Bupivacaine for topical eye anesthesia
Joseph Eldor,
MD
Department of Anesthesia
Cocaine
Albert Niemann
(1880-1921) separated the alkaloid cocaine from the dried leaves of the coca
plant in 1860. He studied the white powder and named it cocaine, also noting
the temporary numbing effect the compound had on his tongue. During the 1880s
in
Koller experimented
on animals and then presented his findings to the Congress of Ophthalmology in
Oxybuprocaine corneal toxicity
Topical
ocular anesthesia has been part of ophthalmology for more than a century. The
most commonly used drugs today are proparacaine, tetracaine, benoxinate (oxybuprocaine) cocaine and lidocaine.
Although generally well tolerated, all these can be toxic, particularly when
abused. The most common toxicities are to the ocular surface, but abuse can
cause deep corneal infiltrates, ulceration and even perforation. Fortunately,
systemic side effects are rare. Cocaine is unique for its higher incidence of
systemic side effects and high abuse potential, both of which impede its
clinical use. When used appropriately, all these drugs are remarkably safe.
They are generally not prescribed for home use, as prolonged abuse of these
drugs can be expected to result in serious complications (1).
Nam
et al. (2) compared
changes in human corneal thickness after the instillation of proparacaine with those after oxybuprocaine
instillation with time over a period of 10 minutes. Eighteen healthy young participants
were recruited. Proparacaine was used in the right
eye and oxybuprocaine in the left. Right and left
baseline corneal thicknesses were measured every 30 seconds for 10 minutes
using a noncontact specular microscope by 1 observer.
Baseline corneal thickness was defined as the average of all values taken over
10 minutes. Changes in corneal thickness were measured every 20 seconds for 10
minutes after the administration of 1 drop of 0.5% proparacaine
onto the right cornea and 1 drop of 0.4% oxybuprocaine
onto the left cornea. Mean baseline right cornea thickness was 531 +/- 45 microm, and that of the left cornea was
531 +/- 42 microm. The corneal thickness after proparacaine increased by 8.6 microm
( approximately 4.5-12.6 microm,
95% CI) and then returned to baseline within 80 seconds. Corneal thickness
after applying oxybuprocaine increased by 7.7 microm (3.6-11.2 microm, 95% CI)
and then returned to baseline within 80 seconds. There was a second transient
increase about 5 minutes later after proparacaine
instillation but no additional transient increase after oxybuprocaine
instillation. Oxybuprocaine is similar to proparacaine in terms of the severity of its effect on
corneal thickness. Corneal thickness instability may occur for 5 minutes after proparacaine administration. Changes in corneal thickness
after topical anesthetic instillation should be considered when performing
measurements for refractive surgery or central corneal thickness in glaucoma
patients.
Asensio et al. (3) determined
changes in corneal thickness after topical anesthesia. Corneal thickness was
measured before and 3 minutes after administration of two drops of oxybuprocaine 0.4% to 26 patients (26 eyes). They analyzed
the corneal thickness of a control group, which was made up of 26 patients (26
eyes) before and 3 minutes after administration of two drops of saline
solution. Corneal thickness was measured with the Orbscan
Topography System II (Bausch Lomb Surg.,
The
effect of topical anaesthetic ointments (4% cocaine,
4% xylocaine, 0.5% proparacaine,
0.2% oxybuprocaine) on the corneal epithelium of
rabbits was examined using a scanning electron microscope (4). Even after a
single application, the more toxic effect of cocaine compared to the other
topical anaesthetics was evident. Cocaine caused
disruption of both the plasma membrane and the cytoplasm. After a single
application, the other preparations caused a marked decrease in the microvilli and microplicae,
disruption of the intercellular spaces and the prominence of the cell nucleus
which under normal condition is not visible. Repeated applications caused
regular cell desquamation and damage to the plasma membrane and cytoplasm. The
damage also affected several cell layers. The cell reactions described are
clearly a consequence of the topical anaesthetics, as
the ointment base itself produced no essential cell damage. The scanning
electron microscope findings were supported by results from the transmission
electron microscope.
The
effect of different local anesthetics (Cocain 4%, Lidocaine 2%, Proparacain)
on the corneal epithelium in rabbits was examined under scanning electron
microscope (5). The experiment was divided into three groups. Group 1 received
one application of two drops of the given local anesthetic for a reaction time
of 5 minutes. Group 2 received two drops of the given anesthetic after 0, 5 and
10 minutes. The cornea was excised after 15 minutes. Group 3 were measured
after a single application of Proparacain using a Schiötz or hand applanation tonometer according to Draeger.
After a single dose of a local anesthetic principally the same changes in the
surface of the cornea were observed with all the preparations used: a distinct
decrease in the number of microvilli and microplicae, disruption of the intercellular spaces and the
prominence of the cell nuclei which under normal conditions are not visible.
After several applications the greater toxicity of Cocain
compared with the other preparations was clearly seen through the disruption of
the plasma membrane and the cytoplasm. The damage effected several layers of
cells. Tonometry when correctly performed causes no
additional damage to the cell surface.- The effect of
local anesthetics on the cell membrane can only take place after the disruption
of the tear film. The results emphasize that local anesthetics should only be
applied when absolutely essential.
With
double-masking procedures, the dose-response curves for 0.1, 0.2, and 0.4% benoxinate and 0.125, 0.25, and 0.50% proparacaine
hydrochloride were determined by monitoring changes in corneal touch threshold
after applying each anesthetic (6). The level of corneal anesthesia necessary
for applanation tonometry was
also determined. The maximum increase in threshold that could be measured
following instillation of 50 microliter of the drug
was 200 mg/mm2. All 6 anesthetic solutions produced this amount of decreased
corneal sensitivity. Recovery from the anesthetic was exponential for all
concentrations; however, the lower doses had the shortest duration. For applanation tonometry, the
corneal threshold for touch must be 75 mg/mm2 or higher. It was concluded that a quarter to a half of
the commonly used anesthetic dose is sufficient for routine tonometric
evaluation.
Sun
et al. (7) compared the onset time, duration of action, corneal toxicity, and
corneal epithelial healing time of 4 topical anesthetic agents in rabbits.
Fifty-six rabbits were treated with 4 topical anesthetics (bupivacaine,
lidocaine, procaine, and benzocaine)
at different concentrations and different pH of solutions. Corneal sensation,
corneal toxicity, and corneal epithelial healing time were measured. The onset
time of all 4 anesthetic agents was within 1 minute; however, bupivacaine and lidocaine
produced significantly longer action than procaine or benzocaine
(P < .05). Buffered bupivacaine and lidocaine had a significantly longer anesthetic effect than
that of the nonbuffered solutions (P < .05). No
significant effect on corneal epithelial healing time or corneal toxicity was
observed. Topical bupivacaine and lidocaine
had a longer anesthetic effect, particularly in buffered solutions. No
significant corneal toxicity was observed.
Judge
et al. (8) determined the relative corneal endothelial toxicities of the
following topical anesthetic agents: bupivacaine HCl 0.75%, unpreserved lidocaine HCl 4%, proparacaine HCl 0.5%, and tetracaine HCl 0.5%. The experiment was conducted using pigmented
rabbits. Approximately nine animals each were randomly assigned to eight
groups. Right eyes received injections of 0.2 ml of one of the four anesthetic
agents at one of two concentrations and left eyes received injections of 0.2 ml
of balanced salt solution. Corneal thickness and clarity were measured before
surgery and on postoperative days 1, 3, and
Gao
et al. (9) studied the effects of Complex Tropicamide
(0.5% Tropicamide and 0.5% phenylephrine
HCI) and Saline solution on corneal thickness in adult myopic patients with the
Orbscan II system in a prospective, nonrandomized,
clinical trial. The thinnest pachymetry of the cornea
was obtained before and 1.5 hours after administration of three drops of
Complex Tropicamide to the left eyes of 58 patients
(58 eyes) and Saline solution to their 31 right eyes, respectively. The corneal
thickness of the other 27 right eyes before and 1.5 hours after eyelid closure
without exposure to eye drops was used as the control group. The thinnest pachymetry of the cornea was significantly higher after
exposure to eye drops in the Tropicamide group (23.36
+/- 15.01 microm; t = -11.855, P < 0.001). Similar
findings were also noted in the Saline group (7.13 +/- 8.11 microm,
t = -4.894, P < 0.001). The difference between the two groups was also
significant (t = 6.737, P < 0.001). There were no statistically changes in
corneal thickness in control group. The drops tested have no effect on the
location of the thinnest corneal site and its distance form the visual axis.
Eye drops including Saline solutions may have significant effects on the
corneal thickness in myopia, and this may have implications for corneal
refractive surgery.
Bupivacaine topical eye
anesthesia
Guzey
et al. (10) investigated the direct toxic effects of bupivacaine
HCl 0.5% and lidocaine HCl 2%, two commonly used injectable
local anesthetic agents, on the corneal endothelium when applied intracamerally. Two groups were formed, each consisting of
12 pigmented rabbits, and 0.2 ml of the anesthetic agent were injected intracamerally into the right eyes. The central corneal
thicknesses and corneal clarities were evaluated preoperatively and at 3, 6, 9,
12 h and 1, 3, 7 days postoperatively. While the central corneal thicknesses
were evaluated by ultrasonic pachymetry, the corneal opacification scored between 0 and 3 was assessed by biomicroscopic examination and photographs. Both bupivacaine and lidocaine caused
corneal thickening in the 3- to 12-hour measurements. In addition, there was
significant corneal opacification in both groups in
the 3-hour and 3-day measurements. The corneal thickening and corneal opacification determined during 3- and 6-hour measurements
in the eyes which received intracameral bupivacaine were significantly higher than those determined
in the lidocaine-injected group. In both groups, the
corneal thickness and corneal clarity scores returned to the preoperative
values on the 1st and 7th days, respectively. When applied into the anterior
chamber at the concentrations supplied commercially, both bupivacaine
and lidocaine cause statistically significant corneal
thickening and clinically significant corneal opacification.
It should be noted that the injection of these agents into the anterior chamber
during the operation at the concentrations supplied commercially may be a
potential risk factor for endothelial injury.
Bupivacaine is a local
ocular anesthetic with a long duration of action when administered by retrobulbar injection. To determine the potential for the
use of bupivacaine as a topical ocular anesthetic,
the onset and duration of action and toxicity of various concentrations of bupivacaine were studied after instillation in rabbit eyes.
The onset and duration of action were not significantly different from that of
topical 0.5% proparacaine. Increasing the pH of the bupivacaine solution from 5.7 to 6.5 nearly doubled the
duration of action, but the increase was not sufficient to be clinically
important. Slit lamp biomicroscopic examination and
scanning electron microscopy showed that bupivacaine
was less toxic to the corneal epithelium than 0.5% proparacaine.
Healing after keratectomy was significantly more rapid in eyes treated with
0.75% bupivacaine, compared with eyes treated with
0.5% proparacaine. These results suggest that bupivacaine may be less toxic to the corneal epithelium
than proparacaine and could be clinically useful for
topical ocular anesthesia, particularly if pharmacologic modifications can
increase the duration of anesthesia provided by this drug (11).
Anderson
et al. (12) examined
whether intracameral bupivacaine
hydrochloride 0.5% is as effective as lidocaine
hydrochloride 1.0% in controlling discomfort of patients during phacoemulsification and posterior chamber intraocular lens
implantation. In rabbits, corneal endothelial cell function, ultrastructure, and viability were evaluated after in vitro
perfusion of bupivacaine 0.5%. In a double-masked,
controlled trial, 48 eyes of 48 patients with uncomplicated age-related
cataract were randomly assigned to receive bupivacaine
0.5% or lidocaine 1.0% intracamerally
before phacoemulsification with a posterior chamber
intraocular lens. Outcome measures such as pain, visual acuity, amount of
sedation, length of surgery, pupil size, intraocular pressure, corneal clarity,
and anterior chamber reaction were compared. In laboratory studies, paired
rabbit corneas were evaluated by endothelial cell perfusion with either bupivacaine 0.5%, bupivacaine 0.5% and glutathione bicarbonate Ringer
solution in a 1:1 ratio or bupivacaine 0.5% buffered
to a pH of 7.0. The paired control corneas were perfused
with glutathione bicarbonate Ringer solution and rates of corneal swelling were
determined. Cell ultrastructure and viability were
also evaluated. In the randomized trial, there was no significant difference in
the pain patients had during surgery or in the early or late postoperative
period. No statistically significant difference was seen between the two groups
in terms of pupil size, intraocular pressure, corneal edema, anterior chamber
reaction, or visual acuity immediately after the operation or on postoperative
day 1. Paired rabbit corneas perfused with bupivacaine 0.5% and bupivacaine
0.5% buffered to a pH of 7.0 swelled significantly (P<.001, P = .009,
respectively), and had corneal endothelial cell damage. Dilution of the bupivacaine 1:1 with glutathione bicarbonate Ringer
solution prevented corneal edema and damage to the corneal endothelium.
Endothelial cell viability was also decreased after perfusion of bupivacaine 0.5% (P<.001). Clinically, bupivacaine 0.5% is as effective as lidocaine
1.0% for anesthesia during phacoemulsification and
posterior chamber intraocular lens implantation. However, in vitro perfusion of
bupivacaine 0.5% damaged the corneal endothelium of
rabbits except when the drug was diluted 1:1 with glutathione bicarbonate
Ringer solution. Surgeons who use 0.2 to 0.5 ml of intracameral
bupivacaine 0.5% should be aware of its potential to
cause endothelial cell damage because of its lipid solubility. The bupivacaine 0.5% should be diluted at least 1:1 with
balanced salt solution before intracameral injection,
followed immediately by phacoemulsification. The
surgeon should ensure that the bupivacaine 0.5% is nonpreserved and packaged in single-use vials or flip-top
containers.
Antibacterial
activity of Bupivacaine topical eye anesthesia
The
antibacterial effect of topical anesthetics may lead to false-negative cultures
from corneal specimens of bacterial keratitis. Pelosini et al. (13) compared the antibacterial effect of 3
unpreserved topical anesthetics to indicate the most appropriate agent for corneal
scrapes. Four bacterial strains (Staphylococcus epidermidis,
Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae)
derived from the most frequently isolated microorganisms from corneal ulcers
were cultured from stored control stocks and clinical specimens. These strains
were used to determine the minimum inhibitory concentration (MIC) of 3
preservative-free anesthetic eye drops: proxymetacaine
0.5%, oxybuprocaine 0.4%, and tetracaine
1%. There was no inhibition of growth seen with proxymetacaine
0.5% (5000 microg/mL) with any of the organisms
except S. epidermidis, which demonstrated a MIC of 2500 microg/mL (equivalent to a dilution of (1/2)). Tetracaine 1% (10,000 microg/mL)
produced a MIC
ranging between 625 and 1250 microg/mL, inhibiting
all 4 strains at the commercially available dilution. Oxybuprocaine
0.4% (4000 microg/mL) resulted to be the second most inhibitory preparation with a MIC ranging between 1000
and 2000 microg/mL. Currently used preservative-free
topical anesthetics differ in bacterial growth inhibition. This in vitro study
showed that proxymetacaine 0.5% is the least
inhibitory on bacterial growth and therefore the most appropriate to be used
before corneal scrapes.
Dantas
et al. (14) investigated the antibacterial activity of topical
anesthetic solutions and their preservatives individually in vitro, to
determine involvement with bacterial growth inhibition. Proparacaine
and tetracaine (in concentrations of 0.125%, 0.25%,
and 0.50%), edetate disodium (EDTA), benzalkonium chloride, EDTA + benzalkonium
chloride, and sterile saline solution were used. Five microliters
of each solution were applied to standard filter paper disks and placed in
Mueller-Hinton agar previously inoculated with known strains of Pseudomonas aeruginosa and Staphylococcus aureus.
Zones of growth inhibition were measured 24 hours later and analyzed. There
were no zones of inhibition in the agar inoculated with P. aeruginosa
to all tested solutions. Benzalkonium chloride alone
and associated with EDTA inhibited growth of S. aureus.
All other solutions did not inhibit S. aureus.
Preservative-free anesthetic solutions seemed not to interfere with bacterial
development in culture media. Benzalkonium chloride
alone and associated with EDTA inhibited development of gram positive bacteria,
S. aureus, but did not inhibit P. aeruginosa.
Topical anesthetics are commonly
used prior to obtaining bacterial cultures in ulcerative keratitis.
Mullin and Rubinfeld
(15) performed an in vitro study designed to test both the bacteriostatic
and bactericidal effects of commercially available preserved topical anesthetic
agents. Proparacaine, tetracaine,
cocaine, and sterile water solutions were applied to filter paper disks, which
were then placed on Mueller-Hinton agar plates that had previously been
inoculated with known quantities of Pseudomonas aeruginosa
and Staphylococcus aureus. After 24 h of incubation,
zones of inhibition were measured and recorded. Proparacaine
strongly inhibited the growth of S. aureus at all
concentrations (0.5%, 0.25%, 0.125%) and inhibited
growth of P. aeruginosa at 0.5% and 0.25% but not at
0.125% concentration. Tetracaine also inhibited S. aureus at 0.5% and inhibited P. aeruginosa
at 0.5% and 0.25% concentrations. Cocaine exhibited no inhibition of S. aureus and exhibited mild inhibition of P. aeruginosa growth only at the 4% concentration. The in
vitro antibacterial effect of topical anesthetics suggests one possible reason
why bacterial culture yields in clinical ulcerative keratitis
are suboptimal. It is proposed that
clinicians consider the use of a 1% or 2% cocaine solution instead of standard
commercial topical anesthetics in the management of individual cases of
ulcerative keratitis and in future clinical bacterial
keratitis studies.
The
antibacterial activities of local anesthetics are recognized. Gocmen et al. (16) investigated in vitro the activity of
topical local anesthetic ointments at clinical doses. The activity of two
different local anesthetic ointments including lidocaine
5% and lidocaine/prilocaine 2.5% was tested against
Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Streptococcus pyogenes
and Enterococcus faecalis
by the disc-diffusion method. Sterile discs containing topical local anesthetic
drugs were prepared taking into account the doses of ointments used in clinical
practice. The validity of the methodology was confirmed using topical
antibacterial mupirocin. The inhibition zones of the
discs were measured. Mupirocin inhibited all the
bacteria. Both local anesthetic ointments were found to be most effective on E.
coli, whereas they had no effects on P. aeruginosa. Lidocaine 5% revealed antibacterial activity against S. aureus, S. epidermidis, E. coli,
S. pyogenes and E. faecalis,
but lidocaine/prilocaine 2.5% showed no activity on
E. faecalis and inhibited S. pyogenes
only at double doses. It was also observed that the antibacterial activity was
in a dose-dependent manner. In the light of these findings, it might be concluded
that topical local anesthetic ointments in routine settings may have a
preventive role against some bacteria.
References:
1. McGee HT, Fraunfelder
FW. Toxicities of topical ophthalmic anesthetics. Expert Opin Drug Saf.
2007 Nov;6(6):637-40.
2.
3. Asensio
I, Rahhal SM, Alonso L, Palanca-Sanfrancisco
JM, Sanchis-Gimeno JA. Corneal
thickness values before and after oxybuprocaine 0.4%
eye drops. Cornea. 2003 Aug;22(6):527-32.
4. Brewitt
H, Bonatz E, Honegger H. Morphological changes of the
corneal epithelium after application of topical anaesthetic
ointments. Ophthalmologica. 1980;180(4):198-206.
5. Brewitt
H, Honegger H. The influence of local anesthetics on corneal
epithelium. A scanning electron microscopic study.
Klin Monatsbl Augenheilkd. 1978 Sep;173(3):347-54.
6. Polse
KA, Keener RJ, Jauregui MJ. Dose-response effects of
corneal anesthetics. Am J Optom Physiol
Opt. 1978 Jan;55(1):8-14.
7. Sun R, Hamilton RC, Gimbel HV. Comparison of 4 topical
anesthetic agents for effect and corneal toxicity in rabbits. J Cataract
Refract Surg. 1999 Sep;25(9):1232-6
8. Judge AJ, Najafi K, Lee DA, Miller KM. Corneal endothelial toxicity
of topical anesthesia. Ophthalmology.
1997 Sep;104(9):1373-9.
9. Gao L, Fan H, Cheng AC, Wang Z, Lam DS. The effects of eye drops on corneal thickness in adult myopia.
Cornea. 2006 May;25(4):404-7.
10. Guzey
M, Satici A, Dogan Z, Karadede S. The effects of bupivacaine
and lidocaine on the corneal endothelium when applied
into the anterior chamber at the concentrations supplied commercially. Ophthalmologica.
2002 Mar-Apr;216(2):113-7.
11. Liu JC, Steinemann TL,
12.
13. Pelosini
L, Treffene S, Hollick EJ.
Antibacterial activity of preservative-free topical anesthetic drops in current
use in ophthalmology departments. Cornea. 2009 Jan;28(1):58-61.
14. Dantas
PE, Uesugui E, Nishiwaki-Dantas
MC, Mimica LJ. Antibacterial activity of anesthetic
solutions and preservatives: an in vitro comparative study. Cornea.
2000 May;19(3):353-4.
15. Mullin GS, Rubinfeld RS. The antibacterial activity
of topical anesthetics. Cornea. 1997 Nov;16(6):662-5.
16. Sedef
Gocmen J, Buyukkocak U, Caglayan O, Aksoy A. In vitro antibacterial effects of topical local anesthetics.
J Dermatolog Treat. 2008;19(6):351-3