Chapter 103. Pathophysiology and Clinical Aspects of Pruritus

Pruritus (itching) is the predominant symptom of skin disease and can best be defined as a sensation that leads to a desire to scratch. All human beings experience this sensation in the course of their lifetime; therefore, it is important to make a distinction between acute itch, which is of a limited period of time ranging from seconds to a week such as the itch related to acute insect bite reaction, and chronic itch, which lasts for months and is the focus of this chapter.1 Chronic itch is a multidimensional phenomenon consisting of sensory, emotional, and cognitive components. In most cases, chronic itch results from interaction of the brain-skin axis. Although itch and pain are separate and distinct sensations, itch has many similarities to pain.2,3 Both itch and pain are unpleasant sensory experiences, follow similar neural pathways, and can severely impair patients’ quality of life. However, the behavioral response patterns differ—pain elicits a reflex withdrawal, whereas itch leads to a scratch reflex.

The limited understanding of itch results from the subjective nature of itching, the absence of specific and sensitive investigational methods to study the neuropathophysiology and molecular basis of itch in humans, the lack of convincing animal models and incomplete knowledge of pharmacologic mediators of pruritus. However, significant progress has been made in the past decade with the discovery of new neural pathways (both histaminergic and nonhistaminergic) as well as novel receptors in humans and animals. The concept that itch is transmitted to the central nervous system (CNS) and processed in the brain should lead to new approaches to antipruritic therapy.4

Itch is a symptom rather than a specific disease entity; therefore, epidemiologic data for itch are limited. Nevertheless, itch has been found to be the dominant skin complaint among all age groups.5 In a large cross-sectional study in Norway, the prevalence of pruritus was approximately 8% among adults.6 Itch is a primary symptom in a diverse range of skin diseases as well as in systemic diseases. The prevalence of pruritus in different dermatologic and systemic diseases is outlined in Tables 103-1 and 103-2.

Pruritus may originate in the skin or in the CNS. There is no single, definitive classification of pruritus. The International Forum for the Study of Itch (IFSI) has proposed a classification that distinguishes three clinical groups of patients as follows14:

• Group I: Pruritus on diseased (inflamed) skin
• Group II: Pruritus on nondiseased (noninflamed) skin
• Group III: Pruritus presenting with severe chronic secondary scratch lesions, such as prurigo nodularis

The first group includes underlying dermatological diseases, while the second and third group includes patients with systemic diseases including diseases of pregnancy and drug-induced pruritus as well as neuropathic and psychiatric diseases. In some patients, more than one cause may account for pruritus (category “mixed”) while in others no underlying disease can be identified (category “others”).14 It is also important to differentiate acute itch from chronic itch because therapies that provide transient itch relief often do not address the pathological processes underlying chronic itch.1 Moreover, the biologic function of nerve fibers most probably differs in chronic itch than acute itch.

Itch–Scratch Cycle

Itch and scratching are interwoven together in both acute and chronic itch conditions. Phylogenetically, itch is probably a mechanism for animals to remove parasites residing in the hairy skin. Scratching is also a behavioral response. A study in humans has shown that repetitive scratching activates the prefrontal cortex in particular, an area of the brain implicated in goal-directed and habit-learning systems.15 It is thus possible that activity induced by scratching in the prefrontal cortex may serve to drive the compulsion to continue scratching and could also account for the highly rewarding aspects of scratching. Furthermore, the hedonic experience of scratching may be associated with release of endogenous opioids. Repetitive scratching in chronic conditions such as atopic dermatitis and psoriasis further damages the skin and causes secretion of neuropeptides and opiates that may further augment the vicious itch-scratch cycle (Fig. 103-1).

Alloknesis: “Itchy Skin”

Alloknesis is a phenomenon in which a normally innocuous stimulus induces itch. For example, application of a fine brush to an itchy site induces itch. Alloknesis is analogous to the better-known allodynia (defined as pain due to stimuli, which does not normally provoke pain). This type of itch is mediated by mechanical mechanoreceptor units as well as an ongoing activity of afferent C nerve fibers and is considered a central neural sensitization response. Alloknesis is common in chronic atopic dermatitis; sweating or slight mechanical stimulation associated with wearing wool exacerbates itch. The exact role of central sensitization in pruritus associated with specific diseases is unknown.3

Itch Transmission in the Skin

The only peripheral tissues from which itch can be evoked are skin, mucous membranes, and cornea. Interestingly, the nerves in the deeper layer of the reticular dermis and subcutaneous fat do not transmit itch and inflammatory skin diseases affecting these areas, such as panniculitis, cause pain but not itch. Removal of the epidermis abolishes perception of pruritus, suggesting that pruritus receptor units are located predominantly within this layer.16 We suspect that the epidermis acts as a receptor for itch, but a specific receptor has not yet been identified. Light microscope and ultrastructural studies of human skin have shown the existence of intraepidermal nerve fibers with “free” nonspecialized nerve endings extending to the stratum granulosum.17 Many epidermal nerve fibers stain positively for neuropeptides implicated in itch transmission. It has recently been shown that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors.18

Keratinocytes express a variety of neural mediators and receptors, all of which appear to be involved in the itch sensation.19 Mediators include opioids, proteases, substance P (SP), nerve growth factor (NGF), and neurotrophin 4 whereas receptors include μ- and κ-opioid receptors, proteinase activated receptor-2 (PAR-2), vanilloid receptors, tropomyosin-related kinase A (TRKA), transient receptor potential vanilloid (TRPV) ion channels, gastrin releasing peptide receptor, and cannabinoid receptors 1 and 2. Keratinocytes also have voltage-gated adenosine triphosphate channels and adenosine receptors similar to C nerve fibers. Because these channels have a role in pain,20 these findings suggest that keratinocytes may act as itch receptors.

Dedicated Itch-Transmitting C Nerve Fibers

Significant advances in our understanding of itch neurophysiology have been achieved in the past decade. Microneurography has helped to disprove the historic concept that pruritus and pain are simply responses of the same neurons to mild versus intense stimuli, respectively. Studies using electric field stimulation coupled with microneurography have identified individual histamine-sensitive C nerve fibers that transmit itch.21 The C nerve fibers have exceptionally slow conduction velocity, unusually wide innervation territories, and represent no more than 5% of total C fibers. These neurons are sensitive to pruritogenic and thermal stimuli as well as capsaicin, but not mechanical stimuli. The co-responsiveness of this subset of C neurons to temperature change as well as pruritic stimuli is of interest because raising the temperature of skin lowers the threshold of receptors to pruritic stimuli22 and most pruritic patients complain of aggravation of pruritus in a warm environment. In chronic itch, spontaneous activity in these C fibers occurs.23 In contrast, the vast majority of C fibers are sensitive to mechanical and heat stimuli and are entirely insensitive to histamine.24

The existence of a subset of dedicated itch-transmitting C neurons receives further support from studies of spinal-cord pathways. Itch-transmitting primary afferent C neurons synapse with secondary transmission neurons that cross over to the contralateral spinothalamic tract and ascend to the thalamus. In the cat, microneurography identified lamina 1 neurons in the lateral spinothalamic tract that selectively responded to histamine, suggesting a central dedicated nerve pathway for itch.25 Other C nerve fibers transmit itch as well. Mechanically induced itch is commonly observed clinically; for example, itch associated with contact with wool cannot be explained by histamine-sensitive nerve fibers. Moreover, in patients with chronic pruritus, electrical or painful stimuli can also induce itch.26–28 Oral antihistamines are ineffective in the treatment of most types of itch, suggesting that nonhistamine-mediated fibers also play an important role. A separate nonhistaminergic itch processing pathway activated by cowhage (Mucuna pruriens) was discovered in peripheral nerve fibers of humans as well as in the spinothalamic tract in primates.29,30 The active ingredient inducing itch by cowhage has been found to be a cystine protease which acts through PAR-2 and PAR-4.31 Therefore, two parallel subpopulations of primary afferent C-fibers and spinothalamic tract neurons transmit itch in humans. Both of these pathways are most probably not itch specific since they also transmit burning sensations and respond to the algogen, capsaicin. In addition, gastrin-releasing peptide (GRP) receptor positive neurons were recently found to constitute a dedicated neuronal pathway for itch in the spinal cord of mice.32 The role of these neurons and their interaction with both histaminergic and nonhistaminergic pathways in humans remains to be elucidated.

The perceived sensation of pruritus can vary greatly in quality. Patients may experience sensations of burning or pricking but the neurophysiologic and psychologic correlates of these differences have not yet been elucidated. Information obtained from itch questionnaires based on previously developed pain questionnaires has enabled us to better understand the different characteristics of itch.7,33–35

The Central Processing of Itch

The central processing of itch has been demonstrated using the neuroimaging techniques of positron emission tomography and functional magnetic resonance imaging in healthy humans and patients with atopic dematitis. In these studies, histamine-induced itch activated various brain areas implicated in sensory and motor function as well as emotion—reflective of the multidimensional aspects of this distressing symptom. A recent study showed that that the central processing of itch in atopic dermatitis is different from that of healthy subjects. The anterior and posterior cingulate cortex as well as the dorsal lateral prefrontal cortex, which are involved in emotions, reward, and memory of negative experiences were significantly activated in patients with atopic eczema but not in healthy subjects.36 The activation of the precuneus, which is located in close proximity to the posterior cingulate cortex seems unique in itch and has rarely been reported in pain imaging. The precuneus is involved in episodic memory retrieval and could be associated with the affective components involved in itch.36,37

Mediators of Pruritus

Histamine

Proteinases

Substance P

Transient Receptor Potential Channels

Gastrin Releasing Peptide Receptor

Opioids

Opioid peptides are potent neurotransmitters and have both a central and a peripheral itch-producing action. Opioids appear to induce itch via two possible mechanisms. First, by degranulation of cutaneous mast cells63 and second, via a direct central and peripheral pruritogenic effect by activating μ-opioid receptors.63–66 Morphine and other endogenous and exogenous μ-opioid receptor agonists are known to cause generalized pruritus.67–70 The concept of central sensitization in chronic pruritus and possible involvement of pruritic mediators located in the CNS is becoming increasingly recognized as important in both cutaneous and systemic diseases. The perception of pruritus is modified by endogenous opiates via central opioid receptors. Generalized pruritus may result from an imbalance between the μ- and κ-opioid systems68,69,71 Activation of μ-opioid receptors stimulates itch perception, whereas κ-opioid-receptor stimulation inhibits μ-receptor effects both centrally and peripherally.68,69,71,72

Neurotrophins

Interleukins

Prostanoids

History

It is of prime importance to determine whether the cause is related to a primary skin disease or systemic disease. Diseases such as skin dryness or scabies may exhibit few primary skin lesions; therefore, careful history and laboratory evaluation can be particularly important. It is important to differentiate between generalized pruritus and localized itch. Careful history, including a full drug history, and physical examination including lymph nodes, are the starting points. The history should take into account the multidimensional nature of itching and should include details of quality, distribution, and timing. Any patient referred with generalized pruritus in the setting of other family members with pruritus should be assumed to have scabies until proved otherwise—skin signs may be clinically inapparent, perhaps confined to a few small nodules on the genitalia. In addition, patients with localized pruritus, especially in a dermatomal distribution, that present with other sensory complaints such as a burning sensation, loss of sensation or increased pain should be evaluated carefully for neuropathic itch. Figure 103-2 is an algorithm showing the approach to a patient with pruritus.

Cutaneous Lesions

Secondary skin lesions characteristic of pruritus include excoriations, lichenification, and hyper- or hypopigmentation. Lichenification results from continuous rubbing or scratching and consists of well-developed, thickened plaques with marked accentuation of skin creases (see Chapter 14). Post-inflammatory hyperpigmentation or hypopigmentation is common in patients with skin phototypes 4 through 6 (see Chapter 75). Lichenified plaques are most commonly distributed in areas the patient can easily scratch or rub (i.e., nape of neck, below the elbow, ankle, buttock, and genitalia). The butterfly sign consists of normal-appearing skin in the middle of the back outlined by a butterfly pattern of contrasting hyperpigmentation in areas subjected to persistent scratching, resulting from the patient's inability to reach the middle of the back. Shiny fingernails may result from prolonged rubbing. Prurigo nodules are excoriated papules that form nodules in patients with chronic pruritus (see Chapter 15). In many cases, this type of itch is accompanied by a painful, burning sensation suggestive of a neuropathic component. Prurigo nodules are frequently associated with emotional stress and obsessive-compulsive disorder; however, they can be also be a manifestation of itch in patients with atopic dermatitis or chronic renal failure. Such nodules are usually distributed over extensor aspects of the limbs.

Some pruritic states have specific clinical patterns. Despite severe pruritus, chronic urticaria usually does not show secondary skin lesions associated with scratching. Neuropathic itch in disease entities, such as postherpetic neuralgia, brachioradial pruritus, and notalgia paresthetica, is typically associated with pain and burning sensation. Atopic dermatitis may also be associated with burning sensation after scratching.89

Laboratory Tests and Special Tests

Laboratory tests to be considered in the evaluation of generalized pruritus are outlined in Box 103-1. Secondary laboratory considerations may include stool examination for ova and parasites, screening for hepatitis B or C, plasma protein electrophoresis, and immunoelectrophoresis. A computed tomography scan of the chest and abdomen may be justifiable to help rule out lymphoma. A skin biopsy is not warranted and only useful to exclude clinically inapparent cutaneous mastocytosis, bullous pemphigoid or cutaneous T cell lymphoma.

(Box 103-2)

Pruritus can significantly impair patients’ quality of life and have an effect on prognosis. Patients with chronic pruritus often have difficulty sleeping, difficulty concentrating, decreased sexual desire and sexual function, agitation, and depression.7,90 In addition, eczematous lesions resulting from scratching can become secondarily infected, particularly in patients with atopic dermatitis. Moreover, in a large multinational study in hemodialysis patients, pruritus was associated with a 17% higher mortality risk.91

Generalized pruritus can wax and wane. Changes in the clinical presentation may be associated with seasonal changes, such as exacerbation of atopic dermatitis in the winter, or changes between dry and humid environments. Pruritus associated with underlying internal disease is often multifactorial, involving both systemic and external factors, including ambient temperature and humidity. Chronic itch associated with skin disease may also include central neural sensitization.28,36

Itch Caused by Skin Disorders

Pruritus in Atopic Dermatitis

(See Chapter 14.) Pruritus in atopic dermatitis remains a controversial area and the molecular basis of pruritus in atopic dermatitis remains largely unexplained.92 Whether itch precedes skin lesions or vice versa is also an unresolved issue. What is certain is that a vicious itch-scratch cycle (see Fig. 103-1) exists in atopic patients, in which scratch damage enhances pruritus. Itching is particularly acute in response to punctate stimuli such as wool fibers. Alloknesis (see Section “Alloknesis: Itchy Skin”) is a prominent feature of the itch of atopic dermatitis and explains the bouts of intense itching associated with sweating, sudden changes in temperature, dressing, undressing, and direct contact with wool.

A central (neurogenic) component to the itch of atopic dermatitis is suggested by the poor response to low sedation H1 antihistamines.93 The intensity of itch in atopic dermatitis has been related to mental factors, and itch may be induced by cognitive stress, such as anxiety, as well as depression.94–97 Of note, itch intensity and disease severity were significantly correlated with brain activity in the anterior cingulate cortex as well as the insula in atopic dermatitis patients.36 Opioid peptides may serve as central and peripheral mediators because opioid antagonists acting at these levels are effective in some patients.98 Interestingly, there is a significant downregulation of μ-opioid receptor expression in the epidermis of atopic dermatitis patients.99 Nocturnal scratching is a major problem in atopic dermatitis, occurs during superficial sleep, and occupies 10%–20% of the total sleeping time, leading to tiredness and irritability.

Psoriasis

Itch in psoriasis is a significant but underrecognized problem in dermatology. Several studies have demonstrated that itch is a principal symptom of psoriasis.100–104 Among psoriasis patients, 77% experience pruritus on a daily basis.90 Dermatologists emphasize observable criteria of psoriasis, such as visible lesions; however, itching frequently occurs in areas of the body where no psoriasis plaques are visible. Scalp itching, in particular, is specific to psoriasis and may require different therapies than pruritus in other areas of the body.103,105

Neuropathic Itch

Postherpetic Neuralgia

Postherpetic neuralgia commonly has neuropathic pain; and often, associated neuropathic itch in 30%–58% of such patients. Pruritus commonly accompanies both acute zoster and postherpetic neuralgia, particularly lesions affecting the head, face, and neck.106,107

Brachioradial Pruritus

Brachioradial pruritus, a localized pruritus, is becoming increasingly common. Patients, usually fair skinned, affluent, and middle aged, habitually indulge in golf, tennis, sailing, or other leisure outdoor activities in sunny climates.108,109 They develop persistent pruritus of the outer surface of the upper arm, elbow, and forearm, associated with clinical evidence of chronic sun damage and xerosis. The itch is often accompanied by a burning sensation. The itch may gradually become more widespread. The pathophysiology is believed to involve compression of spinal nerve roots in C4–C6 and in rare cases it has been associated with spinal nerve tumors.110 Of note, exposure to UV light has been an eliciting factor.111 (See Chapter 90.)

Notalgia Paresthetica

Notalgia paresthetica is a chronic localized itch, affecting mainly the interscapular area especially the T2–T6 dermatomes, but occasionally with a more widespread distribution, involving the shoulders, back, and upper chest. The sensation perceived by the patient is part itch, part paraesthesia. There are no specific cutaneous signs, apart from those attributed to scratching and rubbing. Amyloid deposition in skin biopsies is a secondary event. The current view on etiology is that it is a neuropathic itch due to nerve entrapment of the posterior rami of spinal nerves arising at T2–T6.112,113

Systemic Itch

Pruritus of Chronic Kidney Disease

(See Chapter 150.) Pruritus is one of the most distressing symptoms of chronic kidney disease (CKD). It affects 42% of patients on hemodialysis as reported by the Dialysis Outcomes and Practice Pattern Study (DOPPS).91 The DOPPS report and a large study in Japan showed that CKD-associated itch induces depression, sleep disturbance and increased mortality.91,114 Scratching is common and patients may be heavily excoriated or the skin may appear lichenified or present with prurigo nodules. The back is invariably affected, and the arm bearing the arteriovenous fistula is also a common site in dialysis patients. Patients with CKD associated-pruritus often have dry skin, but correction of this by emollients usually provides minimal relief.

The pathophysiology of CKD-associated pruritus remains poorly understood. Current understanding points towards central roles for the immune and opioidergic systems. It is postulated that the itch associated with CKD is a manifestation of an immune system derangement that results in a proinflammatory state. In line with this theory, immunomodulators such as ultraviolet B light,115 tacrolimus116 and thalidomide117 have been shown to alleviate CKD-associated pruritus. An imbalance of the endogenous opioidergic system has also received recent attention in terms of the pathophysiology of CKD-associated pruritus.118 An increased ratio of serum β-endorphin to dynorphin A has been reported in HD patients compared with healthy controls, and the ratio increased with the increased intensity of itch.119 Moreover, a kappa-receptor agonist, nalfurafine, was shown to significantly decrease itch intensity and excoriations in HD patients.120,121 Other proposed etiologic factors may include elevated calcium levels, release of pruritogenic cytokines during hemodialysis, damage to C nerve fibers, proliferation of sensory nerve endings in skin, increased numbers of dermal mast cells, elevated plasma histamine levels, secondary hyperparathyroidism and abnormal levels of divalent cations.118,122,123 Secondary hyperparathyroidism, though common in patients with renal failure, is a rare cause of renal pruritus. The proliferation of nerve endings in skin is most likely a response to incessant scratching and rubbing, rather than the primary cause of pruritus. Elevation of histamine levels, with or without increased population density of dermal mast cells, is also unlikely to be important because antihistamines are rarely effective.

Pruritus of Cholestasis

(See Chapter 150.) Pruritus of cholestasis is highly distressing. The unique feature of cholestatic pruritus is that the itch initially starts and is most intense in the palms and soles, which is usually not reported in other diseases and later becomes more generalized. Of note, intractable itch in chronic liver disease may be an indication for liver transplantation even in the absence fulminant liver failure.124 Both peripheral and central mechanisms are important. Cholestatic pruritus is associated with high plasma levels of bile salts; however, there is little or no evidence of a correlation between skin or serum concentrations of bile salts and itching125 although administration of cholestyramine, which lowers bile salt levels, does provide some relief. Patients also have elevated plasma opioid levels,126 and pruritus has been shown to improve with treatment with opioid antagonists including naloxone, naltrexone, and butorphanol.127–129 In addition, animal models of cholestasis are associated with elevated levels of opioid peptides and scratching, relieved by naloxone.130,131 Thus, combination of both bile salt-lowering and opioid-directed strategies appear reasonable in the management of pruritus of cholestasis.

Furthermore, recent studies have shown that patients with cholestatic pruritus have elevated serum levels of autotoxin and its substrate lysophosphatidic acid (LPA) a signaling phospholipid. The activity of autotaxin in cholestatic patients’ sera correlated with the intensity of pruritus. LPA and autotaxin may therefore be potential targets in the treatment of cholestatic pruritus.132

Pruritus of Endocrine Disease

(See Chapter 151.) Generalized intractable itching is a recognized feature of thyrotoxicosis and may be a presenting symptom.133 This may be due to increased blood flow, which raises the skin temperature, which, in turn, reduces the threshold to itching.22 Hypothyroidism is less frequently associated with itch. Generalized itching is not a feature of diabetes mellitus.134 However, anogenital itching is a common presenting feature, and is due to mucocutaneous candidiasis. Localized itching of the scalp and lower extremities in the form of lichen simplex chronicus can also be a manifestation of diabetic neuropathy,135 which may respond to topical capsaicin treatment.136 In addition, truncal pruritus of unknown origin has been recently reported to be associated to diabetes and diabetic neuropathy.137

Pruritus in Hematologic Disease and Lymphoreticular Malignancy

(See Chapters 144 and 145.) Itch is common in hematologic disorders. In widespread cutaneous T-cell lymphoma, and erythrodermic forms of cutaneous T-cell lymphoma including Sézary syndrome (T-cell leukemia), intractable itch is difficult to manage. In polycythemia vera, it occurs in approximately 50% of patients, is often precipitated by contact with water (“bath itch”), and is associated with raised blood histamine levels.138,139 In other lymphoproliferative diseases, itch can also be precipitated by contact with water. In Hodgkin disease, it may be a presenting symptom and occurs in between 15%–19% of patients.124,140 It can a be a presenting sign in non-Hodgkins lymphoma also. Of note, recent data has shown functional abnormalities of mast cells in patients with myeloproliferative disease with an increased release of pruritogenic factors, such as histamine, leukotrienes, and IL-31, when compared to normal mast cells.141 In cutaneous mastocytosis (see Chapter 149), itching occurs locally following rubbing the skin, although it can be widespread in severely affected patients, when it is usually associated with systemic symptoms. Itching may occur in patients with myeloid and lymphatic leukemia and myelodysplasia.

Paraneoplastic Pruritus

(See Chapter 153). Chronic itch could be a presenting sign of both hematologic malignancies as well as solid tumors. It may occasionally be present years before the tumor becomes clinically detectable. It could also be present as part of a primary epidermal or dermal skin disease associated with malignancy such as eruptive seborrheic keratosis, malignant acanthosis nigricans, erythroderma, transient acantholytic dermatosis (Grover disease) and dermatomyositis.142 Traditionally, the onset of pruritus in a middle-aged or elderly patient with an otherwise normal-looking skin prompts a thorough investigation for underlying systemic causes, including internal neoplasia, although the latter is an uncommon cause. Full investigation for a causative solid tumor is probably not worthwhile in the absence of other skin or systemic findings suggestive of malignancy even if resources are available.143,144

Pruritus of Human Immunodeficiency Virus Infection

(See Chapter 198.) Itch is an early symptom of human immunodeficiency virus (HIV) disease and may be associated with skin disease or a result of systemic disease (e.g., hepatic, renal, adverse drug reactions, lymphoma, and systemic and skin infections including Staphylococcus aureus and Pityrosporum). However, it may occur as a primary symptom of HIV.145 The most common example is eosinophilic folliculitis. Other common types of itch in HIV are insect bite hypersensitivity reaction, pruritic papules other than eosinophilic folliculitis, and itch associated with skin xerosis and lichenoid dermatitis, as well as exacerbation of seborrheic dermatitis and psoriasis.

Psychogenic Itch

(See Chapter 104.) The prevalence of pruritus among psychiatric inpatients is as high as 42% and appears related to psychosocial stress.146,147 Patients with depression, fibromyalgia, and other somatoform disorders can suffer from severe itch that responds well to selective serotonin reuptake inhibitors (SSRIs). Of importance, delusions of parasitosis is one of the more challenging types of itch that dermatologists encounter. The patient holds a false belief that they are infested with parasites, although careful inspection reveals no supporting clinical findings. The patient often brings “evidence” in the form of collected fragments, although on examination the material proves to be nonspecific debris. The patients often refuse to see a psychiatrist. Delusions of parasitosis is classically treated with typical antipsychotic agents; pimozide is most commonly used by dermatologists. Olanzapine (5 mg/day) is another option to treat this severe type of psychogenic itch. Localized pruritus in the form of prurigo nodularis or anogenital pruritus could be a manifestation of obsessive-compulsive disorders and anxiety.

Miscellaneous Types of Itch

Advanced Age and Itch

Itch is the most common dermatologic symptom among people over 65 years of age.148,149 At least 50% of persons aged 70 years or older suffer from prolonged bouts of troublesome pruritus. Idiopathic itch in the elderly, sometimes referred to inappropriately as senile pruritus, is common and presents a diagnostic and therapeutic challenge. Itch in senescent skin can result from a variety of causes including dry skin, inflammatory skin diseases such as low-grade eczema and scabies, as well as underlying systemic disease, especially cholestasis and renal failure. Several drugs can induce pruritus without a rash including opioids and angiotensin converting enzyme inhibitors. However, in many instances, no cause is found. Although dry skin is probably the most common associated factor, it may not be the cause of pruritus; many elderly patients have senescent skin without xerosis. Other factors may play important roles, such as age-related changes in nerve fibers and loss of input from pain fibers leading to central disinhibition of itch. Additional skin changes in elderly patients that may contribute to itch include decreased skin surface lipids, decreased clearance of transepidermally absorbed materials from the dermis, decreased sweat and sebum production, and diminished barrier repair.150

Itch Associated with Burns and Scars

(See Chapters 66 and 95.) Burn scars are common in both children and adults and are associated with significant pruritus. The reported prevalence rates of mild to severe itching were as high as 87%, 70% and 67% at 3, 12, and 24 months post burn respectively.8 Compared to healthy skin, burn-graft skin displays significantly elevated SP nerve fibers as well as significantly elevated thresholds for pinprick, warming, touch, and vibration.151 Keloids are frequently associated with itch at the periphery of the keloid lesion and less frequently pain in the center of the keloid.152 These findings probably result from entrapment of small nerve fibers.

Aquagenic Pruritus

Originally described by Shelley153 and subsequently characterized by Greaves et al,154 aquagenic pruritus is a rare, intractable pruritus of unknown etiology found mainly in the middle-aged and elderly.155 Characteristically, local itching without visible skin signs is provoked by contact with water. Notably, aquagenic pruritus can be associated with lymphoproliferative disorders such as polycythemia vera.139,156

Unfortunately, there are no general-purpose antipruritic drugs. Treatment of pruritus depends on identifying and removing the cause, whether systemic or cutaneous. False hopes of highly effective treatment for those patients in whom no cause can be found should not be raised. Recently, a kappa opioid receptor agonist, nalfurafine, was officially approved in Japan for clinical use as an antipruritic for CKD-associated pruritus. The antipruritic effects of this drug on other forms of itch still need to be elucidated. It is important to obtain a detailed history, including the precise quality, timing, and distribution of the itch, so that more focused therapy can be instituted. The sensation of itching is heightened if the skin is warm,22,157 therefore measures should be taken to cool the skin down, including tepid showering, light clothes, and air conditioning where appropriate. Cooling lotions, such as calamine lotion or menthol 1%, may help. Of note a subset of chronic itch patients report that hot showers alleviate their itch for several hours.35,90

A general therapeutic ladder for generalized pruritus is presented in Fig. 103-3.

Topical Antipruritic Treatments

There is a lack of controlled studies for most topical antipruritic treatments. Many topical agents are claimed to be effective for pruritus; however, few claims are supported by more than anecdotal evidence. Although capable of relieving pruritus due to inflammatory skin disease, corticosteroids are not intrinsically antipruritic. Antihistamines are only antipruritic if the pruritus is caused by histamine, as in urticaria. However, a number of pharmacologic mechanisms offer promising avenues for treatment of itch. A summary of topical antipruritic treatments is given in Table 103-3.

Barrier Creams and Combination Therapies

Emollients and barrier repair creams often reduce pruritus through improved barrier function. They help the stratum corneum to retain water and provide an exogenous barrier to prevent transepidermal water loss. Such barrier creams are often effective treatments for itch associated with dry skin and atopic dermatitis; however, the mechanism of their antipruritic effects are not fully understood. Restoration of the barrier minimizes fissuring and reduces exposure of C nerve fibers. Atopic dermatitis patients treated with ceramide-dominant emollients demonstrate improved transepidermal water loss and overall severity of skin disease. Lipids, occlusives, and humectants also reduce damage to skin by decreasing contact between skin proteins, lipids, and surfactants. Acidifying the stratum corneum may also reduce itch. High pH solutions increase the swelling of the stratum corneum, change lipid rigidity, and increase secretion of serine proteases, suggesting that neutral or acidic pH solutions are less damaging.158

Topical Salicylates

Clinical trials have shown that applying a topical salicylic acid solution to the skin relieves itch. Topical salicylic acid is a common keratolytic agent and may also increase hydration and soften the stratum corneum by decreasing its pH (see Chapter 222). Topical aspirin significantly reduced pruritus in patients with lichen simplex chronicus—a form of localized itch85; however, oral salicylates do not relieve pruritus except in polycythemia vera.

Topical Immunomodulators

(See Chapter 221.) Although topical immunomodulators, such as tacrolimus and pimecrolimus, are used primarily for atopic dermatitis, these medications are promising antipruritic treatments in other dermatologic diseases as well. Other pruritic dermatoses treated successfully with topical calcineurin inhibitors include chronic irritative hand dermatitis, seborrheic dermatitis, graft-versus-host disease, lichen sclerosus, anogenital pruritus and prurigo nodularis. Tacrolimus and pimecrolimus have both been shown to directly affect C nerve fibers.159,160

Coolants and Counter-Irritants

A distinct subset of sensory neurons may directly sense changes in temperature via receptors of TRP ion channels on cutaneous nerve endings. These include vanilloid receptors, such as TRPV1, which respond to warmth and capsaicin. These receptors act synergistically with other receptors involved in itch, such as PAR-2 and SP receptor (Neurokinin 1). These receptors are targets for treatment of itch. Other receptors from the same family include cold receptors, such as TRPM8. Menthol has been used as a symptomatic topical treatment for pruritus for centuries and relieves itch in some patients by activating nerve fibers that transmit a cool sensation. Menthol may reduce itch via TRPM8 receptors in keratinocytes and nerve fibers.161,162 Menthol 1% cream is popular with patients who have pruritic skin; however, higher concentrations can induce skin irritation.163 Those patients who report that cold showers and ice relieve their itch tend to respond extremely well to treatment with menthol.

Capsaicin

Topical capsaicin, the active compound in the chili pepper, causes release of neuropeptides, including SP, from C nerve fibers. The exact mechanism is not fully understood; however, prolonged application of capsaicin to the skin depletes stores of SP, desensitizes neurons, and abolishes pruritus at the site of application. Capsaicin activates the vanilloid receptor TRPV1, which is abundant in the epidermal layer of the skin.17 Several reports have supported capsaicin's value for localized, chronic pruritic disorders, particularly those of neuropathic origin, including brachioradial pruritus, notalgia paresthetica, postherpetic itch as well as pruritus associated with CKD, psoriasis and atopic dermatitis.164,165 Unfortunately, compliance is poor because initial application causes an intense, transient burning sensation at application sites; however, this usually resolves after using the medication for a few days or with application of a topical anesthetic.107

Topical Anesthetics

Pramoxine

Pramoxine is a topical anesthetic that reduces itch, especially when applied to facial areas, by blocking the transmission of nerve impulses. Double-blind studies have shown that pramoxine inhibits histamine-induced itch in humans and CKD-associated pruritus.166,167

Polidocanol

Polidocanol is a nonionic surfactant with both local anesthetic properties and moisturizing effects. In an open-label study, a combination of 5% urea and 3% polidocanol (Lauromacrogol) was found to significantly reduce pruritus in patients with atopic dermatitis, contact dermatitis, and psoriasis.168

Topical Antihistamines

Doxepin is a tricyclic antidepressant with potent H1- and H2-antihistamine properties and significant atropine-like (anticholinergic) side effects. Doxepin 5% cream has been shown to relieve pruritus in patients with atopic dermatitis in a large placebo-controlled, double-blind study.169 However, percutaneous absorption of doxepin, causing drowsiness, occurs in approximately 25% of patients, limiting its usefulness. Allergic contact dermatitis is also a recognized adverse effect.

Topical Cannabinoids

Uncontrolled trials have shown that topical cannabinoids combined with a barrier cream have an antipruritic effect in patients with atopic dermatitis and uremic pruritus.170

Future Topical Therapies

Although none are currently available, topical drugs that inhibit serine proteases may be an additional mechanism for future antipruritic therapies. Drugs that act in a similar manner to prostaglandin (PG) D2 are currently being tested in humans and may also have a potential therapeutic role in itch.

Systemic Antipruritic Treatments

Antihistamines

(See Chapter 229.) Pruritus due to histamine is mediated exclusively via H1 receptors; H2 antihistamines are ineffective in relieving pruritus. First-generation (classic) H1 antihistamines have marked sedative and atropine-like (anticholinergic) actions. Second generation (minimal- or low-sedation) H1 antihistamines have lower lipophilicity and consequently are associated with less drowsiness and other unwanted side effects. Sedative (first-generation) antihistamines are useful in severe chronic urticaria with or without angioedema because they suppress pruritus and alleviate associated anxiety. Hydroxyzine is especially valuable in this context along with doxepin. Second-generation H1 antihistamines are suitable in the daytime for relief of pruritus due to urticaria; however, the role of these nonsedating antihistamines is limited in other pruritic disorders. A summary of systemic antipruritic treatments is given in Table 103-4.

Opiate Antagonists and Agonist–Antagonists

As previously mentioned, μ-opioid receptor agonists can cause generalized pruritus.67,69–71 μ-Opioid antagonists, such as naloxone and naltrexone, have been used for the treatment of pruritus associated with cholestasis, uremia, and dermatologic diseases. The efficacy of such opioid antagonists is supported by data from controlled clinical trials.64,127,129,171–173 Naltrexone was effective in the treatment of some cases of severe, intractable pruritus.174 However, such μ-antagonists are associated with significant side effects including hepatotoxicity, nausea and vomiting, difficulty sleeping, and reversal of analgesia, among others. κ-Receptor agonists also inhibit μ-receptor effects. In animal models, κ-opioid receptor agonists inhibit pruritus and scratching induced by SP or histamine.68,69 The novel κ agonist, nalfurafine (TRK-820), has been shown to be effective in treatment of severe uremic pruritus.121 Thus, κ agonists are a promising treatment for severe itch.120

Butorphanol is a commercially available opioid agonist-antagonist analgesic with both κ-agonist activity and μ-antagonist activity. Previous studies have found that epidural butorphanol was effective in relieving pruritus associated with epidural morphine.175,176 Intranasal butorphanol is an effective treatment for many patients with chronic, severe, and intractable pruritus due to systemic diseases and inflammatory skin diseases.177

Antidepressants

The oral antidepressant and selective noropinephrine re-uptake inhibitor, mirtazapine, has been shown to relieve itch in some patients.178,179 Unlike other SSRIs, mirtazapine is a central presynaptic α2 noradrenergic inhibitor and specific serotonergic antidepressant. Mirtazapine is a safe medication without serious side effects and may be an effective alternative for the treatment of nocturnal pruritus.179 It has been shown to be effective when used to treat systemic pruritus as well as pruritus of inflammatory skin diseases and in particular nocturnal itch using a low dose of 15 mg at night. A recent open-labeled study showed paroxetine and fluvoxamine, both selective serotonin reuptake inhibitors, to be efficient in the treatment of chronic itch.180

Thalidomide

(See Chapter 235.) Thalidomide has shown antipruritic efficacy in treatment of inflammatory skin diseases, such as prurigo nodularis, actinic prurigo, eczema, and idiopathic elderly pruritus. It is especially useful in pruritus associated with multiple myeloma and lymphoproliferative disease. Thalidomide has been used for years as an immunomodulatory agent whose spectrum of activity is not fully characterized. The antipruritic activity could be related to several mechanisms, including inhibition of TNF-α synthesis. Although TNF-α does not have any direct pruritogenic effect, it is elevated in many pruritic dermatoses. Thalidomide may also act directly as a peripheral and central nerve depressant. The major adverse effects of thalidomide are peripheral neuropathy and teratogenicity.

Neuroleptics

Gabapentin is a structural analog of the neurotransmitter γ-aminobutyric acid and has been used as an anticonvulsant; however, its mechanism of action in the CNS is poorly understood. Studies have shown that gabapentin is effective for treatment of brachioradial pruritus, multiple sclerosis-induced itch, other types of neuropathic itch as well as uremic itch. Gabapentin appears to alter sensation and pruritus associated with itch related to nerve damage in dermatologic and systemic disease. Gabapentin may inhibit central itch pathways, as it does in pain. Pregabalin is a neuropathic pain medication that has a similar structure and function to gabapentin with fewer side effects and can reduce neuropathic itch or alter the sensation of itch in systemic diseases.113,181

Substance P Antagonist

Aprepitant, an oral drug that antagonizes the effect of SP on neurokinin type 1 receptor has recently been shown to be effective against pruritus associated with the Sézary syndrome in a case series of 3 patients.182

Nonpharmacologic Treatments for Itch

Phototherapy

(See Chapter 237.) Phototherapy has been used for more than three decades to treat different types of itch. Reports have suggested that narrow band UVB may be as effective for treatment of pruritus as broadband UVB or psoralen and UVA light. Phototherapy decreases the population density of mast cells by inducing apoptosis, causes peripheral nerve dysfunction, and reduces divalent cations in the skin. Phototherapy is an effective treatment for itch associated with atopic dermatitis, psoriasis, and CKD. Remissions may last for as long as 18 months.

Cutaneous Field Stimulation and Acupuncture

Cutaneous field stimulation (CFS) is a new technique that electrically stimulates afferent fibers, including nociceptive C fibers. CFS has similarities to transcutaneous electrical nerve stimulation, which activates large myelinated nerve fibers; however, CFS more specifically targets unmyelinated C nerve fibers. CFS may act through endogenous central inhibitory mechanisms that are normally activated by scratching.183 In patients with localized itching, CFS significantly reduces patient-reported itch and causes degeneration of epidermal nerve fibers.184 However, CFS is only practical for localized disease. In addition, acupuncture at the correct points showed a significant reduction in type I hypersensitivity itch in both healthy volunteers and patients with atopic eczema.185,186

Behavioral Therapy Targeting the Central Nervous System

Stress and other psychogenic factors are important in chronic itch.187,188 Atopic dermatitis patients have been shown to demonstrate an abnormal sympathetic and parasympathetic response to itch and mental stres.189 Studies have shown that behavioral modification therapy reduces both itching and scratching.190 Other possible behavioral interventions include stress reduction and biofeedback.188 Stress reduction using holistic approaches such as meditation, yoga and mindfulness may have adjunctive role in reducing itch intensity.