Chronic pruritus: still a challenge but new directions of development have been indicated
Department of Dermatology, Venereology and Allergology, Wrocław Medical University
Head of Department: prof. Eugeniusz Baran, MD, PhD
Pruritus is defined as a subjective sensation which provokes a desire to scratch. It could be acute (lasting less than 6 weeks) or chronic (with a 6 week duration or longer) (1). An acute pruritus may be considered as a defensive mechanism, that should protect our body from being hurt by insects or other parasites. On the other hand, a chronic itching represents a significant medical problem, responsible often for marked morbidity, quality of life impairment, and, in some patient population, even for increased mortality (2, 3). Pruritus seems to be a quite frequent symptom, as 8 to nearly 30% of participants of population based studies declared, that they have suffered from itching at least sometimes (4-7). This sensation can accompany not only a long list of skin diseases, but also a number of systemic, neurological or psychiatric conditions. Based on the newest itch classification proposed by the International Forum for the Study of Itch, pruritus could be divided into three major groups according to clinical manifestation: pruritus on primarily diseased, inflamed skin (group I), pruritus on primarily normal, non-inflamed skin (group II) and pruritus with chronic secondary scratch lesions (group III) (8). Furthermore, six categories of pruritus reflecting its pathogenesis have been defined, namely dermatologic, systemic, neurological, psychogenic, mixed and other type of pruritus (8). The new pruritus classification has unified previous attempts of itch categorization and, in addition, included clinical manifestation as an important prerequisite of patient assignment. Therefore, it seems, that it is well fitted both for clinical, as well as for scientific purposes.
Despite a high prevalence of pruritus in general population, treatment of patients with chronic itch remains a challenge. It is related to a complex and multifactorial pathogenesis of this ailment. Antihistamines, the classic antipruritic drugs, are only effective in selected diseases, like urticaria or mastocytosis (i.e. in histaminergic itch), while in other pruritus forms they provide only partial relief or are not satisfactory at all (i.e. in non-histaminergic itch). However, recent decade has brought a number of crucial discoveries in itch knowledge which give a hope for the development of new effective therapeutic strategies in the near future.
The exact pathomechanism of chronic pruritus is still not exactly known. For a long time, pruritus was considered as a subliminal pain, however, currently it is handled as a distinct sensation that admittedly shares some similarities and cross-linking with pain feeling, but possesses separate neurons dedicated solely for itch transmission (9-11). This hypothesis has been supported by a rapidly growing evidence arising over last years. In 2007 Sun et al. (12, 13) identified gastrin-releasing peptide (GRP)-positive dorsal root ganglion neurons, that were itch-specific. Expression of GPR receptors was restricted to lamina I of the dorsal spinal cord. Blockade of these receptors by direct spinal cerebrospinal fluid injection of a GRP receptor antagonist significantly inhibited scratching behavior in three independent itch models, while pain sensation evoked by various stimuli remained unchanged (12, 13). Similar effect was noticed by selective ablation of GRP-positive neurons (13). It was also shown, that these neurons are important to both histamine dependent and histamine independent pathways of itch, however, it seems that they mediated more non-histaminergic itch stimuli (14). Recently, attempts have been made to develop antagonists of these receptors that might be used as a potent antiprutic therapy in the future (15). Interestingly, transmission of itch stimuli by GRP-positive neurons was regulated by Toll-like receptors 3 (TLR-3), which represent other potential target for new antiprutic molecules to be developed (16). In addition, TLR-7, which is activated by imiquimod, has also been shown to mediate pruritus transmission in primary sensory neurons (17, 18).
Central transmission of itch is also modulated by endogenous opioid system. Central activation of μ-opioid receptors (MOR) (e.g. by opiates like morphine) produces pruritus, while activation of κ-opioid receptors (KOR) alleviates itch (19). A relief of itch or decrease of pruritus intensity may be expected during the blockade of MOR by naloxone or naltrexone (MOR antagonists) or by the stimulation of KOR by its agonists like nalfurafine or butorphanol (20-23). Unfortunately, central acting drugs may also produce a number of side effects, like nausea and vominiting, sleeping difficulty, fatigue and reversal of analgesia, which limits their wider use as antipruritic medications (19, 22). However, recent data showed that opioid receptors are also present on peripheral sensory neurons and partake in itch perception (24). As in central nervous system, activation of peripheral MOR produced itching, that could be effectively diminished by subsequent selective activation of peripheral KOR (24). A decrease of pruritus was also noticed after treatment with naloxone (a MOR antagonist) as well as naloxone methiodide (a peripherally restricted MOR antagonist) (24). Furthermore, Nelson et al. (25) reported that endogenous opioid-mediated antinociception in cholestatic mice is peripherally and not centrally mediated, again underlying the importance of peripheral opioid system in itch perception. In addition, Tominaga et al. (26) demonstrated that PUVA therapy diminished MOR immunoreactivity in the skin of patients with atopic dermatitis, and the degree of this decrease significantly correlated with pruritus improvement. It was also suggested, that pruritus in patients with psoriasis may be related to the imbalance of peripheral opioid system, as psoriatic patients with pruritus showed decreased expression of KOR and dynorphin A (the endogenous KOR agonist) within the epidermis in comparison to healthy controls, while the expression of MOR and β-endorphin (the endogenous MOR agonist) was similar in both groups (27). Thus, it seems, that higher MOR tone in the skin may be responsible for pruritus at least in some dermatological diseases. On the other hand, potentiating peripheral KOR activity via KOR selective ligands or inhibiting peripheral MOR would offer a new possibility of itch controlling (28).
A variety of other mediators released by skin cells (e.g. mast cells) were shown to be able to induce or modulate itch by activating approximately 5-20% of primary afferent itch-sensitive C-fibers, which can be divided into multiple subgroups based on pruritogen-sensitivity. A study on chloroquine-induced itch enabled to identify new pruritus receptors on C-fibers, namely Mrgprs, a family of G protein-coupled receptors that are expressed exclusively in peripheral sensory neurons (Mrgprs stays for Mas-related G protein-coupled receptors) (29, 30). These receptors may be activated by endogenous peptides, e.g. BAM8-22 (bovine adrenal medulla 8-22 peptide) and by exogenous substances (e.g. chloroquine) (29). Mice lacking a cluster of Mrgpr genes displayed significant deficits in itch induced by chloroquine but not by histamine. It seems, that Mrgprs are even more important for non-histaminergic itch, than PAR (protease activated receptors), that were also linked with chronic itch sensation (31, 32).
Another promising molecule, that has also recently been identified as an important pruritogen, especially in inflamed skin, is interleukin 31 (IL-31) (33, 34). There was a good correlation between the scratching counts and expression of IL-31 mRNA in mouse model of atopic dermatitis (35) and anti-IL-31 antibodies effectively reduced scratching behavior in these animals (36). It was also clearly demonstrated, that IL-31 is an important cytokine in atopic dermatitis in human, and its level correlated with disease severity, sleeplessness, serum IgE level, and subjective itch intensity (37-39). Allergen-induced pruritus may also be inhibited, at least partially, by histamine blockade. However, it seems, that histamine is able to produce itch both via H1 receptor, as well as due to activation of newly described and cloned H4 receptor (40-43). Importantly, blockade of both receptors provided greater pruritus relief than single receptor inhibition (41, 43). Interestingly, the inhibitory effect of H4 receptor antagonist was greater than those observed with H1 receptor antagonists and histamine H4 receptor-mediated pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons (40). Thus, it could be supposed, that H4 receptor antagonists may be tried in chronic pruritic diseases where H1 blockers were not enough effective (40).
Describing the pathomechanism of itch it can not be forgotten, that to be noticed, each stimulus, including a pruritic one, must be processed by a human brain. It was shown, that acute histamine-induced itch co-activates the anterior cingulate cortex, the insular and primary somatosensory cortices, premotor and supplementary motor areas, cerebellum and thalamus (44-46). However, what is even more important, recent findings demonstrated, that patients suffering from chronic itch showed different brain activation upon acute itch compared to healthy controls. Patients with atopic dermatitis showed higher activity in the contralateral thalamus and in the ipsilateral basal ganglia, while healthy controls had higher activation in the ipsilateral premotor cortex (45, 46). Moreover, the activity in cortical areas involved in affect and emotion correlated to measures of disease severity (46). It seems, that different brain activation might be responsible for itch chronicity and this problem has to gain more attention in the future in order to be able to effectively treat chronic itch.
1. Weisshaar E, Szepietowski JC, Darsow U et al.: European guideline on chronic pruritus. Acta Derm Venereol 2012, doi: 10.2340/00015555-1400 [Epub ahead of print].
2. Narita I, Alchi B, Omori K et al.: Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006; 69: 1626-1632.
3. Chen HY, Chiu YL, Hsu SP et al.: Elevated C-reactive protein level in hemodialysis patients with moderate/severe uremic pruritus: a potential mediator of high overall mortality. Q J M 2010; 103: 837-846.
4. Dalgard F, Svensson A, Holm JA, Sundby J: Self-reported morbidity in Oslo. Associations with sociodemographic factors among adults in a cross-sectional study. Br J Dermatol 2004; 151: 452-457.
5. Ständer S, Schäfer I, Phan NQ et al.: Prevalence of chronic pruritus in Germany: results of a cross-sectional study in a sample working population of 11,730. Dermatology 2010; 221: 229-235.
6. Matterne U, Apfelbacher CJ, Loerbroks A et al.: Prevalence, correlates and characteristics of chronic pruritus: a population-based cross-sectional study. Acta Derm Venereol 2011; 91: 674-679.
7. Misery L, Rahhali N, Duhamel A, Taieb C: Epidemiology of pruritus in France. Acta Derm Venereol 2012 Apr 16, doi: 10.2340/00015555-1342. [Epub ahead of print].
8. Ständer S, Weisshaar E, Mettang T et al.: Clinical classification of itch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol 2007; 87: 291-294.
9. Schmelz M, Schmidt R, Bickel A et al.: Specific C-receptors for itch in human skin. J Neurosci 1997; 17: 8003-8008.
10. Davidson S, Zhang X, Yoon CH et al.: The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J Neurosci 2007; 27: 10007-10014.
11. Steinhoff M, Ikoma A: Dissecting itch and pain sensations in human skin. Pain 2011; 152: 2453-2454.
12. Sun YG, Chen ZF: A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007; 448: 700-703.
13. Sun YG, Zhao ZQ, Meng XL et al.: Cellular basis of itch sensation. Science 2009; 325: 1531-1534.
14. Han N, Zu JY, Chai J: Spinal bombesin-recognized neurones mediate more nonhistaminergic than histaminergic sensation of itch in mice. Clin Exp Dermatol 2012; 37: 290-295.
15. Yao RS, Li TT, Xu J et al.: Design, synthesis, and anti-itch activity evaluation of a series of aromatic amino acid aerivatives as gastrin-releasing peptide receptor antagonists. Med Chem 2012 Jun 26. [Epub ahead of print].
16. Liu T, Berta T, Xu ZZ et al.: TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest 2012; 122: 2195-2207.
17. Liu T, Xu ZZ, Park CK et al.: Toll-like receptor 7 mediates pruritus. Nat Neurosci 2010; 13: 1460-1462.
18. Kim SJ, Park GH, Kim D et al.: Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons. Proc Natl Acad Sci U S A 2011; 108: 3371-3376.
19. Reich A, Szepietowski JC: Opioid-induced pruritus: an update. Clin Exp Dermatol 2010; 35: 2-6.
20. Dawn AG, Yosipovitch G: Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 2006; 54: 527-531.
21. Metze D, Reimann S, Beissert S, Luger T: Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Dermatol 1999; 41: 533-539.
22. Kumagai H, Ebata T, Takamori K et al.: Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant 2010; 25: 1251-1257.
23. Kamei J, Nagase H: Norbinaltorphimine, a selective kappa-opioid receptor antagonist, induces an itch-associated response in mice. Eur J Pharmacol 2001; 418: 141-145.
24. Yamamoto A, Sugimoto Y: Involvement of peripheral mu opioid receptors in scratching behavior in mice. Eur J Pharmacol 2010; 649: 336-341.
25. Nelson L, Vergnolle N, D’Mello C et al.: Endogenous opioid-mediated antinociception in cholestatic mice is peripherally, not centrally, mediated. J Hepatol 2006; 44: 1141-1149.
26. Taneda K, Tominaga M, Negi O et al.: Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch. Br J Dermatol 2011 Apr 1 [Epub ahead of print].
27. Tominaga M, Ogawa H, Takamori K: Possible roles of epidermal opioid systems in pruritus of atopic dermatitis. J Invest Dermatol 2007; 127: 2228-2235.
28. Reich A, Szepietowski JC: Non-analgesic effects of opioids: Peripheral opioid receptors as promising targets for future anti-pruritic therapies. Curr Pharm Des 2012 Jun 28 [Epub ahead of print].
29. Liu Q, Tang Z, Surdenikova L et al.: Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 2009; 139: 1353-1365.
30. Wilson SR, Gerhold KA, Bifolck-Fisher A et al.: TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 2011; 14: 595-602.
31. Liu Q, Weng HJ, Patel KN et al.: The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci Signal 2011; 4: ra45.
32. Steinhoff M, Neisius U, Ikoma A et al.: Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 2003; 23: 6176-6180.
33. Dillon SR, Sprecher C, Hammond A et al.: Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 2004; 5: 752-60, Erratum in: Nat Immunol 2005; 6: 114.
34. Sonkoly E, Muller A, Lauerma AI et al.: IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 2006; 117: 411-417.
35. akaoka A, Arai I, Sugimoto M et al.:Involvement of IL-31 on scratching behavior in NC/Nga mice with atopic-like dermatitis. Exp Dermatol 2006; 15: 161-167.
36. Grimstad O, Sawanobori Y, Vestergaard C et al.: Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis. Exp Dermatol 2009; 18: 35-43.
37. Kim S, Kim HJ, Yang HS et al.: IL-31 Serum Protein and Tissue mRNA Levels in Patients with Atopic Dermatitis. Ann Dermatol 2011; 23: 468-473.
38. Raap U, Weißmantel S, Gehring M et al.: IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol 2012; 23: 285-288.
39. Szegedi K, Kremer AE, Kezic S et al.: Increased frequencies of IL-31-producing T cells are found in chronic atopic dermatitis skin. Exp Dermatol 2012; 21: 431-436.
40. Dunford PJ, Williams KN, Desai PJ et al. Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus. J Allergy Clin Immunol 2007; 119: 176-183.
41. Rossbach K, Wendorff S, Sander K et al.: Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation. Exp Dermatol 2009; 18: 57-63.
42. Cowden JM, Zhang M, Dunford PJ, Thurmond RL: The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. J Invest Dermatol 2010; 130: 1023-1033.
43. Ohsawa Y, Hirasawa N: The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice. Allergy. 2012 Jun 12. doi: 10.1111/j.1398-9995.2012.02854.x. [Epub ahead of print].
44. Drzezga A, Darsow U, Treede RD et al.: Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies. Pain 2001; 92: 295-305.
45. Schneider G, Ständer S, Burgmer M et al.: Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects. Eur J Pain 2008; 12: 834-841.
46. Ishiuji Y, Coghill RC, Patel TS et al.: Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. Br J Dermatol 2009; 161: 1072-1080.
47. Murray CS, Rees JL: Are subjective accounts of itch to be relied on? The lack of relation between visual analogue itch scores and actigraphic measures of scratch. Acta Derm Venereol 2011; 91: 18-23.
48. Weisshaar E, Gieler U, Kupfer J et al.: Questionnaires to assess chronic itch: a consensus paper of the special interest group of the International Forum on the Study of Itch. Acta Derm Venereol 2012 Jun 12, doi: 10.2340/00015555-1402 [Epub ahead of print].
49. Phan NQ, Blome C, Fritz F et al.: Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm Venereol 2011 Dec 15, doi: 10.2340/00015555-1246 [Epub ahead of print].
50. Reich A, Heisig M, Phan NQ et al.: Visual Analogue Scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol 2011 Nov 21, doi: 10.2340/00015555-1265 [Epub ahead of print].
51. Reich A, Halupczok J, Ramus M et al.: New data on the validation of VAS and NRS in pruritus assessment: minimal clinically important difference and itch frequency measurement. Acta Derm Venereol 2011; 91: 636.
52. Ständer S, Blome C, Breil B et al.: Erfassung von Pruritus – aktuelle Standards und Implikationen für die Praxis. Konsensuspaper der Initiative Pruritusparameter der Arbeitsgemeinschaft Pruritusforschung (AGP). Hautarzt 2012; 63: 521-531.
53. Szepietowski J, Reich A: Świąd – patomechanizm, klinika, leczenie. Termedia Wydawnictwa Medyczne, Poznań 2010.
54. Szepietowski JC, Morita A, Tsuji T: Ultraviolet B induces mast cell apoptosis: a hypothetical mechanism of ultraviolet B treatment for uraemic pruritus. Med Hypotheses 2002; 58: 167-170.
55. Balaskas E, Szepietowski JC, Bessis D et al.: Randomized, double-blind study with glycerol and paraffin in uremic xerosis. Clin J Am Soc Nephrol 2011; 6: 748-752.
56. Young TA, Patel TS, Camacho F et al.: A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients. J Dermatolog Treat 2009; 20: 76-81.
57. Chen YC, Chiu WT, Wu MS: Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus. Am J Kidney Dis 2006; 48: 69-76.
58. Szepietowski JC, Szepietowski T, Reich A: Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerol Croat 2005; 13: 97-103.
59. Gunal AI, Ozalp G, Yoldas TK et al.: Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 2004; 19: 3137-3139.
60. Manenti L, Vaglio A, Costantino E et al.: Gabapentin in the treatment of uremic itch: an index case and a pilot evaluation. J Nephrol 2005; 18: 86-91.
61. Vila T, Gommer J, Scates AC: Role of gabapentin in the treatment of uremic pruritus. Ann Pharmacother 2008; 42: 1080-1084.
62. Razeghi E, Eskandari D, Ganji MR et al.: Gabapentin and uremic pruritus in hemodialysis patients. Ren Fail 2009; 31: 85-90.
63. Aperis G, Paliouras C, Zervos A et al.: The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients. J Ren Care 2010; 36: 180-185.
64. Phan NQ, Lotts T, Antal A et al.: Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review. Acta Derm Venereol 2012 Apr 16; doi: 10.2340/00015555-1353 [Epub ahead of print].
65. Wikström B, Gellert R, Ladefoged SD et al.: Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol 2005; 16: 3742-3747.
66. Kumagai H, Ebata T, Takamori K et al.: Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant 2010; 25: 1251-1257.
67. Kremer AE, Martens JJ, Kulik W et al.: Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010; 139: 1008-18, 1018.e1.
68. Kremer AE, Dijk RV, Leckie P, et al.: Serum autotaxin is increased in pruritus of cholestasis, but not of other origin and responds to therapeutic interventions. Hepatology 2012 Apr 2; doi: 10.1002/hep.25748 [Epub ahead of print].
69. Kremer AE, Beuers U, Oude-Elferink RP, Pusl T: Pathogenesis and treatment of pruritus in cholestasis. Drugs 2008; 68: 2163-2182.
70. Chappell LC, Gurung V, Seed PT et al.: Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. Br Med J 2012; 344: e3799.