They are considered to be on the front line of the nervous system, given their high bioactivity and ability to secrete pruritogens.19 They express Protease-Activated Receptor (PAR2), Toll Receptor 3 (TRL3), Histamine Receptors (HR1-HR4), Endothelin A (ETA) and B (ETB), serotonin (5-HTR), Oncostatin M β receptor (OSMRβ), integrin αvβ3, Thymic Stromal Lymphopoietin Receptor (TSLPR), Neuropeptide Y receptors (NPY), including TRPV3 and V4 (Fig. 2)

The indirect pathway of itch induction involves the disruption of the epidermal barrier, leading to an increased inflammatory gradient and transepidermal water loss. This disruption is typically accompanied by the production of pro-inflammatory cytokines (e.g., IL-6) and various chemokines (e.g., CXCL-8, CCL17/TARC, CCL19/MIP-3β, CCL22/MDC, CCL23/MIP-3, CCL4/MIP-1β, and CXCL1/GRO1α), as well as Nerve Growth Factor (NGF) by keratinocytes. The main pruritic mediators released by keratinocytes that can directly activate pruritic nerve endings include TSLP, periostin, ET-1, IL-33, and BNP.19,20

TSLP and other Th2 cytokines may induce periostin secretion, which in turn can stimulate further TSLP release, potentially establishing a pruritic positive feedback loop. One of the most potent pruritic mediators derived from keratinocytes is ET-1, whose production can be triggered by the activation of PAR2, TLR3, TRPV3, and TRPV4. IL-33, a member of the IL-1 family of inflammatory cytokines, is constitutively expressed in the nucleus of keratinocytes and acts as an alarmin, released in response to inflammation or cell damage.20

Initially, IL-33 was shown to act on cells of both the innate and adaptive immune systems, specifically mast cells, Innate Lymphoid Cells type-2 (ILC2), basophils, and type-2 helper T-cells. However, its receptor, ST2, is also expressed on sensory nerve endings in the skin, and its activation leads to an itch response in mice. Additionally, IL-33 is upregulated in Atopic Dermatitis (AD) lesions, potentially contributing to the pruritic phenotype associated with this condition.20

These cells trigger the pruritus-scratch cycle after stimulation by the Piezzo receptor-2.19 The complex formed by Merkel cells and pruriceptive MRGPRA3+ endings (C fibers) in cases of xerosis and prurigo nodularis may be functionally impaired. Merkel cells express TRPM8.19

These innate immune cells are located in the papillary dermis, near nerve fibers, around the pilosebaceous unit, around dermal blood vessels, and are loaded with pruritogens, capable of activating both histaminergic and non-histaminergic pathways.19

• (ii)

  Itch nerve fibers

The cell bodies of the myelinated Alpha-Delta (Aδ) fibers (mechanical itch), unmyelinated C-fibers (CM and CMH), both non-histaminergic, and the unmyelinated C-fibers (CMi/histaminergic) reside in the Dorsal Root Ganglia (DRG) with axons innervating the skin (epidermis and dermis), and dendrites synapsing in the dorsal horn of the spinal cord.18 Pruritus is initiated when endogenous and exogenous pruritogens bind to their receptors on these sensory nerve endings.18

• (iii)

  Itch receptors and channels18,21

There are 3 major classes of itch receptors: G Protein-coupled Receptors (GRPs), Toll-Like Receptors (TLRs) and cytokine receptors (for example, interleukin-31, thymic stromal lymphopoietin, interleukin-4, interleukin-13, interleukin-33, Omcostatin-M [OSM]).18,21 The members of the Mas-related GPCR (MRGPR) involved on itch are represented by MRGPRX1 and MRGPRX4 in humans, and as an example, chloroquine elicits itching through MRGPRA3 stimulation in rodents and MRGPRX1 in humans.21 One class of channels broadly associated with pruritus is the Transient Receptor Potential (TRP) channels. This group includes TRP Vanilloid-1 (TRPV1) and TRP Ankyrin-1 (TRPA1), which activate the Nav1.7 and Nav1.8 sodium channels, thereby propagating the action potential of the itch signal. Both histaminergic and non-histaminergic itch pathways rely on TRP signaling. Table 1 provides a summary of the distinct itch receptors, their activating compounds, and the associated pathways or diseases.22,23

There are several chemical stimuli that trigger itch at different stages, including neuropeptides, amines, cytokines, chemokines, proteases, lipids, and opioids and their respective receptors, as demonstrated in Table 2.24 Mediator related itch implies that pruritus is associated with mediators including histamine, 5-hydroxy tryptamine, proteases, opioid peptides, peptides, and eicosanoids.24

• (iv)

  Histaminergic and nonhistaminergic pathways

Histaminergic and nonhistaminergic sensory nerves constitute the two major pathways of pruritus.18 The histaminergic pathway transmits acute and chronic itch, as in cases of acute or chronic spontaneous urticaria, and is mediated by histamine secreted primarily by mast cells, basophils, and keratinocytes.18 Once released, histamine binds to H1 and H4 receptors on histaminergic nerves, activating TRPV1.18 Nonhistaminergic itch is elicited by nerves that express several receptors, activated by pruritogens other than histamine.18 These pruritogens are released by a variety of effector cells, including mast cells, granulocytes, macrophages, lymphocytes, Innate Lymphoid Cells type-2 (ILC2), keratinocytes, and neurons.18 Recent evidence also suggests that basophils can promote itch mediated by Immunoglobulin E (IgE), independent of mast cells.18

• (v)

  Pruritus in the spinal cord

The itch signal is transmitted through the neuron cell bodies in the DRG to the dorsal horn of the spinal cord (Fig. 3).18 The activated sensory neurons release Gastrin-Releasing Peptide (GRP) which binds to GRP Receptor (GRPR)-positive intermediate neurons (interneurons) in the spinal cord.18 Structural abnormalities of the spinal cord can also modulate the itch signaling pathway, causing localized neuropathic pruritus.18 Specific populations of inhibitory interneurons were involved in the control of itch, and their dysfunction could lead to enhanced itch perception.25 Radiculopathy of cervical nerves a contribute to brachioradial pruritus, whereas in notalgia paresthetica the dorsal rami of intercostal nerves are involved.18

• (vi)

  Itch in the brain (CNS)

Fig. 3.

Pathways inducing and inhibiting the itch in spinal cord. Beside inflammatory mediators, it has long been appreciated that mu opioids (e.g, morphine) can trigger pruritus. Although it is well appreciated that mu opioids trigger itch, in part, within the central nervous system (CNS), mu opioid receptor (MOR) is abundantly expressed on pruriceptors fibers in the skin. Mu opioids act as direct pruritogens. The peripheral itch neurocircuitry have unveiled abroad array of nonhistaminergic pathways within the skin (epidermis and dermis), that can trigger various forms of itch. There are endogenous pathways dedicated to suppressing itch both in the periphery and the CNS. It is well known that mechanical stimuli (e.g., scratching) and pain may suppress the itch. This is likely due, in part, to inhibitory pathways being triggered within the spinal cord. In addition, endogenous kappa opioids, distinct from mu opioids, have been shown to suppress itch by their ability act on sensory neurons, the spinal cord (dorsal horn), and the brain. The activation of kappa opioid receptor (KOR) counterbalances the pruritogenic effect of MOR activation. However, KOR activation in the periphery is predominantly expressed on mechanosensory neurons (mechanoreceptors), rather than on pruriceptors.

DRG, dorsal root ganglion; ILC2, innate lymphoid cell type 2; IL, interleukin, TSLP, thymic stromal lymphopoietin; OSMβ, oncostatin beta, LTC4, leukotriene C4; μ-opioids, mu-opioids; (-), inhibitory effect.

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After transmission through the spinal cord, itch signals running along the spinothalamic tract and reach the thalamus and parabrachial nucleus, followed by brain.18

Pruritus perception involves the primary and secondary somatosensory cortex, insula, and anterior cingulate cortex.18

Histaminergic and nonhistaminergic pruritus also activate distinct areas of the brain and can resemble pain perception. It is very important to remember that brain activation upon pruritic stimulation is different in patients with chronic itch compared to healthy volunteers. This has been shown in functional Magnetic Resonance Imaging (fRMI) studies for instance with atopic dermatitis patients, where the frontostriatal circuit is relevant for the itch. There are top-down inhibitory pathways from the brain stem modulating the itch signal at the spinal level.18 These pathways seem to be affected in patients with chronic itch.26

• (vii)

  Efferent pathway of itch: motor action of scratching

In the CNS (brain), the main neurotransmitters are Noradrenaline (NA) and serotonin (5-HT).19

The population of NA + neurons is located in the locus coeruleus, while their α1 adrenergic receptors are found in inhibitory interneurons of the spinal cord. The 5-HT1A receptor, expressed in GRPR + interneurons, also plays a direct role in the efferent (descending) signaling of itch. The Periaqueductal Gray Matter (PAG) receives input from both the amygdala and the parabrachial nucleus, actively contributing to the central processing of the emotional component of itch.27 A subpopulation of Tachykinin-1-expressing glutamatergic neurons (TAC1+) promotes stimuli that sustain the itch-scratch vicious cycle. The anterior cingulate cortex forms part of a circuit with the anterolateral thalamic nucleus and dorsomedial striatum, modulating histaminergic itch via a spinal circuit dependent on Bhlhb5+ interneurons.19

An essential step in addressing CP involves a meticulous recording of the patient's medical history and a thorough clinical examination. Additionally, an interdisciplinary diagnostic workup, incorporating laboratory tests and imaging studies, is imperative for the diagnosis (Table 4).13

• i

  Chronic pruritus related to dermatological conditions

When a primary dermatosis is present, the differential diagnosis can be defined through a careful consideration of the clinical history and dermatologic examination.34 Unfortunately, CP has been globally misdiagnosed, primarily attributed to the incorrect diagnosis and treatment of patients with chronic scabies, especially in atypical presentations (Fig. 4). Therefore, dermoscopy examination and direct microscopic examination become critical for dermatologists.35,36Table 5 presents the main dermatologic conditions associated with CP.19,37–39

Fig. 4.

(A) Case of chronic pruritus misdiagnosed as drug adverse reactions (case A1-4) and other (B) as atopic dermatitis (case B1-3) presenting as scabies surrepticious, diagnosed by dermoscopy and direct scrapping of the skin guided by dermoscopy. A: A 87-years-old female patient suffering with chronic pruritus during 7 months noticed a history of 15 days of hospitalization due to a clinical hypothesis of drug adverse reaction; A1: erythematous = scaling lesions on face; A2:erythamtosus-descamative interdigital lesions on hands; A3: Dermoscopy of interdigital area showing “jet with contrail” (burrow´s acari) (dotted black arrow) and the “delta wing´s sign” (full black arrow) (30x magnification); A4: optical microscopy (KOH staining, 800x magnification) of the scales collect of the skin oriented by Dermoscopy examination, a female adult Sarcoptes scabei var. hominis showing an egg in the her body). (B) A female patient suffering due to chronic pruritus and scattered papules on trunk during the last 6 months, misdiagnosed as adult atopic dermatitis, treated with first three months with upadacitinib 30 mg/day, and after due to intractable itching, the physician associated dupilumab to treatment; B1: erythematous papules in lateral thigh; B2: dermoscopy showing the “jet with contrail” (dotted black arrow) and full black arrow demonstrating the “delta wing´s sign”, 10x magnification; B3: dermoscopy of plantar lesions showing “jet with contrail” (burrow´s acari) (dotted black arrow) and the “delta wing´s sign” (full black arrow) (400x magnification).

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Biopsy of skin dermatoses, including Hematoxyllin-Eosin stain (HE), immuno-histochemistry (especially in cases where cutaneous lymphoma is a differential diagnosis), and direct immunofluorescence (to rule out autoimmune dermatoses) may be extraordinarily helpful in this scenario if the etiology is not readily evident from history and physical exam alone.34 Some relevant laboratory exams (e.g. IgE serum levels, eosinophils count in peripheral blood, indirect immunofluorescence) are very useful for etiological diagnosis in chronic pruritus.37–39

• ii

  Chronic pruritus secondary to internal or systemic diseases

Normally, it is present as generalized pruritus without a skin primary cutaneous lesion.2 The most attributable cause of generalized pruritus in patients with underlying systemic disease was found to be iron deficiency anemia, which responded to iron replacement.2 In all cases of Generalized Pruritus Without Rash (GPWOR), especially where iron loss is suspected, it is important to enquire about diet (vegetarian or vegan), potential sources of blood loss, previous bariatric surgery, and gastrointestinal symptoms. Iron replacement leads in some patients to complete cessation of pruritus very shortly after to introduction of iron therapy.2

When iron deficiency is suspected but ferritin levels appear to be within the 'normal' range, it may be necessary to check serum iron and total iron-binding capacity as well. A trial of iron replacement should be considered if ferritin levels are below the lower limit of the reference range (15 to 25 µg/L), or if there is anemia or microcytosis not attributable to other causes (e.g., gastrointestinal blood loss, urinary loss, thalassemia trait, or polycythemia). Individuals with unexplained iron deficiency should also be tested for Tissue Transglutaminase (TTG) antibodies, particularly anti-transglutaminase-2 antibodies, provided they have not been excluding gluten from their diet for at least six weeks. If the TTG test results are abnormal, referral to a gastroenterologist for consideration of endoscopy and small bowel biopsy is recommended. A biopsy may be indicated even with a negative TTG result, as IgA deficiency, which is relatively common, can lead to a falsely negative TTG measurement.2

It may also be associated with generalized itch, either in association with hemochromatosis or hiperferritinemia in the absence of hemochromatosis.2

A retrospective population level cohort study included 327,502 eligible patients diagnosed with unspecified itch with matched controls. Comprised 68.1% females, 59.3% white race, 22.2% black race, and a mean age of 42.2 ± 22-years. Pruritus patients had increased 1-year risk of Hodgkin’s lymphoma (RR = 4.42, 95% CI 2.83–6.88), myeloid leukemia (RR = 2.56, 95% CI 1.79–3.67), multiple myeloma (RR = 2.38, 95% CI 1.66–3.42) non-Hodgkin’s lymphoma (RR = 2.35, 95% CI 1.96–2.82), monoclonal gammopathy (RR = 1.90, 95% CI 1.55–2.32), myelodysplastic syndrome (RR = 1.74, 95% CI 1.14–2.64), and lymphocytic leukemia (RR = 1.47, 95% CI 1.07–2.02).40 The authors concluded that undifferentiated pruritus is highest in the first 12-months, and LDH (Lactate Dehydrogenase) has limited diagnostic utility in these patients. Providers should screen patients with undifferentiated pruritus for hematologic malignancies as clinically indicated.40 In patients with chronic pruritus without concomitant dermatologic diagnoses, older age, male sex, liver disease, and tobacco abuse increase the odds of an underlying malignancy.41

Itch can be a prodrome of malignancy, often appearing before other signs and symptoms. It is particularly common in hematologic malignancies, with prevalence estimates of up to 30% in patients with Hodgkin lymphoma, 15% in those with non-Hodgkin lymphoma, and 67% in patients with polycythemia vera. Lymphoproliferative disorders likely involve the expression of Th2-related cytokines, including IL-3 and TSLP.39

Patients with polycythemia vera often experience aquagenic pruritus, triggered by contact with water of any temperature, typically within minutes of exposure, and often more severe with hot water. Other hematologic conditions can also present with generalized pruritus, which may be accompanied by eczematous, urticarial, or lichenified skin findings, such as in hypereosinophilic syndrome. Among solid tumors, there is a notable association between pruritus and cancers of the hepatobiliary system. Although solid malignant tumors are a relatively rare cause of pruritus, Table 6 highlights malignant neoplasms associated with CP and their clinical characteristics.39

Generalized pruritus in malignancy is usually multifactorial.2 It can be a true paraneoplastic symptom, a feature of paraneoplastic dermatoses, secondary to paraneoplastic neuropathy, a consequence of secondary skin involvement by cutaneous or noncutaneous primary tumors, or a side-effect of cancer treatment.2 Paraneoplastic itch is defined as an itch that arises early in the course of malignancy or even precedes its clinical diagnosis. It is not caused by the invasion or compression of the neoplastic mass and typically resolves after the tumor is removed.42 Paraneoplastic skin diseases associated with itch of varying intensity can be classified into two groups: (i) Paraneoplastic syndromes, which include erythroderma, Bazex syndrome, Grover’s disease, the sign of Lesser-Trélat, generalized granuloma annulare, dermatomyositis, and malignant acanthosis nigricans, and (ii) Associated malignancies, which encompass hematological malignancies, and cancers of the head and neck, upper airway, digestive tract, colon, breast, ovaries, and nasopharynx.43 Although pruritus is thought to be an uncommon symptom in other solid malignancies, there have been case reports of itch occurring in patients with non-small-cell lung carcinoma, insulinoma, gastric carcinoid tumors, and other solid malignancies.39 Itching and burning sensation is reported among patients with glucagonoma syndrome. Patients with chronic unexplained pruritus that favors a possibility of underlying malignancy include older age, male sex, possible liver disease, and chronic tobacco usage.2 Also, several cancer treatments, including radiotherapy, can lead to pruritus by a variety of mechanisms.2

Paraneoplastic pruritus should be especially considered when chronic pruritus lasts less than 12-months.2 Many cancer treatments, including radiotherapy, can lead to pruritus by a variety of mechanisms. Treating the underlying malignancy can often alleviate pruritus. When cancer-drug-induced pruritus occurs, it may require modifying or discontinuing the offending medication. And biological therapies are now commonly used in oncology.2 A recent meta-analysis of 33 RCTs concluded that pruritus was a significant side-effect of cancer treatment with this class of agent.44 Pruritus is a common side effect of epidermal growth factor inhibitors, which have either biological or intracellular mechanisms of action.2 Oncology patients receiving biological therapies or chemotherapy (can cause itch by distinct mechanisms, for instance by inducing a small-fibre neuropathy) should be asked about pruritus on review.2

Pruritus is a common symptom in advanced chronic kidney disease, affecting 40%–90% of hemodialysis patients. The itch associated with chronic kidney disease is linked to uremic xerosis and/or neuropathy, systemic inflammation, and an imbalance in the opioid receptor system, characterized by increased μ-opioid receptor activity and decreased κ-opioid receptor activity. Secondary hyperparathyroidism due to chronic kidney disease has also been suggested as a potential cause of generalized pruritus, although the mechanism remains unclear. This hypothesis is supported by small cohort studies that observed an improvement in itch following parathyroidectomy.19,39

Itch is more prevalent in diabetic patients than in healthy controls, with rates of 26% compared to 15%. Pruritus in Diabetes Mellitus (DM) may result from the harmful effects of elevated glucose levels on cutaneous nerve fibers, often manifesting as a consequence of diabetic polyneuropathy, particularly small-fiber neuropathy. Other endocrine disorders that can trigger pruritus include hyperthyroidism and hypothyroidism.39

Cholestasis from hepatobiliary conditions is a common cause of pruritus. These conditions include both primary and secondary causes of biliary obstruction, such as primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, intrahepatic cholestasis of pregnancy, viral hepatitis, and cirrhosis. Cholestatic itch arises from a complex interplay of factors, including bile acids, lysophosphatidic acid, bilirubin, and increased μ-opioid receptor activity.39 Cholestatic pruritus is often characterized by itch that initially affects the palms and soles, becoming more generalized as the disease progresses. The mechanisms behind HCV-associated pruritus are believed to involve HCV-induced cholestasis and the induction of interferon-stimulated genes due to viral overload.20

In the pediatric population, there are some distinct etiologies associated to chronic itch: primary sclerosing cholangitis (itch in 30% of these patients), biliary atresia, Alagille syndrome (45% of patients have itch), progressive familial intrahepatic cholestasis (itch in 76%‒100%) and benign recurrent intrahepatic cholestasis.39

Although their exact pathophysiology remains to be fully elucidated, other potential etiologies of itch may include exposure to heavy metals, vitamin deficiencies, HIV, and other viral infections. Elevated blood levels of heavy metals, such as cadmium and lead, have been associated with chronic itch. Additionally, low levels of vitamin D have been observed in patients with chronic pruritic skin conditions, including atopic dermatitis, psoriasis, and chronic urticaria. Low levels of vitamin B12 have been noted in patients with generalized itch from various systemic causes.39

Pruritus is commonly reported in patients with viral infections, particularly those living with HIV, where it correlates directly with viral load and can be associated with eosinophilia and eosinophilic folliculitis. Chronic itch is a significant comorbidity among HIV-positive patients, affecting 13%–45% of this population.39 Many HIV-positive patients also experience concurrent pruritic disorders, including lichen simplex chronicus, prurigo nodularis, scabies, seborrheic dermatitis, mycosis fungoides, and psoriasis. Additionally, itch in these patients may be caused by xerosis, drug therapies, and photosensitivity.2

Eosinophilia and generalized pruritus are features of parasitic infections, notably helminths such as Strongyloides stercoralis, but also onchocerciasis, cercariae dermatitis (due to skin penetration by cercariae of schistosomes or Trichobilharzia spp. in Western Europe).2 In tropical areas, pruritus may be a feature of arboviruses such as dengue, zika and less frequently, chikungunya infection.2,45

A French prospective study followed 95 patients with pruritus sine materia over a period of five years (1996‒2001). In 40% of cases (38 patients), a systemic cause was identified. The main conditions included toxocariasis (8 cases), hematologic diseases (7 cases), chronic renal failure (6 cases), hypothyroidism (5 cases), and iron deficiency (5 cases). Neoplasms were found in eight cases (8.42%): seven involved hematologic malignancies (3 myeloma, 2 Hodgkin's disease, 2 myeloproliferative syndromes) and one involved a solid tumor (pulmonary adenocarcinoma). Toxocariasis, an often-underestimated disease, was the most frequently identified condition.46

Human toxocariasis is a parasitic disease characterized by the presence of larvae of the genus Toxocara in human tissues.47T. canis and T. cati, found in dog and cat intestines, respectively, are the most common causative agents of the disease.47 Toxocaral larvae usually cause two severe syndromes: visceral larva migrans and ocular larva migrans, depending on the location of the larvae.47

• iii

  Chronic pruritus related to neurogenic, neuropathic or central nervous system conditions

Neuropathic pruritic conditions may originate from the peripheral nervous system or central nervous system.21

The conditions originating from the peripheral nervous system are:21

• a)

  Small fiber neuropathy: metabolic, drug-induced, infectious, or genetic origin (itch starts usually distally and may generalize);

• b)

  Scars and burns: iatrogenic or traumatic (itch on lesional skin);

• c)

  Radiculopathies: compression of a peripheral nerve by degenerative alterations or space-occupying lesions (itch and dysesthesias at the affected dermatome);

• d)

  Postherpetic neuralgia: damage of peripheral nerve by the varicella-zoster virus (itch and dysesthesias at the affected dermatome);

• e)

  Trigeminal trophic syndrome: injury of the sensory fibers of the trigeminal nerve (unilateral dysesthesia and hypoesthesia of the central face. Self-induced ulceration of the nasal ala, cheek, and upper lip).

The conditions originating from the central nervous system are:21

• a)

  Space-occupying lesions: tumors, abscesses, vascular lesions, syringomyelia (clinical features according to affected neural structures);

• b)

  Stroke: Ischemic or hemorrhagic (generalized or unilateral itch);

• c)

  Multiple sclerosis: demyelinating disease (generalized itch or localized at the head and upper back);

• d)

  Neuromyelitis optica: demyelinating disease (depending on injured spinal level);

• e)

  Infectious diseases: meningitis, encephalitis, prion disease;

• f)

  Traumatic brain or spinal cord lesions: accidents or iatrogenic lesions.

Generally, includes brachioradial pruritus, notalgia paresthetica, meralgia paresthetica, scalp pruritus (excluding dermatological diseases), gonalgia paresthetica (saphenous nerve damage), anogenital pruritus, and other conditions.48 The latter is caused by direct damage to the nerve itself.48 Although specific itch conditions have predominant contributors to their pathogenesis, it is most likely that there are multiple etiologies.48

Neuropathic pruritus refers to a group of disorders characterized by chronic itching caused by dysfunction or damage to pruriceptors.48 In these conditions, pruritus is not triggered by external stimuli, such as irritants or allergens, but rather emerges spontaneously.20 The neuropathic itch can occur owing to nerve damage that may be caused by mechanical, metabolic, inflammatory, or cytopathic injury.48

Pruritus neural hypersensitivity is exhibited in the following common neuropathic itch conditions.20 Brachioradial pruritus is characterized by itching on the arms bilaterally. It is often associated with compression or irritation of the nerves of the cervical spine.20 Notalgia paresthetica is a common chronic itch condition characterized by localized itching or burning sensation in the subscapular region and it may be caused by thoracic nerve damage or irritation in the affected area.20 Postherpetic pruritus is a complication of herpes zoster due to nerve damage caused by viral cytopathic changes.20 Finally, scalp pruritus is neuropathic when it occurs independently of any observable cutaneous eruption (e.g., seborrheic dermatitis).20 The damage to the occipital nerves from the cervical spine causes scalp pruritus.20

Painless self-injury from neuropathic itch is far more common on the face than anywhere else on the body.49 For example, itch is far more common after zoster affecting the face than the torso.49 The face is also unclothed and readily accessible to the fingers.49

Nerve fiber compression can cause pruritus in the corresponding dermatome, and nerve fiber degeneration (such as small fibre neuropathy) can cause localized or generalized pruritus.4 Small fiber neuropathy can occur in systemic diseases such as diabetes mellitus, Guillain-Barre syndrome, sarcoidosis, neurofibromatosis type 1 and HIV.2 Diabetic neuropathy can lead to a regional pruritus affecting the trunk.2 Small fiber neuropathy may be too small to produce clinical or electrophysiological changes, and the only investigation that may reveal anything is a skin biopsy with immunohistochemical staining of cutaneous nerve fibers.2

Central nervous system lesions affecting sensory pathways, such as strokes, multiple sclerosis, and cavernous hemangiomas, can lead to central itch. Damage to itch-transducing, conducting, or processing neurons can result in neuropathic pruritus. There are reports of patients developing new self-inflicted injuries decades after strokes or trigeminal surgery, often exacerbated by dementia, which causes uncontrolled scratching. Less common causes of central itch include multiple sclerosis, brain tumors, abscesses, and Sjögren’s syndrome. Rare cases have also been linked to anterior circulation strokes, particularly those affecting the thalamus.49

Neurogenic is a more general term that encompasses a pathologic process arising from the nerve.20 In other words, tumors of the nerve or other pathologies that have nothing to do with sensation or afferent transmission can still be referred to as neurogenic.20

Sensory nerves can contribute to neuroinflammation by releasing neuropeptides, which inflame tissues through efferent pathways. There are two primary ways in which sensory neurons can cause pruritus: (i) Neuropathic itch, where neuropathology leads to excessive afferent itch transmission to the CNS, and (ii) Neuroinflammatory processes, where sensory neurons activate immune cells or other intermediaries to trigger itch. A clear example of this is the release of substance P by sensory neurons, which binds to Mas-related G-protein-coupled receptor member X2 on mast cells, leading to the release of pruritogenic factors such as histamine and LTC4 from mast cells.20

A prime example of the neurogenic itch is Chronic Inducible Urticaria (CIndU). In this condition, various neurologic triggers, including thermal stimuli (heat, cold), mechanical stimuli (friction, pressure, vibration), and autonomic stimuli (acetylcholine), lead to the formation of hives and associated itch. CIndU exemplifies neurogenic itch, where itch is initiated by the nervous system in the absence of clinically defined neuropathic itch, likely through the activation of intermediate mast cells. Additionally, it is widely believed that Prurigo Nodularis (PN) also involves underlying neurogenic itch processes that trigger the development of cutaneous nodules.20

• iv

  Chronic pruritus secondary to somatoform (psychiatric/psychosomathic) disorders

Chronic generalized pruritus is commonly associated with various psychiatric disorders, including depression, anxiety disorders, obsessive-compulsive disorder, substance abuse, and delusional infestation. Somatoform pruritus is characterized by itch where psychological, psychiatric, and psychosomatic factors play a crucial role in the onset, intensity, exacerbation, or persistence of the condition.50

• v

  Chronic pruritus of undetermined/unknown origin (CPUO)

Once both underlying pruritic skin disease and other secondary causes of pruritus have been excluded, an individual may be considered to have CPUO.2 The prevalence of pruritus of unknown cause in individuals with generalized pruritus ranges from 3.6% to 44.5%, with the highest prevalence among the elderly.13,51

The initial clinical approach includes a detailed medical history and full physical examination (including total body skin examination, lymph nodes palpation, liver and spleen examination, lung and heart auscultation, abdomen and pelvis palpation).51 Initial investigation should not only blood samples, but also urinalysis, stool routine, and occult blood, as well as X-Ray chest (radiologist to report), ultrasonography abdomen, and skin biopsy for direct immunofluorescence.52 On Table 7 we described the main laboratory exams and complementary diagnostic approaches for patients with chronic pruritus of unknown origin.

However, in some cases, the underlying cause remains unclear, and is Called Pruritus of Unknown Cause (CPUO).51 As CPUO is a diagnosis of exclusion, patients suffering from it are re-examined periodically.51

CPUO may affect younger patients but is highly prevalent in those aged over 65 years.2 Although many factors are thought to underlie CPUO, physiologic changes associated with aging likely contribute, including epidermal barrier dysfunction, sensory neuropathy, immunosenescence, and aging are characterized by a proinflammatory state with enhanced type-2 immune responses and reduced type-1 immunity.53 In the elderly, besides the possibility of internal malignancy and cutaneous lymphoma, there are two chronic itchy conditions that should be remembered: atypical forms of bullous pemphigoid54,55 and eosinophilic dermatoses with hematological malignancy (Fig. 5).56

• vi

  Drug-induced chronic pruritus

Fig. 5.

Unusual chronic pruritic conditions found on elderly patients: atypical bullous pemphigoid (ABP) (A) and eosinophilic dermatoses with hematological malignancy (B). Atypical lesions of bullous pemphigoid. A1: annular urticarial-like lesions with excoriated hematic crusted lesions; A2: urticarial plaques resembling urticarial vasculitis; A3: erythematous eczematous crusted lesions, with excoriated papules with hematic crusts and hyperchromic residual lesions; A4: direct immunofluorescence positive to IgG in a granular pattern on basal zone membrane of the skin, obtained from normal appearance skin of a 69-years-old female with 2 years complain of chronic itch. Eosinophilic dermatoses of hematological malignancy: image of a patient suffering from chronic itch for 2 years after covid-19, with progressive elevated count of lymphocytes on total blood count and a diagnosis of chronic lymphocytic leukemia. B1: showing erythematous excoriated and exulcerated lesions on ankles; B2: urticarial-like lesion resembling insect bites, and B3: several excoriated lesions on legs due to intense chronic itching.

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Approximately 5% of cases of pruritus are caused by drugs. Drug-induced chronic pruritus may occur with or without a rash.2 Proposed mechanisms of drug-induced pruritus include cholestasis, direct drug or metabolite deposition, alteration of neural signaling, photodermatoses, xerosis or cell stimulation (for example, codeine), however, most cases are idiopathic.2,19 Opioid-induced pruritus is common and affects 2%‒10% of patients receiving oral, 10%‒50% intravenous and 20%‒100% epidural and intrathecal opioids.2 The common culprits of drug-induced pruritus include immune checkpoint inhibitors;39 agents targeting epidermal growth factor receptor, B-Raf proto-oncogene, cytotoxic T-lymphocyte-associated protein-4, and Programmed cell Death protein-1/Programmed cell Death-Ligand-1 (PD-1/PD-1L).39Table 8 displays the most frequent drugs that may induce chronic pruritus.19

The main attitudes include prescribing continuous use of moisturization agents, especially adequate for patients with atopic dermatitis and/or sensitive skin (Table 9).58

For all modalities of approach to treat CP, the experience has shown that it takes a long time before patients respond to treatment (up to 12-weeks); in case of cessation of itch, treatment should not be discontinued too quickly (gradual tapering over at least four weeks).13 The advent of Janus Kinase (JAK) inhibitors has ushered in a transformative paradigm shift, affording quick alleviation of pruritus.59

The range of causal treatments for pruritus includes addressing the underlying dermatosis, avoiding contact allergens, discontinuing medications, and employing specific systemic, neurological, and psychiatric therapies, as well as surgical interventions for tumors. In rare cases, treating or curing the underlying disease may lead to resolution of chronic pruritus. However, exceptions exist, such as short-term pruritus associated with Hodgkin’s disease and early chemotherapy, where the itch may not fully resolve even with treatment of the underlying condition.13

In CP basic therapy with emollients alone or in combination with specific topical, systemic agents and/or UV phototherapy is recommended.13 The first choice of topical treatment in lesional skin is topical corticosteroids, such as hydrocortisone (on the face or intertriginous areas),60 betamethasone valerate, or calcineurin inhibitors (do not combine with UV phototherapy).13 Calcineurin inhibitors may have a particular use in thin and sensitive skin areas, and prolonged use compared to topical corticosteroids.61

Another possible topical agent with antipruritic effect published only in case series or case reports is capsaicin which is indicated in neuropathic pruritus (notalgia paresthetica, brachioradial pruritus, postherpetic pruritus), aquagenic or uremic pruritus.19 In case of residual single nodules the use of intralesional corticosteroid intradermal injection is a possible alternative.18,19

Localized CP may be treated with other agents, but the level of recommendation is based on case studies non-placebo controlled, such as menthol 1% lotion and topical anesthetics.topical antidepressive/histamine.19 intralesional botulinum neurotoxin, gabapentin 6%‒10%, phosphodiesterase inhibitors (crisaborole, difamilast, roflumilast).18,57

Ultraviolet phototherapy [e.g., Narrow Band (NB) UVB 311 nm] constitutes an interesting option for all patients, including the elderly population as it is well tolerated, with few side effects and drug interactions.19,57 Long treatment cycles lead to skin aging and can increase the risk of epithelial skin cancer.54

Excimer lamps also decrease the density of intraepithelial nerve fibers.19 UVA1 (340‒400 nm) decreases the levels of IL-4, IL-13, IL-17 and IL-23.19 Repeated exposure to suberythematogenic doses of both ofUVA1 and NB-UVB decrease IL-31 concentration, whereas high doses have the opposite effect, especially with UVB.19

• • a

    Antihistamines

Second-generation anti-H1 medications such as cetirizine, desloratadine, bilastine, rupatadine, fexofenadine, and levocetirizine are indicated in chronic urticaria. They cause less sleepiness than first-generation antihistamines and also interact with fewer medications. For the treatment of CPUO, the German Guideline for CP indicates as first line recommendation the second-generation H1 antihistamines (up to fourfold dosage).13 Most conditions involving CP have nonhistaminergic pathway involvement, then anti-H1 drugs have suboptimum effects or no effects to treat chronic pruritus.13

Oral first-generation H1 antihistamines, such as diphenhydramine and hydroxyzine, are commonly used as first-line options for CP, except in chronic urticaria, in children with milder cases, mostly due to their sedative properties.58 Side effects such as sedation and confusion from dialysis.58 The standard dosage for children is 5 mg/kg/d of oral diphenhydramine HCl or 2 mg/kg/d of hydroxyzine given at nighttime for sedation.58

• • b

    Antidepressants agents19

These types of medications are indicated for uremic, cholestatic or paraneoplastic pruritus. The peak of the effect is reached after 4‒6-weeks. Adverse effects limit their use, particularly in the case of Selective Serotonin Receptor Inhibitors (SSRIs) and mirtazapine.19 These agents are less useful than gabapentin or pregabalin in neuropathic itch.19

Antidepressants should be used with caution in elderly patients due to reported severe side effects, mainly those of a cardiac nature.57 Serotonin reuptake inhibitors (e.g., paroxetine, fluvoxamine) can be used in somatoform, paraneoplastic, and aquagenic pruritus arising from hematological proliferative conditions.57 Sertraline has proven effective for the treatment of cholestatic pruritus.57 Tetracyclic antidepressants, namely, mirtazapine, amitriptyline, doxepin have also shown antipruritic effects on CP of various origins and beneficial effect on patients with impaired sleep quality due to CP (mirtazapine).57

Table 10 displays the main antidepressant medications used in distinct types of CP.

• • c

    Gabapentinoids19

Gabapentinoids, especially gabapentin and pregabalin, are indicated for the treatment of neuropathic pain and can be also used to treat forms of neuropathy with both localized (e.g., brachioradial pruritus, notalgia/meralgia/gonalgia paresthetica, postherpetic neuralgia) and generalized (e.g., small fiber neuropathy due to diabetes) pruritus.19 Gabapentinoids have also shown efficacy in systemic diseases such as renal insufficiency and aquagenic pruritus.19 Depending on renal function, for adult patients gabapentin’s recommended dose is until 900 mg/day (however, higher doses as 3600 mg/day may be necessary) and pregabalin 75‒225 mg/day.13 In order to reduce the occurrence of side effects, it is important that the dose be slowly increased until therapeutic doses are reached.19 Additionally, the dose should be reduced in senior patients and those with impaired renal function.19 Common side effects include tiredness, dizziness, and weight gain.19 Gabapentinoids have few interactions with other drugs and thus constitute an appealing treatment option for older patients. The dosage of gabapentin in the elderly be initiated at 100–300 mg (pregabalin 25–75 mg) at night and slowly titrated up.62

• • d

    Opioids

The Mu Opioid Receptor (MOR) antagonists and the Kappa Opioid Receptor (KOR) agonists have been shown to be very useful given their role as central pruritus regulators.19 These medications are classified as: (i) KOR agonists difelikefalin for parenteral use in cases of uremic pruritus in patients on hemodialysis; nalfurafin for parental use in patients with cholestatic pruritus, and nalmefene for oral use in cholestatic itch); (ii) KOR agonists/MOR antagonists: nalbufin for parenteral use in patients with uremic pruritus and prurigo nodularis; butorphanol for intranasal use and applied in intractable cholestatic itch; (iii) MOR antagonists: naloxone for parenteral use (reversal of side effects of opioids or intoxication) indicated for the drug-induced itch, brachioradial pruritus and cholestatic itch,19 and systemic administration of intravenous naloxone (0.002‒0.02 μg/kg body weight/min) provides rapid management of pruritus along with a low quantity of side effects;62naltrexone for oral use (50‒150 mg/day), indicated for drug-induced itch, cholestatic itch, Hailey-Hailey disease, lichen planus pilaris, psoriasis, Darier´s disease.19 Low-dose naltrexone administered at 2 mg daily also has antipruritic effects and can be used in patients who cannot tolerate standard doses.18 MOR antagonist receptors, such as naloxone, naltrexone, or nalmefene, have been demonstrated to be effective in reducing itch in chronic urticaria, AD, PN as well as cholestatic and uremic itch.62 In contrast, activation of KORs inhibits pruritus.57 Butorphanol, a kappa-opioid agonist with some mu-opioid antagonist properties, has been shown in case series to effectively reduce itch due to PN, cholestasis, uremic itch, and idiopathic pruritus in elderly patients.62

The most common side effects of opioid modulators include gastrointestinal distress (such as diarrhea and vomiting), drowsiness, fatigue, dizziness, and insomnia. Additionally, there is a risk of liver injury at high doses, which necessitates caution when prescribing these medications to elderly patients.18,62 Patients taking opioid agonists should avoid concurrent use of opioid antagonists, as this can trigger rapid withdrawal symptoms. Long-term use of agonists like butorphanol can also increase the risk of dependence. It is important to note that difelikefalin ‒ a selective kappa-opioid receptor agonist ‒ is FDA-approved only as an injection for the treatment of moderate-to-severe itching associated with chronic kidney disease in adults undergoing hemodialysis. Most other opioid medications used for chronic itch are used off-label.18

• • e

    Bile acids resins and rifampicin

Cholestyramine is a bile acid resin that alleviates itch by sequestering pruritogenic bile acids. Rifampin, an antibiotic, helps reduce itch by promoting the conversion of bile acids to less pruritogenic forms. However, due to its hepatotoxic and nephrotoxic side effects, rifampin is not suitable for long-term use but can be an effective second-line treatment when cholestyramine is insufficient.18

• • f

    Thalidomide

Thalidomide is a nonspecific immunomodulator that may disrupt the degeneration of type C unmyelinated nerve fibers.65 It can be effective in treating uremic pruritus and Prurigo Nodularis (PN). However, notable side effects include sedation, bowel obstruction, and peripheral neuropathy, which typically reverses upon discontinuation of the drug. Thalidomide is classified as a pregnancy category X drug due to its severe teratogenic effects, necessitating strict adherence to the Risk Evaluation and Mitigation Strategies (REMS) program. Thalidomide dosage is recommended in tablets of 50‒200 mg/day.18

• • g

    Immunosuppressive drugs

Systemic immunosuppressive drugs are well-established in the treatment of inflammatory dermatoses, such as atopic dermatitis, psoriasis vulgaris, or cutaneous T-cell lymphoma.57 They should be considered following an unsuccessful treatment with topical or physical alternatives and after the exclusion of contraindications.57 Cyclosporine (2.5‒5 mg/kg/day), methotrexate (7.5‒20 mg weekly), mycophenolate (1‒2 g/day) and azathioprine (1‒3 mg/kg/day, often 50‒100 mg/day) are the most widely used substances.18,57 Due to the complex interactions and undesirable side effect profiles of these drugs, they should be recommended with caution, particularly for older individuals. For instance, increases in retention parameters, liver enzymes, and hypertension are commonly observed. Therefore, a risk-benefit analysis should be conducted before initiating systemic immunosuppressive therapy, and patients should be thoroughly informed about the potential risks and side effects.57

• • h

    Biologic therapies and oral small molecules

Dupilumab (600 mg initial, 300 mg Q2W), a monoclonal antibody targeting the receptor for IL-4, has been shown in large RCTs to reduce symptoms and improve quality of life in those with moderate to severe AD.18 The average age of participants in these trials was under 50, providing little evidence of efficacy in the elderly population.18 We have gained clinical experience using this drug in older patients with success, including an 87-year-old with itch and PN refractory to other treatments.63

Adverse effects have not been specifically detailed for the elderly, but in the general adult population, they include conjunctivitis, headache, and injection site reactions. There is no demonstrated increased risk of secondary infections, such as herpes viral infections or urinary tract infections, that would be of particular concern when prescribing to older patients.18 Several additional biologic therapies including targets of IL-31RA (nemolizumab for PN and AD), rocatinlimab (anti-OX40, in clinical trial for AD and PN), amlitelimab (anti-OX40 L, in clinical trial for AD) and lebrikizumab/tralokinumab (anti-IL-13, for AD) anti-OSMRβ (vixarelimab for PN) may control CP.64

Oral JAK inhibitors show promise in early phase trials for their antipruritic properties particularly, several itching dermatoses, including AD, PN, and chronic idiopathic pruritus).18,59,63 Baricitinib (JAK1/2-1), abrocitinib (JAK-1) and upadacitinib (JAK-1) are already approved for AD in several countries. JAK inhibitors such as tofacitinib (5‒10 mg/day) have adverse effects that should be strongly considered when used in the elderly including increased risk of herpes and other infections.18,65,66 A phase II clinical trial (NCT05038982) evaluating the efficacy of abrocitinib 200 mg during 12-weeks for reducing pruritus in adults with CPUO and prurigo nodularis was recently completed and is awaiting the publication of the results.66,67

Based on the identification that JAK1 is expressed in neurons coupled with evidence of type 2 immune responses in CPUO, severe and refractory CPUO patients maybe could have benefits in the use of oral JAK inhibitors (not indicated to patients > 65-year-old in the atopic dermatitis setting).53 Dupilumab is currently being investigated in RTCs enrolling patients with CPUO.68,69