Topical anaesthetics in dermatology

The use of topical anaesthetic agents in dermatological procedures and a new combination product recently approved in the UK are discussed.

Low concentrations of local anaesthetics, such as lidocaine and benzocaine, have been used for many years in proprietary products to relief the pain and discomfort associated with haemorrhoids, teething, mouth ulcers and sore throats.

More recently, one formulation of lidocaine has been licensed as a medicated plaster (Versatis) for the treatment of post-herpetic neuralgia. Topical anaesthetics have proved to be useful as a ‘pre-numbing’ treatment for several procedures, such as cryotherapy, curettage of molluscum contagiosum and before intralesional injection of corticosteroids.

Moreover, the pain associated with minor dermatological procedures, such as laceration repair, can now be effectively managed using topical anaesthetics rather than the traditional method of intradermal injection of lidocaine.

Although effective, intradermal injection often causes brief but significant pain as the local anaesthetic is deposited and diffuses through the skin. This pain and discomfort can be problematic, especially in children who have a lower pain threshold, increased anxiety and needle phobia. Furthermore, anaesthetic injections can cause oedema and wound margin distortion when used in laceration repair.

In recent years, the number of superficial dermatological cosmetic procedures undertaken has increased and topical anaesthetic agents have been found to be useful in managing the pain associated with such procedures. Figures from the British Association of Aesthetic Plastic Surgeons show that in 2012 its members performed more than 43,000 cosmetic procedures.¹

History of topical anaesthetics

The term ‘anaesthesia’ refers to a loss of sensation or feeling, in contrast to ‘analgesia’, which refers to a loss of sensation of pain (although anaesthesia will also encompass loss of pain). For instance, when a dentist fills a tooth, the local anaesthetic, while numbing the area, also numbs pain associated with the procedure.

The first topical anaesthetic discovered was the alkaloid cocaine, which was first extracted from the plant Erythroxylon coca in 1860 by Albert Niemann. He assumed that the compound must have an anaesthetic effect because, historically, the Incas had chewed the leaves of the plant as a way of relieving pain.

However, it was not until 1884 that it was shown that ophthalmic procedures could be performed without general anaesthesia by applying cocaine to the conjunctiva.²

Nevertheless, the use of cocaine was not without risks, and between 1884 and 1891 there were reports of 13 deaths and 200 cases of systemic toxicity associated with the use of the drug as a local anaesthetic.³

Other anaesthetic agents were subsequently developed, including procaine (1904) and lidocaine (1943), which was marketed in 1948. Other agents have been developed since then, but lidocaine has become the most widely used local anaesthetic.

Classification

Chemically, anaesthetics are weak bases and possess a similar chemical structure consisting of three main components: a hydrophobic aromatic ring at one end of the molecule linked to an intermediate chain via an ester or amide bond and, at the other end, a hydrophilic tertiary amine.

The esters are hydrolysed in the body by plasma cholinesterase enzymes, giving rise to para-amino benzoic acid, which is a known potential irritant, whereas the amides are more stable and are metabolised by the liver, although little of the drug is normally absorbed systemically when used topically. Some of the commercially available agents and their constituents are shown in the Table 1.

Mode of action

To exert an anaesthetic effect, the agent must penetrate through the stratum corneum to its site of action in the dermis, which contains the blood and nerve endings. Factors that influence penetration to the dermis include the pKa of the anaesthetic and lipid solubility. If the pKa of the anaesthetic is close to the pH of the skin, the drug exists mainly as the base salt, which penetrates more easily through the stratum corneum than the ionised form.

Lipid solubility is influenced by the length of the intermediate chain, and drugs with a longer lipid chain diffuse more easily through to the dermis. The duration of anaesthesia is influenced by the degree of protein binding, which is greater for compounds with a larger intermediate chain. In addition, the degree of anaesthesia induced also depends on the length of time the product is left on the skin.

Once inside the nerve cell, the anaesthetic dissociates, liberating the ionised moiety, which is the active form. Although chemically distinct, ester and amide anaesthetics have the same mode of action, which involves blockade of the sodium channels, preventing the influx of sodium ions needed to generate an action potential and hence propagation of a nerve impulse.

Techniques to enhance the penetration into the dermis include tape stripping, using a degreasing agent such as acetone or iontophoresis, which uses an electric current to enhance absorption of the ionised form through the skin barrier. Furthermore, application of heat or occlusion can also enhance penetration and, in practice, it is recommended that topical anaesthetic agents are applied under occlusion.

Clinical efficacy of topical anaesthetics

The ideal topical anaesthetic would provide full and reliable anaesthesia on intact skin after a short period of time and have no systemic side effects. The ability of topical agents to induce anaesthesia compared with conventional intradermal injection has been examined in several randomised trials and efficacy assessed based on visual analogue scales or other validated methods such as numerical and verbal rating of pain.

In one comparative review of randomised controlled studies on the use of topical anaesthetics versus infiltration in laceration repair, it was concluded that topical agents provided at least equivalent analgesic efficacy compared to intradermal infiltration.⁴

Adverse effects

The adverse effects of topical anaesthetics are generally localised reactions such as irritation, erythema and pruritis, although in rare circumstances, anaphylactic reactions can occur. Nevertheless, systemic adverse effects such as purpura have been reported following use of EMLA cream.⁵ In general, systemic side effects tend to occur when the creams are applied over large areas of skin for prolonged periods of time, especially if the skin is occluded after application.

For example, one such case documented systemic toxicity attributed to lidocaine in a 21-month-old baby after excessive use of EMLA cream prior to curettage of molluscum contagiosum.⁶ Another potential systemic adverse effect is methaemoglobinaemia, and this has also been observed in a patient using EMLA.⁷ In 2007, the US Food and Drug Administration issued a public health advisory warning on the potential life-threatening side-effects of topical anaesthetics when used for cosmetic procedures (see Table 2).

New topical anaesthetic Pliaglis

In February 2013, a new topical anaesthetic cream, Pliaglis, which contains equal amounts of lidocaine and tetracaine (7%), was launched in the UK, having been launched in the US the previous year. It contains the highest concentration of each ingredient in a eutectic mixture and is licensed for use on intact skin to provide local anaesthesia prior to superficial dermatological procedures. The advantage of Pliaglis is that it includes a patented phase change technology so that, when applied to the skin, it forms a peel on exposure to air that conforms to the skin topography.

In other words, unlike other topical anaesthetic agents, which are applied under occlusion and subsequently rubbed off before a procedure, Pliaglis is applied to the area requiring anaesthesia and creates a self-occlusive environment that allows penetration through the skin. As the cream dries, the flexible membrane created on the surface of the skin is simply peeled away.

• Quantity

The amount of topical anaesthetic needed is determined from an estimate of body surface area (expressed in cm2). The manufacturer for Pliaglis, for example, recommends that, to treat an area of approximately 50cm2, a 1-mm thick layer of roughly 6.5g (which is nearly half of a 15g tube) is used. Further advice on the amount of cream required to treat specific body surface areas is given in the Summary of Product Characteristics (SPC).⁸

Pliaglis is normally applied up to 30 minutes before a procedure such as hair removal or dermal filler injections, although, for procedures that are associated with greater pain, for example, vein ablation or tattoo removal, Pliaglis should be applied for up to 60 minutes beforehand.

• Toxicity

The systemic toxicity of Pliaglis is likely to be low and the SPC reports that application of 59g (four 15g tubes) for up to 120 minutes over 400cm² produced plasma levels of lidocaine of 220ng/ml but levels of tetracaine were not measurable. To put this into perspective, lidocaine central nervous system toxicity occurs at levels of 1000ng/ml,⁸ thus on current evidence it seems unlikely that Pliaglis when used appropriately would give rise to lidocaine toxicity.

The local adverse effects of Pliaglis are similar to other topical anaesthetic agents and include local reactions at the site of application such as erythema (affecting nearly 50% of patients), skin discolouration (16%) and oedema (14%). Nevertheless, these adverse effects are mild and transient, resolving spontaneously after treatment.

• Clinical efficacy

There are several placebo-controlled trials using Pliaglis to manage the pain associated with the following superficial dermatological procedures:

• Cryotherapy
• Laser-assisted hair and tattoo removal
• Collagen injections
• Pulsed dye laser treatment for telangiectasia and port-wine stain removal
• Non-ablative facial resurfacing
• Vein ablation.

The evidence for the efficacy of Pliaglis in the management of the pain associated with these procedures has been reviewed by Kim.⁹ In general, all studies demonstrate a significantly greater median pain score for patients using placebo compared with Pliaglis. Moreover, the studies also show that a significantly greater proportion of patients self-reported adequate anaesthesia with Pliaglis compared with placebo.  However, the meta-analysis by Kim included only placebo-controlled studies.

The comparative anaesthetic efficacy of Pliaglis has been investigated in one trial against EMLA cream, which demonstrated significantly lower pain scores in those treated with Pliaglis (referred to as S-Caine in the study).¹⁰

However, because this study compared a cream with an air-dried peel, the differences in formulation could have influenced the outcome.

Furthermore, although both products were applied for the same period of time (30 minutes), the SPC for EMLA recommends an application time of at least 60 minutes, so it is possible that patients might not have experienced the full anaesthetic effect from EMLA cream.

Conclusions

Pliaglis appears to be an effective topical anaesthetic agent that is suitable for a range of superficial dermatological procedures. Other currently available topical anaesthetics, such as LMX4 or Ametop, are only licensed prior to venepuncture or venous cannulation, so EMLA cream is the only product licensed for use in dermal procedures.

EMLA cream has a long history of use and a good safety profile whereas practitioners have yet to gain familiarity and confidence with using Pliaglis.

Moreover, Pliaglis is considerably more expensive than EMLA cream (£22.95/15g versus £10.25/30g).

Whether the purported benefit of the air-dried membrane is perceived by health professionals as a sufficiently advantage that warrants a change in practice remains to be seen.

Key points

• The term ‘anaesthesia’ refers to a loss of sensation or feeling and this is invariably associated with analgesia or loss of pain sensation
• Anaesthetic agents in low doses have been used for many years in proprietary products to treat the pain and discomfort associated with haemorrhoids, sore throats and mouth ulcers
• Topical anaesthetics have traditionally been applied as ‘numbing agents’ before needle insertion, especially in children, but are increasingly used to relieve the pain associated with superficial dermal procedures including dermabrasion, laser-assisted procedures such as tattoo removal and prior to injection of dermal fillers
• Evidence suggests that in laceration repair, topical anaesthetics provide comparable analgesia to intradermal injection and placebo-controlled studies show that patients also achieve satisfactory analgesia with these agents in superficial dermatological procedures
• A recently introduced topical anaesthetic, Pliaglis, combines lidocaine and tetracaine in a high-strength eutectic mixture with a novel phase-changing delivery system that forms an air-dried membrane that is peeled away before the surgical procedure.

Author

Rod Tucker PhD MRPharmS
Honorary Research Associate, Faculty of Health and Social Care, University of Hull, UK
Email: [email protected]

References