Itch is difficult. It cannot be seen, cannot be easily measured, and can be very difficult to treat. Almost anything can cause it, and specific treatments are useful in some circumstances, whereas the very same treatments may be useless in others. Because it is a condition perceived to be located on the skin, many patients seek care from dermatologists and these patients may comprise some of the most challenging and frustrating cases encountered by dermatologists. This review examines itch. We will cover the causes of itch, review cutaneous neurophysiology, discuss the components of a pruritic stimulus, and discuss both topical and systemic treatment options for this common dermatologic complaint.
Itch (pruritus) is defined as an unpleasant sensation that evokes the desire to scratch 1. It is believed that the sensation exists to promote scratching in order to remove a pruritogen, which may have originated when most pruritogens were noxious agents 2. Thus, it is thought to have originated as a self-protective means to guard the body from irritating chemicals or insults 3.
Itch is categorized as either acute or chronic. The latter may be further broken down into subtypes that are pruriceptive, neuropathic, neurogenic, or psychogenic in origin 1. Pruriceptive itch originates from activation of primary afferent nerve terminals and is typically associated with insect bites or an intradermal injection of a pruritic substance 4. Neuropathic itch results from nerve injury, and examples may include an itch following varicella zoster infection or nerve trauma 5. Neurogenic itch results from the activation of the central nervous system and may or may not include activation of sensory nerve fibers 6. It occurs in disease states such as kidney failure 6. Finally, psychogenic itch results from an underlying mental illness and may include some degree of somatization and delirium 7.
A pruritic signal consists of three components: detection, transmission, and interpretation (discussed below). Thinking about pruritus in this way may be useful when approaching patients as it may permit classification of the complaint into a general category of either aberrant detection, transmission, or interpretation of a signal. Numerous treatments exist to combat pruritus (multiple discussed below), and each treatment acts to inhibit or reverse one or more of these three components of the pruritic signal. Classification, therefore, may help a physician tailor treatments to more specifically address the problem even if the exact cause of pruritus is not immediately clear.
There are three components of a pruritic stimulus. First, the stimulus must be detected, second the stimulus must be transmitted, and finally the stimulus must be interpreted. The following section will break down the pruritic signal and discuss each of these three components separately.
Neurons that detect itch
Nociceptors are high-threshold peripheral receptors or sensory neurons that transduce and encode noxious stimuli. They can be divided into mechano-sensitive nociceptive afferents, which respond to noxious mechanical stimuli, and mechano-insensitive afferents. These nociceptors can be further subcategorized into unmyelinated and slow-conduction C-fibers and thinly myelinated and faster-conduction A-fibers 8.
The neurons that are responsible for detecting itch are called pruriceptors. Pruriceptors are a subset of nociceptors that respond to one or more pruritic substances (pruritogens). Most pruriceptors are C-fibers, although a small number are A-fibers as well. Importantly, there are no ‘itch-only’ neurons. However, ‘pain-only’ neurons do exist and these are not capable of transmitting pruritic stimuli. Therefore, in addition to responding to pruritic chemicals, pruriceptors may have heat receptors, mechanoreceptors, or both. This may explain why hot and cold stimuli may exacerbate or relieve pruritus, and painful stimuli may outcompete pruritic sensations (scratching) 8.
Pruritogens are both exogenous and endogenous itch-causing compounds that bind to and activate itch-sensitive neurons 9. We have listed and briefly discussed several common, or clinically important, pruritogens. Table 1 lists several common pruritogens and their associated receptors.
Histamine is the most well-studied pruritogen. It originates from dermal mast cells and interacts with pruriceptive C-fibers 1. More specifically, histamine binds to G-protein-coupled receptors (GPCR) and histamine receptors (H1–4), the latter of which have been localized on the dorsal root ganglion neurons 10. H1 receptors have been identified as the primary histamine receptor responsible for stimulating the sensation of itch 11.
Cowhage is a tropical plant that is a well-known itch inducer in experimental settings. On skin contact, cowhage spicules release a substance known as mucunain, which is a ligand for proteinase-activated receptor 2 12. Notably, the literature suggests that proteinase-activated receptor 2 may play a role in the itching sensation in atopic eczema 13.
5-Hydroxytryptamine (5-HT, or serotonin) is another known pruritogen that stimulates cutaneous C-fibers 14. Studies in mice have shown that 5-HT is responsible for causing itch by binding to the 5-HT2 receptor subtype and, when injected intradermally into the rostral back of mice, elicits scratching at the injected site, with a bell-shaped dose–response relationship. The specific receptor subtype for 5-HT responsible for itch in humans is currently unknown; however, peripherally, human skin-produced serotonin and keratinocytes, melanocytes, and fibroblasts have been shown to have 5-HT receptors 15.
Acetylcholine is a pruritogen that can evoke both itch sensations and pain sensations 14. In mice, antagonizing the muscarinic M3 receptor was able to block scratching behavior 16. In humans, studies have shown that patients with atopic dermatitis (AD) have a 10-fold higher concentration of acetylcholine in their skin compared with healthy individuals, suggesting a role for this chemical in that disease state 17.
Substance P (SP) is a neuropeptide that plays a role in stimulating itch by influencing the release of histamine from mast cells. Studies have demonstrated that SP binds to neurokinin-1 (NK1) receptors 18, which may lead to SP-induced mast cell degranulation. Other studies have also revealed that SP may stimulate Mas-related gene X2 (MrgX2) receptors, which are GPCRs expressed in human mast cells 19. SP is also one neurotransmitter responsible for linking a pruritic signal from the skin to neurons that transmit itch to the brain 8. As discussed later two treatments of pruritus target this neuropeptide. Capsaicin, a topical treatment for pruritus, partly works by depleting stores of SP 20. Aprepitant, a systemic treatment for pruritus, antagonizes the NK1 receptor 21.
Wahlgren and colleagues demonstrated that intradermal interleukin-2 (IL-2) can cause localized pruritus. A single dose of 20 μg recombinant human IL-2 was injected intradermally into eight patients with AD and eight healthy controls. In both patients and controls, IL-2 provoked a low-intensity local itch, with maximal intensity between 6 and 48 h, and erythema, with maximal extension between 12 and 72 h. Intradermal IL-2 injection also mediated other effects, which included infiltration of dermal T cells, spongiosis, and activation of keratinocytes in both AD patients and healthy controls 22.
Familial primary localized cutaneous amyloidosis is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. Arita et al. 23 demonstrated that mutations in the IL-31 receptor and mutations in the oncostatin M-specific receptor gene, a component of the IL-31 receptor, may underlie this chronic itching disorder.
Nerve growth factor
Groneberg and colleagues 24 investigated the gene expression and regulation of nerve growth factor (NGF) in AD and the human mast cell line (HMC)-1 at the molecular level. They successfully demonstrated that keratinocytes express high levels of NGF and that increased expression of NGF was found in AD lesions, in association with increased systemic NGF plasma levels.
Other notable nonhistaminergic pruritogens that have been studied include bovine adrenal medulla 8–22 peptide, chloroquine, and β-alanine 8.
Transmission and modulation
Once detected, a pruritic signal must be successfully transmitted from the periphery to the central nervous system for interpretation. To accomplish this, pruriceptive and nociceptive primary sensory neurons project to the dorsal horn of the spinal cord. These neurons provide input to interneurons and other projection neurons that send signals to the brainstem or forebrain through the spinothalamic tract. Interneurons may influence pruriceptive spinothalamic tract neurons and the signals they transmit by modulating these signals with either excitatory or inhibitory functions. Overactive excitatory interneurons in the presence of inactive or underactive inhibitory interneurons may result in a ‘spontaneous’ itch sensation. In addition, loss of itch-inhibiting interneurons in the dorsal horn of the spinal cord can lead to an increase in itch-related behaviors 8.
In some circumstances, tactile stroking of the skin may cause an itch sensation from an area of skin that surrounds the application of a pruritogen (alloknesis), or an itch sensation may be enhanced to the point where it evokes a greater intensity of itch (hyperkinesis) or even pain (hyperalgesia) in this surrounding area. In other circumstances, innocuous tactile stroking of the skin may cause a pain sensation (allodynia) in an area of skin that surrounds the application of certain remedies used to treat pruritus, such as capsaicin. Interneuron function may explain the phenomenon of alloknesis and allodynia, although they represent complex processes not fully understood. These phenomena may result from sensitization of nociceptive neurons or the interneurons that modulate their function in the dorsal horn of the spinal cord. Sensitized neurons may show a greater or weaker than normal response to innocuous stimuli, causing itch or pain in situations that normally would not result in such sensations 8.
Importantly, interneurons contain receptors for opioids and therefore are modulated by opiates. This explains why narcotics (such as morphine) may cause pruritus. It has been shown that intrathecally administered morphine (a μ-receptor agonist) induces itch and causes scratching behavior in mice 24. Furthermore, Umeuchi et al.25 showed that intracerebroventricular administration of β-funaltrexamine, a selective μ-opioid receptor antagonist, inhibited scratching behavior induced by intradermal SP in mice. Thus, μ-opioid receptor antagonists may have a therapeutic role in preventing and stopping pruritus (naloxone and naltrexone are examples) 26.
In recent years it has not only strictly become apparent that it is the μ-opioid system that is important for regulating pruritic signals but also that the balance between the μ-opioid and κ-opioid systems may contribute to promoting or inhibiting pruritic signals. Experiments demonstrated that κ-opioid receptors antagonize the sensation of itch and scratching, whereas μ-opioid receptors promote itch sensation – a discovery that has led to the development of a new drug called nalfurafine, as discussed below.
Once the pruritic signal reaches the central nervous system it must be decoded and interpreted.
Decoding pruritic signals
The fact that there are no ‘itch-only’ nociceptive fibers creates an obvious problem. How is the brain to decipher which signals are actually pruritic and which are painful? Competing theories exist for how this occurs. One proposed solution theorizes that selective activations of certain kinds of pruriceptive neurons (such as those containing the Mas-related GPCR member A3, or MRGPRA3 receptor) trump other signals and determine the sensation of itch versus pain 8. It was demonstrated that in mice in which the transient receptor potential cation channel, subfamily V, member 1 (TRPV1 – a pain-specific receptor) was expressed in MRGPRA3 neurons (neurons capable of transmitting itch), itch was exhibited instead of pain in response to application of capsaicin (the usual stimuli for TRPV1, which would otherwise have elicited a painful burning sensation) 27. This finding lends credence to the idea that one mechanism of interpreting itch is based on the activation of specific neurons that send out action potentials that lead to a specific sensation of pruritus, irrespective of the stimulus itself 8. Another proposed solution theorizes that the decoding of pruritic stimuli is based on a ‘population model’ in which the relative activity of neurons, some for itch and some for pain, are sufficiently great enough to detect one sensation versus the other. In this model, whether one detects itch or pain is related to sufficient activation of itch versus pain neurons rather than the activation of a specific neuron itself 28. Other theories of intensity, temporal, and spatial models exist but currently have insufficient support or evidence in the literature 8.
Interpreting pruritic signals
After the pruritic signal is decoded, the brain must interpret it. Research has permitted us to glimpse at the areas of the brain responsible for this task. Hsieh and colleagues used functional PET to measure regional cerebral blood flow during pruritic stimuli to investigate the central processing of itch in 10 healthy volunteers after subcutaneous injections of histamine. Results demonstrated that the posterior sector of the anterior cingulate cortex (Brodmann area 24) is related to the sensorial aspect of itch sensation, whereas the premotor cortical areas and the inferior parietal lobule may be involved in preparation for the intended action resulting from an itch (i.e. scratching) 29. Other studies using functional MRI scans demonstrated that, while neural activity in the posterior cingulate cortex and posterior insula is much higher with itching than with pain, pain induced activation of the thalamus for several minutes. The findings may suggest that activation of distinct areas of the brain may be responsible for the perceptual differences in pain versus itch 30.
Numerous efficacious topical and systemic treatments exist for combating pruritus by interfering with one or more of the three components of the pruritic stimulus (detection, transmission, or interpretation). We discuss several of these treatments by focusing on the mechanism of action when known and the clinical scenario where these treatments have been reported to be useful (Tables 2 and 3).
Capsaicin is the active compound found in chilli pepper and activates TRPV1 receptors, leading to desensitization 8 (Table 2). It causes depletion of stores of SP and calcitonin gene-related peptide and its uses have mainly been limited to localized disorders of neuropathic origin, including notalgia paresthetica, brachioradial pruritus, postherpetic neuralgia, and hemodialysis-associated pruritus. In one case report, trigeminal postherpetic neuralgia was safely and effectively treated with capsaicin 8% patch 47. Side effects include burning and neuronal degeneration at the sites of application 8.
Menthol works by activating TRPM8 and TRPA1 receptors, which results in a cool sensation. It is useful as a topical treatment because sensations of cold may outcompete sensations of itch. The side effect is mainly local irritation 8.
Pramoxine is a topical anesthetic. It works by decreasing the nerve membrane permeability to sodium ions, thereby blocking the transmission of nerve fibers. It is used mainly as therapy for histamine-induced itch and pruritus from end-stage renal disease. In a randomized, double-blind, controlled trial in a hemodialysis center, pramoxine 1% lotion was shown to decrease the itch intensity by 61% compared with control lotion in a population of 28 individuals with moderate to severe uremic pruritus receiving hemodialysis for at least 3 months 48.
Tacrolimus is an immunosuppressant drug that is currently used for the treatment of AD and pruritus. It is thought to have a direct effect on neurons by desensitizing TRPV1 and calcium channels. In addition, it may directly decrease pruritus through inhibition of IL-2 production by activated T cells by inhibition of calcineurin (a protein phosphatase), which ultimately inhibits nuclear factor of activated T-cells-1. Indirectly, tacrolimus may decrease pruritus by reducing inflammation over the area on which it is applied. It is mainly used for treatment of itch related to inflammation. Because it desensitizes TRPV1 channels, side effects are mainly limited to transient burning 49.
Emollients can also be used safely for pruritus; they help repair and minimize microfissures that may expose nerve fibers. One benefit of using emollients for treatment of pruritus is the relatively safe side-effect profile, except for contact allergies to vehicle preparations 2.
Aspirin has been used topically to treat itch. Yosipovitch and colleagues conducted a double-blind, crossover placebo trial to evaluate the efficacy of topical aspirin solution with dichloromethane in the treatment of lichen simplex chronicus, an intractable itchy dermatosis. Results demonstrated that a significant therapeutic response was achieved in 46% of patients who completed the study compared with 12% of patients receiving placebo. Furthermore, the aspirin-treated patients experienced an average decrease in the visual analog scale (a tool to rate pruritus intensity before and during therapy) of 2.18 versus 0.69 in those receiving placebo (P=0.03) 49.
Topical steroids are mentioned for completeness as they are often used to combat pruritus. Topical steroids do not directly interfere with pruritic signals but are useful at combating pruritus when it directly results from inflammation in the skin. Without primary skin pathology, however, they tend to be of little use 2.
Antihistamines work by inhibiting H1 and H2 receptors (Table 3). First-generation antihistamines are useful in treating chronic urticaria. Second-generation antihistamines are also suitable for daytime relief of pruritus from urticaria. Other uses for antihistamines are for mastocytosis and allergic contact. The main side effect for this class of medication is that of sedation 2.
Naloxone and naltrexone
Naloxone and naltrexone are μ-opioid receptor antagonists. In a pilot study to evaluate the efficacy and safety of naltrexone in the treatment of severe intractable pruritus, 50 patients with pruritus caused by internal diseases (which included cutaneous lymphoma, AD, xerosis cutis, macular amyloidosis, and psoriasis among others) were enrolled. Results demonstrated significant therapeutic response in 35 of 50 patients within 1 week. Of note, naltrexone had a significantly high antipruritic effect in nine of 17 cases of prurigo nodularis, which subsequently led to healing of skin lesions. The side effects of this class of drugs can be significant, including hepatotoxicity, nausea and vomiting, insomnia, and pain 50.
Nalfurafine is a κ-opioid receptor agonist. As discussed above the balance between the μ-opioid and κ-opioid systems may contribute to promoting or inhibiting pruritic signals. Nalfurafine has been used for renal pruritus, and side effects include insomnia and psychiatric disturbances. Wikstrom et al. 50 conducted a double-blind, randomized study to measure the effect of treating uremic pruritus in patients undergoing routine hemodialysis. Results demonstrated significant reductions in ‘worst itching’, itching intensity, sleep disturbances, and excoriations for the treatment group.
Butorphanol is a κ-opioid agonist/μ-opioid antagonist that is used for pruritus associated with systemic disease; side effects include nausea/vomiting, dependence, and possible psychiatric disturbances. In a case series of five patients, butorphanol was used successfully to treat pruritus in patients presenting with a diagnosis of prurigo nodularis, primary biliary cirrhosis, idiopathic elderly pruritus, non-Hodgkin’s lymphoma, and perforating collagenosis 31.
Aprepitant is an antagonist of NK1 receptors. It has been used successfully to treat pruritus secondary to malignancy (including Sézary syndrome and small cell lung cancer) in addition to brachioradial pruritus 21,32. A 3-day-only dosage of 125 mg on day 1 and 80 mg on days 2 and 3 with repetition every 2 weeks has been shown to be effective in five patients with erythrodermic cutaneous T-cell lymphoma 51. Side effects include fatigue and hiccups 51.
Thalidomide is an anti-inflammatory, immunomodulatory drug that inhibits tumor necrosis factor-α. Case studies have shown thalidomide to be successfully used to treat prurigo nodularis. Side effects include peripheral neuropathy, drowsiness, and teratogenicity 33,34.
Doxepin is both a topical medication and oral medication. The medication is thought to modulate histamine receptors, norepinephrine receptors, dopamine receptors, and serotonin receptors 35. It has been used for both inflammatory and noninflammatory causes of pruritus, renal-associated pruritus, and AD. Side effects that have been associated with this medication include somnolence, dizziness, psychiatric disturbances, arrhythmias, constipation, anemia, and agranulocytosis 35,36. A randomized controlled trial demonstrated that 10 mg oral doxepin, twice a day for 1 week, resulted in complete resolution of pruritus in 14 of 24 patients with end-stage renal disease 36.
Paroxetine is a selective serotonin reuptake inhibitor that has been used for pruritus secondary to malignancy (both hematologic and solid) and medications. Known side effects include sexual dysfunction, sedation, insomnia, and weight gain. In a prospective, double-blind, randomized trial, paroxetine at a dose of 20 mg daily was shown to be successful in decreasing the pruritus intensity scores of patients with solid tumors, hematologic malignancies, and other nonmalignant or idiopathic conditions 37.
Mirtazapine is a serotonin and norepinephrine inverse agonist, which, like paroxetine, has been used to treat patients with pruritus secondary to malignancy. Case reports in the literature have shown its efficacy in treating pruritus in one patient with severe atopic eczema since childhood and in another patient with chronic neurotic excoriations and dermatographia of 1-year duration 38. The literature has also supported its use in patients with cholestasis, renal failure, and, as mentioned, malignancies 39. Dosages that have been reported to be effective range from 7.5 to 15 mg qhs, with side effects that may include sedation and weight gain 38.
Gabapentin is a structural analog of the inhibitory neurotransmitter GABA. Uses of this medication include treating pruritus secondary to neuropathic itch, postburn pruritus, postherpetic neuralgia, and malignancy-associated pruritus. Side effects may include peripheral edema, sedation, abdominal pain, dizziness, and withdrawal 40,41.
Ultraviolet-based therapy has been demonstrated to treat a variety of pruritic conditions, such as chronic renal failure, AD, HIV, aquagenic pruritus, urticaria pigmentosa, polycythemia vera, pruritic folliculitis of pregnancy, chronic liver disease, and acquired perforating dermatosis. The ultraviolet-based therapies include broadband UVB (BB-UVB, 290–320 nm), narrowband UVB (311–313 nm), broadband UVA (320–400 nm), and UVA1 (340–400 nm) 42.
Although the mechanism of action of UV-based therapies for pruritus is not completely understood, some theories suggest that both BB-UVB and UVA1 increase levels of the inhibitory cytokine IL-10 in keratinocytes, which decreases the production of interferon-γ in Th1 cells 43. In addition, exposure to BB-UVA may lead to the degeneration of Schwann cells and perineural cells in the dermis, which may decrease pruritus 42,44,45.
In a recent study by Seckin et al.46 46 patients underwent narrowband UVB phototherapy for either uremic pruritus and ‘idiopathic pruritus’ three times a week with a mean number of 22 treatments. Results demonstrated improvements in the mean visual analog scale in both the uremic pruritus patients and ‘idiopathic pruritus’ patients, suggesting that narrowband UVB may be effective and well tolerated in patients with generalized pruritus.
Itch is a complex and common dermatologic complaint that involves circuitry from the skin to the spinal cord to the brain. There exist numerous pruritogens that cause pruritic signals to be sensed by specific sensory neurons, which transmit the signal to projection neurons and to modulatory interneurons that then deliver the signal to the brain, which then decodes and interprets it. Many topical and systemic therapies have been used successfully to treat chronic pruritus and pruritus secondary to systemic diseases during detection, transmission, and interpretation.
When approaching the patient with complaints of pruritus it may be helpful for the clinician to take into account the pathophysiologic mechanisms behind pruritus in general. If the clinician is able to classify the patient as having pruritus from either the detection, transmission, or interpretation of a pruritic signal she or he may be better able to tailor a therapy for that patient that specifically targets the classified origin of the pruritic signal. Further research on the mechanisms of, and therapies for, pruritus are needed that may better our understanding of and add to the current host of existing therapeutic strategies.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2015 Egyptian Women's Dermatologic Society
capsaicin; cowhage; histamine; itch; neurophysiology; pruritus