The recent growth in the demand for cosmetic and invasive dermatologic procedures has resulted in increased use of topical anesthetics, which are necessary to control pain and ensure patient satisfaction and safety. Some types of topical anesthetics have been introduced to diminish patient discomfort, including EMLA® cream (lidocaine 2.5% and prilocaine 2.5%; AstraZeneca, London, UK), which is the most widely used topical anesthetic agent and is an amide anesthetic composed of 25 mg/ml of lidocaine and 25 mg/ml of prilocaine in an oil-in-water emulsion1. Product recommendations suggest applying EMLA® to intact skin, under occlusion, for at least one hour. The application duration is directly correlated with analgesia depth, which reaches 3 mm after 60 minutes and 5 mm after 120 minutes2. EMLA® cream may cause several adverse reactions, from allergic contact dermatitis to serious systemic toxicity. Prilocaine can cause serious allergic contact dermatitis and methemoglobinemia, which may result in cyanosis, respiratory insufficiency, or, on rare occasions, even death3. Systemic absorption of lidocaine can also cause dose-dependent adverse effects on the central nervous system4. However, when EMLA® was applied to a 1,296-cm² area, the concentration in the blood did not exceed 1,100 ng/ml for lidocaine and 200 ng/ml for prilocaine. In clinical settings, no systemic side effects would be expected in typical cases when applying 5 g to 10 g of EMLA® cream5.

Brimonidine gel (0.33%, Mirvaso®; Galderma SA, Lausane, Switzerland) is a highly selective α2-adrenergic receptor agonist with potent vasoconstrictive activity and has received United States Food and Drug Administration (FDA) approval for treating facial erythema due to rosacea. It improves moderate to severe erythema after the first application with a rapid onset of action within 30 minutes and a reduction in erythema for up to 12 hours6. Recently, Gerber reported observing that brimonidine gel effectively reduces post treatment erythema after daylight-activated photodynamic therapy7. Also, Schleichert and Weiss8 demonstrated the use of brimonidine gel as an efficient hemostatic agent in dermatologic surgery. These experimental trials demonstrate the vasoconstrictive properties of topical brimonidine gel, but there have been no evaluations of the additional effect of brimonidine gel when used in combination with EMLA®.

For example, Spencer demonstrated that epinephrine prolongs analgesia duration, including local infiltration of lidocaine, in a dose-related manner. The magnitude of epinephrine–induced vasoconstriction correlated with analgesia duration, which may explain why local vasoconstriction decreases the systemic absorption rate of anesthesia despite the local toxicity of epinephrine that decreases wound healing and promotes cell death9.

Therefore, herein, we report for the first time on the efficacy of the combined use of topical brimonidine and EMLA® as an aid in post treatment erythema and effective anesthesia in dermatologic procedures.

Topical anesthetics including lidocaine and prilocaine inhibit nerve-fiber depolarization, thus blocking action-potential transmission10. The painful stimuli are transmitted by small unmyelinated nerve fibers, which are more sensitive to anesthetics than myelinated fibers that transmit other types of sensations. Consequently, patients may feel pressure and vibration even while being insensitive to pain11. Like epinephrine, the adjuvant effect of adding clonidine to local anesthetics for nerve block has been examined. Clonidine, an α₂ adrenergic agonist, significantly shortened the time to onset of sensory block and also prolonged the duration of local anesthesia12.

However, prolongation of nerve blockade duration by clonidine is not mediated by an α-adrenergic mechanism via local vasoconstriction; rather, it likely involves I_h channel blockade. In other words, clonidine enhances activity-dependent hyperpolarization by inhibiting the I_h channel13. Also, because α₂ adrenoreceptors are not present on the axon on the normal peripheral nerve, I_h channel blockade activity, not α₂ adrenoreceptor activity, contributes to enhancing prolongation by clonidine14. However, in another study assessing human cutaneous nerve blockade, local vasoconstrictive effects might slow lidocaine absorption, suggesting that prolongation of the nerve block was at least partially pharmacokinetically mediated15. In accordance with clinical studies, it is assumed that the adjuvant effect of brimonidine in prolonging anesthesia could be more potent, since it is 7- to 12-fold more α₂-selective than clonidine16.

Braun et al.17 demonstrated that applying topical brimonidine reduced laser-associated post treatment erythema and, thus, may improve the tolerability of ablative lasers. After two-hour applications, the patients showed nearly complete regression of laser-induced erythema, an effect that lasted up to 12 hours. Brimonidine was approved to treat facial erythema and is often prescribed to rosacea patients; consequently; its vasoconstrictive activity is expected to reduce facial erythema and flushing after laser therapy.

In this study, we analyzed the adjuvant effect of brimonidine gel on a specific use of EMLA®. The EMLA® and brimonidine mixture significantly lowered post treatment erythema up to 60 minutes after the laser procedure via cutaneous vasoconstriction. However, we observed no significant differences in post treatment erythema between both sides 24 hours after the procedure. The likely reason for this is that the pharmacologic action time of brimonidine is about 12 hours; thus, no significant difference was observed between the two groups by 24 hours after the procedure.

Patients also reported significantly lower post procedural pain with the EMLA® and brimonidine combination treatment 30 and 60 minutes after the procedure than with the EMLA®-only treatment. We further showed that adjuvant brimonidine subsequently extended the duration of anesthesia via I_h channel blockade and it enhanced patient comfort. Alternatively, these outcomes may be associated with the vasoconstrictive effect, exhibiting reduced post treatment erythema because patients often reported post procedure hot flush or heating sensations as pain. However, pain during the procedure was not different between two groups after receiving the EMLA® and brimonidine combination than after receiving EMLA®-only. This demonstrated that brimonidine did not diminish the time to onset of sensory block or enhance the potency of anesthesia; rather, it prolonged the anesthesia duration.

Both topical agents were well tolerated and showed no systemic toxicity or drug-related adverse events, with the exception of one case of allergic contact dermatitis to EMLA®. Though brimonidine is formulated for less central nervous system (CNS) penetration, topical brimonidines that are systemically absorbed may cause central α₂ agonism, leading to CNS depression, bradycardia, and hypotension1819. Also, there may be potential for over-absorption of brimonidine when used in conjunction with ablative device procedures. Therefore, to avoid poisoning from systemic exposure to excessive doses, clinicians should apply topical brimonidine prior to ablative laser treatment, limit the total application dose and this must be wiped off immediately before the laser procedure. The study is limited by its small sample size. Through further robustly-designed studies, ideal dosage, mixture regimen, and safety guidelines can be established. Although the optimal dose of brimonidine and the exact mechanisms of its effects are not definitely known, brimonidine can be used as an effective adjuvant agent when added to topical anesthetics.