successful treatment of the skin disease. Inflammatory skin diseases and xerosis are common causes of generalized pruritus.
Inflammatory skin disease — Therapeutic approaches to common inflammatory skin diseases associated with generalized pruritus are reviewed separately. Examples include:
●Atopic dermatitis (see "Treatment of atopic dermatitis (eczema)", section on 'Controlling pruritus')
●Asteatotic and nummular eczema (see "Overview of dermatitis (eczematous dermatoses)")
●Scabies (see "Scabies: Management")
●Pruritic dermatoses of pregnancy (see "Dermatoses of pregnancy")
Xerosis (dry skin) — Xerosis is common in older adults and in people living in northern climates, where home heating during the winter results in very low relative humidity. Interventions that may improve xerosis and related pruritus include [1,59]:
●Use of mild cleansers – Traditional soaps alkalinize the skin and can cause damage to the natural skin moisture barrier, thereby worsening xerosis and aggravating pruritus. Synthetic detergent (syndet) cleansers or other mild cleansers are preferred. Syndet cleansers typically have a low pH that approximates the normal acidic pH of the skin. They tend to be less irritating than traditional soaps and may optimize skin barrier function [60,61].
In addition, there is some evidence to suggest that serine proteases involved in the pathogenesis of pruritus are inhibited by low pH agents . Low pH topical agents may reduce activity of serine proteases, such as mast cell tryptase, which is known to activate protease-activated receptor 2 (PAR2) on skin nerve fibers .
●Routine use of skin moisturizers – Daily use of moisturizers, which contain substances that promote epidermal hydration (humectants such as glycerin, lactic acid, or topical urea) and/or substances that reduce water loss from the skin (occlusives such as petrolatum), is a crucial component of xerosis management [63,64]. Moisturizers and/or occlusives should be applied immediately after bathing and gentle drying of the skin.
Thicker, greasier products tend to be more effective for maintaining skin moisture but may be perceived as uncomfortable or unsightly by some patients. Greasier preparations may be better accepted by patients for use at bedtime.
●Avoidance of excessive and aggressive skin washing – Excessive washing (eg, multiple times per day) can worsen dry skin, particularly when hot water is used to bathe. Lukewarm or warm water is preferable for bathing, and patients should be instructed to avoid aggressive scrubbing of the skin.
●Use of a humidifier – Increasing the relative humidity of indoor air during the winter may be beneficial for patients who are prone to xerosis.
Asteatotic eczema that results from xerosis may be treated with topical corticosteroids. (See "Overview of dermatitis (eczematous dermatoses)", section on 'Asteatotic eczema'.)
Prurigo nodularis — Prurigo nodularis is a disorder characterized by the development of multiple symmetrically distributed, firm, pruritic nodules in patients with chronic pruritus. Treatment involves measures to control pruritus, disrupt the itch-scratch cycle, and improve skin lesions. The treatment of prurigo nodularis is reviewed in detail separately. (See "Prurigo nodularis".)
Systemic disorders — Generalized pruritus may occur in association with disorders such as renal disease (uremic pruritus), liver disease (cholestatic pruritus), endocrine disease (thyroid disease or diabetes), hematologic malignancies, infection (eg, HIV), systemic rheumatic disease (eg, dermatomyositis, systemic sclerosis, Sjögren's syndrome), multiple sclerosis, and psychiatric disorders. (See "Pruritus: Etiology and patient evaluation", section on 'Systemic disorders'.)
Specific approaches to some of these conditions are reviewed separately.
●Uremic pruritus (see "Uremic pruritus")
●Cholestatic pruritus (see "Pruritus associated with cholestasis")
Hematologic disorders, cutaneous lymphoma, and paraneoplastic pruritus:
●Polycythemia vera (see "Prognosis and treatment of polycythemia vera", section on 'Management of refractory symptoms')
●Mycosis fungoides (see "Treatment of early stage (IA to IIA) mycosis fungoides", section on 'Pruritus' and "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Pruritus' and "Treatment of Sézary syndrome", section on 'Pruritus')
●Various hematologic disorders and malignancies (see "Overview of pruritus in palliative care", section on 'Hematologic diseases, tumor infiltration, paraneoplastic pruritus')
Systemic rheumatic disease:
●Psychiatric disorders (see "Skin picking (excoriation) disorder and related disorders" and "Treatment of delusional infestation")
Drug-related pruritus — Medication adverse reactions and substance use disorders (opioids, cocaine, amphetamines) may cause generalized pruritus.
Chronic pruritus of unknown origin — Chronic pruritus of unknown origin is defined as chronic pruritus in the absence of an identifiable etiology . The best approach to generalized chronic pruritus of unknown origin is unclear . Our approach to the treatment of these patients is similar to the approach described here. (See 'Selection of therapy' above.)
EMERGING THERAPIES — Emerging therapies for pruritus include Janus kinase (JAK) inhibitors and other agents:
●Janus kinase inhibitors – Tofacitinib, a specific Janus kinase (JAK) 1 and JAK3 inhibitor primarily used for the treatment of rheumatoid arthritis, has demonstrated antipruritic effects in both atopic dermatitis and psoriasis [67,68]. Upadacitinib and abrocitinib, JAK1 inhibitors, have demonstrated antipruritic effects in patients with atopic dermatitis in randomized trials [69-73]. Baricitinib selectively inhibits JAK1 and JAK2 and was associated with decreased pruritus of atopic dermatitis in phase 2 trials . (See "Treatment of atopic dermatitis (eczema)", section on 'Upadacitinib' and "Treatment of atopic dermatitis (eczema)", section on 'Abrocitinib'.)
Inhibition of interleukin (IL) 31, a cytokine that has been implicated in pruritus and has been found at increased levels in patients with atopic dermatitis and cutaneous T cell lymphoma, prurigo nodularis, stasis dermatitis, and bullous pemphigoid, may represent an additional therapeutic pathway [75-79]. Studies with nemolizumab, an IL-31 receptor antibody, had shown significant, antipruritic effect in prurigo nodularis in a phase 2 study  and atopic dermatitis in a phase 3 study .
●Serlopitant – Phase 2, randomized trials support efficacy of serlopitant, an investigational neurokinin 1 receptor antagonist, for psoriatic pruritus and chronic pruritus [81,82]. However, serlopitant was not effective for pruritus associated with prurigo nodularis in phase 3, randomized trials .
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: Pruritus".)
SUMMARY AND RECOMMENDATIONS
●Overview – Generalized pruritus, widespread pruritus that is not limited to a specific body area, can occur in association with a variety of disorders. Treatment of pruritus is generally indicated because of the profound, negative impact of pruritus on quality of life. (See 'Introduction' above.)
●General approach – A multifaceted, therapeutic approach is often indicated for generalized pruritus. Key components include:
•Treatment of the underlying disorder
•Elimination of aggravating factors
•Antipruritic therapies (table 1A-B)
●Common initial therapies – Topical therapies (eg, cooling lotions) and oral sedating antihistamines are common initial medical interventions for pruritus because of the well-tolerated natures of these therapies. The sedating effects of first-generation antihistamines are beneficial for patients with difficulty sleeping due to pruritus. The role for nonsedating antihistamines in pruritus that is not primarily histamine mediated is less clear. (See 'Common initial therapies' above and 'Role of antihistamines' above.)
●Other therapies – Other interventions may be helpful for pruritus that cannot be managed with common initial therapies. Subsequent therapies include anticonvulsants (eg, gabapentin, pregabalin) and antidepressants (eg, mirtazapine). Phototherapy is an alternative approach that may be beneficial for some patients. Opioid receptor antagonists, opioid receptor agonists, and other systemic agents are typically reserved for severe or refractory pruritus. (See 'Other therapies' above.)
●Chronic pruritus of unknown origin – The cause of pruritus cannot always be identified, contributing to uncertainty regarding the best approach to treatment. For patients with chronic pruritus of unknown origin that cannot be adequately controlled with topical therapy and nighttime administration of oral sedating antihistamines, we suggest a trial of oral antidepressant or anticonvulsant therapy (Grade 2C). Opioid receptor antagonists and opioid receptor agonists are options for severe pruritus of unknown origin that fails to respond to antidepressant and anticonvulsant therapy.