BJD
Correspondence
British Journal of Dermatology
Capsaicin 8% cutaneous patch: a promising treatment for brachioradial pruritus? DOI: 10.1111/bjd.13501 DEAR EDITOR, We would like to report on successful treatment of brachioradial pruritus (BRP) with a single application of a high-dose capsaicin patch. Five patients (four women; 54– 69 years old) had been suffering from BRP, confirmed by magnetic resonance tomography, for 72 months (median). The intraepidermal nerve fibre density (IENF) in itchy skin was reduced (44 11 fibres mm 1) compared with their intraindividual nonlesional IENF (174 102 fibres mm 1) (P < 005). Pruritus intensity on the visual analogue scale (VAS, range 0–100) ranged from 50 to 80 (average 64 114 points; median 65); pain intensity on the VAS ranged from 5 to 90 (average 58 333 points; median 65). Dermatological examinations showed scratch lesions in dermatomes C5/C6 in all patients.
As previous therapies with anticonvulsants (n = 3) and nonspecific therapies (antihistamines, n = 2) failed, we stopped the medication and in all patients applied the topical capsaicin 8% patch (Qutenzaâ), with each patch containing a total of 179 mg capsaicin (640 lg cm 2). The patch was applied exactly to the itchy area for 60 min (Fig. 1) after pretreatment with topical lidocaine 25% containing emollient for 60 min. All patients reported burning pain during the application which lasted for up to 12 h (average 52 40 h; median 4 h). Directly after removal of the patch, the skin showed self-limited erythema. As shown in Figure 2, 3 weeks after a single treatment with no other therapy, pruritus intensity was dramatically reduced to 9 points (SD 89; median 10; P = 0002). The mean itch reduction was 85% (SD 136%) measured by a dynamic score (100% = complete relief). Pain intensity reduced to an average of 6 points (SD 89; median, 0 points; P = 003). Patients reported improvement starting the day after treatment with capsaicin. The quality of life as measured by the
(a)
(b)
(a)
(b)
Fig 1. Brachioradial pruritus before and directly after capsaicin patch application. (a) Before treatment. (b) Transient erythema directly after treatment.
Fig 2. Pain (a) and pruritus (b) intensities (average SD value, Visual Analogue Scale) before and after a single application of capsaicin patch. © 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1669–1689
1669
1670 Correspondence
Dermatology Life Quality Index improved from 114 80 points (very large effect on quality of life) to 50 37 (small effect) without being significant. Three months after a single application, reduction of itch and pain intensity was still significant (itch: average VAS 8 131 points; median 0; P = 0002; mean itch reduction 89 167%; pain: average VAS 4 89; median 0; P = 0015) (Fig. 2). Quality of life values were nearly the same as they were 3 weeks after treatment. BRP is a localized neuropathic syndrome consisting of itch and pain.1 It occurs usually on the dorsolateral part of the forearms, corresponding to dermatomes C5/C6. The primary causes of BRP are believed to be compressions of the cervical spinal cord.2 Accordingly, the most effective reported treatments are the anticonvulsants gabapentin and pregabalin, and even antidepressants have been used in the treatment of BRP.3 However, not all patients experience complete remission under systemic therapy4 and some suffer from a variety of side-effects. Morphological studies demonstrated damaged and degenerated skin nerves resulting in a reduced total IENF density in BRP;5 this was the case in our patients. It is still not clear if the damaged skin nerves are a consequence of central nerve fibre compressions, which produce smaller amounts of neurotrophins and neuropeptides to be transported to the periphery, or are secondary to trauma, such as mechanical irritation by scratching.6 Capsaicin is derived from plants of the genus Capsicum and binds to the transient receptor potential ion channel vanilloid 1 (TRPV1) on cutaneous histamine-sensitive and mechanosensitive C- and Ad-fibres. Continuous topical application of capsaicin results in defunctionalization of the TRPV1 and inhibition of the generation of itch and pain.7,8 There are several hypotheses on the exact mode of action of high capsaicin concentrations on skin nerves9 including the inactivation of voltage-gated Na+ channels, overwhelming of intracellular Ca2+ buffering capacity with subsequent cytoskeleton breakdown, and interruption of fast axonal transport by activation of calcium-dependent proteases.8 Furthermore, it has been proposed that loss of mitochondrial function may render affected nerve processes unable to maintain plasma membrane integrity and thus cause collapse of nerve endings at depth.8 The exact mechanism of action of capsaicin in BRP is unknown, but is has proved effective as continuous cream application and, as shown here, as a single 8% patch application in pruritus. Previously, effects were shown in neuropathic pain.10–12 BRP is believed to be the result of initial damage to the cervical spinal cord; however, our data argue for an important role of the peripheral nerves in BRP. By eradication of the diseased epidermal nerves and regrowth of anatomically normal nerves,13,14 normal function can be restored, which would hinder the development of itch and pain symptoms. In summary, a single application of the high-concentration capsaicin patch led to a quick and long-lasting relief of itch and pain in patients with BRP. The reports of our British Journal of Dermatology (2015) 172, pp1669–1689
patients were congruent; all experienced relief starting the day after therapy. Similar results were observed in a 65-year woman suffering from BRP and treated with a capsaicin patch.15 This underlines once more using a 8% capsaicin patch is a promising, though expensive, new treatment strategy for BRP (€340/patch). More data from randomized controlled trials are needed to determine the long-term effect and to better understand the underlying mechanisms of the effect. 1
Department of Dermatology, Competence Center Chronic Pruritus, and 2Institute for Medical Informatics, University Hospital of M€unster, Von-Esmarch-Str 58, 48149 M€unster, Germany 3 Institute and German Center for Health Services Research in Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany E-mail: [email protected]
C. ZEIDLER1 H . L U€ L I N G 1 A . D I E C K H O€ F E R 1 N. OSADA2 F. SCHEDEL1 S. STEINKE1 M. AUGUSTIN3 S . S T A€ N D E R 1
References 1 Stumpf A, St€ander S. Neuropathic itch: diagnosis and management. Dermatol Ther 2013; 26:104–9. 2 Marziniak M, Phan NQ, Raap U et al. Brachioradial pruritus as a result of cervical spine pathology: the results of a magnetic resonance tomography study. J Am Acad Dermatol 2011; 65:756–62. 3 Masuda PY, Martelli ACC, Wachholz PA et al. Brachioradial pruritus – descriptive analysis of Brazilian case series. J Dtsch Dermatol Ges 2013; 11:530–5. 4 Mirzoyev SA, Davis MD. Brachioradial pruritus: Mayo Clinic experience over the past decade. Br J Dermatol 2013; 169:1007–15. 5 Wallengren J, Sundler F. Brachioradial pruritus is associated with a reduction in cutaneous innervation that normalizes during the symptom-free remissions. J Am Acad Dermatol 2005; 52:142–5. 6 Schuhknecht B, Marziniak M, Wissel A et al. Reduced intraepidermal nerve fibre density in lesional and nonlesional prurigo nodularis skin as a potential sign of subclinical cutaneous neuropathy. Br J Dermatol 2011; 165:85–91. 7 Peppin JF, Pappagallo M. Capsaicinoids in the treatment of neuropathic pain: a review. Ther Adv Neurol Disord 2014; 7:22–32. 8 Kim YS, Chu Y, Han L et al. Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain. Neuron 2014; 81:873–87. 9 Cobzaru A. High-concentration capsaicin patch (qutenza) – a new step in treatment of neuropathic pain. Maedica (Buchar) 2012; 7:88–9. 10 Simpson DM, Gazda S, Brown S et al. Long-term safety of NGX4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain. J Pain Symptom Manage 2010; 39:1053– 64. 11 Backonja MM, Malan TP, Vanhove GF, Tobias JK. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med 2010; 11:600–8. 12 Mou J, Paillard F, Turnbull B et al. Efficacy of Qutenzaâ (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database. Pain 2013; 154:1632–9.
© 2014 British Association of Dermatologists
Correspondence 1671 13 Simone DA, Nolano M, Johnson T et al. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci 1998; 18:8947–59. 14 O’Neill J, Brock C, Olesen AE et al. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 2012; 64:939–71. 15 Hardy J, Uthurriague C, Bibas N et al. Brachioradial pruritus revealing cervicomedullary astrocytoma and treated with 8% capsaicin patches. Ann Dermatol Venereol 2014; 141:374–5.
(a)
Funding sources: none. Conflicts of interest: none declared.
(b)
Persistent alopecia induced by vismodegib DOI: 10.1111/bjd.13630 DEAR EDITOR, Basal cell carcinoma (BCC) accounts for 80% of nonmelanoma skin cancers. Although most BCCs are readily treated by various surgical methods, these lesions occasionally, if not treated, progress to an advanced state. In this state the lesions are no longer amenable to surgery or radiation therapy (locally advanced BCC) or, more rarely, the lesions spread to distant sites (metastatic BCC). Vismodegib is a known inhibitor of the Sonic hedgehog pathway (Shh), and is approved by the U.S. Food and Drug Administration and the European Medicines Agency. It is the first systemic treatment for patients with locally advanced or metastatic BCC that is not amenable to surgery and radiation.1 Reversible alopecia is a well-known side-effect of vismodegib.2 Less than 50% hair loss is considered grade 1 alopecia, and ≥ 50% loss is considered grade 2 alopecia, according to the Common Terminology Criteria for Adverse Events version 4.0. We treated 65 patients (between July 2011 and March 2014) with vismodegib for locally advanced BCCs. All patients received oral vismodegib 150 mg daily. Among these, four patients presented with persistent alopecia (grade 2) even several months (mean 15 months) after stopping the treatment. Case 1 is a 54-year-old woman with a history of xeroderma pigmentosum and hypothyroidism (for which she was taking levothyroxine). She was treated with vismodegib for multiple BCCs between February 2010 and November 2010, when the treatment was interrupted (patient’s wish) due to alopecia (grade 2). This alopecia remained unchanged for more than 22 months after stopping the treatment, and her BCC also did not change (Fig. 1a,b). Case 2 is a 48-year-old man who presented with retroauricular BCC associated with multiple lymph node involvement and pulmonary metastases. He was treated with vismodegib between October 2011 and April 2012, and although the response to the treatment was excellent clinically, the treatment was interrupted because of alopecia (grade 2). This
© 2014 British Association of Dermatologists
Fig 1. Case 1, (a) just before starting vismodegib therapy and (b) 22 months after stopping treatment.
alopecia remained unchanged up to 18 months after stopping vismodegib. Case 3 is a 27-year-old man diagnosed with Gorlin syndrome, who received vismodegib between September 2011 and August 2012 for multiple BCCs. The treatment was suspended on the patient’s request due to alopecia (grade 2). This alopecia persisted for up to 1 year after stopping the treatment. Case 4 is a 92-year-old woman with history of type 2 diabetes mellitus (for which she was taking gliclazide), who presented with right lower eyelid BCC, treated with vismodegib between August 2011 and February 2013. The lesion has completely disappeared; however, the patient developed alopecia (grade 2), which remained unchanged for 14 months after stopping the treatment, whereas her disease remained in remission. There is no demographic or clinical criterion that differentiates these four patients from the other patients treated with vismodegib in our centre, and there was no baseline hair loss noticed in these patients. Furthermore, we did not observe any difference in the onset of alopecia between these four patients and the others, whose alopecia was reversible. This suggests that persistent alopecia as a side-effect of vismodegib cannot be predicted. Common reversible adverse events reported with vismodegib include muscle spasms (68%), dysgeusia (51%), alopecia (63%), fatigue (36%) and weight loss (46%).2 Amenorrhoea
British Journal of Dermatology (2015) 172, pp1669–1689
Correspondence
British Journal of Dermatology
Capsaicin 8% cutaneous patch: a promising treatment for brachioradial pruritus? DOI: 10.1111/bjd.13501 DEAR EDITOR, We would like to report on successful treatment of brachioradial pruritus (BRP) with a single application of a high-dose capsaicin patch. Five patients (four women; 54– 69 years old) had been suffering from BRP, confirmed by magnetic resonance tomography, for 72 months (median). The intraepidermal nerve fibre density (IENF) in itchy skin was reduced (44 11 fibres mm 1) compared with their intraindividual nonlesional IENF (174 102 fibres mm 1) (P < 005). Pruritus intensity on the visual analogue scale (VAS, range 0–100) ranged from 50 to 80 (average 64 114 points; median 65); pain intensity on the VAS ranged from 5 to 90 (average 58 333 points; median 65). Dermatological examinations showed scratch lesions in dermatomes C5/C6 in all patients.
As previous therapies with anticonvulsants (n = 3) and nonspecific therapies (antihistamines, n = 2) failed, we stopped the medication and in all patients applied the topical capsaicin 8% patch (Qutenzaâ), with each patch containing a total of 179 mg capsaicin (640 lg cm 2). The patch was applied exactly to the itchy area for 60 min (Fig. 1) after pretreatment with topical lidocaine 25% containing emollient for 60 min. All patients reported burning pain during the application which lasted for up to 12 h (average 52 40 h; median 4 h). Directly after removal of the patch, the skin showed self-limited erythema. As shown in Figure 2, 3 weeks after a single treatment with no other therapy, pruritus intensity was dramatically reduced to 9 points (SD 89; median 10; P = 0002). The mean itch reduction was 85% (SD 136%) measured by a dynamic score (100% = complete relief). Pain intensity reduced to an average of 6 points (SD 89; median, 0 points; P = 003). Patients reported improvement starting the day after treatment with capsaicin. The quality of life as measured by the
(a)
(b)
(a)
(b)
Fig 1. Brachioradial pruritus before and directly after capsaicin patch application. (a) Before treatment. (b) Transient erythema directly after treatment.
Fig 2. Pain (a) and pruritus (b) intensities (average SD value, Visual Analogue Scale) before and after a single application of capsaicin patch. © 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1669–1689
1669
1670 Correspondence
Dermatology Life Quality Index improved from 114 80 points (very large effect on quality of life) to 50 37 (small effect) without being significant. Three months after a single application, reduction of itch and pain intensity was still significant (itch: average VAS 8 131 points; median 0; P = 0002; mean itch reduction 89 167%; pain: average VAS 4 89; median 0; P = 0015) (Fig. 2). Quality of life values were nearly the same as they were 3 weeks after treatment. BRP is a localized neuropathic syndrome consisting of itch and pain.1 It occurs usually on the dorsolateral part of the forearms, corresponding to dermatomes C5/C6. The primary causes of BRP are believed to be compressions of the cervical spinal cord.2 Accordingly, the most effective reported treatments are the anticonvulsants gabapentin and pregabalin, and even antidepressants have been used in the treatment of BRP.3 However, not all patients experience complete remission under systemic therapy4 and some suffer from a variety of side-effects. Morphological studies demonstrated damaged and degenerated skin nerves resulting in a reduced total IENF density in BRP;5 this was the case in our patients. It is still not clear if the damaged skin nerves are a consequence of central nerve fibre compressions, which produce smaller amounts of neurotrophins and neuropeptides to be transported to the periphery, or are secondary to trauma, such as mechanical irritation by scratching.6 Capsaicin is derived from plants of the genus Capsicum and binds to the transient receptor potential ion channel vanilloid 1 (TRPV1) on cutaneous histamine-sensitive and mechanosensitive C- and Ad-fibres. Continuous topical application of capsaicin results in defunctionalization of the TRPV1 and inhibition of the generation of itch and pain.7,8 There are several hypotheses on the exact mode of action of high capsaicin concentrations on skin nerves9 including the inactivation of voltage-gated Na+ channels, overwhelming of intracellular Ca2+ buffering capacity with subsequent cytoskeleton breakdown, and interruption of fast axonal transport by activation of calcium-dependent proteases.8 Furthermore, it has been proposed that loss of mitochondrial function may render affected nerve processes unable to maintain plasma membrane integrity and thus cause collapse of nerve endings at depth.8 The exact mechanism of action of capsaicin in BRP is unknown, but is has proved effective as continuous cream application and, as shown here, as a single 8% patch application in pruritus. Previously, effects were shown in neuropathic pain.10–12 BRP is believed to be the result of initial damage to the cervical spinal cord; however, our data argue for an important role of the peripheral nerves in BRP. By eradication of the diseased epidermal nerves and regrowth of anatomically normal nerves,13,14 normal function can be restored, which would hinder the development of itch and pain symptoms. In summary, a single application of the high-concentration capsaicin patch led to a quick and long-lasting relief of itch and pain in patients with BRP. The reports of our British Journal of Dermatology (2015) 172, pp1669–1689
patients were congruent; all experienced relief starting the day after therapy. Similar results were observed in a 65-year woman suffering from BRP and treated with a capsaicin patch.15 This underlines once more using a 8% capsaicin patch is a promising, though expensive, new treatment strategy for BRP (€340/patch). More data from randomized controlled trials are needed to determine the long-term effect and to better understand the underlying mechanisms of the effect. 1
Department of Dermatology, Competence Center Chronic Pruritus, and 2Institute for Medical Informatics, University Hospital of M€unster, Von-Esmarch-Str 58, 48149 M€unster, Germany 3 Institute and German Center for Health Services Research in Dermatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany E-mail: [email protected]
C. ZEIDLER1 H . L U€ L I N G 1 A . D I E C K H O€ F E R 1 N. OSADA2 F. SCHEDEL1 S. STEINKE1 M. AUGUSTIN3 S . S T A€ N D E R 1
References 1 Stumpf A, St€ander S. Neuropathic itch: diagnosis and management. Dermatol Ther 2013; 26:104–9. 2 Marziniak M, Phan NQ, Raap U et al. Brachioradial pruritus as a result of cervical spine pathology: the results of a magnetic resonance tomography study. J Am Acad Dermatol 2011; 65:756–62. 3 Masuda PY, Martelli ACC, Wachholz PA et al. Brachioradial pruritus – descriptive analysis of Brazilian case series. J Dtsch Dermatol Ges 2013; 11:530–5. 4 Mirzoyev SA, Davis MD. Brachioradial pruritus: Mayo Clinic experience over the past decade. Br J Dermatol 2013; 169:1007–15. 5 Wallengren J, Sundler F. Brachioradial pruritus is associated with a reduction in cutaneous innervation that normalizes during the symptom-free remissions. J Am Acad Dermatol 2005; 52:142–5. 6 Schuhknecht B, Marziniak M, Wissel A et al. Reduced intraepidermal nerve fibre density in lesional and nonlesional prurigo nodularis skin as a potential sign of subclinical cutaneous neuropathy. Br J Dermatol 2011; 165:85–91. 7 Peppin JF, Pappagallo M. Capsaicinoids in the treatment of neuropathic pain: a review. Ther Adv Neurol Disord 2014; 7:22–32. 8 Kim YS, Chu Y, Han L et al. Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain. Neuron 2014; 81:873–87. 9 Cobzaru A. High-concentration capsaicin patch (qutenza) – a new step in treatment of neuropathic pain. Maedica (Buchar) 2012; 7:88–9. 10 Simpson DM, Gazda S, Brown S et al. Long-term safety of NGX4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain. J Pain Symptom Manage 2010; 39:1053– 64. 11 Backonja MM, Malan TP, Vanhove GF, Tobias JK. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med 2010; 11:600–8. 12 Mou J, Paillard F, Turnbull B et al. Efficacy of Qutenzaâ (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database. Pain 2013; 154:1632–9.
© 2014 British Association of Dermatologists
Correspondence 1671 13 Simone DA, Nolano M, Johnson T et al. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci 1998; 18:8947–59. 14 O’Neill J, Brock C, Olesen AE et al. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 2012; 64:939–71. 15 Hardy J, Uthurriague C, Bibas N et al. Brachioradial pruritus revealing cervicomedullary astrocytoma and treated with 8% capsaicin patches. Ann Dermatol Venereol 2014; 141:374–5.
(a)
Funding sources: none. Conflicts of interest: none declared.
(b)
Persistent alopecia induced by vismodegib DOI: 10.1111/bjd.13630 DEAR EDITOR, Basal cell carcinoma (BCC) accounts for 80% of nonmelanoma skin cancers. Although most BCCs are readily treated by various surgical methods, these lesions occasionally, if not treated, progress to an advanced state. In this state the lesions are no longer amenable to surgery or radiation therapy (locally advanced BCC) or, more rarely, the lesions spread to distant sites (metastatic BCC). Vismodegib is a known inhibitor of the Sonic hedgehog pathway (Shh), and is approved by the U.S. Food and Drug Administration and the European Medicines Agency. It is the first systemic treatment for patients with locally advanced or metastatic BCC that is not amenable to surgery and radiation.1 Reversible alopecia is a well-known side-effect of vismodegib.2 Less than 50% hair loss is considered grade 1 alopecia, and ≥ 50% loss is considered grade 2 alopecia, according to the Common Terminology Criteria for Adverse Events version 4.0. We treated 65 patients (between July 2011 and March 2014) with vismodegib for locally advanced BCCs. All patients received oral vismodegib 150 mg daily. Among these, four patients presented with persistent alopecia (grade 2) even several months (mean 15 months) after stopping the treatment. Case 1 is a 54-year-old woman with a history of xeroderma pigmentosum and hypothyroidism (for which she was taking levothyroxine). She was treated with vismodegib for multiple BCCs between February 2010 and November 2010, when the treatment was interrupted (patient’s wish) due to alopecia (grade 2). This alopecia remained unchanged for more than 22 months after stopping the treatment, and her BCC also did not change (Fig. 1a,b). Case 2 is a 48-year-old man who presented with retroauricular BCC associated with multiple lymph node involvement and pulmonary metastases. He was treated with vismodegib between October 2011 and April 2012, and although the response to the treatment was excellent clinically, the treatment was interrupted because of alopecia (grade 2). This
© 2014 British Association of Dermatologists
Fig 1. Case 1, (a) just before starting vismodegib therapy and (b) 22 months after stopping treatment.
alopecia remained unchanged up to 18 months after stopping vismodegib. Case 3 is a 27-year-old man diagnosed with Gorlin syndrome, who received vismodegib between September 2011 and August 2012 for multiple BCCs. The treatment was suspended on the patient’s request due to alopecia (grade 2). This alopecia persisted for up to 1 year after stopping the treatment. Case 4 is a 92-year-old woman with history of type 2 diabetes mellitus (for which she was taking gliclazide), who presented with right lower eyelid BCC, treated with vismodegib between August 2011 and February 2013. The lesion has completely disappeared; however, the patient developed alopecia (grade 2), which remained unchanged for 14 months after stopping the treatment, whereas her disease remained in remission. There is no demographic or clinical criterion that differentiates these four patients from the other patients treated with vismodegib in our centre, and there was no baseline hair loss noticed in these patients. Furthermore, we did not observe any difference in the onset of alopecia between these four patients and the others, whose alopecia was reversible. This suggests that persistent alopecia as a side-effect of vismodegib cannot be predicted. Common reversible adverse events reported with vismodegib include muscle spasms (68%), dysgeusia (51%), alopecia (63%), fatigue (36%) and weight loss (46%).2 Amenorrhoea
British Journal of Dermatology (2015) 172, pp1669–1689
![[Brachioradial pruritus revealing cervicomedullary astrocytoma and treated with 8% capsaicin patches].](/assets/img/hold.png)
