Amitriptyline and bromazepam in the treatment of vibratory angioedema

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ABSTRACT: Vibratory angioedema is a rare form of physical urticaria, hereditary or acquired, which occurs at body sites exposed to vibrations. Pathogenic ...
Dermatologic Therapy, Vol. 27, 2014, 361–364 Printed in the United States · All rights reserved

© 2014 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPY ISSN 1396-0296

THERAPEUTIC HOTLINE Amitriptyline and bromazepam in the treatment of vibratory angioedema: which role for neuroinflammation? Fabrizio Guarneri, Claudio Guarneri & Herbert Ryan Marini Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

ABSTRACT: Vibratory angioedema is a rare form of physical urticaria, hereditary or acquired, which occurs at body sites exposed to vibrations. Pathogenic mechanisms of disease are not completely clear and, consequently, current pharmacological treatment is sometimes unsatisfactory. We report the case of a horn player affected by acquired vibratory angioedema, relapsing after prolonged use of the instrument and resistant to systemic antihistamines and corticosteroids, which successfully responded to therapy with low doses of amitriptyline and bromazepam. A neuroinflammatory mechanism can be likely implicated in the pathogenesis of vibratory angioedema, in line with many different cutaneous/ mucosal diseases involving a complex interplay of homeostatic/allostatic systems. Furthermore, in mucosal diseases, such as vibratory angioedema, physical/psychological stressors have a relevant role. In such cases, because of the complex interplay between nervous and immune system, the pharmacological activity of benzodiazepines and typical antidepressants may downregulate neuroinflammation. KEYWORDS: allostasis, amitriptyline, bromazepam, neurogenic inflammation, vibratory angioedema

Introduction Vibratory angioedema is a rare form of physical urticaria, hereditary or acquired, which occurs at body sites exposed to vibrations (1). Few studies are available on the pathogenic mechanisms of this disease, which are currently not completely clear. Consequently, treatment can sometimes be difficult, particularly in case of failure of antihistamines and corticosteroids: reports on the efficacy of alternative drugs are anecdotal, and based on an empirical approach.

Address correspondence and reprint requests to: Fabrizio Guarneri, MD, Associate Professor, Department of Clinical and Experimental Medicine, University of Messina, AOU Policlinico “G. Martino”, pad. H, 4th floor, Via Consolare Valeria, Gazzi 98125 Messina, Italy, or email: [email protected].

We report a case of acquired vibratory angioedema, resistant to systemic antihistamines and corticosteroids, which successfully responded to therapy with low doses of amitriptyline and bromazepam administered because of the suspected pathogenic role of neuroinflammation.

Case report A 20-year-old, male Caucasian came to observation because of repeated episodes of labial angioedema unresponsive to various oral antihistamines and corticosteroids, which occurred in the last 5 months after prolonged use (1–2 hours) of his wind instrument, a horn. The patient reported that he had been studying music and playing his instrument since the age of 14, and that he was currently preparing for an exam to become part of an important orchestra. Also, he reported that neither

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the materials of the horn nor maintenance procedures and products had ever been modified. Personal history was negative for noteworthy diseases, including allergies and urticaria-angioedema. Patch tests were undertaken in the SIDAPA (Società Italiana di Dermatologia Allergologica, Professionale ed Ambientale – Italian Society of Allergologic, Professional and Environmental Dermatology) baseline series (FIRMA, Florence, Italy), plus the materials of the mouthpiece of the instrument (silver, brass and its components, copper and zinc) and the product used for cleaning the mouthpiece (toothpaste). Haptens were tested in Hayes’ chambers (Hayes Service BV, Alphen, The Netherlands). Results were negative at Day 2 and Day 4. Routine blood exams, coagulation parameters and complement factors C3, C4 and C1 inhibitor were within normal values; parasitological examination of stools, search for infectious foci and autoantibodies yielded negative results. An attempt was made by the patient to replace the original mouthpiece with an equivalent made of titanium, but this did not improve the clinical picture. We diagnosed acquired vibratory angioedema (personal and familial history was negative for this condition), and suspected the possible involvement of neuroinflammation in its pathogenesis, on the basis of previous experience with such mechanism (2–5). Thus, we suggested therapy with amitriptyline 6 mg/day and bromazepam 0.6 mg/ day. At follow-up visits after 1 and 2 months of treatment, our patient reported a remarkable increase of the threshold of reactivity to vibrations: no clinical manifestations had been observed as a consequence of daily use of the instrument for up to 2 hours, and the only episode of labial angioedema had occurred after an unusually long practice session (4 hours).

Discussion To the best of our knowledge, as of May 2, 2014, only nine cases of acquired vibratory angioedema can be found in PubMed, two of which (6,7) are similar to ours. Few and sometimes contradictory data exist on its pathogenic mechanism(s): Ting et al. (8) and Keahey et al. (9) reported that vibratory stimuli in patients induce rapid rise and fall in plasma histamine and observed mast cell degranulation at stimulated sites, while Lawlor et al. (10) found no evidence of mast cell degranulation. It is well known that mast cells secrete several mediators, which may play a crucial role to trigger and/or sustain a neuroinflammatory

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mechanism; the stimulation threshold for mast cell activation shows significant interindividual and intraindividual variability because of constitutional as well as occasional – endogenous or exogenous – factors. Substances, such as histamine, serotonin and prostaglandins, can act directly on receptors located on sensory nerve endings (11), while others, such as tryptase, directly activate peripheral nerves (12). Consequently, a neuroinflammatory mechanism can be likely implicated in the pathogenesis of vibratory angioedema, in line with many different skin/mucosal diseases (psoriasis, photodermatosis, perioral dermatitis, burning mouth syndrome, oral lichen planus, etc.) involving a complex interplay of homeostatic/allostatic systems (13). When stimulated, free nerve terminals release an array of neuromediators as calcitonin generelated peptide, substance P, and neurokinin-A, which are vasoactive, pruritogenic etc., and stimulate mast cells and lymphocytes, leading, in turn, to amplification of inflammatory signals (11). As previously reported, labial mucosa is highly innervated by nerve fibers type C and Aδ, whose stimulation may cause a local release of inflammatory mediators (4) which not only participate in the transmission of sensory impulses, but also in cutaneous/mucosal phlogosis. It appears useful to remind that inflammatory mediators typical of cutaneous/mucosal diseases are not exclusively produced by nerve fibers (14). Overall, the peculiar combination of the clinical features observed in our patient lets us hypothesize that neuroinflammation could play an important pathogenic role in vibratory angioedema on the basis of the following key points: (i) localization of vibratory angioedema in the territory innervated by sensory free endings of trigeminal nerve, (ii) temporal association with a psychological/ physical stressor, (iii) resistance to conventional therapy but optimal response to antidepressants and/or benzodiazepines. Then, we propose, in agreement with previous clinical observations referred to various cutaneous/mucosal pathological conditions (2–5), that a conventional axon reflex and/or an indirect reflex mechanism involving localized efferent parasympathetic fibers could be implicated (FIG. 1). Axon reflex is a peculiar physiological mechanism caused by passage of nerve impulses from a sensory ending to the effector organ along divisions of the nerve fiber without traversing a “reflex center”, while the indirect pathway mechanism requires central processing of trigeminal input (2–5). The first mechanism appears more

Vibratory angioedema and neuroinflammation

FIG. 1. Schematic representation of neurogenic inflammation model and possible modulatory effect of benzodiazepines and typical antidepressants in vibratory angioedema.

likely in our patient, because the clinical picture is not typical of indirect reflex (wider spreading of edema, discomfort and pain because of involvement of other trigeminal branches would be expected). Furthermore, in mucosal diseases, such as vibratory angioedema, physical/psychological stressors (e.g., stress linked to an upcoming exam, as in the case of our patient) have a relevant role. In such cases, the pharmacological activity of benzodiazepines and typical antidepressants may downregulate neuroinflammation, through restoration of normal signal modulation in peripheral nerves by central nervous system and/or direct effect on local neuroinflammation (FIG. 1). In this scenario, benzodiazepines bind to type A receptors for gamma-aminobutyric acid, promoting the neuronal membrane hyperpolarization, which in turn reduces neuronal excitability; the

recent demonstration of type A receptors for gamma-aminobutyric acid localization also in the peripheral nerves indicates that benzodiazepines could act not only centrally but also peripherally (15). Moreover, antidepressants administration in patients affected by different skin diseases along with psychological disorders allows to achieve satisfactory results (4), reinforcing the positive effects obtained by benzodiazepine administration. In fact, in our patient, low doses of benzodiazepine (bromazepam) in combination with a typical antidepressant (amytriptiline) may have effectively modulated the neuroinflammatory pathway, which is not completely inhibited by conventional treatments and can contribute to the persistence of inflammation. Overall, the above data and the clinical features let us hypothesize that neuroinflammation might play a possible concausal role in the pathogenesis

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of the vibratory angioedema here described. Consequently, treatment with neuropsychotropic drugs, such as benzodiazepines and/or antidepressants, at low doses could be a useful therapeutic option in such patients. Of course, further experimental and clinical investigations are required to better characterize the uncertain physiopathology of vibratory angioedema, also considering the possible implications for the pharmacological therapy and outcomes of this disease.

Conflict of interest All authors have no conflict of interest.

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5. Guarneri F, Guarneri C, Marini H. Oral lichen planus and neurogenic inflammation: new observations and therapeutic implications from four clinical cases. Dermatol Ther 2014 Feb 18. [Epub ahead of print]. 6. Patruno C, Ayala F, Cimmino G, Mordente I, Balato N. Vibratory angioedema in a saxophonist. Dermatitis 2009: 20: 346–347. 7. Sarmast SA, Fang F, Zic J. Vibratory angioedema in a trumpet professor. Cutis 2014: 93: E10–E11. 8. Ting S, Reimann BE, Rauls DO, Mansfield LE. Nonfamilial, vibration-induced angioedema. J Allergy Clin Immunol 1983: 71: 546–551. 9. Keahey TM, Indrisano J, Lavker RM, Kaliner MA. Delayed vibratory angioedema: insights into pathophysiologic mechanisms. J Allergy Clin Immunol 1987: 80: 831–838. 10. Lawlor F, Black AK, Breathnach AS, Greaves MW. Vibratory angioedema: lesion induction, clinical features, laboratory and ultrastructural findings and response to therapy. Br J Dermatol 1989: 120: 93–99. 11. Steinhoff M, Ständer S, Seeliger S, Ansel JC, Schmelz M, Luger T. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 2003: 139: 1479–1488. 12. Walsh LJ. Mast cells and oral inflammation. Crit Rev Oral Biol Med 2003: 14: 188–198. 13. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007: 87: 873–904. 14. Zegarska B, Lelin ´ ska A, Tyrakowski T. Clinical and experimental aspects of cutaneous neurogenic inflammation. Pharmacol Rep 2006: 58: 13–21. 15. Magnaghi V, Ballabio M, Consoli A, Lambert JJ, Roglio I, Melcangi RC. GABA receptor-mediated effects in the peripheral nervous system: a cross-interaction with neuroactive steroids. J Mol Neurosci 2006: 28: 89–102.