Emla Mechanism of Action

Pharmacotherapeutic Group: Local anaesthetics of the amide-type. ATC Code: N01B B20.
Pharmacology: Pharmacodynamics: EMLA Cream 5% provides dermal anaesthesia through the release of lidocaine and prilocaine from the cream into the epidermal and dermal layers of the skin and the accumulation of lidocaine and prilocaine in the vicinity of dermal pain receptors and nerve endings. Lidocaine and prilocaine are amide-type local anaesthetic agents. They both stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby producing local anaesthesia.
The quality of anaesthesia depends upon the application time and the dose.
EMLA Cream is applied to intact skin under an occlusive dressing. The time needed to achieve reliable anaesthesia of intact skin is 1-2 hours, depending on the type of procedure.
In clinical studies of EMLA on intact skin, no differences in safety or efficacy (including anaesthetic onset time) were observed between geriatric patients (aged 65-96 years) and younger patients.
The duration of anaesthesia following the application of EMLA Cream for 1-2 hours is at least 2 hours after removal of the dressing.
The depth of cutaneous anaesthesia increases with application time. In 90% of patients the anaesthesia is sufficient for the insertion of a biopsy punch (4 mm diameter) to a depth of 2 mm after 60 min and 3 mm after 120 min EMLA treatment. EMLA is equally effective and has the same anaesthetic onset time across the range of light to dark pigmented skin (skin types I to VI).
The use of EMLA prior to measles-mumps-rubella or intramuscular diphtheria-pertussis-tetanus-inactivated poliovirus-Haemophilus influenzae b or Hepatitis B vaccines does not affect mean antibody titres, rate of seroconversion, or the proportion of patients achieving protective or positive antibody titres post immunization, as compared to placebo-treated patients.
Absorption from the genital mucosa is more rapid and onset time is shorter than after application to the skin.
After a 5-10 min application of EMLA to female genital mucosa the average duration of effective analgesia to an argon laser stimulus which produced a sharp, pricking pain was 15-20 min (individual variations in the range 5-45 min).
Reliable anaesthesia for the cleansing of leg ulcers is achieved after an application time of 30 minutes in most patients. An application time of 60 minutes may improve the anaesthesia further. The cleansing procedure should start within 10 minutes of removal of the cream. Clinical data from a longer waiting period are not available. EMLA reduces the postoperative pain for up to 4 hours after debridement. EMLA reduces the number of cleansing sessions required to achieve a clean ulcer compared to debridement with placebo cream. No negative effects on ulcer healing or bacterial flora have been observed.
EMLA produces a biphasic vascular response involving initial vasoconstriction followed by vasodilatation at the application site (see Adverse Reactions). Irrespective of the vascular response, EMLA facilitates the needle procedure compared to placebo cream.
In patients with atopic dermatitis, a similar but shorter vascular reaction is seen, with erythema occurring after 30-60 minutes, indicating more rapid absorption through the skin (see Precautions).
Pharmacokinetics: The systemic absorption of lidocaine and prilocaine from EMLA is dependent upon the dose, area of application and application time. Additional factors include thickness of the skin (which varies in different areas of the body), other conditions such as skin diseases, and shaving. Following application to leg ulcers, the characteristics of the ulcers may also affect the absorption.
Intact skin: Following application to the thigh in adults (60 g cream/400 cm² for 3 hours), the extent of absorption was approx 5% of lidocaine and prilocaine. Maximum plasma concentrations (mean 0.12 and 0.07 μg/ml) were reached approx 2-6 hours after application.
The extent of systemic absorption was approx 10% following application to the face (10 g/100 cm² for 2 hours). Maximum plasma levels (mean 0.16 and 0.06 μg/ml) were reached after approx 1.5-3 hours.
Plasma levels of lidocaine and prilocaine in both geriatric and non-geriatric patients following application of EMLA to intact skin are very low and well below potentially toxic levels.
Children: Following the application of 1.0 g EMLA Cream in neonates below 3 months of age, to approx 10 cm² for one hour, the maximum plasma concentrations of lidocaine and prilocaine were 0.135 μg/ml and 0.107 μg/ml respectively. Following the application of 2.0 g EMLA Cream in infants between 3 and 12 months of age, to approx 16 cm² for four hours, the maximum plasma concentrations of lidocaine and prilocaine were 0.155 μg/ml and 0.131 μg/ml respectively. Following the application of 10.0 g of EMLA Cream in children between 2 and 3 years of age, to approx 100 cm² for two hours, the maximum plasma concentrations of lidocaine and prilocaine were 0.315 μg/ml and 0.215 μg/ml respectively. Following the application of 10.0-16.0 g EMLA Cream in children between 6 and 8 years of age, to approx 100-160 cm² for two hours, the maximum plasma concentrations of lidocaine and prilocaine were 0.299 μg/ml and 0.110 μg/ml respectively.
Genital mucosa: After the application of 10 g EMLA Cream for 10 minutes to vaginal mucosa, maximum plasma concentrations of lidocaine and prilocaine (mean 0.18 μg/ml and 0.15 μg/ml respectively) were reached after 20-45 minutes.
Leg ulcer: Following a single application of 5 to 10 g of EMLA Cream to leg ulcers with an area of up to 64 cm² for 30 minutes, the maximum plasma levels of lidocaine (range 0.05-0.25 μg/ml, one individual value of 0.84 μg/ml) and of prilocaine (0.02-0.08 μg/ml) were reached within 1-2.5 hours.
After an application time of 24 hours to leg ulcers with an area of up to 50-100 cm², the maximum plasma levels of lidocaine (0.19-0.71 μg/ml) and of prilocaine (0.06-0.28 μg/ml) were usually reached within 2-4 hours.
Following repeated application of 2-10 g EMLA Cream to leg ulcers with an area of up to 62 cm² for 30-60 minutes 3-7 times a week for up to 15 doses during a period of one month, there was no apparent accumulation in plasma of lidocaine and its metabolites monoglycinexylidide and 2,6-xylidine or of prilocaine and its metabolite ortho-toluidine. The maximum observed plasma levels for lidocaine, monoglycinexylidide and 2,6-xylidine were 0.41, 0.03 and 0.01 μg/ml respectively. The maximum observed plasma levels for prilocaine and ortho-toluidine were 0.08 μg/ml and 0.01 μg/ml respectively.
Toxicology: Preclinical safety data: In animal studies the toxicity noted after high doses of either lidocaine or prilocaine, alone or in combination, consisted of effects on the central nervous and cardiovascular systems. When lidocaine and prilocaine were combined, only additive effects were seen, with no indication of synergism or unexpected toxicity. Both compounds were shown to have a low oral acute toxicity, providing a good safety margin in the event that EMLA is inadvertently swallowed. No drug-related adverse effects were seen in the reproduction toxicity studies, using either compound separately or together.
Neither local anaesthetic showed a mutagenic potential in either in vitro or in vivo mutagenicity tests. Cancer studies have not been performed with either lidocaine or prilocaine alone or in combination, due to the indication and duration of therapeutic use of these drugs.
A metabolite of lidocaine, 2,6-dimethylaniline, and a metabolite of prilocaine, o-toluidine, showed evidence of mutagenic activity. These metabolites have been shown to have carcinogenicity potential in preclinical toxicological studies evaluating chronic exposure. Risk assessments comparing the calculated maximum human exposure from intermittent use of lidocaine and prilocaine, with the exposure used in preclinical studies, indicate a wide margin of safety for clinical use.
Local tolerance studies using a 1:1 (w/w) mixture of lidocaine and prilocaine as an emulsion, cream or gel indicated that these formulations are well tolerated by intact and damaged skin and mucosal membranes.
A marked irritative reaction was seen after single ocular administration of a 50 mg/g lidocaine + prilocaine 1:1 (w/w) emulsion, in an animal study. This is the same concentration of local anaesthetics and a similar formulation as for EMLA cream and patch. This ocular reaction may have been influenced by the high pH of the formulation of the emulsion (approximately 9), but is probably also partly a result of the irritative potential of the local anaesthetics themselves.