Itching for Knowledge About Wound and Scar Pruritus

This overview is meant to whet the appetite for more knowledge about pruritus in skin and wound patients. There are excellent books with entire chapters dedicated to the different components involved in itch.^1,2 

For most healthy mammals, the sensation of itch is something rarely thought about. It occurs, the area is brushed or scratched, and the cycle typically ends. For protective reasons, the body alerts of a possible threat (ie, mosquito, thorn, etc.), and once the threat is removed, the sensation cycles down. Unfortunately, for millions of humans and animals, it can be difficult to turn off the itch-scratch cycle, leading to chronic pruritus.^3,4 Up to 100% of patients with atopic dermatitis, chronic idiopathic urticaria, psoriasis, burns, and possibly liver disease suffer from debilitating itch.^3-8 The number of patients affected by itch grows even larger when those with xerosis, hypertrophic scars, keloids, kidney disease, and hidradenitis suppurativa are included.^3,9-12 The negative impact itch has on depression, anxiety, and quality of life (QoL) is similar to that of chronic pain and should not be ignored.^3,7,13,14 

The elusive and complex nature of itch contributes to the lack of study and effective treatments options. A consensus paper from the International Forum on the Study of Itch¹³ helpfully outlines the key factors that should be used when assessing itch: intensity, localization, frequency and duration, sensory qualities, aggravating and relieving factors, opinion on origin, treatment, affective dimensions, disability or impairments, QoL, coping, itch cognitions, and scratch response. A second consensus paper focused on clinical trial testing of antipruritics and scoring itch was released a year later to encourage the use of valid methods for better comparison of study results.¹⁵ There are a variety of itch questionnaires, some of which are disease specific, but many stem from the McGill Pain questionnaire.^16-20

Utilizing a multidimensional tool that captures many aspects of patient pruritus episodes provides a rich dataset of information on the complexities of itch. Simply assessing the intensity and frequency of the itch episode is not enough; however, coupling this information with each character sensation, location, and QoL issue can provide information on how itch is affecting the patient and what potential treatments might be most effective. The sensory characteristics of itch (tickling, stinging, crawling, stabbing, pinching, and burning) can present alone or in combination with other sensations.¹⁷ Affective dimensions of itch provide an insight on itch impact on QoL and include bothersome, annoying, unbearable, and worrisome.¹⁷ Patients with atopic dermatitis, uremia, and burn scars each have different etiologies, and it is not surprising that the itch sensory and affective dimensions of these patients also are different. In Table 1,^6,21-27 the comparison of different subject diagnoses with the 6 sensory dimensions of itch shows stinging and burning are quite elevated in burn survivors, yet burning itch in uremic patients is not common.^6,21-27 Likewise, the affective itch dimension unbearable in burn survivors is about 3 times as high as that reported in uremic patients (Table 2).^6,21,23-28 The likelihood of one antipruritic being effective in both populations is slim, and thus the clinician should consider a variety of therapeutic options. It should be noted that the severity (none, mild, moderate, severe) of the sensory and affective dimensions should be taken into account. Stinging is the most reported chronic sensation in burn survivors, but the most severe chronic sensations were crawling and burning.²⁶ The type of itch that causes the most distress to the patient may not always be the most frequently reported symptom.

Itch can be considered acute if it lasts < 6 weeks or chronic if it exceeds 6 weeks, except in the burn community which measures acute itch as < 3 to 6 months post injury.^13,26,29,30 Itch is classified into 4 main categories: pruritoceptive, neuropathic, neurogenic, and psychogenic.^31,32 Pruritoceptive itch, also known as dermatologic itch, is due to inflammation or damage to the skin and may have sensations of crawling or tickling.^31-33 Neuropathic itch is caused by nerve damage and is typically perceived as burning, stinging, and paresthesia sensations.^31-33 Neurogenic itch (or systemic itch) does not have any nerve damage, and the perception comes from the central nervous system (CNS).^31,32 Psychogenic itch is associated with psychological abnormalities that can be further subcategorized.^14,31,32 Patients suffering from itch may have a combination of itch classes involved in the presentation. Burn survivors likely have a combination of pruritoceptive, neuropathic, and, for some, a subtype of psychogenic itch from their injuries, whereas uremic patients have neurogenic itch from unfiltered toxins. This again suggests that effective therapies for itch relief would likely require different agents. 

Unlike other peripheral symptoms, itch can be initiated by the CNS simply by verbal or visual suggestion.⁴ Also known as contagious itch, the sensation can be elicited in individuals without persistent itch but tends to be much more intense in patients with chronic pruritus.^4,14 Nonhuman primates also demonstrate contagious itch after watching scratching videos compared with control videos.³⁴ Little research into the reverse activation of periphery neurons has been studied but is theorized that it could be part of the mirror empathy system and/or classic conditioning.⁴ Exploring this area of CNS activation may help elucidate future therapies, and recent neuroimaging studies of the brain suggest multiple areas are involved in the itch-scratch cycle.³⁵

Intensity and itch activation can be affected by stress or other itch triggers.¹⁴ Stress can be induced by the constant pruritus or from daily living activities, but regardless of where the stress originates, from, its presence increases the intensity and frequency of the itch.¹⁴ As seen in Table 3,^6,21-28,36 stress, dryness, sweat, and often heat tend to trigger itching episodes or make pruritus worse regardless of the clinical diagnosis.^6,21-28,36 There are some environmental effects and activities that can trigger itching in some patient populations but calm the itch in others, such as rest and hot water. There are very few nonpharmacological effects that appear to relieve pruritus consistently, but cold water and, for some, cold temperatures and sleep seem to provide relief regardless of the clinical diagnosis related to itch. Educating patients to be aware of these triggers and relievers and to determine their personal aggravators and soothers could help avoid itch episodes from becoming so severe. 

Understanding how stress impacts itch is important, but the impact of the lack of sleep on itch is another key area of awareness.^3,14,37 Sleep allows the body to rest, heal, and recuperate while preparing it for the next day of activities. Unfortunately for the pruritic patient, evening and nighttime is when itch increases, especially in the extremities and torso.³⁷ Disturbed or lack of sleep leads to an increase in fatigue, stress, negative mood, and a reduced ability to cope, concentrate, learn, or work, which can in turn can lead to additional stress, impairing healing and exacerbating the itch cycle.^14,37 In Table 4,^{6,21,24-28,38} the difficulty in falling asleep and staying asleep due to pruritus is a problem patients with itch frequently experience.^{6,21,23-28,38} What is strikingly absent from Table 4 is information on sleeping medications from most studies. It is unclear if soporifics are not routinely offered, if the soporifics do not work, or if patients refuse to use them. What is clear from prior Table 3 is when sleep is achieved, it relieves itch for many patients. 

Understanding itch allows clinicians to help educate, empathize, and search for better treatment options for patients with wounds, scars, and itch. Unlike some dermatological diseases with compromised skin, which start with an itchy lesion and can develop into a wound, patients that have an open wound can develop pruritus and the itch can remain years after the wound is closed.³⁹ Experimentally, where the epidermis is removed, itch sensation cannot be induced until reepithelialization, but other sensations such as pain are still active.⁴⁰

Burn injuries are known to have extensive pain during the injury and recovery and that chronic pain and itch persist within the scar.¹⁰ The injury itself is traumatic and causes neuropathic and dermapathic damage. As a result, the subsequent burn scar is often a product of the original injury, multiple surgeries, and possible engraftment, not to mention subjected to potential infection and a variety of systemic pharmacological antibiotics and opioids, all of which can affect the nerve fibers.^{10,29,30,39,41-43} During the initial healing process, the itch can become so severe that patients will scratch until the area bleeds in order to try to obtain relief from the pruritus.⁸ Research has documented that burn scar itch, regardless of size, can last for years; even over 17 years for some patients.^30,39,44 Risk predictors associated with chronic itch are younger age, female sex, burn size, deep dermal damage, early episodes of posttraumatic stress disorder, skin grafting, and thick scars.^29,30,44,45

Hypertrophic scars (HTS) and keloid development following injury are well known in the burn community. Patients with HTS or keloids have an impaired QoL that is statistically significant for itch, pain, and restricted mobility from the scar.^11,46 Risk factors for developing HTS include burn severity, female sex, time to healing, infection, and multiple surgeries; several of which overlap itch risk predictors.^42,43,47 Keloid scars, regardless of type of injury, share some similarities with HTS, such as development following injury, skin dryness, and itchiness; recent research has suggested both scar types are influenced by chronic inflammation of the reticular dermis.⁴⁸ The cellular component and the outward appearance of keloids are distinctly different from HTS, and small nerve fiber neuropathic abnormalities with abnormal thermosensory thresholds have been documented.^49,50 In a keloid study,⁵⁰ itch was felt more at the edge and reported by more subjects while pain was felt more centrally within the scar, and 43% of the keloids tested were positive for allodynia. Comparisons of neuropathic abnormalities between keloids and HTS have not been studied extensively.    

Epidermolysis bullosa (EB) is a rare genetic disorder in which slight mechanical trauma to the skin can cause blistering, subsequently forming a wound.⁵¹ Like burns, acute and chronic pain and pruritus is a well-known burden for EB patients.⁵¹ A recent itch study²⁸ assessed EB pruritus and found that patients with a severe form of EB with more skin involvement had a higher frequency of itch episodes than other forms of EB. All patients with EB reported that healing wounds were the itchiest followed by periwound skin, dry skin, and infected wounds.²⁸ Compared to nonwounded skin, these areas were statistically significantly more pruritic.²⁸ 

Chronic wounds often present with itching, but little research has explored relationships between itch frequency and chronic wound etiology.⁵² A recent review⁵² of itch in the chronic wound literature found that xerosis, venous ulcers, and burns were associated most with pruritus. A prospective study of 200 mixed etiology chronic wounds (trauma, pressure, diabetic/neuropathic, venous, arterial, mixed vascular, and other)⁵² found that 28% of patients had wound-related itch. This study⁵² also found lower extremity wounds were more likely to be itchy than wounds on the upper body and venous ulcer wounds were significantly itchier than other chronic wound types. Wound shape, age, or sensation in the wound area did not predict likelihood of itch; however, there was statistically significantly more itch in wounds that were larger, had pitting edema, or had more granulation tissue.⁵² 

The wound care community is often called on to treat geriatric patients who are known to have multiple comorbidities, often take multiple medications, and are predisposed to having a wound; in addition, many are presumed to have senile itch.^9,38,53 A recent study³⁸ specifically assessed the presence of pruritus in 302 elderly nursing home and ambulatory populations, however, wounds were not a specific category. Patients who were statistically significantly more likely to have chronic itch were those with xerosis, any comorbidity, diabetes mellitus, or chronic venous insufficiency.³⁸ In this study, 69% of the patients with itch had xerosis and 67% of all patients with itch and xerosis were female.³⁸ Of patients with pruritus, 96% had 1 or more chronic comorbidities, but medications were not different between patients with or without itch. The term senile itch is defined as “chronic pruritus of an elderly person with no known cause or rash.”⁵³ True senile itch is likely to have multifactorial causes and appears in part to be due to skin aging and the pathological decline of tissue health, and it may be more frequent in males.⁵³ Clinicians should take care to not assume every geriatric patient has senile itch, especially since xerosis prevalence is elevated in the elderly, but realize that itch can negatively impact the QoL regardless of its cause and consider therapies to relieve the itch. 

An assessment of some conflicting reports and a few studies trying to determine if itch is a common symptom in diabetes mellitus was inconclusive.⁵⁴ Patients with diabetes are known to have dry, calloused skin, and research has shown that acquired ichthyosis seems to be correlated to microvascular complications and the duration of the disease.⁵⁵ The scaling and thickening of the skin can lead to increased dryness and itch. In the aforementioned geriatric study,³⁸ 36% of patients with type 2 diabetes reported chronic itch. In diabetic or neuropathic ulcers, 16% reported wound-related itch. The loss of sensation in the lower extremities from disease progression likely contributes to the perceived itch differences found in different anatomical locations.   

There are some similarities across these different wound care populations. Dry skin from abnormal ceramide, natural moisturizing factor, and sebum production (regardless if from age, injury, or disease) increases the probability and intensity of the itch episode.^45,49,53,55 Compression to relieve edema can help relieve itch of scars and wounds to some extent.^49,52,56 Larger and/or deeper skin involvement tends to be a risk predicator for pruritus.^{28,42,43,48,52} Pain will often accompany itchy wounds and skin.^{10,27,28,33,50,52} Healing wounds often seem to be itchier than other skin and wounds.^8,28,52 This is likely multifactorial and could be from inflammation, nerve fiber injury and/or regrowth, and irregular perception modulation between the new epidermis and the nerve endings within the epidermis as well as developing new coping skills. Understanding similarities and differences in itch perceptions and outcomes within the wound care community should improve research and treatment options.

Humans typically have an average of 1.9 m² of skin.⁵⁷ Within the skin, there are primary afferent neurons ready to transmit sensory information from the nerve endings to their cell bodies in the dorsal root ganglia (DRG) and trigeminal ganglia.^40,58 Itch signals run through the central branches of the sensory neurons to the superficial dorsal horn of the spinal cord for processing and modulation.^40,58 Once specific regions of the brain are activated, itch is then perceived.  

Within 1 cm² of skin, there may be up to 1000 afferent free and corpuscular nerve fibers.⁴⁰ The afferent nerve fibers are mostly small diameter, nonmyelinated C fibers (conduction 0.5 m/sec to 2 m/sec); medium diameter, thin myelinated Aδ fibers; and some larger diameter, myelinated Aβ fibers (conduction 4 m/sec to 70 m/sec).^40,59 The A fibers transmit tactile sensitivity, temperature, and noxious sensations and have a role in the perception of itch.^40,60 Of the C fibers, approximately 80% are polymodal because they can respond to thermal, mechanical, and chemical stimuli.⁶¹ The remaining 20% of C fibers are not responsive to mechanical stimuli, and only 5% of these C fibers are specific for itch.⁶¹ Research suggests there may be multiple neuronal subtypes of itch receptors.⁵⁸ Though, in an inflamed environment, the itch nociceptors are sensitized and become receptive to mechanical stimuli and the non-itch Aβ fibers begin transmitting the itch signal, which is known as alloknesis.⁶¹ This leads to an increase in stimuli reception and broadcasting, and when the Aδ fibers are sensitized, stimuli are no longer needed to continue the itch cycle, which is known as punctate hyperknesis.⁶¹  

Free C-fiber nerve endings are located in the dermis and epidermis.⁴⁰ These thin axons can be more than 100 cm in length, reaching from the epidermis to the nerve body.⁴⁰ Schwann cell-axon complexes reside in the dermis within the perineuronal layers and the endoneurium.⁴⁰ During and following injury, the Schwann cells provide mechanical protection and can guide regenerating nerve fibers. Interactions of the axons with pruritogens, epithelial cells, and immune cells can trigger an itch sensation.⁶² It should be noted that if the epidermis is removed, itch cannot be elicited though pain can.⁴⁰ 

Although itch and pain have distinct pathways, there is some overlap and cross-talk between the circuits. Clinically, pain can inhibit the itch sensation and some pain relievers can induce itch.⁵⁸ Patients with chronic pain often present with itch symptoms and in some diseases, chronic itch is associated with pain sensations.^{10,27,28,33,52} The mechanoreceptor Aβ fibers within the skin that normally transmit a touching sensation can undergo sensitization and instead induce pain (allodynia) or itch (alloknesis). Likewise, the Aδ fibers, which normally transmit pinprick pain, can produce pain (punctant hyperalgesia) or itch (punctate hyperknesis) once sensitized.⁶¹ There also appears to be some overlap of signaling molecules for pain and itch.⁶² 

In acute itch, the itch nociceptors are sensitive to histamine and act on the downstream transient receptor potential cation channel subfamily V member 1 (TRPV1) to transmit the itch sensation.^58,63 Even though TRPV1 plays a major role in itch transduction, research suggests histaminergic itch uses additional signaling pathways.^63,64 Clinically, patients with pruritus frequently do not respond to antihistamine therapy.^65,66 Furthermore, research⁵⁸ into nonhistamenergic itch has shown numerous peripheral nervous system (PNS) signaling molecules that are completely independent from the histamine pathway in TRPV1-deficient mice. In particular, protease-activated receptor 2 (PAR2), toll-like receptor (TLR), and the mas-related G protein-coupled receptor (Mrgpr) family each appear to be heavily involved in chronic itch signaling.^58,59

Protease-activated receptor 2

It is in these histamine-independent receptors that potential elucidation and possible new treatments are likely to be discovered. Skin of patients with chronic itch often have high levels of inflammatory proteases, including tryptase and cathepsin S, which can further perpetuate the inflammation by activating PAR2.⁶⁷ Immune cells, endothelial cells, nerve fibers, keratinocytes, and DRG can express PAR2, and once activated, it can prompt keratinocytes to secrete the pruritogenic cytokine thymic stromal lymphopoietin (TSLP), which in turn can activate neurons, expressing TRPV1, TRPA1, and/or TSLP receptors, thus perpetuating the itch cycle.^59,68,69 In addition, PAR2 is expressed on some TRPV1 nociceptors and once PAR2 and TRPV1 activate, neuropeptides substance P and calcitonin gene-related product (CGRP) are released, creating neurogenic inflammation, a proinflammatory environment, and immediate increase of pruritus, erythema, edema, and vasodilation.^64,69,70 In patients with atopic dermatitis and chronic itch, keratinocyte PAR2 expression appears to correlate with the severity of the disease and tryptase levels are elevated.^67,69 When injected intradermally into patients with atopic dermatitis, PAR2 agonist or tryptase also produces an enhanced and prolonged histamine-independent itch.^59,67 It is interesting that elevated serum levels of mast cell tryptase correlated to itch severity on dialysis patients, suggesting yet another caveat to the tryptase and PAR2 activation via pruritogenic substances in renal failure.⁷¹ Knowing the involvement of the cells and their signaling pathways provides multiple potential intervention points and the possible use of antagonists to provide symptom relief. At this time though, more elucidation of the activation and inhibition of PARs is required.  

Toll-like receptor

Another area being explored for knowledge and possible therapeutic targets is TLRs. Both PNS and CNS neurons, keratinocytes, and immune cells broadly express TLRs and play a large role in innate immune response as well as inflammatory disease conditions and noninfectious disorders.^59,72,73 There are several different TLRs on sensory neurons and many have been implicated in itch signaling in conjunction with TRPV1, especially TLR3 and TLR7.^59,72,74,75 Toll-like receptors constantly scan the extracellular space, cytoplasm, and endolysosomal compartments for pathogen-associated molecular patterns (PAMPS) and danger-associated molecular patterns (DAMPs) from cellular or tissue damage and once found, immediately upregulate proinflammatory signals and the innate immune system.^76,77 Activation of TLRs is associated with both chronic pain and chronic itch with proinflammatory mediators upregulating additional mediators that affect both pathways. For example, DAMP TLR activation of microglia and astrocytes causes sensitization and pain hypersensitivity through the release of proinflammatory cytokines like tumor necrosis factor alpha, chemokines, enzymes, and prostaglandins.^74,78,79 Likewise, TLR activation of DRG neurons appears to indirectly influence the excitability and itchiness of DRG neurons via proinflammatory cytokines like interleukin 1β and mediators like CGRP and prostaglandin E2.⁸⁰ Mast cells are well known for inducing immunoglobulin E-mediated allergic inflammation and these cells express most TLRs, which once activated, the cell degranulates, releasing proinflammatory cytokines, chemokines, and histamines, thereby activating the adaptive immune response.⁷⁴ Lastly, mast cells and keratinocytes produce nerve growth factor, which is known to be upregulated in chronic itch through TLR and can cause nerve sprouting and hyperinnervation.^62,74 Toll-like receptor-activated cytokines and chemokines probably assist in both peripheral and central sensitization of itch.⁷³  

The dual function of TLRs in itch signaling and promoting a proinflammatory environment make these receptors attractive therapeutic targets. Work is underway in developing and testing TLR agonists and antagonists against cancer and autoimmune diseases. There is still much to be learned about the TLR itch mechanisms. 

Mas-related G protein-coupled receptor

Mas-related G protein-coupled receptors are an assortment of GPCRs that can sense noxious mechanical stimuli, pruritogens, itch, temperature, and even taste and olfaction chemosensations.^59,81 There are more than 50 distinct genomic sequences for Mrgprs in mice and 18 in humans, and the receptors are subdivided into broad groups known as A, B, C, D, and X.^59,81 Expressions of the groups are different between newborns and adults as is the co-expression of CGRP.^81,82 Substance P expression has not been detected in newborns or adults with the exception of MrgprX2 found on mast cells.^82,83 Mas-related G protein-coupled receptor A3, MrgprC11, and MrgprD itch sensing receptors are the most studied in the family and have some distinct and overlapping activation and signaling properties.⁸¹ Both MrgprA and MrgprD neurons are widely expressed and share the most overlap.⁵⁹ Mas-related G protein-coupled receptor A3 neurons only innervate the skin and are sensitive to a minimum of 4 pruritogens, but pain sensitivity is not impacted if the receptors are ablated.^59,82 Like MrgprA3 neurons, MrgprD fibers also innervate the epidermis up into the stratum granulosum, but MrgprD appears to be constitutively expressed in most tissues and is affected by fluctuations in β alanine levels.^59,81

The Mrgpr family of receptors is interesting because their expression changes over time and has distinct properties. The shared sensitivity of itch and pain makes the Mrgpr receptors a prime target for topical therapeutic development since they can be found within the epidermis. These enigmatic receptors will require much more research to elucidate how best they can be used in combating pruritus.

Education and communication with the patient about itch, how it affects them, and potential ways to mitigate their itch is extremely important. By understanding the importance of intercepting itch at its earliest stages, the patient and clinician can work together to minimize the itch episode as much as possible. As with any therapy, care must be taken to determine the best risk-benefit ratio. Because itch is a multifaceted symptom, finding the most beneficial treatment regimen for each patient can take time and may vary from patient to patient. To help ensure the best treatment results possible, patients should be aware of their itch triggers and what helps relieve itch, as previously shown in Table 3. 

Nonpharmacologic therapies can provide relief and often can help improve relief when used in combination with other treatments.^51,56 Some therapies such as distraction, prayer, hypnosis, and meditation interact with the cognitive aspect of itch. Others such as behavior modification or intervention rely on avoidance of itch triggers and scratching. Therapies such as cooling, compression, massage, laser, and transcutaneous electrical nerve stimulation change the skin stimuli so the resultant sensation is one other than itch. Use of immunomodulators to adjust the inflammatory milieu and neurotransmitters also has been used to a small extent. 

There are a variety of possible topical and systemic therapies suggested to relieve pruritus and more are in development.⁶⁶Table 5 highlights the most commonly used pharmacological therapies against itch, but for some, specific use for pruritus is an off-label indication.⁶⁶ Treatment ladders or therapy strategies based on etiology help clinicians determine which therapies to consider and an order in which to try treatments as the risk increases.^84,85 Topical treatments typically have the lowest risk and are often begun first regardless of what may be causing episodes of itch. For most chronic itch patients, emollients and antihistamines are the first therapies initiated for localized itch.^{9,51,53,56,84,85} Use of emollients to improve skin condition and repair barrier function is typically a small but necessary role in relieving itch. Other topicals provide relief by cooling the skin. To prevent the nerve fiber from transmitting the itch signal, some topicals can disrupt the ion channels that are required for communication with the DRG. As therapies fail or cannot achieve a satisfactory relief, other treatment options are initiated. Anticonvulsants, antidepressants, and opioids have all been used with some success to interrupt the itch signaling pathways. Use of systemic therapies in conjunction with topical and nonpharmacologic therapies are common in order to provide as much relief as possible.^{9,37,51,53,56,66,84,85} 

The culmination of multiple sensory, cognitive, and emotional factors results in a unique itch sensation with variations on this complicated theme. In the wound care arena, itch can be found everywhere, from the young EB patients to the geriatric patients to the staff working long shifts. Even though itch may not seem like a high priority when evaluating a patient, it could be a high priority for the patient, and thus, should be a clinical priority as well. 

Thank you to the patients with itch who participate in studies; you help advance pruritis research towards knowledge and relief.

Affiliation: Precision Consulting, Missouri City, TX

Correspondence: Laura K.S. Parnell, MSc, Precision Consulting, 6522 Harbor Mist, Missouri City, TX 77459; l-parnell@earthlink.net 

Disclosure: Ms. Parnell is the current president of the Wound Healing Foundation; all views in this manuscript are the author’s and not the official position of the Wound Healing Foundation.