Professional Documents
Culture Documents
Review Article
Detrimental effect of
preservatives in eyedrops:
implications for the treatment of
glaucoma
Christophe Baudouin
Department of Ophthalmology III, Quinze-Vingts National Ophthalmology
Hospital, Paris, France
ABSTRACT.
Antiglaucoma medications are often associated with ocular adverse reactions
such as dry eye, and burning or stinging sensations. These undesirable effects
may lead to treatment discontinuation and reduced quality of life in patients
with glaucoma. Antiglaucoma medications usually contain benzalkonium chloride (BAK) as a preservative. Animal studies, in vitro studies and in vivo
experiments have demonstrated various adverse effects of BAK. Clinical studies have also shown an increased incidence of adverse events with BAK and
have demonstrated that the withdrawal of preservatives reduces these effects.
Collectively, these data suggest that preservative-free antiglaucoma treatments
have clinically relevant benets for patients.
Key words: antiglaucoma medications benzalkonium chloride glaucoma preservatives
doi: 10.1111/j.1755-3768.2008.01250.x
Introduction
Glaucoma is characterized by optic
neuropathy, as determined by both
structural changes and functional
decits. Glaucoma can be subdivided
into primary open-angle glaucoma
(POAG), which has an insidious and
slow onset, and angle-closure glaucoma (ACG), which is usually more
acute (World Health Organization
2007a). Quigley & Broman (2006) estimate that 60.5 million people worldwide will have the disease by 2010
and this number will increase to about
80 million by 2020. Approximately
75% of these patients will have
716
tearing (21% versus 14%, respectively) and itchy eyelids (18% versus
10%, respectively) were consistently
higher with preserved eyedrops. The
prevalence of signs and symptoms was
dose-dependent, increasing with the
number of preserved eyedrops used.
Furthermore, when patients were
either switched to preservative-free
drugs or given less preservative-containing drugs, all symptoms and signs
improved (Pisella et al. 2002). Similar
data were obtained when equivalent
studies were performed in Italy, Belgium and Portugal (Jaenen et al
2007). Although there were some
minor differences between the countries, pooled data from a total of 9658
patients also demonstrated that the
incidence of ocular signs and symptoms was signicantly (p < 0.0001)
higher in patients receiving preserved
eyedrops, and that the incidence of
these signs and symptoms decreased
signicantly (p < 0.0001) by switching to a preservative-free formulation
or by reducing the amount of preser-
Clinical symptoms
60
50
40
30
20
10
0
Pain/
Foreign Stinging/
discomfort body
burning
during sensation sensation
instillation
(A)
70
Tolerability issues
associated with current
antiglaucoma
medications
70
Dry
eyes
Tearing
Eyelid
itching
60
50
40
30
20
10
0
(B)
Pain/
Foreign Stinging/
discomfort
body
burning
during
sensation sensation
instillation
Dry
eyes
Tearing
Eyelid
itching
Fig. 1. The incidence of ocular symptoms in (A) patients who switched from preservative-containing to preservative-free antiglaucoma medications and (B) patients who decreased their
exposure to preservative-containing antiglaucoma medications; p < 0.0001 for all comparisons.
(Data from Jaenen et al. 2007).
717
70
60
50
40
30
20
10
0
Anterior Posterior Eczema Hyperaemia Follicles Fluorescein Superficial
blepharitis blepharitis
staining punctate
keratitis
(A)
70
60
50
40
30
20
10
0
(B)
Anterior Posterior
blepharitis blepharitis
Fig. 2. Incidence of ocular signs in (A) patients who switched from preservative-containing to
preservative-free antiglaucoma medications, and (B) patients who decreased their exposure to
preservative-containing antiglaucoma medications; p < 0.0001 for all comparisons. (Data from
Jaenen et al. 2007).
718
(group 2); patients receiving betablockers and miotics (group 3), and
patients taking beta-blockers, miotics
and sympathomimetics (group 4). The
surgery success rates in these groups
were 90% (group 1), 93% (group 2),
72% (group 3) and 45% (group 4).
Surgical outcomes in patients who
had received beta-blockers and miotics
(group 3) or all three medications
(group 4) were signicantly less successful than in those treated with minimal topical therapy (p < 0.01 and
p < 0.001, respectively). All treatments used in the study contained preservatives. Given the differences in
effects on the conjunctiva in the combination therapy arms (groups 3 and
4) compared with those in the single
or limited therapy arms (groups 1 and
2), the authors speculated that the
degree of exposure to preservatives
may also contribute to effects on the
conjunctiva (Broadway et al. 1994b)
and therefore likely to impact on the
success of ltration surgery.
Longterm therapy induces several
adverse effects such as the inammation of the conjunctiva with a consequent lower success rate for any
ltration surgery. The failure rate of
trabeculectomy was also signicantly
correlated to longterm (> 1 year) topical antiglaucoma therapy (p < 0.001)
(Lavin et al. 1990). Topical medications may thus exert adverse effects on
the conjunctiva, which result in excessive time taken in postoperative wound
healing and further brosis (Broadway
et al. 1994b). Therefore, the use of
topical antiglaucoma drugs can be
considered one of the risk factors for
failure of ltration surgery, and accurate investigation of drug-induced
inammation of the conjunctiva
should be used as a tool to classify
patients at high risk of ltration failure
(Broadway & Chang 2001).
The use of longterm antiglaucoma
medications is related to conjunctival
foreshortening and shrinkage, which
may be associated with an ocular
pemphigoid-like condition or evolve
into severe scarring conjunctivitis with
denitive corneal opacities (Schwab
et al. 1992).
Other effects related to cataracts
Preservative-containing prostaglandin
analogues lower intraocular pressure
(IOP) and are widely used to treat
POAG. Although these medications
are generally well tolerated, their use
is associated with topical side-effects
(Noecker et al. 2003; Parrish et al.
2003). According to a survey by Stewart et al. (2002a), these side-effects
lead to additional telephone calls,
more ofce visits and increased drug
discontinuation. This is in line with
the ndings of Nordmann et al.
(2003) and Zimmerman et al. (2007),
who found that side-effects caused by
antiglaucoma medications containing
preservatives can lead to additional
costs and resource use. However, to
our knowledge, the cost-effectiveness
analyses performed to date comparing
the various antiglaucoma therapies
have not incorporated the cost of
managing side-effects into their calculations (Stewart et al. 2002b; Costagliola et al. 2003).
In summary, the administration of
preserved antiglaucoma medications is
associated with signicant ocular
adverse effects. These effects cause
discomfort and pain, lead to the premature discontinuation of treatment,
result in a lower quality of life, and
impact the outcome of eventual glaucoma surgery. Furthermore, although
no formal cost-effectiveness analyses
are available, we would speculate that
these ocular effects are also likely to
be associated with an overall increased
cost of therapy.
Toxicity or allergy?
The adverse events observed with the
use of antiglaucoma medications may
result from either an allergic or a
toxic reaction. Although allergy can
occur in a small proportion of
patients, toxicity is probably the predominant cause. The side-effects may
be caused by either the active compound of the antiglaucoma medication, or, as is more likely, the
preservatives included within the
formulation.
Toxicity of preservatives:
animal models
The most common preservative in
antiglaucoma medications and other
topical ophthalmic preparations is
benzalkonium chloride (BAK). This is
a quaternary ammonium compound
composed of a mixture of alkylbenzyldimethylammonium chloride homologues with n-C12H25, n-C14H29 and
n-C16H33 comprising a major portion
of the alkyl groups present (United
States PharmacopeiaNational Formulary [USPNF] 2005). It is commonly used at concentrations of
0.004)0.025%. Several investigations
using animal models have suggested
the existence of links between BAK
and cytotoxic effects on several components of the eye. The key studies
are outlined here and a full list of references is provided in Table 1.
Tear lm
719
Table 1. Summary of studies investigating the effects of different antiglaucoma therapies on the
various components of the eye.
Tear lm
Animal studies
Wilson et al. 1975
Pisella et al.
2000, 2002
Conjunctiva
Cornea
Trabecular cells
Burnstein 1980
Dormans & van
Logten 1982
Lopez Bernal &
Ubels 1991
Ichijima et al. 1992
Imayasu et al. 1992
Becquet et al. 1998
Baudouin et al. 1999
Furrer et al. 1999, 2001
Noecker et al. 2004
Takahashi 1982
SaarinenSavolainen et al.
1998
Ito et al. 2006
Samples et al.
1989
Hamard et al.
2002, 2003
Human cells
(ex vivo)
Broadway et al. 1994a
Baudouin et al.
1999
Baudouin 1996
Baudouin et al.
1994, 1999, 2004
Pisella et al. 2004
Ariturk et al. 1996
Nuzzi et al. 1998
Sherwood et al. 1989
Albietz & Bruce 2001
Dogan et al. 2004
Hong et al. 2006
Clinical studies
Wilson et al. 1975
Herreras et al. 1992
Kuppens et al. 1995
Yalvac et al. 1995
720
Debbasch et al.
2001a, 2001b
Pisella et al. 2004
Guenoun et al.
2005a, 2005b
Toxicity of preservatives:
human cell lines
Lemp &
Zimmerman 1988
de Jong et al. 1994
Levrat et al. 1999
Eleftheriadis et al. 2002
Kozobolis et al. 2005
Jaenen et al. 2007
Toxicity of preservatives:
evidence from clinical
studies
Evidence from animal studies and
human tissue cell culture experiments,
which suggests that preservatives can
cause detrimental effects on the supercial ocular tissues, is supported by
evidence from clinical studies (Wilson
et al. 1975; Lemp & Zimmerman 1988;
Sherwood et al. 1989; Herreras et al.
1992; Baudouin et al. 1994; Broadway
et al. 1994a; de Jong et al. 1994; Kuppens et al. 1995; Yalvac et al. 1995; Ariturk et al. 1996; Baudouin 1996;
Baudouin & de Lunardo 1998; Nuzzi
et al. 1998; Levrat et al. 1999; Albietz
& Bruce 2001; Eleftheriadis et al.
2002; Dogan et al. 2004; Pisella et al.
2004; Kozobolis et al. 2005; Manni
721
70
60
50
Normal
Timolol without BAK
Latanoprost
Timolol with BAK
40
30
20
10
0
HLA-DR
Fig. 3. Inammatory markers with latanoprost, preserved and unpreserved timolol and normal
controls. * p = 0.01 compared with normal controls; p 0.009 compared with the other
three groups. ABC = antibody-binding capacity; BAK= benzalkonium chloride; HLADR = human leucocyte antigen DR; ICAM-1 = intercellular adhesion molecule-1. (Reproduced with permission from Pisella et al. Investigative Ophthalmology & Visual Science, 2004;
45: 13601368 (copyright of the Association for Research in Vision and Ophthalmology).
722
Development of subconjunctival
brosis without clinical signs of intolerance has frequently been documented in patients who have taken
antiglaucoma medication for long periods of time (Baudouin et al. 1994).
The brosis is believed to result from
an increase in the broblast density in
the subepithelial substantia propria,
linked with an increase in inammatory cells (Sherwood et al. 1989; Baudouin et al. 1999). This brosis,
together with inammatory inltrates
and cytokine release, plays a role in
postoperative brotic scarring reaction
and therefore contributes to surgical
failure (Broadway et al. 1994b). Immunohistochemical analyses of conjunctival and trabecular surgical specimens
from patients treated with antiglaucoma eyedrops revealed that samples
from patients who were receiving treatment had signicantly greater expression of broblastic and inammatory
markers compared with samples from
non-treated participants. Furthermore,
patients who received multiple therapies had a greater expression of markers
compared
with
those
on
monotherapy (Baudouin et al. 1999).
Effects of preservatives
on safety: evidence from
clinical trials
Most studies imply a direct correlation
between the presence of preservatives
and the symptoms experienced during
Preserved versus
preservative-free therapies: pharmacokinetics,
pharmacodynamics and
efcacy parameters
Two recent clinical trials comparing
the respective pharmacokinetic and
pharmacodynamic proles of preserved and preservative-free tauprost
demonstrated no signicant differences in these parameters between the
two formulations (Hamacher et al.
2007; Uusitalo et al. 2007). There
were no signicant differences between
formulations with regard to pharmacokinetics parameters of AUC0-last,
Cmax and tmax, and systemic bioavailability was comparable between
groups (Hamacher et al. 2007).
There is no difference in efcacy
between preserved and preservativefree formulations (Liesegang 1998;
Albietz & Bruce 2001; Hamard et al.
2003). In a trial using tauprost, the
estimated overall treatment difference
(preservative-free versus preserved) in
the reduction of IOP was 0.01
mmHg (95% CI ) 0.46 to 0.49;
p = 0.96) (Hamacher et al. 2007).
Results from a recent study demonstrated total equivalence in IOP control between two formulations of
travoprost, one containing BAK and
the other using an ionic buffered
preservative system (Lewis et al.
2007). Easty et al. (2006) tested nonpreserved T-Gel 0.1% versus preserved T-Gel 0.1% and demonstrated
that both formulations resulted in a
mean IOP reduction of 24%. A comparative study of 2% carteolol with
and without preservative conrmed
similar efcacies between the two
formulations and comparable reduc-
tions in IOP
Lunardo 1998).
(Baudouin
&
de
Conclusions
Animal studies and in vitro studies
have demonstrated that preservatives
such as BAK cause harmful effects to
several eye structures, including the
tear lm, cornea, conjunctiva and trabecular cells.
The detrimental effects of BAK are
also recognized by the regulatory
authorities. For example, the European
summaries of product information for
both bimatoprost and travoprost, both
of which contain BAK, include the following text: Benzalkonium chloride
has been reported to cause punctate
keratopathy and or toxic ulcerative
keratopathy, may cause eye irritation
and is known to discolour soft contact
lenses. Close monitoring is required
with frequent or prolonged use of
Lumigan Travatan in dry eye
patients, or in conditions where the
cornea is compromised. Benzalkonium
chloride may cause eye irritation
(Alcon, Inc. 2004; Allergan, Inc. 2006).
The same warning has been issued for
Xalatan (Pzer, Inc. 2006).
Furthermore, data from clinical trials suggest that these adverse effects
are correlated to the increase in clinical symptoms in patients treated with
preservative-containing antiglaucoma
medications. Reducing exposure to
preservatives may reduce adverse
events, which could lead to better tolerability, fewer incidents of treatment
discontinuation and higher levels of
adherence in patients treated with
antiglaucoma medications. This in
turn would improve outcomes for
these patients, in terms of both glaucoma management and quality of life,
which may contribute to reducing the
costs of longterm glaucoma complications. It is most likely that the outcomes of glaucoma surgery would
improve in line with a decrease in
inammation of the conjunctiva at the
time of surgery. Moreover, although
no studies on this topic have been
published to date, a signicant number of surgical procedures are performed in patients with poor tolerance
to the drugs they require to control
IOP, and when the maximally tolerable medical treatment is insufcient to
stabilize glaucoma. Extending the lim-
Acknowledgements
The author received editorial and
writing support in the preparation of
this manuscript, funded by Santen Oy,
Tampere, Finland. The author is fully
responsible for the content of this
paper. The author is a consultant for
and has received research grants from
Alcon, Inc., Allergan, Inc., Pzer,
Inc., Santen Oy and Laboratoires
Thea SA.
References
Albietz JM & Bruce AS (2001): The conjunctival epithelium in dry eye subtypes: effect
of preserved and non-preserved topical
treatments. Curr Eye Res 22: 818.
Alcon, Inc. (2004): Travatan Summary of
Product
Information.
http://www.
alcon.com/alcon-products/pharmaceutical.asp. [Accessed 27 September 2007.]
Allergan, Inc. (2006): Lumigan Product
Information. http://www.lumigan.com/prescribing_information.aspx. [Accessed 27
September 2007.]
Ariturk N, Oge I, Baris S, Erkan D, Sulu Y
& Koc F (1996): The effects of antiglaucomatous agents on conjunctiva used for various durations. Int Ophthalmol 20: 5762.
Baudouin C (1996): Side-effects of antiglaucomatous drugs on the ocular surface. Curr
Opin Ophthalmol 7: 8086.
Baudouin C (2001): The pathology of dry eye.
Surv Ophthalmol 45(Suppl. 2): 211220.
Baudouin C & de Lunardo C (1998): Shortterm comparative study of topical 2% carteolol with and without benzalkonium
chloride in healthy volunteers. Br J Ophthalmol 82: 3942.
Baudouin C, Garcher C, Haouat N, Bron A
& Gastaud P (1994): Expression of inammatory membrane markers by conjunctival
723
724
timolol: a short-term study in glaucomatous patients with and without allergic conjunctivitis. Graefes Arch Clin Exp
Ophthalmol 239: 809814.
Costagliola C, Parmeggiani F & Sebastiani A
(2003): Assessing the cost-effectiveness of
switching from a beta-blocker to latanoprost in the treatment of ocular hypertension. Expert Opin Pharmacother 4: 1775
1788.
De Saint Jean M, Brignole F, Bringuier AF,
Bauchet A, Feldmann G & Baudouin C
(1999): Effects of benzalkonium chloride
on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci 40:
619630.
De Saint Jean M, Baudouin C, Di Nolfo M,
Roman S, Lozato P, Warnet JM & Brignole F (2004): Comparison of morphological and functional characteristics of
primary-cultured human conjunctival epithelium and of WongKilbourne derivative
of Chang conjunctival cell line. Exp Eye
Res 78: 257274.
Debbasch C, Brignole F, Pisella PJ, Warnet
JM, Rat P & Baudouin C (2001a): Quaternary ammoniums and other preservatives
contribution in oxidative stress and apoptosis on Chang conjunctival cells. Invest
Ophthalmol Vis Sci 42: 642652.
Debbasch C, Pisella PJ, De Saint Jean M,
Rat P, Warnet JM & Baudouin C (2001b):
Mitochondrial activity and glutathione
injury in apoptosis induced by unpreserved
and preserved beta-blockers on Chang conjunctival cells. Invest Ophthalmol Vis Sci
42: 25252533.
Detry-Morel M (2006): Side-effects of glaucoma medications. Bull Soc Belge Ophtalmol 299: 2740.
Dogan AL, Orhan M, Soylemezoglu F, Irkec
M & Bozkurt B (2004): Effects of topical
antiglaucoma drugs on apoptosis rates of
conjunctival epithelial cells in glaucoma
patients. Clin Experiment Ophthalmol 32:
6266.
Dormans JA & van Logten MJ (1982): The
effects of ophthalmic preservatives on corneal epithelium of the rabbit: a scanning
electron microscopical study. Toxicol Appl
Pharmacol 62: 251261.
Easty DL, Nemeth-Wasmer G, Vounatsos
JP, Girard B, Besnainou N, Pouliquen P,
Delval L & Rouland JF (2006): Comparison of a non-preserved 0.1% T-Gel eye gel
(single dose unit) with a preserved 0.1%
T-Gel eye gel (multidose) in ocular hypertension and glaucomatous patients. Br J
Ophthalmol 90: 574578.
Eleftheriadis H, Cheong M, Sandeman S,
Syam PP, Brittain P, Klintworth GK,
Lloyd A & Liu C (2002): Corneal toxicity
secondary to inadvertent use of benzalkonium chloride preserved viscoelastic material
in cataract surgery. Br J Ophthalmol 86:
299305.
Fellman RL, Sullivan EK, Ratliff M et al.
(2002): Comparison of travoprost 0.0015%
and 0.004% with timolol 0.5% in patients
with elevated intraocular pressure: a 6-
of living rabbit cornea treated with benzalkonium chloride. Cornea 11: 221225.
Imayasu M, Moriyama T, Ohashi J, Ichijima
H & Cavanagh HD (1992): A quantitative
method for LDH, MDH and albumin levels in tears with ocular surface toxicity
scored by Draize criteria in rabbit eyes.
CLAO J 18: 260266.
Ito T, Ohguro H, Mamiya K, Ohguro I &
Nakazawa M (2006): Effects of antiglaucoma drops on MMP and TIMP balance in
conjunctival and subconjunctival tissue.
Invest Ophthalmol Vis Sci 47: 823830.
Jaenen N, Baudouin C, Pouliquen P, Manni
G, Figueiredo A & Zeyen T (2007): Ocular
symptoms and signs with preserved and
preservative-free glaucoma medications.
Eur J Ophthalmol 17: 341349.
de Jong C, Stolwijk T, Kuppens E, de Keizer
R & van Best J (1994): Topical timolol
with and without benzalkonium chloride:
epithelial permeability and autouorescence
of the cornea in glaucoma. Graefes Arch
Clin Exp Ophthalmol 232: 221224.
Kass MA, Heuer DK, Higginbotham EJ
et al. (2002): The Ocular Hypertension
Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of
primary open-angle glaucoma. Arch Ophthalmol 120: 701713.
Kozobolis VP, Detorakis ET, Maskaleris G,
Koukoula SC, Fountoulakis N, Chrysochoou F & Konstas AG (2005): Corneal
sensitivity changes following the instillation
of latanoprost, bimatoprost, and travoprost
eyedrops. Am J Ophthalmol 139: 742743.
Kuppens EV, de Jong CA, Stolwijk TR, de
Keizer RJ & van Best JA (1995): Effect of
timolol with and without preservative on
the basal tear turnover in glaucoma. Br J
Ophthalmol 79: 339342.
Lavin MJ, Wormald RPL, Migdal CS &
Hitchings RA (1990): The inuence of
prior therapy on the success of trabeculectomy. Arch Ophthalmol 108: 15431548.
Lemp MA & Zimmerman LE (1988): Toxic
endothelial degeneration in ocular surface
disease treated with topical medications
containing benzalkonium chloride. Am J
Ophthalmol 105: 670673.
Lemp MA, Holly FJ, Iwata S & Dohlman
CH (1970): The precorneal tear lm. I.
Factors in spreading and maintaining a
continuous tear lm over the corneal surface. Arch Ophthalmol 83: 8994.
Levrat F, Pisella PJ & Baudouin C (1999):
Clinical tolerance of antiglaucoma eyedrops with and without a preservative.
Results of an unpublished survey in Europe. J Fr Ophtalmol 22: 186191.
Lewis RA, Katz GJ, Weiss MJ et al. (2007):
Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety
and efcacy. J Glaucoma 16: 98103.
Lichter PR, Musch DC, Gillespie BW, Guire
KE, Janz NK, Wren PA, Mills RP & the
Collaborative Initial Glaucoma Treatment
Study Group (2001): Interim clinical outcomes in the Collaborative Initial Glau-
725
726
Young TL, Higginbotham EJ, Zou X & Farber MD (1990): Effects of topical glaucoma
drugs on stulized rabbit conjunctiva. Ophthalmology 97: 14231427.
Zimmerman TJ, Hahn SR, Gelb L, Tan HK,
Kim EE & Shah SN (2007): The effect of
hyperaemia on open-angle glaucoma
(OAG) treatment. Annual Meeting of the
European Society of Ophthalmology
(SOE), 912 June 2007, Vienna, Austria.
Abstract FP-GLA-036.