Eutectic Lidocaine/Prilocaine Cream

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Abstract
Eutectic lidocaine/prilocaine cream 5% is a eutectic mixture of the local anaesthetics lidocaine (lignocaine) 25 mg/g and prilocaine 25 mg/g that provides dermal anaesthesia/analgesia following topical application. The principal indication in which eutectic lidocaine/prilocaine cream has been studied is the management of pain associated with venipuncture or intravenous cannulation, where significantly greater pain relief than placebo, with equivalent efficacy to ethyl chloride spray and lidocaine infiltration, has been demonstrated. In dermatological surgery, eutectic lidocaine/prilocaine cream offers effective pain relief in children undergoing curettage of molluscum contagiosum lesions, and in adults undergoing split-skin graft harvesting. Particular benefit has also been shown with use of eutectic lidocaine/prilocaine cream in association with treatment of condylomata acuminata in both men and women, and it appears to provide a useful alternative to lidocaine infiltration in this context. Further research in such indications as paediatric lumbar puncture, minor otological surgery, and minor gynaecological, urological and andrological procedures is likely to further broaden the profile of clinical use for eutectic lidocaine/prilocaine cream. Eutectic lidocaine/prilocaine cream has a very favourable tolerability profile, transient and mild skin blanching and erythema being the most frequent adverse events to occur in association with its application to skin. The potential for inducing methaemoglobinaemia, attributed to a metabolite of the prilocaine component of the formulation, prohibits its use in infants younger than 6 months. In summary, eutectic lidocaine/prilocaine cream is a novel formulation of local anaesthetics that has proven to be effective and well-tolerated in the relief of pain associated with various minor interventions in adults and children. Studies in healthy volunteers have indicated that application of eutectic lidocaine/prilocaine cream for at least 60 minutes before venous cannulation affords significantly greater pain relief than placebo. The maximal depth of analgesia to needle insertion after application of eutectic lidocaine/prilocaine cream was identified as 5mm, obtained 30 minutes after application for 90 minutes, or during the 60 minutes after application for 120 minutes. Local blood flow, as well as epidermal and dermal thickness appear to be important factors affecting the efficacy of eutectic lidocaine/prilocaine cream. Efficacy, as determined by the response to argon laser stimulation, increased with increasing application time for sites including the back, cheek, cubital fossa and dorsum of the hand, while an inverse relationship held for application to the forehead. Onset of analgesia was rapid when eutectic lidocaine/prilocaine cream was applied to the back, but declined rapidly after discontinuation. In contrast, after application to the cubital fossa and the hand, onset of analgesia was slower but increased for up to 60 minutes after removal, followed by a slow decline. In children aged approximately 2 to 13 years undergoing venipuncture, a ‘thick layer’ of eutectic lidocaine/prilocaine cream, defined as 2ml (approximately 2g) applied to an area measuring 30 by 32mm on the dorsum of the hand, was significantly more effective than a ‘thin layer’, defined as 0.5ml of the cream applied over the same area, in providing pain relief. 91% of patients in the ‘thick layer’ group experienced ‘no pain’ vs 69% in the ‘thin layer’ group. Volunteer studies have also indicated analgesic efficacy of eutectic lidocaine/prilocaine cream greater than that of placebo in individuals undergoing subcutaneous injection or tourniquet inflation. Eutectic lidocaine/prilocaine cream also provided greater local anaesthesia of the tympanic membrane than lidocaine spray in 1 study. Findings from a study in volunteers undergoing fibreoptic airway endoscopy, however, suggested that eutectic lidocaine/prilocaine cream 1ml provided less effective topical anaesthesia of the nasal mucosa than lidocaine 4% solution, 2% gel or five 10mg doses of a spray. Eutectic lidocaine/prilocaine cream appeared to provide a similar degree of local analgesia to a 10% lidocaine spray applied to the gingival membrane in 1 volunteer study. Preliminary findings suggest that the analgesia obtained with eutectic lidocaine/prilocaine cream may be later in onset and/or reduced in magnitude in Black compared with White subjects. Vascular effects of eutectic lidocaine/prilocaine cream, such as skin blanching (reflecting vasoconstriction) and erythema (indicating vasodilatation), have occurred after application times of 30 to 60 minutes, and 2 hours, respectively. While the vasoconstriction may be partly associated with the technique of applying eutectic lidocaine/prilocaine cream under occlusion, the vasodilatation appears to be a specific effect of eutectic lidocaine/prilocaine cream. Notwithstanding the possible occurrence of vasoconstriction, eutectic lidocaine/prilocaine cream does not appear to compromise the efficacy of pulsed dye laser treatment of port wine stains. Vascular responses may be greater when eutectic lidocaine/prilocaine cream is applied to diseased skin. Eutectic lidocaine/prilocaine cream appears to inhibit the flare, but not the wheal, response to histamine, indicating that it alleviates the neurogenic component of inflammation. The rates of percutaneous absorption of lidocaine and prilocaine vary according to the location and condition of the skin. Moreover, plasma prilocaine concentrations tend to be lower than those of lidocaine. Maximum plasma concentrations of the anaesthetics were attained within 2 to 2.5 hours of applying eutectic lidocaine/prilocaine cream to normal facial skin. In contrast, the maximum plasma lidocaine concentration was lower (18 vs 150 μg/L) and not reached until 5 hours after the same dosage (10 g/100cm2 for 2 hours) was first applied to normal forearm skin. Studies in children and infants have revealed that widely varying maximum plasma lidocaine and prilocaine concentrations can be expected within 2 to 4 hours of applying the cream to normal skin. The rate of percutaneous absorption of lidocaine and prilocaine from skin affected by psoriasis or dermatitis appears to be increased compared with normal skin. Reported plasma concentrations of lidocaine were in the range 16 to 450 μg/L 1 hour after applying eutectic lidocaine/prilocaine cream (4 to 6 g/25cm2) to the skin of patients with these conditions. A study in children about to undergo surgical treatment of molluscum contagiosum reported that maximum plasma anaesthetic concentrations were reached within 2 to 3 hours of applying a total dose of 10 to 16g eutectic lidocaine/prilocaine cream to a total of 100 to 160cm2 of affected skin. Maximum plasma anaesthetic concentrations following application of eutectic lidocaine/prilocaine cream were 10- to 100-fold less than those considered toxic. Almost all of the clinical studies on the use of eutectic lidocaine/prilocaine cream as a local anaesthetic have been in patients undergoing minor medical and surgical procedures. Controlled trials have demonstrated analgesic efficacy of eutectic lidocaine/prilocaine cream significantly greater than that of placebo in children aged between 3 months and 17 years undergoing venipuncture or venous cannulation, and it was reported to facilitate the procedure in some, but not all, studies. In addition, the analgesic efficacy of eutectic lidocaine/prilocaine cream was equivalent to that of lidocaine infiltration or ethyl chloride spray in children undergoing venous cannulation. Initial reports have shown that the patch formulation offers a suitable alternative to the cream in children undergoing venipuncture. Two double-blind trials in paediatric patients undergoing lumbar puncture found that the analgesic efficacy of eutectic lidocaine/prilocaine cream was significantly greater than that of placebo. In adults undergoing arterial cannulation prior to surgery, eutectic lidocaine/prilocaine cream treatment was associated with lower pain scores than placebo, and compared with lidocaine infiltration in 1 double-blind study. In patients undergoing cannulation for haemodialysis, use of eutectic lidocaine/prilocaine cream was not only associated with significantly greater pain relief than placebo, but also significantly facilitated cannulation in comparison with both placebo and lidocaine infiltration. Controlled trials of the use of eutectic lidocaine/prilocaine cream prior to venipuncture in adults have also shown significant benefit over placebo. In patients undergoing split-skin graft harvesting, eutectic lidocaine/prilocaine cream (30 g/100cm2) provided satisfactory analgesia in approximately 90% of patients. In children undergoing curettage of molluscum contagiosum lesions, pain after eutectic lidocaine/prilocaine cream treatment was rated as ‘none’ or ‘slight’ in over 90% of patients, vs 54% with placebo. Eutectic lidocaine/prilocaine cream has also been effective in relieving pain in patients undergoing laser treatment of facial port wine stains, was superior to placebo in patients undergoing surgical debridement of leg ulcers and equivalent to prilocaine infiltration in patients undergoing punch or excision skin biopsy. Eutectic lidocaine/prilocaine cream (at least 1g/lesion) has provided effective analgesia for removal of condylomata acuminata in both men and women in several controlled trials, with eutectic lidocaine/prilocaine cream providing a satisfactory, and more comfortable, alternative to lidocaine infiltration in 2 studies. In female patients with lesions on vulval mucosal membranes, application times of 5 to 15 minutes appear to provide optimal analgesia. In urology, eutectic lidocaine/prilocaine cream may be of benefit as an adjunct to extracorporeal shock wave lithotripsy for the removal of urinary calculi, with greater efficacy in males than females reported in 1 study. Efficacy equivalent to that of lidocaine infiltration has also been shown in a controlled study. Pilot studies and other preliminary trials of eutectic lidocaine/prilocaine cream in obstetrics, gynaecology and andrology have indicated benefit in a variety of procedures, including laser treatment of cervical intraepithelial neoplasia, vulval biopsy, lumbar epidural catheterisation in labour, drainage of non-lactational breast abscesses, and separation of preputial adhesions in boys. There have been a number of studies indicating efficacy of eutectic lidocaine/prilocaine cream for local anaesthesia of the tympanic membrane during myringotomy and ventilation tube insertion, in patients without tympanic perforation. Analgesic efficacy with eutectic lidocaine/prilocaine cream appears to be similar to that of lidocaine iontophoresis, prilocaine injection, or cocaine. While eutectic lidocaine/prilocaine cream was more convenient to use than the other agents, it should not be used in patients in whom penetration of the cream to the middle ear is possible. Other potentially painful procedures in which eutectic lidocaine/prilocaine cream has been studied include retrobulbar injection in cataract surgery, removal of arch bars in mandibular fracture, dermal puncture in electromyography, and paediatric percutaneous renal biopsy. Local skin reactions (mainly blanching and erythema) have occurred in 56% of patients treated with eutectic lidocaine/prilocaine cream. These effects are mild and transient, and resolve spontaneously within 1 to 2 hours after removing the cream. Methaemoglobinaemia, attributed to a metabolite of prilocaine, has been reported in an infant aged 3 months treated with eutectic lidocaine/prilocaine cream and receiving concomitant cotrimoxazole (trimethoprim/sulfamethoxazole) administration, which may also be associated with this adverse event. A subsequent study in infants less than 3 months of age, while noting statistically significant small increases in methaemoglobin levels, did not observe clinically significant methaemoglobinaemia in any infant; similar findings were reported from studies in children aged between 3 months and 6 years. Use of eutectic lidocaine/prilocaine cream is, however, contraindicated in infants less than 3 months of age. A thick layer of eutectic lidocaine/prilocaine cream 5% is applied to intact skin under an occlusive dressing for at least 1 hour before the procedure. For needle insertion or surgical treatment of localised lesions, approximately 2.5g of the cream should be applied to 20 to 25cm2 of skin. For more painful procedures that involve larger areas of skin, approximately 1.5 to 2g/10cm2 should be applied for at least 2 hours. In infants aged less than 12 months, eutectic lidocaine/prilocaine cream should not be applied for more than 4 hours. Its use is contraindicated in all infants aged less than 3 months and in those aged up to 12 months who are also receiving methaemoglobin-inducing agents. Eutectic lidocaine/prilocaine cream should not be used in any clinical situation in which its penetration beyond the tympanic membrane is possible.

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