Samuel Hafemreffer described pruritus in the seventeenth century in the same way we recognize this symptom today, that is, an unpleasant and uncomfortable somatic sensation for the patient,1 with a substantial sensorial, emotive, and motivational component causing an irresistible desire to itch. Translational medicine has enabled the identification of new participants in its complex pathophysiology.2 An interaction between skin, the immune system, and the nervous system triggers and sustains pruritus in the long term. As the poet Ogden Nash said, ‘Happiness is scratching yourself every time you feel an itch.’ However, patients with chronic pruritus experience a substantial negative impact on their quality of life.

Ständer et al.3 reported that 22–26% of the general population suffers from chronic pruritus. Leader et al.4 reported a figure of between 8% and 28% of the general population as suffering from this condition. Specifically, pruritus is present in 78% of patients aged over 65 years,5 87% of atopic patients,6 84% of patients with psoriasis,7 35% of patients in hemodialysis,8 and 45% of patients with HIV infection.9 The cause of pruritus is never determined in up to 44.5% of patients (pruritus of unknown origin).10

Pruritus is considered chronic when it lasts for more than 6 weeks. The different types of pruritus are shown in Table 1.

We can classify pruritus according to whether the origin is dermatologic, systemic, neurologic, psychogenic, of mixed origin, or others (this latter category includes idiopathic). However, the classification recommended by the International Forum for the Study of Itch (IFSI)11 has 3 groups:

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  Group I or primary: chronic pruritus on altered or inflamed skin (primarily).

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  Group II or somatoform (previously denoted pruritus sine materia): chronic pruritus in an area of skin previously not involved. Pruritus in this group is also sometimes denoted as invisible dermatosis. An example is dermatitis factitia. A classic sign during the examination is the butterfly sign (Fig. 1).

  
  

  Figure 1.

  Butterfly sign.

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  Group III or predominance of excoriation: chronic pruritus with itching lesions.

The algorithm in Fig. 2 can be followed to identify the group in which each patient belongs.

Figure 2.

Algorithm for classification of pruritus.

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Table 2 shows some of the diseases most frequently associated with pruritus.

Premonitory pruritus is when the condition appears months or even years before a systemic or neoplastic disease. Studies have been published of the risk of hematological neoplasms12 or bile duct neoplasms in patients previously diagnosed with pruritus.

Table 3 shows the important details in the medical history of patients with pruritus, both in general terms and for specific orientation according to its origin.

Fig. 3 shows the main diagnoses according to site.

Figure 3.

Dermatoses and pruritus according to site.

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Diagnosis of pruritus is based on clinical observation. Patients with pruritus classified as group II and III are candidates for additional tests, depending on the medical history and suspected diagnosis. Patients with skin lesions may need microbiological cultures, skin biopsy (with or without immunofluorescence detection), indirect immunofluorescence, 24-h urine test for porphyrias, and study of fresh samples for mycosis and scabies. The general blood workup should include creatinine, urea, estimated glomerular filtration rate, potassium, glucose, ferritin, bilirubin, transaminases (GOT, GPT, GGT), alkaline phosphatase, lactate dehydrogenase, thyroid stimulating hormone, complete hemogram, urinalysis (reactive strip), globular sedimentation rate (GSR), and C reactive protein (CRP). Study of fasting bile acids levels in blood should be requested for pregnant patients if there is suspicion of cholestasis.

Table 4 shows the specific additional tests for patients with pruritus.13

Imaging tests are requested in accordance with the initial clinical suspicion. Chest X-ray is considered standard, but abdominal ultrasound, computed tomography, magnetic resonance imaging, gastroscopy, ultrasound-guided lymph node biopsy, etc. can also accompany the laboratory work-up as per the clinician's judgment. Management of patients with pruritus requires multidisciplinary teams and collaboration across specialties.

In clinical practice, the most widely used scales are the numerical evaluation scale (NES) and the visual analog scale (VAS). A scale validated in Spanish is available, under license, the ItchyQoL,14 a 22-item questionnaire that measures symptoms, functions, emotions, and self-perception. Comparing outcomes in improvement in pruritus in clinical trials is a complex task with certain limitations because there is no standard measurement of pruritus severity, and different measurement instruments are used.

In recent years, the close relationship between the skin, immune system, and nervous system has been extensively investigated. The participation of each of these systems plays a fundamental role, both in the development of pruritus and in sustaining the condition in the long term. Although each system is presented separately, in truth, they do not exist in isolation but rather as a whole. Fig. 4 shows a schematic and summarized representation of the main pruritogenic mediators and receptors.

Figure 4.

A multitude of receptors are expressed in the nerve endings of cutaneous C fibers. Depolarization is triggered by calcium ion entry through TRPA1 and TRPV1. These are activated by binding to the receptor of the corresponding molecule. The different pruritogens are released by keratinocytes, mastocytes, Th2 lymphocytes, macrophages, and fibroblasts. They form positive feedback loops with different pruritogens such as periostin and TSLP. Release by nerve endings of substance P (SP) and calcitonin-gene related peptide (CGRP) act on keratinocytes and Langerhans cells, respectively, potentiating the neuroinflammatory environment. Abbreviations: 5HT, serotonin; ACh, acetylcholine; CB1-CB2, cannabinoid receptor; ET-1, endotelin-1; ET-1R, ET-1 receptor; H1R-H4R, histamine receptor; KOR, kappa opioid receptor; MOR, mu opioid receptor; NGF, neuron growth factor; NK-1R, neurokinnin-1 receptor; ST2, IL-1-like receptor; TrkA, tropomyosin kinase A receptor.

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Peripheral axons are projected directly toward the posterior horn of the spinal cord (exterior region of lamina I and II for peptidergic pathways, and the interior region of lamina II for nonpeptidergic pathways), after passing through the dorsal root ganglion. Between 2% and 5% of the spinal neuronal population participates in transduction of pruritus, where NK-1R is the main receptor. The presence of excitatory interneurons (SP+ and GRPR+) and inhibitory ones (GABA+) plays a key role in modulating ascending signaling in pruritus. These interneurons express VGLUT2 (vesicular glutamate transporter), neurotensin, and somatostatin. The presence of BHLH+ (basic helix loop helix) interneurons is very important given that they regulate neurogenesis and define neuronal identity within the spinal cord. The BHLHB5+ interneurons are of the inhibitory type,57 and can be activated by menthol, capsaicin, or dynorphin. They express somatostatin and NPY receptors. Another population of inhibitory interneurons are the GABAergic ones, localized in lamina I and III. The neurons also coexpress the glycine receptor,58 another inhibitory neurotransmitter. When a clear excitatory polarization of excitatory GRPR+ interneurons is present, recruitment of enkephalinergic interneurons is induced to mitigate the intense stimulus for itching. Another subpopulation of excitatory interneurons expresses SOM+. This expression enhances pruritus signaling to second-order neurons. Activation of BHLHB5+ with dynorphin decreases the sensation of pruritus. Signaling via the pruriceptive fibers that reach the posterior horn induces secretion of nppb, which activates excitatory interneurons of gastrin secretor peptide. Fig. 5 shows a schematic view of the above.

Figure 5.

The depolarized C fibers that transmit the pruriceptive signal release nppb when they reach lamina I and II of the posterior horn of the spinal cord, stimulating the excitatory interneurons that express GRP. Another of the excitatory interneurons expresses the NK-1 receptor for substance P. There are inhibitory interneurons, BhbIB5 is one of these. These are important in that they release dynorphin A, and also GABA and glycine, thereby impeding central signaling of pruritus. Loss of this inhibitory function is one of the causes of central sensitization in pruritus. Abbreviations: BHLHB5, B helix-loop-helix protein; GRP, gastrin-releasing peptide; GRPR, GRP receptor; NK-1R, neurokinin receptor 1; nppb, natriuretic polypeptide b.

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Interneurons are implicated in the door control theory, the aim of which is to control the nociceptive and non-nociceptive signaling in the central nervous system. Loss of control could be responsible for central pruritus signaling,59 present in patients with chronic pruritus. Activation of inhibitory interneurons is crucial to prevent signaling from passing to second-order neurons projected into the central nervous system, where pruritus is processed and will give rise to the motor component (scratching), but also the emotive component (pleasure after scratching), necessary to sustain the pruritus-scratching cycle.60

Thanks to neurobiology, today, we know the areas of the brain implicated in the pruritus circuit. The first station that receives the fibers of the spinothalamic and trigeminothalamic tract is the thalamus (mainly the ventrobasal complex), and the parabrachial nucleus.61 The thalamus for its part contains neurons that can be activated by pruritogens, whether histaminergic or nonhistaminergic. More than 70% of the neuronal population of the posteromedial region of the ventrobasal area of the thalamus responds to more than one type of pruritogen. In the somatosensory cortex, the intensity and localization of the pruritus is processed, and the motor signal for scratching is emitted. The prefrontal cortex and amygdala mediate the emotive and pleasure component implicated in scratching.62 The amygdala63 is activated by pruritogenic stimuli and deactivated by scratching; it participates actively in the sensory and affective process of pruritus. GABAergic neurons have been detected in the periaqueductal gray matter and the ventral tegmental area. These neurons participate in the disagreeable and aversive perception of pruritus. They are activated with active pruritus in the patient, possibly playing an important role in the patient's addiction to scratching. There is a true motivational component in pruritus, namely, the urgent need for scratching. The anterior cingulate cortex and motor and premotor cortex participate in this process. In fact, these neurons are deactivated when the patient actively scratches.

The main neurotransmitters are noradrenaline (NA) and serotonin (5-HT).64 The main population of NA+ neurons are localized in the locus coeruleus, whereas their adrenergic receptors α1 are present in the spinal cord inhibitory interneurons.65 The 5-HT1A receptor expressed in GRPR+ interneurons also participates directly in the descending signaling of pruritus. The periaqueductal gray matter (PAG) receives signals both from the amygdala and the parabrachial nucleus, actively participating in the processing of pruritus. A subpopulation was discovered of tachykinin-1 expressing glutaminergic neurons (TAC1+) that facilitated the itch-scratch cycle.66 Ablation of these neurons reduces scratching induced by pruritus, while activation generates the action of scratching. The anterior cingulate cortex forms a circuit with the anterolateral thalamic nucleus and the dorsomedial striatum, modulating pruritus of histaminergic origin through the spinal circuit dependent on BHLHB5 interneurons.67

The author declare that he has no conflicts of interest.