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Practical tip: Precooling topical calcineurin inhibitors tube;

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Practical tip: Precooling topical calcineurin inhibitors tube; reduces burning sensation
Sultan Al-Khenaizan MBBS FRCPC DABD
Dermatology Online Journal 16 (4): 16
Consultant Dermatologist, Assistant Professor, College of Medicine, Division of Dermatology, Department of Medicine, King
Abdulaziz Medical City, Riyadh, King Saud Bin Abdulaziz University for Health Sciences. [email protected]

Abstract
Burning sensation at the site of application is the most common side effect of topical calcineurin
inhibitors and is considered the most common reasons for premature discontinuation. Here, we analyze
the possible mechanism(s) and offer a simple practical tip to mitigate this adverse effect. Simple cooling
of the tube, immediately before use, does reduce the burning sensation and enable most intolerant
patients to use the medication comfortably. We also discuss the possible explanation(s) for the success of
this maneuver.

Tacrolimus ointment (Protopic, Astellas) and pimecrolimus cream (Elidel, Novartis) are two topical
calcineurin inhibitors, currently approved for the treatment of atopic dermatitis. The most important
clinically relevant side effect is transient application site burning and stinging at the beginning of topical
therapy [1, 2]. In clinical trials, the most common side effect was a burning sensation of the skin,
occurring in 46 to 58 percent of patients treated with TCIs. This side effect was most frequent early in the
course of treatment and was reported with both short term and long term use. This adverse effect is
usually noticed in the first 2 weeks of treatment and is considered the most common reason for
premature discontinuation [3].

The mechanism of topical calcineurin inhibitor-induced burning is not clear. Topical application of
pimecrolimus or tracrolimus has been shown to increase the release of substance P (SP) and calcitonin
gene-related peptide (CGRP) from primary afferent nerve fibers in murine skin [4]. In addition, topical
calcineurin inhibitors cause mast cell degranulation releasing mediators such as histamine and tryptase,
which may induce pruritus and burning by binding to the corresponding receptors (histamine receptor 1,
proteinase-activated receptor 2) on sensory nerve fibers [4].

Here we suggest a simple practical tip to further reduce this bothersome adverse effect. We simply advice
our patients to place the topical calcineurin inhibitor tube in the refrigerator for 15 to 20 minutes prior to
skin application. The patient should be warned not to chill the tube for a prolonged time because this
might cause the medication to be inspissated and difficult to extract. In addition, profound cooling can
cause pain by itself, by stimulating the mechano-cold sensitive C and Aδ fibers [5]. When the pre-cooled
medication is applied, most intolerant patients are able to use it with much less or no discomfort. We
found this measure highly useful and it will allow the most intolerant patients (usually rosacea patients
or patients with facial dermatitis) to use the medication with minimal discomfort. In our practice in a hot
climate this tip was practical and welcomed by most patients.

How the pre-cooling of the topical calcineurin inhibitors mitigates the burning sensation is not exactly
clear. Cooling is a safe way to achieve immediate relief of pain from superficial wounds or burns; even
deeper tissues such as joints or an inflamed appendix can sometimes be reached by cooling’s beneficial
beneficial effects [6]. Despite its widespread clinical use, the precise physiological responses to
therapeutic cooling have not been fully elucidated. Cooling effects on pain sensation and perception are
well-known, but there are many postulated mechanisms. Cooling of the skin decreases sensitivity of
nerve endings and decreases neurotransmission. Skin cooling decreases conduction time and synaptic
activity in peripheral nerves; this may help to mitigate the burning sensation [7]. The sensory conduction
velocity showed an 18.3 percent decrease after 16 minutes of ice application in one study [7]. It has also
been reported that nerve transmission ceases at between 9°C and 18°C; it takes approximately 9 minutes
of ice application to achieve this temperature [8]. When the temperature of the skin rises back to 15.6°C,
the pain returns when pricked with a pin [9]. Sustained beneficial effects of cooling also include anti-
inflammatory actions through the inhibition of neurogenic inflammation, with diminished release of the
vasoactive sensory neuropeptides substance P and calcitonin gene-related peptide (CGRP) [10].

References
1. Reitamo S, Wollenberg a, Schopf E. et al. Safety and efficacy of 1 year of tacrolimus ointment
monotherapy in adults with atopic dermatitis. Arch Dermatol 2000; 36:999-1006. [PubMed]

2. Eichenfield LF, Lucky AW, Boguiniewicz M et al. Safety and efficacy of pimecrolimus (ASM 981) cream
1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad
Dermatol 2002; 46:495-504. [PubMed]

3. Reitamo S, Ortonne J, Sand C, Bos J, Cambazard F, Bieber T, Gronhoj-Larsen C, Rustin M, Floster-Holst

4. Stander S, Stander H, Seeliger S, Luger TA, Steinhoff M, Topical pimecrolimus and tacrolimus
transiently induce neuropeptide release and mast cell degranulation in murine skin, Britis Association of
Dermatologists 2007, British Journal of Dermatology 2007; 156:1020-1026. [PubMed]