Review Understanding Itch in Systemic Sclerosis in Order To

Review

Understanding itch in systemic sclerosis in order to improve patient quality of life T.M. Frech1, M. Baron2

1University of Utah, University of Utah ABSTRACT Mechanisms of pruritus and Veterans Affair Medical Center, Salt Pruritus is a common complaint in The pathophysiology of pruritus has Lake City, UT, USA; systemic sclerosis (SSc) and impairs been recently reviewed (3-8). These 2Jewish General Hospital, McGill patients’ quality of life. Little is known reviews broadly suggest that itch may University, Montreal, Quebec, Canada. about the pathogenesis of itch in SSc, originate from interplay between skin Tracy M. Frech, MD, MS but complex and multi-factorial mech- inflammation and the nervous system. Murray Baron, MD anisms of itch are appreciated in many Pruritogens, which may be mechanical, Please address correspondence to: chronic diseases. This review discusses Tracy M. Frech, MD, MS, electrical, thermal, or low pH stimuli 4B200 SOM 30 N 1900 E, the putative mechanisms of the patho- in origin, can directly stimulate nerve Salt Lake City, UT 84132, USA. genesis of itch to better understand the fibre endings, or may do so via media- E-mail: [email protected] mechanisms that may be relevant to tors released from resident cells in the Received on November 20, 2012; accepted pruritus in SSc. It discusses possible skin, particularly mast cells (9, 10). in revised form on May 28, 2013. therapeutics in the context of this com- The perception of itch depends on the Clin Exp Rheumatol 2013; 31 (Suppl. 76): plex pathogenesis. neurotransmission/neuromodulation of S81-S88. signal from the skin to brain and thus © Copyright Clinical and Introduction can be modulated at multiple levels Experimental Rheumatology 2013. Systemic sclerosis (SSc, scleroderma) throughout the nervous system, includ- is a chronic, multisystem disease char- ing the level of the skin, spinal cord, Key words: pruritus, systemic acterised by vasculopathy, fibrosis, and or brain (Fig. 1). As such, the goal of sclerosis autoimmunity. Pruritus has not been pruritus treatment is to remove the extensively studied in SSc. We have source of pruritogen, prevent or block demonstrated that 45% of patients the effect of local mediator release, complain of pruritus on most days and and/or interrupt the perception of itch that patients complaining of itch have at various points along nervous system more significant skin involvement, conduction. worse respiratory symptoms, and a greater number of gastrointestinal tract Pruritogens complaints (1). SSc patients with pru- Pruritogens are chemical mediators ritus have significantly worse mental that activate or sensitise nociceptor ter- and physical function and greater dis- minals to elicit or exacerbate pruritus. ability than patients without pruritus They can be generated within the skin (2). The origin of itch in SSc, whether or outside the skin (11). Although we systemic- or dermis-derived, and its re- commonly think of pruritogens as act- lationship to vasculopathy and fibrosis ing peripherally, in fact they may also is unclear. Nonetheless, an understand- act centrally. Their receptors have been ing the mechanism of itch in SSc is found in various intracutaneous cell important to improving patient quality types, peripheral and central nerves, Funding: the project described was of life. as well as sensory neurons (12). As supported by the National Center for Complex and multifactorial mecha- such, pruritus is associated with many Research Resources and the National nisms of itch are appreciated in many inflammatory, dermatologic, and - sys Center for Advancing Translational chronic diseases. Little is known about temic conditions. Sciences, National Institutes of Health, the pathogenesis of itch in SSc, we through Grant 8UL1TR000105 (formerly UL1RR025764). The content is solely the undertook this review of the putative Histamine responsibility of the authors and does not mechanisms of the pathogenesis of itch Although a multitude of mediators ca- necessarily represent the official views of and its treatment in other diseases to pable of stimulating afferent nerves the NIH. better understand the mechanisms that leading to itch exist, the classic inflam- Competing interests: none declared. may be relevant to itch in SSc. matory pruritogen is histamine, a prod-

S-81 REVIEW Understanding itch in SSc to improve QoL / T.M. Frech & M. Baron uct of mast cells. In atopic dermatitis (AD) an increase in plasma histamine has been demonstrated, presumably generated by antigen/IgE-stimulated degranulation of mast cells in the gut and/or skin (10). Importantly, similar abnormalities have been noted in SSc. Elevated levels of histamine were found in 18/32 (56%) patients with SSc and was more common in patients with diffuse disease (74%), in contrast to limited disease (31%) (13). In AD anti-histamine therapy is often not effective in relieving itch, suggesting that although there may be an excess histamine release, there are also likely to be other mediators in skin equally important in itch generation (11). The complexity of management required for AD suggests that there may be many altered neurophysiological mediators of itch in this condition, which are important to consider in management of SSc-pruritus (14). Preformed histamine is present in large amounts in mast cell granules. Thus, after cell activation, can be immediately released into the surrounding area in which it induces itch via H1R (histamine Fig 1. The neurology of itch. 1 receptors) on nerve fibres (8). Experi- ments in mice demonstrated that the erate itching; capsaicin always induces and the adaptive immune response in decreased threshold in response to H3R pain but never pruritus; and serotonin, an attempt to restore connective tissue antagonism activates H1R and H4R on acetylcholine, and bradykinin induced homeostasis (21, 22). Local production sensory neurons, which in turn results pain more often than pruritus (19). of cytokine in damaged skin can induce in the excitation of histamine-sensitive Thus, a better understanding of cuta- itch and immune dysregulation (23). afferents and elicits the sensation of neous mechano-insensitive C-fibres in Modulation of lipid mediators, pro- itch (15). Thus, H3R and H4R may be SSc may help clarify the painful and duced by mast cells have been studied of particular interest in SSc since H3R pruritic aspects of this disease. in the treatment of pruritus and may be can suppress itch, whereas H4R not of interest in SSc (5). only induces the sensation of itch, but Non-histamine mast cell-derived One lipid mediator, lysophosphatidic also modulates dendritic cell migration pruritogens: acid (LPA) may be of particular inter- through skin and can influence T cell re- Due to the central role of histamine in est in SSc. LPA is a potent signalling actions (15, 16); possibly linking itch to certain forms of pruritus, attention has phospholipid that can activate mast immune mediated fibrosis. been paid to the role of mast cells in cell LPA receptors, which when in the Histamine acts on a specific subgroup various conditions associated with pru- perivascular location results in vascu- of mechano-insensitive C-fibres, which ritus. The mast cell may be relevant to lar inflammation (24). Of interest, se- are also sensitive to other mediators itch but not necessarily via histamine rum samples from cholestatic patients (17). An ‘intensity theory’ suggests that release. complaining of pruritus contain higher both itching and pain result from the ac- Mast cell-derived mediators are of amounts of LPA (25). This study hy- tivation of nociceptors, but to a different three basic types and include: (1) pre- pothesised that the LPA accumulation extent, with a weak one leading to itch- formed mediators, such as histamine in the circulation of cholestatic patients ing and a stronger one to pain (18). As and heparin, stored in secretory gran- activated sensory neurons. LPA has such, the sensitivity profile of human ules, (2) newly-synthesised lipid me- also been reported to be elevated in cutaneous C-nociceptors determine diators, and (3) chemokines and cy- SSc , but secreted from activated plate- perception; histamine tends to provoke tokines (20). Mast cells produce and lets (26). Studies suggest that increased pruritus and rarely pain; prostaglandin secrete these substances in order to local formation of LPA near unmyeli- E(2) (PGE2) causes preferentially mod- influence the innate immune system nated nerve endings can cause itch

S-82 Understanding itch in SSc to improve QoL / T.M. Frech & M. Baron REVIEW

(25). The role of LPA/LPA1 pathway antagonist, are both used for treatment decrease in nerve fibre density stains, inhibition as a potential effective new of pulmonary arterial hypertension in including VIP immunostaining and mi- therapeutic strategy for SSc dermal fi- SSc, the study of the effect of these crovascular abnormalities in SSc skin brosis was suggested in a mouse model medications on itch in SSc is indicated. (41). Since itch is most significant in (27). Thus, in addition to fibrosis the early SSc with significant skin involve-

LPA/LPA1 axis may be important in the Neuropeptides ment (42), neuropeptides may have a pruritus of SSc. Neuropeptides from unmyelinated role as a biomarker in SSc or for studies nerve ending may be responsible for of pruritus therapeutic responsiveness. Prostaglandin E (2) itch. The mast cell-nerve functional In sum, neuropeptides can induce the PGE2 is a proinflammatory cytokine, units at sites near unmyelinated nerve release histamine from skin mast cells which is reported to be a potent vasodi- fibres have been associated with- dif and can also directly act as pruritogens. lator and a weak pruritic agent in nor- ferential secretion and degranulation Neuropeptides, such as CGRP, VIP, sP, mal skin and in patients with AD (28). which may explain varying responsive- and ET-1, play an important role in the PGE2 production and the expression of ness to therapeutics used for itch and maintenance of tissue integrity in the cytosolic phospholipase A2 (cPLA2), account for some of the challenge in skin and may serve as potential bio- cyclooxygenase (COX)-1, and COX-2 studying itch (34). As discussed above, marker of itch, as their levels vary with (enzymes that regulate PGE2 produc- once a mast cell degranulates, in addi- itch perception (43, 44). tion) were found to be upregulated in tion to histamine, many other substanc- Temperature mediated itch, through fibroblasts from SSc skin. PGE2 pro- es, such as proteases, lipid mediators, thermosensitive transient receptor po- duction and COX-2 expression were and cytokines are released. These sub- tential (TRP) channels nociceptive inhibited by combined therapy using stances subsequently activate and may neurons are another skin-originating 8-methoxypsoralen and long wave ul- cause further release of neuropeptides, itch mechanism that is independent of traviolet light (PUVA therapy) (29). which enhances tissue damage. Since mast cell activation (45) (46, 47). Di- The beneficial effect of PUVA on itch mast cells can behave as an immune rect mechanical nerve fibre activation in SSc has been suggested and warrants cell, endocrine cell, or even as senso- in the skin, possibly due to a lack of further study (30). rial neurons based on the microenvi- moisture in the skin, is also implicated ronment of damage and mast cells ex- in pruritus associated with aging (48). Endothelin hibit a flexibility and reciprocity with Thus, understanding the neurology of Endothelin-1 (ET-1) is generated by a neuropeptide signaling, which induce itch as it relates to neuropeptides, tem- variety of cell types, including endothe- and sustain pruritus (5, 35). Thus, the perature, and mechanical stimuli, in lial cells, vascular smooth muscle cells, study of neuropeptide induced pruritus, SSc is important. and leukocytes (31). In a study of the especially as it relates to the mast cell, effect of ET-1 in human skin, the vaso- may prove challenging in SSc. Opioid receptors dilator response to ET-1 was found to Nonetheless, an understanding of the Exogenous opioids are recognised pru- be neurogenic in origin (defined as that neuropeptide influence on itch may ritogens (49). Itch or pruritus is evoked by mediated nociceptive fibres) and also have implications for understand- by direct activation of opioid receptors, was in part mediated by the local re- ing SSc pathogenesis as the skin may which have recently been identified in lease of nitric oxide (32). In this study, be the source of both itch and disease the skin (50). These receptors synapse ET-1 was classified as a neuropeptide progression. CRGP is a particularly with the spinal cord, thus are also con- and itch was found to be independent of interesting neuropeptide in its relation- sidered a part of neurogenic itch (12). mast cell-derived histamine (32). While ship to both itch and the vasculopathy Although the sources of itch in SSc are it is recognised that ET-1 signalling is of SSc. Calcitonin related gene peptide unknown, some clues may derive from through specific G-protein-coupled ETA (CRGP) is composed of two separate the information available regarding and ETB receptors, the downstream sig- peptides (CRGPα and CRGPβ), which itch related to opioid receptors in other nalling mediators for itch in humans are nearly identical at an amino acid similar skin diseases, such as hyper- are unknown. ET-1 may induce itch level. CRGPα is known to cause va- trophic scaring (50). Since proinflam- by acting directly on nerve endings, or sodilatation and relaxes smooth muscle matory and profibrogenic cytokines through indirect actions via release of cells (36). It can be administered as are known to play an important role endogenous mediators such as hista- a therapeutic agent in SSc for digital in the itch seen in hypertrophic scars mine from mast cells (33). In mice, data vasculopathy (37). Both substance P and may be modified through modula- supports that ET-1 may signal through (sP) and CGRP can cause mast cell de- tion of opioid receptors, understanding the ET (A) receptor to induce pruritus granulation (38), which can induce and the role of opioid receptors in itch may sensation, while ET (B) receptor may sustain itch. Vasoactive intestinal pep- have relevance to SSc (51). antagonise the pruritus evoked by ET-1 tide (VIP) is another neuropeptide that (33). As endothelin antagonists such as is recognised to contribute to itch (5) The nervous system and itch in SSc bosentan, a non-selective ET(A)/ET(B) and is upregulated in SSc skin (39, 40). In addition to the role of peripher- antagonist and ambrisentan, an ET(A) There is a direct correlation between ally released neuropeptides in itch, the

S-83 REVIEW Understanding itch in SSc to improve QoL / T.M. Frech & M. Baron nervous system plays an important role to thermal, mechanical, or chemical mental stress and depression increase in transmission of these stimuli and in noxious stimuli, providing several pos- pruritus perception (65) and anti-depres- their modulation. As discussed above, sible therapeutic options (56). sants have a role in pruritus manage- the unpleasant sensation that provokes SSc may reduce the number of nerve ment (66). The ability to modulate itch a desire to scratch can originate from endings or make them more sensitive. away from the cutaneous nociception is stimulation of unmyelinated nerve fi- This hypothesis raises the possibil- evidenced by the use of psychosomatic bres in the skin by locally released ity that SSc-itch may be peripherally counseling and food allergen dietary pruritogens. Subsequently, the stimu- neurogenic in nature and may change therapy for refractory pruritus in certain lated pathway acts through synapses over time and with disease severity. A AD individuals (67-69). Therapeutics that pass through the dorsal horn of the reduction of sensory and autonomic in- that act centrally may have implications spinal cord, the contralateral spinotha- nervation in both sclerotic and appar- in SSc-pruritus therapy. Nocturnal pru- lamic tract, the posterolateral ventral ently uninvolved skin has been reported ritus may have a strong psychological thalamic nucleus and then to the so- in SSc (41) with mast cell association component (70). Thus, studies of pruri- matosensory cortex of the post-central early in the pathologic process (57). tus should consider the effects of itch on cingulated gyrus (Fig. 1) (52). As such, Of particular interest, nerve abnormali- mental health and sleep in SSc as well skin pathology, peripheral neuropathy, ties in SSc can improve with improved as the distress of chronic disease on the central nervous system sensitisation, oxygenation of tissue (58). Ultrasound, perception of itch. and the cognito-affective aspects of itch computed tomography, and magnetic must be understood in order to treat it resonance have detected nerve abnor- Therapy of itch effectively (12). The complexity of the malities in 70% of SSc patients com- Anti-histamine transmission of itch is highlighted by plaining of neurologic disturbances in The first line therapy for itch is anti- systemic medical conditions, such as the hands (59). Interestingly, a subset of histamines because of their well known end-stage renal disease, chronic liver cutaneous pruritogen sensitive C-fibres, effect of on urticaria. Anti-histamine disease, and malignancy. These condi- which originate superficially in the skin studies yielded disappointing results tions are associated with itch, which and are insensitive to histamine, high- for many systemic itch conditions may be influenced at various points light that identifying the origin of itch such as uremic pruritus, post-burn in this transmission pathway and have initiation may be critical for choice of pruritus, and cholestatic pruritus (71). proven difficult to study (53, 54). therapy for itch modulation in SSc (48, Anti-histamines do not block the syn- Itch could result form a normal level 60). thesis of histamine or its release from of pruritogen acting on abnormal pe- Independent of skin changes, peripheral mast cells, but work at the histamine ripheral sensors. Thus, pruritus in SSc nerve endings, dorsal root ganglia, the receptor level, which may account could arise either from abnormalities spinal cord and CNS can amplify or for this disappointing result. It is pos- of nerve fibre endings in SSc skin, suppress pruritus over time (61). Upon sible that transduction of chronic itch from the presence of an excess of mast stimulation, cells of the dorsal horn of is through non-histaminergic receptors cells, and/or from the release of local the spinal cord can release sP and CGRP (60). If anti-histamines are ineffective mediators in skin. Like other chronic into peripheral tissues, causing the de- for interrupting nociception, then both inflammatory medical conditions, the granulation of mast cells and influenc- transmission and perception of itch oc- role of chemokines (derived not only ing vascular endothelial cell character- curs. The most plausible explanation from mast cells, but possibly also from istics in the skin (56). This stimulation for chronic itch is that one or more of other peri-vascular immune cells) on could be one central mechanism of itch the many other mast cell mediators re- SSc itch is also of interest. Serum stud- generation. Similarly, neuropeptides leased after various stimuli may also be ies have suggested the association of can act in the spinal cord to increase responsible for itch and are not affected certain chemokines with the severity of synaptic strength between nociceptors by anti-histamines (5, 72, 73). skin involvement in SSc (55). and spinal neurons, which enhances Neuropeptides may be responsible for As discussed above, understanding the symptoms (62). This synaptic strength the perception of itch in patients that role of cutaneous C fibre nerves in SSc has been suggested as important more are nonresponsive to anti-histamines. is an interesting target. Since nocic- central mechanism of itch in chronic Neuropeptide levels of VIP, CRGP, eptors are present in the skin, muscle, disease (63), and may highlight the im- and sP correlate with mast cell load joints, and gastrointestinal tract and re- portance of understanding disease dura- (74). Further, support of the possibil- spond to potentially damaging stimuli tion when studying SSc itch. ity that mediators other than histamine by sending nerve signals to the spinal Lastly, cognitive factors may modulate released from mast cells may be impor- cord and brain, understanding the ac- the perception of itch. Not surprisingly, tant in the itch of SSc, comes from a tivation of itch pathways in this multi- psychiatric or psychosomatic conditions study of ketotifen. The mast cell-stabi- organ disease may prove challenging. are thought to significantly contribute to lising drug ketotifen was studied in a Nonetheless, the initiation of the sensa- pruritus and highlight the complexity of randomised, prospective, double blind, tion of itch and its modulation can oc- itch perception (64). While pruritogens placebo-controlled trial in 24 SSc pa- cur at various sites of origin in response are not well defined in psychiatric itch, tients. While no significant improve-

S-84 Understanding itch in SSc to improve QoL / T.M. Frech & M. Baron REVIEW ments in the clinical parameters, pul- nism of action (81). Phototherapy has more centrally. Double blind, placebo monary function, global assessments, been shown to reduce the number of controlled trials are needed to deter- and mast cell release were noted, pruri- CGRP-immunoreactive nerve fibres mine optimal dosing of MOR antago- tus tended to improve in the group tak- (82). Since the modulation effect is nists in SSc, as low dose naltrexone has ing the active drug. These results were thought to be peripheral without unto- virtually no reported adverse effects. based on a small sample size therefore ward central nervous system effects, Naltrexone is a MOR antagonist pri- they are suggestive not definitive. it is an attractive therapeutic option to marily used in management of alco- study in SSc. Additionally, the effects hol and opioid dependence. It has also Gabapentin of phototherapy on VIP and gastrointes- been used off-label to treat cancer and As conventional treatment modalities tinal tract symptoms have been reported autoimmune disease (94). Low dose such as antihistamines lack efficacy, (83). The potential effect of photother- naltrexone (LDN), 4.5 mg or less taken new therapeutic strategies, which affect apy on neurogenic inflammation in SSc at night may inhibit cell proliferation, the neuronal mechanisms underlying warrants further research. reduces inducible nitric oxide synthase chronic pruritus, have been suggested activity, decrease apoptosis of oligo- (8). Gabapentin, an anticonvulsant and Opioid modulation dendrocytes, and inhibits activation gamma-aminobutyric acid agonist, has – μ-opioid antagonists of mast cells (95, 96). Through these both central and peripheral effects on A number of skin cell types, including mechanisms it is hypothesised that pruritus. It impedes transmitting no- dermal mast cells, keratinocytes, fibro- LDN may modulate neuropathic and/ ciceptive sensations to the brain, thus blasts and macrophages express MOR or neurogenic itch (54, 97). Pilot trials suppressing pruritus. Its effect on pru- as well as other opioid receptors (84). of LDN for pruritus, pain, and quality ritus is mediated through inhibition of Activation of MOR in the skin elicits of life (QOL) in gastrointestinal tract CRGP, modulation of μ-opioid recep- pruritus and inflammation, while acti- diseases have also been successful (98, tors (MOR), and it has an acute inhibi- vation of cutaneous κ-opioid receptors 99). However, the site of action, mini- tory effect on sP (76). Gabapentin is has an anti-pruritic effect (84). Cen- mal effective dosing, and preferable safe and found to be effective in uremic tral versus peripheral site activation is route of LDN administration are yet to pruritus, cancer/haematologic causes, proposed as a potential mechanism for be confirmed (100, 101). opioid-induced itch, post-burn pruri- opioid induced itch and its modulation, tus, as well as pruritus of unknown ori- with μ- and κ-opioid receptor agonists – κ-opioid agonists gin (77). Further research may be war- acting synergistically for analgesia, but Nalfurafine hydrochloride is a selective ranted to establish whether gabapentin inversely in terms of pruritic properties kappa-opioid receptor agonist and has influences mast cell-induced pruritus (85). Thus, central MOR act to reduce a potent antipruritic effect on uremic and its potential utility in SSc. primary nocireceptor activity (85). Un- pruritus through central kappa-opioid like anti-histamines, which act at the receptor activation in non-clinical phar- Phototherapy tissue level, MOR may influence a macological studies (102). Nalfurafine Phototherapy with ultraviolet (UV) central perception of the effect caused (a potent κ-receptor agonist) reduced light on the skin has proven useful for by mast cell degranulation. This high- itch in a meta-analysis of two ran- treating a number of chronic inflam- lights that identification of both the domised, double blind, placebo- con- matory, sclerosing, and neoplastic skin duration as well as the source of itch trolled studies of uremic pruritus (103, diseases. Research suggests that this in SSc is important to understand its 104). While statistical significance was effect is via its immunomodulating ac- proper treatment. shown, clinical efficacy on pruritus tions, including apoptosis of infiltrating This mechanism of MOR antagonism was only modest (103). More research T-cells, suppression of cytokine levels, is of interest in SSc because MOR in SSc and PBC is needed to evaluate and reduction in Langerhans and mast antagonists have been studied in pri- dosing and the long-term safety and cell numbers (78). The therapeutic ef- mary biliary cirrhosis (PBC), another efficacy of nalfurafine, as well as to fect is related to the dose (low, medium, disease that can occur in SSc patients define its role on mast cells (105). As high), wavelength (UVA: 320–400 nm; and is characterised by pruritus. (86- κ-receptor agonists have been shown to UVB 320–290 nm) penetration of the 88). The therapeutic effects of MOR produce peripheral antinociceptive ef- skin, and use with concurrent therapies antagonists, naloxone, naltrexone, and fects in inflamed subcutaneous tissues (i.e. psoralen or PUVA). Pertinent to nalmefene have been studied in PBC (106), these agents may be particularly SSc, is that phototherapy may modulate and cholestatic pruritus (89-93). In appropriate for SSc whose itch is asso- endothelial dysfunction (vasculopathy) general, agreement exists that MOR is ciated with erythematous or warm skin. (79). Furthermore, UVA1 phototherapy effective. Unlike antihistamines, which reduces the density of dermal mast cells act on a single component of mast – Mixed κ-opioid agonistic and and pruritus (80). Chemical modifica- cells degranulation and are targeted at µ-antagonistic tions of pruritogens in the skin or al- a peripheral level, MOR antagonists Butorphanol is a drug that exhibits both tered skin sensitivity to pruritogens are may influence additional neuropeptide κ-agonistic and μ-antagonistic proper- proposed as another potential mecha- perception both at the dorsal horn and ties, thus combining the beneficial ef-

S-85 REVIEW Understanding itch in SSc to improve QoL / T.M. Frech & M. Baron fects of the previous mentioned drug Conclusion 3. CHEN SC: Pruritus. Dermatol Clin 2012; 30: classes. A study of CRGP and vasodi- Pruritus is a common but under-rec- 309-21, ix. 4. IKOMA A, CEVIKBAS F, KEMPKES C, STEIN- lation has suggested a potential effect ognised symptom in SSc. It has an HOFF M: Anatomy and neurophysiology of on the neuro-vascular axis (107). Bu- important influence on quality of life. pruritus. Semin Cutan Med Surg 2011; 30: torphanol appeared to be effective in 5 The close physical relationship of mast 64-70. patients with intractable itch associated cells to both vessels and nerves that 5. METZ M, GRUNDMANN S, STANDER S: Pruritus: an overview of current concepts. with various systemic or inflammatory is reported in SSc may play a role in Vet Dermatol 2011; 22: 121-31. skin diseases (108). This study had lim- disease pathogenesis and pruritus (57, 6. PAUS R, SCHMELZ M, BIRO T, STEINHOFF itations including a small sample size 111, 112). In other systemic diseases M: Frontiers in pruritus research: scratching the brain for more effective itch therapy. and open-label design; consequently, characterised by neurogenic itch, such J Clin Invest 2006; 116: 1174-86. further larger-scale, randomised, con- as post-burn, cholestatic liver disease 7. STEINHOFF M, CEVIKBAS F, IKOMA A, trolled trials are needed. Importantly, and uremia, anti-histamines are usu- BERGER TG: Pruritus: management algo- its effect is primarily through the cen- ally ineffective, possibly due to other rithms and experimental therapies. Semin Cutan Med Surg 2011; 30: 127-37. tral nervous system, thus it has the mediators besides histamine which are 8. STANDER S, WEISSHAAR E, LUGER TA: potential untoward side effects of res- released from mast cells and modulate Neurophysiological and neurochemical ba- piratory depression and stimulation of perception of itch. sis of modern pruritus treatment. Exp Der- the emetic center, which are not ideal In these anti-histamine refractory dis- matol 2008; 17: 161-9. 9. IKOMA A, FARTASCH M, HEYER G, MI- for SSc patients. Thus, like MOR an- eases, neuropeptides may be impor- YACHI Y, HANDWERKER H, SCHMELZ M: tagonist, optimal dosing clarification is tant and a neuropathic/neurogenic ap- Painful stimuli evoke itch in patients with critical. It has low oral and nasal bio- proach is often necessary for pruritus chronic pruritus: central sensitization for availability due to extensive first-pass relief. While gabapentin, μ-opioid itch. Neurology 2004; 62: 212-7. 10. HANIFIN JM: Pharmacophysiology of atopic metabolism, however intramuscular antagonists, κ-opioid agonists, mixed dermatitis. Clin Rev Allergy 1986; 4: 43-65. and intravenous dosing is not practical κ-opioid agonistic and μ-antagonistic, 11. ZHANG H, YANG Y, CUI J, ZHANG Y: Gain- for outpatient management of pruritus. and phototherapy are under investiga- ing a comprehensive understanding of pru- Topical formulations have been studied tion in many of these conditions, the ritus. Indian J Dermatol Venereol Leprol 2012; 78: 532-44. in rats, and may hold promise for hu- use of these agents in SSc is an attrac- 12. TEY HL, YOSIPOVITCH G: Targeted treat- mans (109). Nonetheless, due to its po- tive concept. Nonetheless the use of ment of pruritus: a look into the future. Br J tential modulation of both central and these agents for treatment of itch in Dermatol 2011; 165: 5-17. 13. FALANGA V, SOTER NA, ALTMAN RD, peripheral itch perception, influence SSc is unaccompanied by clear dosing KERDEL FA: Elevated plasma histamine lev- on mast cells, and purported effects guidelines, particularly with regards to els in systemic sclerosis (scleroderma). Arch on both pruritus and gastrointestinal LDN. Additionally, central nervous Dermatol 1990; 126: 336-8. symptoms, it is of interest in treatment system effects of opioid antagonists 14. PAPOIU AD, WANG H, NATTKEMPER L et al.: A study of serum concentrations and of pruritus in SSc. must be taken seriously particularly as dermal levels of NGF in atopic dermatitis they relate to the respiratory and gas- and healthy subjects. Neuropeptides 2011; Treatment of pruritus in SSc trointestinal tract (113). These poten- 45: 417-22. To our knowledge there has been only tial side effects are particularly impor- 15. ROSSBACH K, NASSENSTEIN C, GSCHWANDTNER M et al.: Histamine H1, one publication reporting the results of tant as the main goal for pruritus man- H3 and H4 receptors are involved in pruri- treatment of pruritus in SSc exists. In agement is improving patient quality of tus. Neuroscience 2011; 190: 89-102. our case series, three SSc patients that life. Clinical trial design for pruritus in 16. BAUMER W, WENDORFF S, GUTZMER R et had failed anti-histamines, had a signif- SSc should focus on quality of life out- al.: Histamine H4 receptors modulate dendritic cell migration through skin--immu- icant improvement with LDN in pruri- comes and should include mechanistic nomodulatory role of histamine. Allergy tus as measured by the 10-point faces studies to better clarify the pathogen- 2008; 63: 1387-94. (110). This small case series suggests esis of SSc related pruritus as it relates 17. HANDWERKER HO: Microneurography of LDN may potentially be an effective, to the vasculopathy and fibrosis and the pruritus. Neurosci Lett 2010; 470: 193-6. 18. IKOMA A, STEINHOFF M, STANDER S, YO- highly tolerable, and inexpensive treat- complex interplay of pruritogens, their SIPOVITCH G, SCHMELZ M: The neurobiol- ment for pruritus in SSc. In the one pa- receptors, and neural pathways. ogy of itch. Nat Rev Neurosci 2006; 7: 535- tient in this small case series who was 47. 19. SCHMELZ M, SCHMIDT R, WEIDNER C, re-biopsied after 6 months of therapy, References HILLIGES M, TOREBJORK HE, HANDWERK- the decrease in perivascular mast cells 1. RAZYKOV I, THOMBS BD, HUDSON M, BAS- ER HO: Chemical response pattern of differ- was the most significant feature found SEL M, BARON M and the Canadian Scle- ent classes of C-nociceptors to pruritogens roderma Research Group: Prevalence by microscopic evaluation. Thus, while and algogens. J Neurophysiol 2003; 89: and clinical correlates of pruritus in patients 2441-8. the etiology of pruritus in SSc is un- with systemic sclerosis. Arthritis Rheum 20. STONE KD, PRUSSIN C, METCALFE DD: clear, the role of opioid influence on 2009; 61: 1765-70. IgE, mast cells, basophils, and eosinophils. mast cells is intriguing. Furthermore, 2. El-BAALBAKI G, RAZYKOV I, HUDSON M J Allergy Clin Immunol 2010; 125 (Suppl. et al.: The association of pruritus with qual- this pilot study suggested its effects on 2): S73-80. ity of life and disability in systemic sclero- 21. SIGAL LH: Basic science for the clinician GIT symptoms might warrant further sis. Arthritis Care Res (Hoboken) 2010; 62: 53: mast cells. J Clin Rheumatol 2011; 17: investigation. 1489-95. 395-400.

S-86 Understanding itch in SSc to improve QoL / T.M. Frech & M. Baron REVIEW

22. GOTTWALD T, COERPER S, SCHAFFER M, 38. FOREMAN JC: Substance P and calcitonin SSc clnical features and the effect of pros- KOVEKER G, STEAD RH: The mast cell- gene-related peptide: effects on mast cells taglandin E1 treatment. Clin Exp Rheumatol nerve axis in wound healing: a hypothesis. and in human skin. Int Arch Allergy Appl 2012; 30 (Suppl. 71): S44-9. Wound Repair Regen 1998; 6: 8-20. Immunol 1987; 82: 366-71. 56. McCOY ES, TAYLOR-BLAKE B, ZYLKA MJ: 23. TSAI JC, FEINGOLD KR, CRUMRINE D, 39. MATUCCI-CERINIC M, GIACOMELLI R, CGRPalpha-expressing sensory neurons WOOD LC, GRUNFELD C, ELIAS PM: Perme- PIGNONE A et al.: Nerve growth factor and respond to stimuli that evoke sensations of ability barrier disruption alters the localiza- neuropeptides circulating levels in systemic pain and itch. PLoS One 2012; 7: e36355. tion and expression of TNF alpha/protein sclerosis (scleroderma). Ann Rheum Dis 57. MALANDRINI A, SELVI E, VILLANOVA M et in the epidermis. Arch Dermatol Res 1994; 2001; 60: 487-94. al.: Autonomic nervous system and smooth 286: 242-8. 40. TERENGHI G, BUNKER CB, LIU YF et al.: muscle cell involvement in systemic sclero- 24. BOT M, de JAGER SC, MACALEESE L et al.: Image analysis quantification of peptide-im- sis: ultrastructural study of 3 cases. J Rheu- Lysophosphatidic Acid Triggers Mast Cell- munoreactive nerves in the skin of patients matol 2000; 27: 1203-6. driven Atherosclerotic Plaque Destabiliza- with Raynaud’s phenomenon and systemic 58. PROVITERA V, NOLANO M, PAPPONE N et tion by Increasing Vascular Inflammation. sclerosis. J Pathol 1991; 164: 245-52. al.: Axonal degeneration in systemic scle- J Lipid Res 2013. 41. PROVITERA V, NOLANO M, PAPPONE N et rosis can be reverted by factors improving 25. OUDE ELFERINK RP, KREMER AE, BEUERS al.: Distal degeneration of sensory and au- tissue oxygenation. Rheumatology (Oxford) U: Mediators of pruritus during cholestasis. tonomic cutaneous nerve fibres in systemic 2007; 46: 1739-41. Curr Opin Gastroenterol 2011; 27: 289-93. sclerosis. Ann Rheum Dis 2005; 64: 1524-6. 59. MANETTI M, MILIA AF, BENELLI G, MES- 26. TOKUMURA A, CARBONE LD, YOSHIOKA 42. RAZYKOV I, THOMBS BD, HUDSON M, SERINI L, MATUCCI-CERINIC M, IBBA- Y et al.: Elevated serum levels of arachi- BASSEL M, BARON M: Prevalence and clini- MANNESCHI L: The gastric wall in systemic donoyl-lysophosphatidic acid and sphingo- cal correlates of pruritus in patients with sclerosis patients: a morphological study. sine 1-phosphate in systemic sclerosis. Int J systemic sclerosis. Arthritis Rheum 2009; Ital J Anat Embryol 2010; 115: 115-21. Med Sci 2009; 6: 168-76. 61: 1765-70. 60. JOHANEK LM, MEYER RA, FRIEDMAN RM 27. CASTELINO FV, SEIDERS J, BAIN G et al.: 43. LUGER TA: Neuromediators--a crucial com- et al.: A role for polymodal C-fiber afferents Amelioration of dermal fibrosis by genetic ponent of the skin immune system. J Der- in nonhistaminergic itch. J Neurosci 2008; deletion or pharmacologic antagonism of matol Sci 2002; 30: 87-93. 28: 7659-69. lysophosphatidic acid receptor 1 in a mouse 44. LEE CH, YU HS: Biomarkers for itch and 61. BUDDENKOTTE J, STEINHOFF M: Patho- model of scleroderma. Arthritis Rheum disease severity in atopic dermatitis. Curr physiology and therapy of pruritus in aller- 2011; 63: 1405-15. Probl Dermatol 2011; 41: 136-48. gic and atopic diseases. Allergy 2010; 65: 28. NEISIUS U, OLSSON R, RUKWIED R, LIS- 45. BIRO T, TOTH BI, MARINCSAK R, DOBROSI 805-21. CHETZKI G, SCHMELZ M: Prostaglandin E2 N, GECZY T, PAUS R: TRP channels as novel 62. SEYBOLD VS: The role of peptides in central induces vasodilation and pruritus, but no players in the pathogenesis and therapy of sensitization. Handb Exp Pharmacol 2009; protein extravasation in atopic dermatitis itch. Biochim Biophys Acta 2007; 1772: 194: 451-91. and controls. J Am Acad Dermatol 2002; 47: 1004-21. 63. GREAVES MW, KHALIFA N: Itch: more than 28-32. 46. HAGERMARK O: Peripheral and central me- skin deep. Int Arch Allergy Immunol 2004; 29. KANEKURA T, HIGASHI Y, KANZAKI T: Cy- diators of itch. Skin Pharmacol 1992; 5: 1-8. 135: 166-72. clooxygenase-2 expression and prostaglan- 47. ZEGARSKA B, LELINSKA A, TYRAKOWSKI 64. FERM I, STERNER M, WALLENGREN J: din E2 biosynthesis are enhanced in scle- T: Clinical and experimental aspects of cuta- Somatic and psychiatric comorbidity in pa- roderma fibroblasts and inhibited by UVA neous neurogenic inflammation. Pharmacol tients with chronic pruritus. Acta Derm Ve- irradiation. J Rheumatol 2001; 28: 1568-72. Rep 2006; 58: 13-21. nereol. 2010; 90(4): 395-400. 30. KROFT EB, BERKHOF NJ, van de KERKHOF 48. TWYCROSS R, GREAVES MW, HANDWERK- 65. KRISHNAN A, KOO J: Psyche, opioids, and PC, GERRITSEN RM, de JONG EM: Ultravio- ER H et al.: Itch: scratching more than the itch: therapeutic consequences. Dermatol let A phototherapy for sclerotic skin diseas- surface. QJM 2003; 96: 7-26. Ther 2005; 18: 314-22. es: a systematic review. J Am Acad Derma- 49. FRIEDMAN JD, DELLO BUONO FA: Opioid 66. STANDER S, WEISSHAAR E: Medical treat- tol 2008; 59: 1017-30. antagonists in the treatment of opioid-in- ment of pruritus. Expert Opin Emerg Drugs 31. STANDER S, SCHMELZ M: Chronic itch and duced constipation and pruritus. Ann Phar- 2012; 17: 335-45. pain--similarities and differences. Eur J macother 2001; 35: 85-91. 67. MAGERL M, PISAREVSKAJA D, SCHEUFELE Pain 2006; 10: 473-8. 50. CHENG B, LIU HW, FU XB: Update on pru- R, ZUBERBIER T, MAURER M: Effects of a 32. KATUGAMPOLA R, CHURCH MK, CLOUGH ritic mechanisms of hypertrophic scars in pseudoallergen-free diet on chronic sponta- GF: The neurogenic vasodilator response to postburn patients: the potential role of opi- neous urticaria: a prospective trial. Allergy endothelin-1: a study in human skin in vivo. oids and their receptors. J Burn Care Res 2010; 65: 78-83. Exp Physiol 2000; 85: 839-46. 2011; 32: e118-25. 68. RING J, ALOMAR A, BIEBER T et al.: Guide- 33. LIANG J, KAWAMATA T, JI W: Molecular 51. SALGADO RM, ALCANTARA L, MENDO- lines for treatment of atopic eczema (atopic signaling of pruritus induced by endothe- ZA-RODRIGUEZ CA et al.: Post-burn hy- dermatitis) part I. J Eur Acad Dermatol lin-1 in mice. Exp Biol Med (Maywood) pertrophic scars are characterized by high Venereol 2012; 26: 1045-60. 2010; 235: 1300-5. levels of IL-1beta mRNA and protein and 69. RING J, ALOMAR A, BIEBER T et al.: Guide- 34. FORSYTHE P, BIENENSTOCK J: The mast TNF-alpha type I receptors. Burns 2012; 38: lines for treatment of atopic eczema (atopic cell-nerve functional unit: a key component 668-76. dermatitis) Part II. J Eur Acad Dermatol of physiologic and pathophysiologic re- 52. MELA M, MANCUSO A, BURROUGHS AK: Venereol 2012; 26: 1176-93. sponses. Chem Immunol Allergy 2012; 98: Review article: pruritus in cholestatic and 70. PATEL T, ISHIUJI Y, YOSIPOVITCH G: Noc- 196-221. other liver diseases. Aliment Pharmacol turnal itch: why do we itch at night? Acta 35. TORE F, TUNCEL N: Mast cells: target and Ther 2003; 17: 857-70. Derm Venereol 2007; 87: 295-8. source of neuropeptides. Curr Pharm Des 53. BUENSE R, DUARTE IA, BOUER M: Local- 71. RAAP U, STANDER S, METZ M: Pathophysi- 2009; 15: 3433-45. ized scleroderma: assessment of the thera- ology of itch and new treatments. Curr Opin 36. BENEMEI S, NICOLETTI P, CAPONE JG, De peutic response to phototherapy. An Bras Allergy Clin Immunol 2011; 11: 420-7. CESARIS F, GEPPETTI P: Migraine. Handb Dermatol 2012; 87: 63-9. 72. METZ M, LAMMEL V, GIBBS BF, MAURER Exp Pharmacol 2009; 194: 75-89. 54. GREAVES MW: Recent advances in patho- M: Inflammatory murine skin responses to 37. NIHTYANOVA SI, BROUGH GM, BLACK CM, physiology and current management of itch. UVB light are partially dependent on en- DENTON CP: Clinical burden of digital vas- Ann Acad Med Singapore 2007; 36: 788-92. dothelin-1 and mast cells. Am J Pathol 2006; culopathy in limited and diffuse cutaneous 55. BANDINELLI F, Del ROSSO A, GABRIELLI A 169: 815-22. systemic sclerosis. Ann Rheum Dis 2008; et al.: CCL2, CCL3, and CCL5 chemokines 73. CUOMO R, D’ALESSANDRO A, ANDREOZZI 67: 120-3. in systemic sclerosis: the correlation with P, VOZZELLA L, SARNELLI G: Gastrointes-

S-87 REVIEW Understanding itch in SSc to improve QoL / T.M. Frech & M. Baron

tinal regulation of food intake: do gut mo- MIYACHI Y: Immunological features of pa- a quantitative systematic review of rand- tility, enteric nerves and entero-hormones tients with primary biliary cirrhosis (PBC) omized trials. Eur J Anaesthesiol 2001; 18: play together? Minerva Endocrinol 2011; overlapping systemic sclerosis: a compari- 346-57. 36: 281-93. son with patients with PBC alone. J Gastro- 102. NAKAO K, MOCHIZUKI H: Nalfurafine -hy 74. MAINTZ L, WARDELMANN E, WALGEN- enterol Hepatol 1998; 13: 897-901. drochloride: a new drug for the treatment BACH K et al.: Neuropeptide blood levels 89. BERGASA NV, TALBOT TL, ALLING DW of uremic pruritus in hemodialysis patients. correlate with mast cell load in patients with et al.: A controlled trial of naloxone infu- Drugs Today (Barc) 2009; 45: 323-9. mastocytosis. Allergy 2011; 66: 862-9. sions for the pruritus of chronic cholestasis. 103. WIKSTROM B, GELLERT R, LADEFOGED SD 75. GRUBER BL, KAUFMAN LD: A double-blind Gastroenterology 1992; 102: 544-9. et al.: Kappa-opioid system in uremic pruri- randomized controlled trial of ketotifen ver- 90. BERGASA NV, ALLING DW, TALBOT TL et tus: multicenter, randomized, double-blind, sus placebo in early diffuse scleroderma. al.: Effects of naloxone infusions in patients placebo-controlled clinical studies. J Am Arthritis Rheum 1991; 34: 362-6. with the pruritus of cholestasis. A double- Soc Nephrol 2005; 16: 3742-7. 76. TAKASUSUKI T, YAKSH TL: The effects of blind, randomized, controlled trial. Ann 104. KUMAGAI H, EBATA T, TAKAMORI K, intrathecal and systemic gabapentin on spi- Intern Med 1995; 123: 161-7. MURAMATSU T, NAKAMOTO H, SUZUKI H: nal substance P release. Anesth Analg 2011; 91. CARSON KL, TRAN TT, COTTON P, SHA- Effect of a novel kappa-receptor agonist, 112: 971-6. RARA AI, HUNT CM: Pilot study of the use nalfurafine hydrochloride, on severe itch in 77. ANAND S: Gabapentin for pruritus in pallia- of naltrexone to treat the severe pruritus 337 haemodialysis patients: a Phase III, ran- tive care. Am J Hosp Palliat Care 2012. of cholestatic liver disease. Am J Gastro- domized, double-blind, placebo-controlled 78. DAWE RS: Ultraviolet A1 phototherapy. Br J enterol 1996; 91: 1022-3. study. Nephrol Dial Transplant 2010; 25: Dermatol 2003; 148: 626-37. 92. BERGASA NV, SCHMITT JM, TALBOT TL et 1251-7. 79. BREUCKMANN F, STUECKER M, ALTMEY- al.: Open-label trial of oral nalmefene ther- 105. NARITA I, IGUCHI S, OMORI K, GEJYO F: ER P, KREUTER A: Modulation of endothe- apy for the pruritus of cholestasis. Hepatol- Uremic pruritus in chronic hemodialysis pa- lial dysfunction and apoptosis: UVA1-medi- ogy 1998; 27: 679-84. tients. J Nephrol 2008; 21: 161-5. ated skin improvement in systemic sclero- 93. TERG R, CORONEL E, SORDA J, MUNOZ AE, 106. HASSAN AH, PZEWLOCKI R, HERZ A, STEIN sis. Arch Dermatol Res 2004; 296: 235-9. FINDOR J: Efficacy and safety of oral nal- C: Dynorphin, a preferential ligand for 80. GOBELLO T, MAZZANTI C, SORDI D et al.: trexone treatment for pruritus of cholestasis, kappa-opioid receptors, is present in nerve Medium- versus high-dose ultraviolet A1 a crossover, double blind, placebo-con- fibers and immune cells within inflamed tis- therapy for urticaria pigmentosa: a pilot trolled study. J Hepatol 2002; 37: 717-22. sue of the rat. Neurosci Lett 1992; 140: 85- study. J Am Acad Dermatol 2003; 49: 679- 94. Low-dose naltrexone: tricking the body to 8. 84. heal itself. Exp Biol Med (Maywood) 2011; 107. WILLIAMSON DJ, SHEPHEARD SL, COOK 81. KREMER AE, BEUERS U, OUDE-ELFERINK 236: vii-viii. DA, HARGREAVES RJ, HILL RG, CUMBER- RP, PUSL T: Pathogenesis and treatment of 95. AGRAWAL YP: Low dose naltrexone therapy BATCH MJ: Role of opioid receptors in neu- pruritus in cholestasis. Drugs 2008; 68: in multiple sclerosis. Med Hypotheses 2005; rogenic dural vasodilation and sensitization 2163-82. 64: 721-4. of trigeminal neurones in anaesthetized rats. 82. WALLENGREN J, SUNDLER F: Photother- 96. DONAHUE RN, McLAUGHLIN PJ, ZAGON Br J Pharmacol 2001; 133: 807-14. apy reduces the number of epidermal and IS: Low-dose naltrexone targets the opioid 108. DAWN AG, YOSIPOVITCH G: Butorphanol CGRP-positive dermal nerve fibres. Acta growth factor-opioid growth factor receptor for treatment of intractable pruritus. J Am Derm Venereol 2004; 84: 111-5. pathway to inhibit cell proliferation: mecha- Acad Dermatol 2006; 54: 527-31. 83. GOUNARIS A, ALEXIOU N, COSTALOS C, nistic evidence from a tissue culture model. 109. LIM GJ, ISHIUJI Y, DAWN A et al.: In vitro DANIILIDOU M, BAKOLEAS V, CONSTAN- Exp Biol Med (Maywood) 2011; 236: 1036- and in vivo characterization of a novel li- TELLOU E: Gut hormone levels in neonates 50. posomal butorphanol formulation for treat- under phototherapy. Early Hum Dev 1998; 97. MIYAMOTO T, NOJIMA H, KURAISHI Y: ment of pruritus. Acta Derm Venereol 2008; 51: 57-60. Intradermal cholinergic agonists induce 88: 327-30. 84. REICH A, SZEPIETOWSKI JC: Non-analgesic itch-associated response via M3 muscarinic 110. FRECH T, NOVAK K, REVELO MP et al.: effects of opioids: Peripheral opioid recep- acetylcholine receptors in mice. Jpn J Phar- Low-dose naltrexone for pruritus in sys- tors as promising targets for future anti-pru- macol 2002; 88: 351-4. temic sclerosis. Int J Rheumatol 2011; 2011: ritic therapies. Curr Pharm Des 2012. 98. SMITH JP, STOCK H, BINGAMAN S, 804296. 85. KO MC, SONG MS, EDWARDS T, LEE H, MAUGER D, ROGOSNITZKY M, ZAGON IS: 111. HAWKINS RA, CLAMAN HN, CLARK RA, NAUGHTON NN: The role of central mu Low- dose naltrexone therapy improves STEIGERWALD JC: Increased dermal mast opioid receptors in opioid-induced itch in active Crohn’s disease. Am J Gastroenterol cell populations in progressive systemic primates. J Pharmacol Exp Ther 2004; 310: 2007; 102: 820-8. sclerosis: a link in chronic fibrosis? Ann In- 169-76. 99. KARIV R, TIOMNY E, GRENSHPON R et al.: tern Med 1985; 102: 182-6. 86. REYNOLDS TB, DENISON EK, FRANKL HD, Low-dose naltreoxone for the treatment of 112. BAE S, SAGGAR R, BOLSTER MB et al.: LIEBERMAN FL, PETERS RL: Primary bil- irritable bowel syndrome: a pilot study. Dig Baseline characteristics and follow-up in iary cirrhosis with scleroderma, Raynaud’s Dis Sci 2006; 51: 2128-33. patients with normal haemodynamics versus phenomenon and telangiectasia. New syn- 100. MILLER JL, HAGEMANN TM: Use of pure borderline mean pulmonary arterial pres- drome. Am J Med 1971; 50: 302-12. opioid antagonists for management of sure in systemic sclerosis: results from the 87. MURRAY-LYON IM, THOMPSON RP, ANSELL opioid-induced pruritus. Am J Health Syst PHAROS registry. Ann Rheum Dis 2012. ID, WILLIAMS R: Scleroderma and primary Pharm 2011; 68: 1419-25. 113. HEYER GR, HORNSTEIN OP: Recent studies biliary cirrhosis. Br Med J 1970; 3: 258-9. 101. KJELLBERG F, TRAMER MR: Pharmaco- of cutaneous nociception in atopic and non- 88. AKIMOTO S, ISHIKAWA O, TAKAGI H, logical control of opioid-induced pruritus: atopic subjects. J Dermatol 1999; 26: 77-86.

S-88