Topical Anesthesia During Minor Surgical and Needle-Related Procedures in Infants and Children

Introduction

Topical and local anesthetic agents remain key components of providing analgesia in infants and children for minor surgical and needle-related procedures including intravenous cannulation of procedural sedation. As the science of pediatric pain medicine has advanced, the immediate deleterious physiologic effects, as well as the potential for the long-term impact of inadequately treated painful invasive procedures, have been demonstrated.^1,2 Although frequently used in the awake child for topical analgesia prior to peripheral venous cannulation, these agents may also be used to provide superficial analgesia for more invasive needle-related procedures such as lumbar puncture or bone marrow aspiration. In these latter settings, topical analgesia may limit the requirements for procedural sedation and potentially decrease the incidence of adverse hemodynamic and respiratory effects.

History of Local Anesthetic Agents

The history of the use of local anesthetic agents for medicinal and other purposes dates back thousands of years to the first local anesthetic, cocaine, derived from the plant Erythroxylon coca, which is indigenous to the valleys of South America. Although its first use in Western medicine for eye surgery in 1884 is attributed to Dr Carl Koller, a Viennese ophthalmologist, its first documented use as a local anesthetic in surgery actually occurred in approximately 800 AD when cocaine-filled saliva formed by the chewing of coca leaves was dripped onto the skull to provide topical anesthesia for trephination.³ In Western society, cocaine was originally isolated by Albert Niemann in 1859, who reported its local anesthetic effect (numbing) on the tongue. The work of Dr Koller revolutionized surgery in the field of ophthalmology by allowing for painless eye surgery without the need for general anesthesia. Although the use of cocaine as a local anesthetic spread rapidly, its limited safety margin with significant risk of toxicity and addictive potential led to the search for safer alternatives and its eventual abandonment as a topical anesthetic agent. In 1905, a German chemist, Alfred Einhorn, synthesized a new local anesthetic agent, procaine. He subsequently trademarked the name Novocain, which is derived from the Latin words “nov” meaning new and “caine,” a common chemical nomenclature for alkaloids used as anesthetics. Novocain’s relative safety and effectiveness made it a widely used local anesthetic for several decades in the medical and dental fields. It became the standard of care for local anesthetic agents until the development of lidocaine in 1948. In the last 20 years, a number of new topical creams and devices have become commercially available that can provide reliable cutaneous analgesia without the use of a needle and with increasingly shorter onset times.

The first topical anesthetic cream to gain significant use in clinical practice was EMLA (eutectic mixture of local anesthetics) originally introduced into the clinical market by Astra Pharmaceutical Production AB, Södertälje, Sweden, which received approval by the US Food and Drug Administration (FDA) in December 1992. The term eutectic is a chemical descriptor that signifies a combination of 2 or more substances that has a lower melting point than each individual substance. In the case of EMLA, the mixture of the 2 local anesthetic agents, lidocaine and prilocaine, has a lower melting point than either anesthetic alone. Because of this property, the EMLA compound remains in liquid form at room temperature, which enhances penetration of the skin, thereby facilitating the onset of its local anesthetic properties. Following its introduction into clinical practice, the potential applications of topical anesthetic creams like EMLA expanded to most minor procedures that involved cutting the skin or piercing it with a needle, including intravenous cannulation, phlebotomy, removal of superficial skin lesions, lumbar puncture, and vaccinations. Over the years, the options for topical anesthesia have expanded with the intent of improving efficacy, shortening onset times, and increasing the depth of penetration into the layers of the skin.

Local Anesthetic Agents: General Chemical and Physical Properties

A brief review of the pharmacology of local anesthetic agents may be helpful to provide insight into their use topically and the potential, albeit rare, adverse effects of these agents. The 2 chemically distinct classes of local anesthetic agents include amino esters and amino amides. When considering current clinical practice, the amino esters include procaine, chloroprocaine, and tetracaine while the amides include lidocaine, mepivacaine, prilocaine, bupivacaine, levobupivacaine, and ropivacaine. These 2 classes of local anesthetic agents differ in their site of metabolism, plasma half-lives, adverse effect profile, and potential for allergic reactions. Amino esters are metabolized in the plasma by cholinesterases, while amino amides are metabolized in the liver. Given their metabolism, the half-life of the amino esters is relatively constant across all age ranges because the plasma cholinesterases are distributed in body water with less variation, based on gestational and chronologic age. Their metabolism is generally rapid and hence even with excessive dosing, local anesthetic system toxicity is rare. Because the amides are dependent on hepatic metabolism, there are significant age and developmental differences in their metabolism.^4,5 Additionally, the potential for allergic reactions may vary between the esters and the amides. Para-aminobenzoic acid is a metabolite of amino ester breakdown and may result in allergic reactions, whereas amino amides have a diminished allergic potential.

Local anesthetic agents differ in intrinsic potency, onset of action, duration of action, and their ability to produce differential sensory and motor blockade. Both classes of local anesthetic agents block sodium channels in the nerve membrane, thereby interfering with depolarization and propagation of nociceptive input. The non-ionized portion of the local anesthetic agent penetrates the lipid membrane, while the ionized portion reversibly blocks the inner aspect of the sodium channel. Penetration of the lipid membrane of the nerve and therefore lipid solubility is the primary determinant of potency. Agents with a higher potency (bupivacaine, tetracaine, and ropivacaine) are more lipid soluble.⁶ The onset of action of a local anesthetic agent is determined primarily by the pKa, which is generally a reflection of the strength of an acid.^7,8 The pKa of local anesthetic agents is generally close to the physiologic range, varying from 7.6 to 9.1. The closer the pKa is to the physiologic pH of 7.4, the more rapid the onset of action because there will be a greater percentage of local anesthetic agent in the non-ionized form at physiologic pH, thereby promoting penetration of the nerve membrane. Lidocaine has a pKa of 7.7, which means that 35% of the drug is non-ionized at a pH of 7.4, resulting in a relatively rapid onset of blockade. In contrast, tetracaine has a pKa of 8.6 and therefore only 5% is in the non-ionized form at a tissue pH of 7.4, resulting in a slower onset of blockade.

Duration of action is determined primarily by the degree of protein binding.⁹ Local anesthetic agents bind to protein receptors in the sodium channels. A higher degree or avidity of protein binding produces a longer-lasting blockade of sodium channels and a longer duration of action. Bupivacaine, tetracaine, and ropivacaine are all extensively protein-bound and hence are long-acting local anesthetic agents. Local vasodilation can also affect duration of action by removing the local anesthetic agent more quickly from the site of action.¹⁰ The local vasodilatory effects noted with lidocaine result in a shorter duration of action and also lay the clinical groundwork for the common practice of adding epinephrine, usually in a concentration of 5 µg/mL or 1:200,000, to commercial preparations of lidocaine to prolong its duration of action. The strength or extent of the block provided by any local anesthetic can be increased by increasing the concentration or the volume of the local anesthetic.¹¹ However, higher plasma concentrations of the local anesthetic agent will also be achieved, thereby increasing the risks of local anesthetic system toxicity.

Topical Anesthetic Agents for Needle-Related Procedures

The stratum corneum of the skin provides an effective barrier to aqueous local anesthetic agents and until the early 1990s, cutaneous analgesia for intravenous catheter placement could only be achieved by injecting the local anesthetic agent directly into the skin or subcutaneous space. In 1980, emergency department physicians began using topical anesthesia for laceration repair with the placement of an anesthetic solution containing tetracaine, epinephrine, and cocaine into a wound.¹² Subsequently, investigators began actively investigating ways to facilitate the penetration of local anesthetic agents across the skin.¹²

Novel delivery forms for topical anesthesia have been developed in the last 30 to 40 years to allow for the provision of cutaneous analgesia without injection into the skin. These have included either changing the physical properties of the local anesthetic preparations to make them more lipophilic (e.g., eutectic mixtures or liposomal preparations) or the development of relatively noninvasive and non-painful techniques to disrupt the epidermis to make it easier for the local anesthetic to penetrate the stratum corneum (e.g., iontophoresis and jet-propulsion injectors). Although the initial topical preparations included a mixture of lidocaine and prilocaine, subsequent preparations have included tetracaine, lidocaine, or the two in combination. In general the lidocaine-prilocaine cream provides effective topical analgesia in 60 minutes, while preparations with tetracaine have a shorter onset time of approximately 30 minutes. The reduction in onset time may make the use of these agents more practical in busy clinical settings.

Eutectic Mixture of Lidocaine and Prilocaine.

EMLA cream, the first topical anesthetic commercially available for use on intact skin, was introduced into clinical practice in the United States by AstraZeneca in 1992. EMLA is a mixture of the local anesthetic agents prilocaine and lidocaine, which when combined in equal amounts form a liquid at room temperature. During the 1990s EMLA became the most extensively used and studied topical anesthetic cream, with several clinical trials demonstrating its efficacy in reducing the pain of superficial cutaneous procedures including venipuncture and placement of an intravenous cannula. A meta-analysis of 7 controlled trials in children and adults demonstrated that EMLA cream reduced the pain of venipuncture and venous cannulation in most patients (85%).¹³ Additional clinical trials demonstrated its efficacy in reducing pain for other needle-stick procedures such as lumbar puncture, heel stick, immunization, and circumcision. Potential drawbacks that may hamper its widespread acceptance and use include the longer onset time (at least 60 minutes); limitation of its depth of penetration; the potential to cause cutaneous vasoconstriction, which can make venous cannulation more difficult; and the recognized side effect, which is specific to prilocaine; the development of methemoglobinemia (see below). Although 60 minutes is the minimum recommended application time by the manufacturer, longer application times (more than 90 minutes) may be associated with better quality of analgesia. Even with longer application times (3−4 hours), depth of penetration is no more than 6 mm, thereby limiting its utility of more invasive procedures without additional subcutaneous infiltration.¹⁴

A rare yet dangerous adverse effect of one of the local anesthetic agents in EMLA is the formation of methemoglobinemia from a metabolite of prilocaine. The metabolite oxidizes the iron moiety of the hemoglobin molecule from the normal reduced (2⁺) or ferrous state to the 3⁺ or ferric state, known as methemoglobinemia. Methemoglobin is unable to carry oxygen effectively and depending on the native hemoglobin concentration, methemoglobin concentrations in excess of 10% to 20% can cause systemic symptoms related to tissue hypoxia. Normally, the body can covert small amounts of methemoglobin back to hemoglobin through the NADH-methemoglobin reductase enzyme system. Development of methemoglobin is generally more rapid and problematic in neonates and infants because fetal hemoglobin is more sensitive to oxidative stresses, facilitating the conversion of ferrous to ferric iron, and there is reduced enzyme function given hepatic immaturity. In clinical practice, reports of methemoglobinemia related to the prilocaine in EMLA cream have been exceedingly rare, occurring primarily in neonates or in susceptible individuals with application on large surface areas, on denuded skin, on mucous membranes, for a prolonged period of time, and covering with an occlusive dressing.

Amethocaine (Tetracaine) Gel.

Amethocaine gel (Ametop, initial manufacturer was Smith & Nephew, Andover, Massachusetts, USA) is a topical aqueous gel preparation of 4% amethocaine (tetracaine) that is widely available in Europe and Canada. Because the company has not sought approval by the FDA, it is not available for clinical use in the United States. Tetracaine gel preparations may offer potential advantages over EMLA cream, including a more rapid onset of analgesia within 30 to 45 minutes; vasodilation at the application site, which has been proposed to facilitate vascular access, although outcome studies are not available; a longer duration of anesthesia (approximately 4−6 hours) due to a depot effect in the stratum corneum; and a decreased risk of methemoglobinemia.¹⁵ Although amethocaine gel is not available in the United States, other topical preparations with tetracaine in a gel form are available either alone or with other local anesthetic agents such as lidocaine. Additionally, a tetracaine-lidocaine mixture is commercially available as the Synera patch (initial manufacturer was ZARS, Pharma, Salt Lake City, Utah, USA - see below).

Liposomal Lidocaine.

Liposomes are microscopic multilamellar vesicles containing several lipid (phospholipids and cholesterol) bilayers dispersed in an aqueous medium. The liposomal structure enhances penetration of the epidermis and protects against rapid degradation of the local anesthetic agent, prolonging the duration of analgesia. Although tetracaine was the first local anesthetic to be encapsulated into a liposome to facilitate penetration through the stratum corneum, a commercial preparation of liposomal tetracaine has not yet been marketed. However, a liposomal preparation of 4% lidocaine was developed and subsequently marketed as an over-the-counter topical anesthetic agent (ELA-Max 4%, initially manufactured by Ferndale Laboratories, Ferndale, Michigan, USA). Incorporation of lidocaine into a liposomal vehicle speeds analgesic onset to approximately 30 to 45 minutes and negates the need for an occlusive dressing, although most health care providers generally cover the cream with a dressing to keep it in place. Because of the excellent safety profile of the product, it has received approval for over-the-counter use by the FAD. Several prospective randomized trials in children and adults have demonstrated no clinical difference in efficacy between liposomal lidocaine 4% applied for 30 minutes and EMLA 5% after a 60-minute application.¹⁶⁻¹⁸ Adverse events have generally been limited to local cutaneous reactions such as pallor, redness, and mild pruritus at the application site. Even when applied in neonates (application amount of 1 g), measured plasma lidocaine levels have remained low at <300 ng/mL.¹⁹

Heated Lidocaine-Tetracaine Patch.

The Synera patch or S-Caine Patch was a unique delivery system that used a patented controlled heat-assisted drug delivery system (CHADD) to accelerate the onset of cutaneous analgesia to 20 minutes. The device consisted of a 2.5" × 3.0" patch containing a eutectic mixture of 70-mg lidocaine and 70-mg tetracaine in a ratio of 1:1 by weight, a bio-adhesive layer, and a heating element that was activated by oxidation on exposure to ambient air, generating heat at 39°C to 41°C.^20–22 Cutaneous heating accelerated the solubility, diffusion, and analgesic onset time of the 2 local anesthetic agents. Despite its apparent efficacy in clinical trials, production of the Synera patch, was been discontinued and it is no longer available in the United States.

Summary

The placement of an intravenous cannula remains a source of considerable anxiety and pain, especially for young children. The search for the optimal technique and agents to provide topical dermal anesthesia has been ongoing for the last 40 to 50 years. The current FDA-approved agents can be used to provide effective topical dermal analgesia for various superficial needle procedures, including intravenous catheter placement and venipuncture, with only minor clinical differences in onset time, and with tetracaine gels generally providing a more rapid onset than combinations of lidocaine and prilocaine (EMLA cream or patch). When used properly, these agents have a wide margin of safety with a limited adverse effect profile. Regardless of the agents used and the route of administration, the practitioner must have a thorough understanding of the local anesthetics in the preparation, appropriate dosing recommendations, and potential toxicity of these agents’ dosing ranges.

ABBREVIATIONS

EMLA

eutectic mixture of local anesthetics

FDA

US Food and Drug Administration