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450 Journal of Anaesthesiology Clinical Pharmacology | October-December 2015 | Vol 31 | Issue 4
Topical anesthetics are being widely used in numerous medical and surgical sub-specialties such as anesthesia, ophthalmology,
otorhinolaryngology, dentistry, urology, and aesthetic surgery. They cause superficial loss of pain sensation after direct application.
Their delivery and effectiveness can be enhanced by using free bases; by increasing the drug concentration, lowering the
melting point; by using physical and chemical permeation enhancers and lipid delivery vesicles. Various topical anesthetic
agents available for use are eutectic mixture of local anesthetics, ELA-max, lidocaine, epinephrine, tetracaine, bupivanor, 4%
tetracaine, benzocaine, proparacaine, Betacaine-LA, topicaine, lidoderm, S-caine patch™ and local anesthetic peel. While using
them, careful attention must be paid to their pharmacology, area and duration of application, age and weight of the patients
and possible side-effects.
Key words: Topical anesthesia, Eutectic mixture of local anesthetics, iontophoresis, local anesthetic, skin permeation enhancer,
sonophoresis, uses and side-effects of topical anesthetics
Topical anesthesia
Mritunjay Kumar, Rajiv Chawla, Manish Goyal
Department of Anesthesiology and Intensive Care, Govind Ballabh Pant Hospital, New Delhi, India
Introduction
Injections of local anesthetics are painful. It can worsen needle
anxiety, and can cause tissue edema, which distorts the surgical
site. Use of topical anesthesia can avoid all these problems
and is becoming a routine in clinical practice.
Topical anesthesia is defined as superficial loss of sensation
in conjunctiva, mucous membranes, or skin, produced by
direct application of local anesthetic solutions, ointments,
gels or sprays.
The first local anesthetic (cocaine) was a topical anesthetic and
was serendipitously discovered to have anesthetic properties,
when Albert Niemann in 1860, like many chemists of that
era tested his newly isolated compound and noted that it
caused numbing of the tongue.[1] In 1884, Karl Koller, an
ophthalmic surgeon, demonstrated that general anesthesia
could be avoided for ophthalmic procedures by using cocaine
application to the conjunctiva.[2] The discovery of various
amide and ester local anesthetics, their topical preparations
and delivery systems in due course of time opened the gate of
immense possible uses of topical anesthetics.
Mechanism of Action
Topical anesthetics reversibly block nerve conduction near
their site of administration by targeting free nerve endings
in the dermis or mucosa, thereby producing temporary loss
of sensation in a limited area. Nerve impulse conduction is
blocked by decreasing nerve cell membrane permeability to
sodium ions, possibly by competing with calcium-binding sites
that control sodium permeability. This change in permeability
decreases depolarization and increases excitability threshold
until the ability to generate an action potential is lost.
Pharmacology
Topical anesthetics are weak bases. They are made up of three
important components: An aromatic ring, an intermediate
length ester or amide linkage and a tertiary amine. The
aromatic ring is primarily responsible for the lipid solubility
that allows diffusion across the nerve cell membrane,
determining the intrinsic property of these agents.[3-5] Protein
binding of these agents depend on both the aromatic and
amine portion.[6]
Abstract
Address for correspondence: Dr. Mritunjay Kumar,
N-207, Vivek Vihar, Sector 82, Noida, U.P. - 201304, India.
E-mail: dr.mritunjay@gmail.com
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Journal of Anaesthesiology Clinical Pharmacology | October-December 2015 | Vol 31 | Issue 4 451
Onset of action, anesthesia depth, and duration of action
are determined by the pKa level, pH level, lipid solubility,
protein binding, and vasodilatory effects of the specific local
anesthetic. Other factors, which play important roles, are the
site of application (faster onset at mucosa and sites with thin
stratum corneum), vascularity of tissues in the area applied,
the surface area, and duration of application.
Ester-type topical anesthetics are metabolized by plasma
cholinesterase and other nonspecific esterases, while amide
anesthetics are primarily metabolized in the liver via
microsomal enzymes. Ester anesthetics are known to cause
allergic manifestations on contact, while it is said to be a rare
occurrence with amide anesthetics.[7-9] Para-amino benzoic
acid (PABA), an ester hydrolysis metabolite is also known
to be associated with allergic manifestations.[10]
Skin Penetration Routes
There are three pathways to cross the stratum corneum, which
is the main barrier for topical anesthetic agent delivery:[11]
Intercellular route (through the intercellular spaces of the cornified
keratinocytes), para or transcellular route (through the cornified
cells) and transappendageal route or shunt pathway (through
the openings of the hair follicles and sweat glands) [Figure 1].
Topical anesthetics are also able to penetrate mucosal surfaces,
such as the mouth, genitals, and conjunctiva more easily than
through a keratinized surface because of the absence of a
stratum corneum.
Factors Determining the Dermal
Drug Delivery
Drug form
Free bases are lipophilic and can penetrate the stratum
corneum on its own whereas the salt forms require special
delivery systems to do so.
Melting point and eutectic mixtures
The lower the melting point, the better the penetration is.
Eutectic mixtures have a lower melting point, thus better
penetration than either component by itself.
Concentration of drug in vehicle
Higher the concentration of drug in the vehicle, higher the
rate of penetration.
Skin permeation enhancers
These compounds, promote skin permeability by increasing
the permeability of the stratum corneum temporarily and
reversibly. They can be:
a. Solvents, e.g., water, alcohols, glycerol, low molecular
weight ethers, sucrose esters,[12] silicone fluids etc.,
b. Surfactants[13] e.g., ionic, nonionic, bile salts or
c. Miscellaneous chemicals, e.g., urea, anticholinergic drugs.
Permeation enhancers under trial are eucalyptol, soya bean
casein.[14]
Physical means of enhancing permeation
Skin penetration of topically applied anesthetics can be
enhanced by following physical measures:
a. Exfoliation of the skin.
b. Degreasing by alcohol.
c. By covering the application area with a dressing or patch
of nonporous material such as micropore and tegaderm.
Following energy-dependent active measures are being
used/tried to enhance drug delivery across the skin.[15]
d. Iontophoresis [Figure 2] (low voltage current to drive charged
drugs through skin).[16] The amount of drug delivered via
iontophoresis is dependent on the current and the duration
of delivery. Lignocaine HCl 10%/adrenaline 0.1% topical
iontophoretic patch (LidoSite) is the first Food and Drug
Administration (FDA) approved prefilled active anesthetic
patch. Disadvantages of ionotrophoresis technique are:
Figure 2: IontophoresisFigure 1: Skin penetration routes
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452 Journal of Anaesthesiology Clinical Pharmacology | October-December 2015 | Vol 31 | Issue 4
i. Can cause skin irritation at higher current densities
or upon longer application,[17]
ii. Prolonged application can also cause electrochemical
polarization in the skin, which decreases the
magnitude of current flow through the skin,
iii. The mild electrical sensation can be uncomfortable
for some patients.
iv. The apparatus is expensive and bulky, and
v. It cannot be used over large surface areas of the body.
e. Electroporation (uses short electrical impulses of high
voltage to create transient pores in the skin).[18] The
electrical pulses are applied only for fraction of a second;
the interval between subsequent pulses allows the skin to
depolarize.[19] Therefore, polarization of skin does not
interfere with the current flow or drug diffusion.
f. Sonophoresis or phonophoresis [Figure 3] (low frequency,
ultrasonic energy to disrupt stratum corneum)[20] — The
ultrasound enhances drug delivery by cavitation, micro
steaming and heating. The frequencies used can be high
in the range of 0.7-16 MHz or low frequency in the
range of 20-100 kHz. Low frequency sonophoresis can
allow transdermal delivery of both hydrophilic and high
molecular mass permeants at therapeutic levels.
g. Magnetophoresis/magnetokinesis (application of
magnetic field to enhance permeation).[21]
h. Thermal energy (heat à increases skin permeability).
i. Erbium:YAG laser pretreatment.[22]
j. Skin pretreatment with a hand-applied, plastic
microneedle array.[23]
Delivery from Lipid Vesicles
Liposomes, niosomes, and transfersomes are examples of
lipid vesicles.
Liposomes are microscopic vesicles, which are composed
of one or more lipid bilayers arranged in concentric fashion
enclosing an equal number of aqueous compartments capable
of entrapping lipid soluble or water-soluble drugs. The lipids
used are typically phospholipids such as lecithin. Drug
molecules can either be encapsulated in the aqueous space
or intercalated into the lipid bilayer depending upon its
physicochemical characteristics.[24,25] Studies with radioactive
or fluorescence-labeled phospholipids have shown that
the liposomes disperse in the upper layers of the stratum
corneum, without further penetration into the epidermis,
dermis or deeper.[26] Fisher et al. in their study found that
5% liposome-encapsulated tetracaine produced better
superficial local anesthesia than 5% eutectic mixture of local
anesthetics (EMLA).[27] Disadvantages of liposomes are
their instability, and the predisposition of phospholipids to
oxidative degradation.
Niosomes (microvesicles) are similar to liposomes, but are
prepared from nonionic surfactants. They tend to be smaller
in diameter than liposomes, and may have unilamellar
(one layer), or multilamellar structures. They are more stable
and may provide faster penetration to the stratum corneum
than liposomes. They do not go deeper either.
Transfersomes are prepared using bile salt (sodium cholate)
molecules. Unlike liposomes, transfersomes appear to be
highly deformable and researchers claim that they can transport
through pores, which are 5 times smaller than their size.
Various Topical Preparations
Eutectic mixture of local anesthetics
Eutectic mixtures are compounds, which melt at lower
temperatures than any of their components, permitting higher
concentrations of anesthetics for use. It is 5% oil in water
emulsion cream with a melting point of 18°C and consists of
25 mg/mL of lignocaine, 25 mg/mL of prilocaine, a thickener,
an emulsifier, and distilled water adjusted to a pH level of
9.4. EMLA is applied in a thick layer (1-2 g/10 cm2, up to a
maximal dose of 20 g/200 cm2) to intact skin. Pediatric dosing
is shown in Table 1. After application, the area is covered
with a patch of tegaderm or clear plastic wrap to facilitate
penetration through the stratum corneum. Depth of anesthesia
depends on the contact time with EMLA. Anesthetic effect
has been shown to reach a maximal depth of 3 mm after a
60-min application, and 5 mm after a 120-min application.
Dermal analgesia can be expected to increase for up to 3 h
Figure 3: Sonophoresis
Table 1: Pediatric dosing of EMLA
Age and body weight
requirements (kg)
Maximum total
dose of EMLA
cream (g)
Maximum
application
area (cm2)
Maximum
application
time (h)
0 up to 3 months or <5 1 10 1
3 up to 12 months and >5 2 20 4
1-6 years and >10 10 100 4
7-12 years and >20 20 200 4
EMLA = Eutectic mixture of local anaesthetics
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Journal of Anaesthesiology Clinical Pharmacology | October-December 2015 | Vol 31 | Issue 4 453
under occlusive dressing and persist for 1-2 h after removal
of the cream. EMLA should not be applied to the palms and
soles because of variable penetration. EMLA is a pregnancy
category B agent, but caution should be exercised when
being administered to a nursing mother, because lignocaine
is excreted through breast milk (AstraZeneca insert).
Tetracaine, adrenaline (epinephrine),
and cocaine (TAC)
Consists of 0.5% tetracaine, 0.05% adrenaline, and
11.8% cocaine. It was the first topical anesthetic mixture
found to be effective for nonmucosal skin lacerations to
the face and scalp. A dose of 1 ml/cm of laceration can
be applied using a cotton-tipped applicator with firm
pressure that is maintained for 20-40 min. However, it
is no longer being used because of general concern about
toxicity and expense, and federal regulatory issues involving
medications containing cocaine.[28]
Lidocaine, epinephrine, and tetracaine (LET)
Safer and more cost-effective alternative to TAC, contains
4% lignocaine with 0.1% epinephrine and 0.5% tetracaine.
LET is used on nonmucosal skin lacerations by placing a
few drops directly into the wound. A cotton-tipped applicator
with 1-3 mL of the gel or solution is then applied directly to
the wound with firm pressure for 15-30 min. It can be safely
used in children older than 2 years of age. LET is slightly
less effective on extremity lacerations. Because LET contains
epinephrine, application to end-arteriolar parts of the body,
such as the digits, should be avoided. Caution must also be
exercised when contemplating the use of LET in contaminated
wounds, complex wounds, or wounds larger than 6 cm. LET
and TAC do not work on intact skin.[28]
Bupivanor
It contains 0.48% bupivacaine and 1:26000 norepinephrine.
Bupivanor is an effective alternative to TAC and lidocaine
infiltration for local anesthesia during laceration repair,
especially on the face and scalp.[29]
ELA-max
It contains 4 or 5% (ELA-max 5) lignocaine cream in a
liposomal matrix and is FDA-approved for the temporary relief
of pain resulting from minor cuts and abrasions. ELA-max 5
is marketed for temporary relief of anorectal pain. ELA-max is
applied to intact skin for 15-40 min with or without occlusion
and provides a longer duration of anesthesia compared to
nonliposomal preparations. Maximum area of application
is 600 cm2. In children weighing less than 20 kg, a single
application of ELA-max cream should not be applied to an
area larger than 100 cm2.[30]
Betacaine-LA
It contains lignocaine, prilocaine and phenylephrine. Betacaine-
LA is a proprietary anesthetic and exact concentration of its
ingredients is a trade secret. The pocket insert of the product
reports concentrations of lignocaine and prilocaine to be
4 times that of EMLA and so, it should not be applied to
an area larger than 300 cm2 in adults and is not advocated
for use in children.[30]
4% tetracaine (amethocaine)
It is a long acting ester anesthetic in lecithin gel base, with
a recommended application time of 30-min under occlusive
dressing and maximum dose limit of 50 mg.[30]
Topicaine
Topicaine is 4% lignocaine in a gel microemulsion drug
delivery system. The recommended application time by the
manufacturers is 30-60 min. The maximum area of application
is 600 cm2 in adults and 100 cm2 in children.[30]
S-Caine Patch™ and local anesthetic peel
The patch (manufactured by ZARS, Inc., Salt Lake
City, UT, US) contains a 1:1 eutectic mixture of
70 mg lignocaine and 70 mg tetracaine base, with a
disposable, oxygen activated heating element, which helps
in accelerating transcutaneous delivery and analgesic
effect of local anesthetics. The heating element generates
a controlled level of heating (39°C-41°C) over a period
of 2 h. [31,32]
Lidoderm patch
Lidoderm is comprised of an adhesive material containing 5%
lignocaine. Each adhesive patch contains 700 mg of lignocaine
(50 mg/g adhesive) in an aqueous base. It has been recently
approved by the FDA for the treatment of pain caused by
postherpetic neuralgia.
Proparacaine or proxymetacaine
About 0.5% solution is suitable for ophthalmic use. With
a single drop, the onset of anesthesia usually begins within
30 s, the maximum anesthetic effect is achieved at 5-min and
duration of corneal anesthesia is 15-25 min.
Miscellaneous agents with topical anesthetic potential
8-10% capsaicin[33] (act on transient receptor potential
vanilloid 1, i.e., the transient receptor potential channel of
the vanilloid receptor family subtype 1); tetradotoxin,[34,35]
0.8% nalbuphine,[36] ethyl chloride spray[37] etc.
Clinical applications
a. For local analgesia on intact skin-EMLA, 4% tetracaine,
S-Caine Patch™.
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b. Minimize discomfort prior to injections or before
intravenous and arterial line[38] access-EMLA, 4%
tetracaine.
c. For symptomatic relief of chronic pain-heated lidocaine/
tetracaine patch has potential utility for managing
myofascial trigger points.[39] Successful treatment of
trigeminal neuralgia by topical anesthetic oxybuprocaine
or proxymetacaine instilled in the eye of the affected side
is also reported.[40,41]
d. To relieve pruritus and pain due to minor burns, skin
eruptions (e.g., herpes, sunburn, insect bites), stings,
poison ivy, and minor cuts and scratches.-EMLA,
lidocaine, epinephrine, and tetracaine (LET), bupivanor,
ELA-max.
e. To assist awake fiberoptic intubation-topical application,
“spray as you go” technique, using MADgic device
etc., 2% or 4% lignocaine.
f. In ophthalmology and optometry-0.5% proparacaine,
0.4% oxybuprocaine, 2% lignocaine aqueous gel and
drops, 0.5% tetracaine.
To numb the outermost layers of the cornea and conjunctiva to:
1. Perform a contact/applanation tonometry.
2. Perform a Schirmer’s test.
3. Remove small foreign bodies.
4. During procedures as cryotherapy, shave biopsy,
curettage of molluscum contagiosa, and laceration
repair.
5. Cataract phacoemulsification and minor laser surgeries.
6. Intravitreal injection.[42]
g. In dentistry-to numb oral tissues before administering
a dental local anesthetic and for symptomatic relief in
aphthous stomatitis-2-8% lignocaine, benzocaine 10%
and 20%, EMLA.
h. Otorhinolaryngology, for the day care and office based
procedures[43] like:
1. Topical anesthesia of the tympanic membrane for
tympanocentesis; myringotomy; transtympanic
injection of gentamicin or steroids; and pressure
equalizing tube placement, removal, or manipulation
- using topical 80-90% liquefied phenol[44] (provides
an effective full-thickness analgesia with an immediate
effect), a solution of 8% tetracaine base in 70%
isopropyl alcohol[45] or EMLA.[46]
2. Indications in nasal cavity include examination
using rigid or flexible endoscopes, nasal
debridement, control of epistaxis, treatment of nasal
fractures,[47] and management of abscesses and
hematomas.-Commonly administered in conjunction
with a vasoconstricting substance such as 0.05%
oxymetazoline for decongestion of mucosal edema.
3. In oral cavity and oropharynx-to assist in awake
fiberoptic intubation or laryngoscopy, local
examination,[48] closure of a laceration, incision and
drainage of a peritonsillar abscess, and treatment
of patients who have sustained severe dentoalveolar
trauma like maxillomandibular fixation for mandible
fractures. The topical anesthetics applied to the
mucous membranes in the oral cavity can be useful
in alleviating the pain associated with infiltration
of local anesthetics, which can be a source of great
apprehension for many patients.
4. Topical anesthesia of the larynx helps in diagnostic
laryngoscopy and bronchoscopy, transnasal
esophagogastroduodenoscopy, and placement of an
endotracheal tube when awake intubation is indicated
either electively or emergently.
i. For superficial dermatologic, esthetic, and laser
procedures like venipuncture,[49] hair and warts removal,
split thickness skin graft harvesting,[50] shave or excision
biopsy, dermabrasion for tattoo removal, venous leg ulcer
debridement, curettage and electrosurgery, treatment of
port-wine stains etc.,-EMLA 5%.
j. For minor penile surgery like circumcision, short frenulum
plasty, meatotomy, fulguration of penile and urethral warts.
Also for, temporary relief of premature ejaculation when
applied to the glans of the penis.[51]-EMLA 5%, benzocaine.
Contraindications
Ester group topical anesthetics are contraindicated in patients
with known allergy to PABA, sulfonamides and hair dyes.
Adverse effects
Burning or stinging at the administration site.
Systemic toxicity-due to excess dosage, repeated use,
particularly in patients on risk like infants or children or
elderly, or patients with liver disease etc. Manifestations can
be as follows:
• Nonspecific-metallic taste, circumoral numbness,
diplopia, tinnitus, dizziness.
• Central nervous system (CNS): High plasma
concentration can produce CNS excitation (agitation,
confusion, muscle twitching, seizure), or CNS depression
(drowsiness, obtundation, coma or respiratory arrest).
Solutions that contain epinephrine may add to the CNS
stimulatory effect.
• Cardiovascular: Hypertension, tachycardia, ventricular
arrhythmias (ventricular tachycardia, torsades de pointes,
ventricular fibrillation, or progressive hypotension,
conduction block, bradycardia or asystole. Local
anesthetics that contain epinephrine may cause
hypertension, tachycardia, and angina.
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• Treatment as per local anesthetic systemic toxicity
treatment guidelines[52] of the American Society of
Regional Anesthesia and Pain Medicine (ASRA)
and encompasses airway management, cardiovascular
support, seizure suppression and use of 20% intralipid.
• Allergic reaction to local anesthetics - local anesthetics
with a PABA ester-type structure seem to cause most
anesthesia-related allergic reactions.
• Gag-reflex suppression may occur with oral administration.
• Methemoglobinemia (with prilocaine[53] and benzocaine[54])
- signs and symptoms of methemoglobinemia
(methemoglobin >1%) include dyspnea, cyanosis,
headache, fatigue, exercise intolerance, dizziness and loss of
consciousness. Arterial blood with elevated methemoglobin
shows a characteristic chocolate-brown color. Severe
methemoglobinemia (methemoglobin >50%) manifests
as dysrhythmias, seizures, coma and death (>70%).
Treatment includes supplemental oxygen, hyperbaric
oxygen therapy, exchange transfusion and intravenous
administration of the antidote, 1% methylene blue.[55]
• Others-skin discoloration, swelling, neuritis, tissue
necrosis and sloughing etc.
Because the risk of adverse events with improper application
is real, physicians must exercise caution and good judgment
while using topical anesthetics.
Conclusion
Topical anesthetics play an important role in decreasing
the pain associated with ophthalmological, superficial
dermatological, aesthetic and laser procedures, minor
surgeries, venipuncture etc. With very wide varieties of
agents and delivery devices being improvised upon every day,
it seems time is not far off when we can completely abolish
use of infiltrative local anesthesia. But, users should be well
aware about the pharmacology of the agents being used and
possible adverse events.
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How to cite this article: Kumar M, Chawla R, Goyal M. Topical anesthesia.
J Anaesthesiol Clin Pharmacol 2015;31:450-6.
Source of Support: Nil, Confl icts of Interest: None declared.
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