Practical guide for the diagnosis and treatment of localized and generalized cutaneous pruritus (chronic itch with no underlying pruritic dermatosis)

Abstract

Itch, also known as pruritus, is one of the most prevalent symptoms observed in dermatological practices. Itch frequently arises from primary pruritic dermatoses, although it may also manifest in the absence of a primary pruritic skin rash. The latter itchy condition is referred to as "cutaneous pruritus" in the Japanese guidelines published in 2020. Cutaneous pruritus can be classified into two categories based on its distribution: localized cutaneous pruritus and generalized cutaneous pruritus. Localized cutaneous pruritus is indicative of a neuropathic cause, whereas generalized cutaneous pruritus suggests underlying systemic disease(s), drug-induced itch, psychogenic itch (also known as functional itch disorder), or chronic pruritus of unknown origin (CPUO). Systemic diseases associated with cutaneous pruritus include disorders of iron metabolism, chronic kidney disease, chronic liver disease (especially cholestasis), endocrine/metabolic diseases, hematological disorders, and malignant solid tumors. CPUO is a term used to describe chronic itch that is often generalized and for which no underlying cause can be identified despite a comprehensive and careful diagnostic workup. A variety of treatment approaches are available for cutaneous pruritus, including device-based physical therapies (such as phototherapy) and medications that act on the itch-perception processing pathway from the skin, peripheral sensory nerves, the spinal cord, to the brain. This review presents an overview of the current knowledge regarding cutaneous pruritus, from its underlying pathophysiologic mechanisms to the diagnostic procedures and treatment approaches that are currently available.

Keywords: cutaneous pruritus; generalized pruritus; itch; localized pruritus; neuropathic itch.

FIGURE 1

Itch pathway from the skin to the brain and targeted approaches for itch. The four consecutive steps of the skin, peripheral sensory nerve fibers, the spinal cord, and the brain are of importance in the sense of itching. A variety of treatment approaches targeting these four steps are currently in use in clinical practice. JAK, Janus kinase; PDE4, phosphodiesterase‐4.

FIGURE 2

Itch transduction in cutaneous sensory nerve fibers. Pruritogens (substances that elicit itch) stimulate peripheral sensory nerve fibers in the skin via their receptors, thereby generating action potentials through the opening of ion channels, including transient receptor potential (TRP) A1 and V1 and voltage‐gated sodium channels (Na_v), particularly Na_v1.7. JAK, Janus kinase; STAT, signal transducer and activator of transcription.

FIGURE 3

Itch neural circuit from the skin to the brain. Neural itch signals are transmitted from the skin to the brain. In the spinal cord, the transmission of itch signals is subject to modulation by the opioid and/or GABA systems. Interneurons express propruritic mu opioid receptors (MORs) and antipruritic kappa opioid receptors (KORs). MORs potentiate neural itch signals when stimulated by endogenous opiates (beta‐endorphin) or exogenous ligands such as morphine. KORs attenuate itch signals in response to dynorphin A and GABA from inhibitory interneurons. Inhibitory interneurons are positively regulated by both nociceptors from the periphery and the descending inhibitory pathway that originates from the brain. DRG, dorsal root ganglion; GABAR, GABA receptor.

FIGURE 4

Mechanisms of action of targeted approaches for cutaneous pruritus in sensory nerve fibers. Biologics target cytokines or cytokine receptor components. Janus kinase 1 (JAK1) inhibitors regulate the generation of action potentials in nerve fibers. Analgesics/anesthesia and antidepressants act on voltage‐gated sodium channels (Na_v). IL, interleukin; OSMR, oncostatin M receptor; STAT, signal transducer and activator of transcription; TRP, transient receptor potential.

FIGURE 5

Mechanisms of antipruritic action of antidepressants in the central nervous system. Antidepressants activate the descending adrenergic itch‐inhibitory pathway in the spinal cord and the brain. Note, antidepressants also act on sodium channels on peripheral nerve fibers (see Figure 4). DRG, dorsal root ganglion; GABAR, GABA receptor; MOR, mu opioid receptor; KOR, kappa opioid receptor.

FIGURE 6

Mechanisms of action of opioid receptor modulators in the treatment of itch. Nalfurafine, an opioid receptor modulator approved in Japan for intractable itch in patients undergoing hemodialysis and those with chronic kidney disease, acts on antipruritic kappa opioid receptors (KORs) expressed by nociceptors in the periphery as well as interneurons in the spinal cord. Difelikefalin, another opioid receptor modulator, favorably activates peripheral KORs. DRG, dorsal root ganglion; GABAR, GABA receptor; MOR, mu opioid receptor.

FIGURE 7

Mechanism of action of GABAergic drugs in the treatment of itch. GABAergic drugs have been demonstrated to downregulate itch‐conveying intermittent neurons in the spinal cord, as well as to activate the descending itch‐inhibitory pathway. DRG, dorsal root ganglion; GABAR, GABA receptor; MOR, mu opioid receptor; KOR, kappa opioid receptor.

FIGURE 8

Causes of cutaneous pruritus. Cutaneous pruritus can be classified into two categories based on its distribution: Localized cutaneous pruritus and generalized cutaneous pruritus. Localized cutaneous pruritus is indicative of neuropathic cause, whereas generalized cutaneous pruritus suggests underlying systemic disease(s), drug‐induced itch, psychogenic itch (also known as functional itch disorder), or chronic pruritus of unknown origin (CPUO). BRP, brachioradial pruritus.

FIGURE 9

Diagnostic procedures for cutaneous pruritus. The initial step is to ascertain whether presence of primary rash is present on the skin. In the absence of pruritic rash, a diagnosis of cutaneous pruritus can be made, and further examination determines which type of cutaneous pruritus the patient has. CKD‐aP, chronic kidney disease–associated pruritus.