Acta Ophthalmologica 2008

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

Acta Ophthalmol. 2008: 86: 716726

2008 The Author
Journal compilation 2008 Acta Ophthalmol

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

POAG. Glaucoma is the second leading cause of blindness in the world

and is predicted to account for over 8
million cases of blindness by 2010
rising to over 11 million by 2020
(Quigley & Broman 2006). If the disease is diagnosed at an early stage,
medical, surgical or laser treatment
can be effective (van der Valk et al.
2005; World Health Organization
2007a). Medical treatment is predominantly used as rst-line therapy, and
most patients with chronic glaucoma
are treated medically (Lindblom
2006). If effective, medical treatment
is administered over the longterm, and
therefore the majority of patients

receive several decades of treatment.

Based on data from clinical trials, the
tolerability of glaucoma treatments
seems satisfactory: few patients are
withdrawn from medication as a result
of local intolerance or allergy. These
results provide reassurance that longterm medical antiglaucoma treatments
are not harmful and can be used
throughout the patients lifespan.
However, there are several major
differences between clinical trials and
the real-world progress of antiglaucoma therapy. Clinical trials are usually
of short duration (6 months1 year),
and patients usually only receive one
test or reference therapy. Patients with
known hypersensitivity to the therapy
or to the preservative contained within
the product, and patients who have
active ocular surface diseases such as
dry eye, chronic allergy or severe blepharitis are often not included in such
trials (Watson & Stjernschantz 1996;
Fellman et al. 2002; Manni et al.
2004). In population-based studies,
the prevalence of dry eye in elderly
patients (aged 65 years) varies
between 15% and 34% (Smith et al.
2007). Impaired tear lm may therefore interfere with topical treatments
in a high proportion of patients, as
the ocular surface disease may be
encouraged by the drug(s) and or
preservatives, and may also reduce
the resistance of the cornea and
conjunctiva to the presence of toxic or
irritant compounds.

Acta Ophthalmologica 2008

Another major difference with clinical trials is the number of drugs

chronically administered to the ocular
surface. In clinical practice, patients
with glaucoma are treated for a lifetime. Therefore, because of the progressive nature of the disease, a
signicant majority of patients receive
multiple therapies concomitantly. For
example, the Ocular Hypertension
Treatment Study demonstrated that
approximately 40% of patients initially diagnosed with ocular hypertension were using more than one drug
after 5 years (Kass et al. 2002), and
the Collaborative Initial Glaucoma
Treatment Study showed that 75% of
patients were using two or more drugs
within 2 years of initial glaucoma
treatment (Lichter et al. 2001). This
cumulative use of polytherapy over
time is likely to increase the incidence
of adverse events. Therefore, there are
likely to be discrepancies between the
outcomes observed in clinical trial
settings and those seen in longterm
treatment, with a higher incidence of
side-effects
expected
in
clinical
practice.

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

Ocular surface changes, including

burning or stinging sensations, dry eye
and tearing, have been described after
the longterm administration of topical
antiglaucoma agents (Pisella et al.
2002). For example, a prospective epidemiological survey was conducted in
2002 in 4107 glaucoma patients to
assess the effects of preserved and
preservative-free eyedrops on ocular
symptoms and conjunctival, corneal
and palpebral signs during clinical
practice (Pisella et al. 2002). All symptoms were signicantly more prevalent
in patients using preserved drops
compared with those using preservative-free treatment. For example, discomfort upon instillation (43% in the
preserved group versus 17% in the
non-preserved group), burning or
stinging sensations (40% versus 22%,
respectively), foreign body sensation
(31% versus 14%, respectively), dry
eye (23% versus 14%, respectively),

60

Impact of symptoms on treatment

compliance

Discomfort following instillation of

eyedrops may lead to patient discontinuation of treatment. In a small
study of 83 patients adverse effects
was listed as the third most common
reason for non-compliance (after forgetting to administer the dose and
inappropriately
administering
the
treatment) (Chawla 2007). In a larger
survey of 13 977 patients and 103
ophthalmologists, Zimmerman et al.
(2007) showed that approximately half
the patients (55.4%) discontinued their
index medication within the rst
90 days. Prostaglandin-treated patients
who identied adverse events as a

Preservative-containing antiglaucoma medications

Preservative-free antiglaucoma medications

50
40
30
20
10
0
Pain/
Foreign Stinging/
discomfort body
burning
during sensation sensation
instillation

(A)
70

Patients with symptoms (%)

Tolerability issues
associated with current
antiglaucoma
medications

Patients with symptoms (%)

70

vative-containing treatment (Figs 1

and 2) (Jaenen et al. 2007). Based on
these data, it seems that the use of
ophthalmic solutions containing preservatives can cause an increase in
ocular surface changes manifesting as
adverse events.

Dry
eyes

Tearing

Eyelid
itching

Preservative-containing antiglaucoma medications

Decreased number of preservative-containing antiglaucoma medications

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

Acta Ophthalmologica 2008

Patients with signs (%)

70

Preservative-containing antiglaucoma medications

Preservative-free antiglaucoma medications

60
50
40
30
20
10
0
Anterior Posterior Eczema Hyperaemia Follicles Fluorescein Superficial
blepharitis blepharitis
staining punctate
keratitis

(A)

Patients with signs (%)

70

Preservative-containing antiglaucoma medications

Decreased number of preservative-containing antiglaucoma medications

60
50
40
30
20
10
0

(B)

Anterior Posterior
blepharitis blepharitis

Eczema Hyperaemia Follicles Fluorescein Superficial

staining punctate
keratitis

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).

signicant problem were more likely

to have poorer adherence to medication (p = 0.04). Almost all physicians
(97%) perceived side-effects as a
barrier to adherence (Zimmerman
et al. 2007).
Impact of symptoms on quality of life

The side-effects of antiglaucoma treatment can also have an impact on

patient quality of life. Nordmann et al.
(2003) investigated the quality of life
associated with topical glaucoma treatment in 204 randomly selected patients
with glaucoma or ocular hypertension.
Almost 93% of the patients experienced at least one side-effect. Among
these, 25.4% experienced a burning
sensation, 20.8% blurred vision and
20.2% tearing. Poor vision-related
quality of life was associated with the
presence of local side-effects leading to
poor patient satisfaction and reduced
adherence. Dissatised patients also
visited their ophthalmologists more
frequently (3.50 visits per year) compared with patients who were at least
rather satised (2.27 visits per year)
(Nordmann et al. 2003).

718

Longterm exposure to antiglaucoma

medications, and especially to the preservatives they contain, can lead to
the condition of dry eye. Preservatives
decrease the stability of the tear lm
(Detry-Morel 2006). Miljanovic et al.
(2007) studied the impact of dry eye
syndrome on quality of life as part of
the Womens Health Study and Physicians Health Study (450 women, 240
physicians) and concluded that dry
eye syndrome is linked to a measurable adverse impact on quality of life.
Effects on surgery outcomes

There have been several reports of

longterm topical combination therapy
causing the failure of glaucoma surgery (Broadway et al. 1994a, 1994b).
The effect of different longterm antiglaucoma treatments on the results of
glaucoma ltration surgery were studied by Broadway et al. (1994b). A
total of 124 patients underwent ltration surgery and were followed for
6 months. Subjects were divided
into four groups: patients who
received minimal topical therapy
(group 1); patients on beta-blockers

(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

The use of antiglaucoma medications

has also been associated with the
development of cataracts. The Blue

Acta Ophthalmologica 2008

Mountains Eye Study showed that

antiglaucoma therapy can increase
the risk of cataract formation (odds
ratio [OR] 1.90, 95% condence
interval [CI] 0.923.92) (Chandrasekaran et al. 2006). Longterm followup in the Ocular Hypertension
Treatment Study demonstrated an
increased rate of cataract extraction
and cataract ltration surgery in
patients receiving medication (7.6%)
compared with the observation group
(5.6%) (hazard ratio 1.56, 95% CI
1.052.29) (Herman et al. 2006).
Furthermore, the use of preserved
timolol was associated with a higher
incidence of cystoid macular oedema
after cataract surgery compared with
preservative-free
timolol
(Miyake
et al. 2003).
Impact on cost

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

The tear lm is important because it

functions as both a lubricating and
protective layer. The cornea holds the
tear lm on its surface, probably with
the aid of mucin-producing goblet
cells throughout the conjunctiva
(Lemp et al. 1970). Over 30 years ago,
Wilson et al. (1975) demonstrated that
0.01% BAK hastened the drying of
the precorneal tear lm in rabbits.
The compound shortened the length
of time taken for dry spots to appear
on the corneal surface by a factor of
about four (Wilson et al. 1975). More
recently, Pisella et al. (2000) found
that albino rabbits given a preserved
beta-blocker (Timoptol 0.25% and
0.50%, preserved with 0.01% BAK;
MSD-Chibret, Paris, France) displayed a signicantly greater reduc-

tion in tear lm break-up time

compared with those given a non-preserved beta-blocker (Timabak 0.25%
and 0.50%; Laboratoires Thea SA,
Paris, France). Through the loss of
the protective layer, an impaired tear
lm will cause dry eye symptoms and
corneal damage, and also convey
cytotoxic inammatory mediators
throughout the ocular surface (Baudouin 2001).
Conjunctiva and cornea

Using a rabbit model, Furrer et al.

(2001) demonstrated that 28 days of
treatment with beta-blockers preserved in BAK 0.01% or benzododecinium bromide 0.012% resulted in
microlesions covering nearly 9% of
the corneal surface.
Administration of solutions containing BAK 0.01% has been linked
to the inltration of immunocompetent cells into the limbus and bulbar
conjunctiva in rats (Becquet et al.
1998). The inammatory reaction was
associated with severe damage to the
cornea and conjunctiva, including epithelial alterations and keratinization.
Several other animal studies have
shown that preservatives are linked to
the onset of chronic brosis in the
conjunctiva (Mietz et al. 1994, 1997;
Noecker et al. 2004).
Noecker et al. (2004) investigated
the extent of epithelial and corneal
damage associated with Purite
(Allergan, Inc, Irvine, California, USA),
a stabilized oxychloro complex, and
with topical antiglaucoma medications
preserved with BAK. Fifteen New
Zealand white rabbits were randomized to six treatment groups: articial
tears (Refresh Tears, carboxymethyl
cellulose 0.5% twice daily; Allergan,
Inc.); brimonidine Purite 0.15%
twice daily; bimatoprost 0.03% once
daily; dorzolamide 2% twice daily;
timolol maleate 0.5% twice daily, or
latanoprost 0.005% once daily, for
30 days. The bimatoprost, dorzolamide, timolol and latanoprost solutions
contained
BAK
at
concentrations of 0.005%, 0.008%,
0.001% and 0.02%, respectively. The
dorzolamide, timolol and latanoprost
groups experienced signicantly more
changes in both the cornea and the
conjunctiva than did the groups with
articial tears (containing Purite)
and brimonidine Purite (p = 0.001).

719

Acta Ophthalmologica 2008

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

Young et al. 1990

Mietz et al.
1994, 1997
Becquet et al. 1998

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

Chou et al. 1985

Baudouin et al.
1999

Takahashi 1982

Samples et al. 1989

De Saint Jean et al.

1999, 2004

SaarinenSavolainen et al.
1998
Ito et al. 2006

Samples et al.
1989
Hamard et al.
2002, 2003

Baudouin et al. 1999

Noecker et al. 2004
Ito et al. 2006

Yee et al. 2006

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

Schwab et al. 1992

Levrat et al. 1999
Jaenen et al. 2007
Albietz &
Bruce 2001

Nuzzi et al. 1998

Baudouin &
de Lunardo 1998
Kozobolis et al. 2005
Manni et al. 2005

Treatment with glaucoma medications

that contained higher levels of BAK
resulted in greater damage to the cornea and conjunctiva compared with
treatment with preparations preserved
with lower concentrations of BAK.
Bimatoprost, containing the lowest
concentration of BAK, was associated
with signicantly less corneal and conjunctival damage (Noecker et al.
2004).

720

Many studies have also demonstrated

the effects of BAK on human tissuederived cells cultured in vitro. The key
studies are outlined here and a full list
of references is provided in Table 1.
Conjunctival cells

Human cell lines

(in vitro)

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

Other eye structures

In addition to damaging the cornea

and conjunctiva, preservatives may
also cause severe lesions in the retina.
In pigmented rabbits, subconjunctival
injection of timolol 0.5% or befunolol
1% preserved with BAK caused retinal lesions, retinal detachment, loss of
visual acuity and atrophy of the pigmented epithelium of the retina and
choroids (Chou et al. 1985).

De Saint Jean et al. (1999) studied the

effect of different concentrations of
BAK (0.10.0001%) on a continuous
human conjunctival cell line: the
WongKilbourne derivative of Chang
conjunctiva. Cells were treated for
10 mins and were assessed before
treatment and at 3, 24, 48 and
72 hours after treatment. Benzalkonium chloride at concentrations of 0.1%
and 0.05% caused immediate cell
lysis. Exposure to 0.01% BAK was
associated with cell death within
24 hours, and doses of 0.0050.0001%
induced apoptotic cell death at
24)72 hours in a dose-dependent
manner. These ndings suggest that
BAK at concentrations as low as
0.0001% causes cell death, and that
cell destruction is BAK concentrationdependent (De Saint Jean et al. 1999).
Pisella et al. (2004) compared the
toxicities of 0.005% latanoprost preserved with 0.02% BAK, 0.5% timolol preserved with 0.02% BAK,
unpreserved 0.5% timolol and 0.02%
BAK alone on the WongKilbournederived human conjunctival cell line.
Cells were treated for 15 mins and
subsequently left to recover for 0, 4
and 24 hours in a normal medium.
Both latanoprost and timolol were
associated with toxic proapoptotic
effects on conjunctival cells, whereas
no toxic effect was observed with unpreserved timolol. Both medications
were less toxic than BAK alone. These
ndings suggest that the preservative
itself causes the damage, and that preservative alone is even more harmful
than preservatives within medications
(Pisella et al. 2004).
Trabecular and corneal cells

Benzalkonium chloride at a concentration of 0.002% inhibits the growth of

human trabecular cells and corneal
cells in vitro (Samples et al. 1989).
Studies performed on human immortalized trabecular cells have shown
that even a short exposure (15 mins)

Acta Ophthalmologica 2008

to BAK 0.0001% induced apoptosis.

The fact that betaxolol preserved with
0.0001% BAK showed a moderate
proapoptotic effect, whereas unpreserved betaxolol did not display
any apoptosis, further supports the
BAK-dependence of cellular apoptosis
(Hamard et al. 2002). These results
conrm that BAK alone can trigger
apoptosis in more than 95% of
healthy cells and glaucoma donorderived trabecular cell lines (Hamard
et al. 2003).
Lens cells

Goto et al. (2003) investigated the

effects of latanoprost, timolol maleate
and BAK on the secretion of chemical
mediators of stress and wound healing
in a human lens epithelial cell line.
The results showed that BAK alone
caused the most damage by strongly
stimulating the expression of soluble
chemical mediators of stress (prostaglandin
E2,
interleukin-1a
and
interleukin 6) in lens epithelial cells.
These effects were also observed with
BAK-containing latanoprost or timolol formulations, but to a lesser extent
than with BAK alone (Goto et al.
2003).
In summary, evidence from several
animal studies and human cell line
experiments supports the hypothesis
that antiglaucoma therapies containing
the preservative BAK are associated
with various adverse reactions on
surface and deep ocular tissues.

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

et al. 2005; Hong et al. 2006). The key

studies are outlined here and a full list
of references is provided in Table 1. It
should be noted that at least one study
in the literature showed no signicant
difference in the histologic parameters
between 18 patients receiving at least
12 months of antiglaucoma treatments, when compared with 18 age
matched controls (Banu 1995).
Tear lm

Ocular surfaces of 20 patients with

POAG receiving 0.5% timolol (0.01%
BAK) or bi-therapy with 0.5% timolol plus 1% dipivefrin (0.04% BAK)
were evaluated and compared with
those of 20 healthy control participants receiving placebo (Kuppens
et al. 1995). Schirmers test values
were signicantly lower in the two
treatment groups when compared with
placebo (means 10.40 1.58 mm,
8.20 1.55 mm and 12.70 2.21 mm,
respectively; both p < 0.001), and
tear lm break-up times were signicantly abnormal in both treatment
groups (p < 0.001). This study suggests that the toxic effects on the tear
lm increase with the number of antiglaucoma therapies containing BAK
administered (Yalvac et al. 1995).
A subsequent study corroborated
the link between longterm use of antiglaucoma treatment drops containing
preservatives and tear lm modications. A total of 132 subjects were
assigned to one of the following
groups: 29 patients with POAG were
given timolol 0.5% twice daily (group
A); 23 POAG patients received timolol 0.5% twice daily plus pilocarpine
2% three times daily (group B); 20
healthy participants were given BAK
twice daily (BAK group), and 60
healthy recipients did not receive any
therapy (group C). Schirmers test
resulted in average readings of
11.31 5.12 mm for group A, 9.08
3.20 mm for group B, 10.01
3.40 mm for the BAK group, and
14.64 6.17 mm for group C. The
differences between participants receiving treatment containing BAK or
BAK alone compared with those not
receiving therapy were signicant
(p < 0.05) (Nuzzi et al. 1998).
Conjunctiva and cornea

Longterm use of preservatives leads to

corneal damage. The effect of topical

timolol with and without BAK on the

epithelial permeability and autouorescence of the cornea has been investigated in patients with POAG or
ocular hypertension. The corneas of
21 patients were examined during
treatment with timolol preserved with
BAK at concentrations of 0.25% or
0.5%. After 2 weeks, patients were
switched to treatment with timolol
without BAK. Corneal epithelial permeability
decreased
signicantly
(mean decrease per patient 27%;
p = 0.025), whereas corneal autouorescence increased signicantly (mean
increase per patient 6%; p = 0.003).
These results suggested an improvement in corneal epithelial function following the withdrawal of BAK (de
Jong et al. 1994).
In line with these data, the results
from the large survey showed that
signs of damage to the conjunctiva,
cornea and eyelids signicantly
decreased when patients were switched
from preserved to preservative-free
medication, or even when the number
of eyedrops containing BAK was
decreased. This effect demonstrated
the dose-dependency of BAK-induced
manifestations (Jaenen et al. 2007).
Furthermore, numerous reports have
shown that even without evident symptoms or clinical manifestations, inammation is abnormally observed in the
conjunctival epithelium. Inltration of
immunocompetent cells into the outer
layers of the epithelium has therefore
been reported (Sherwood et al. 1989;
Liesegang 1998). All immuno-inammatory markers and mediators of the
conjunctival epithelium of patients
with glaucoma were found to be signicantly increased compared with healthy
controls (Baudouin et al. 2004, 2007;
Pisella et al. 2004). The intensity of this
inammatory reaction seems to be
related to the number of antiglaucoma
medications used, and the duration of
treatment (Ariturk et al. 1996). The
human leucocyte antigen DR (HLADR) and the intercellular adhesion
molecule-1 (ICAM-1) were both signicantly higher in patients treated with
preserved drugs compared with those
treated with preservative-free therapies
(Baudouin et al. 2004; Pisella et al.
2004). Patients who received preservative-free treatments showed mild or no
inammatory response (Fig. 3) (Baudouin et al. 2004; Pisella et al. 2004).
Furthermore, the two chemokine

721

Acta Ophthalmologica 2008

Fluorescence levels (ABC x 1000)

70

60
50

Normal
Timolol without BAK
Latanoprost
Timolol with BAK

40
30
20

10
0
HLA-DR

ICAM-1 (CD 54)

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).

receptors CCR4 and CCR5 were also

found to be over-expressed in
glaucoma patients receiving longterm
treatment (Costagliola et al. 2001),
suggesting that the chronic use of
antiglaucoma topical drugs induces a
complex network of inammatory
reactions.
The conjunctival cytology specimens of patients on longterm antiglaucoma medication also have
distinct characteristics, including epithelial keratinization, squamous metaplasia and a reduction in the number
of goblet cells (Table 2) (Costagliola
et al.
2001).
Histomorphological
changes to the epithelium can appear
as early as 2 weeks after the start of
antiglaucoma treatment (Lewis et al.
2007).
Table 2. Histopathological changes linked
with preserved antiglaucoma medications.
Reproduced with permission from Liesegang,
Cornea 1998;17:574583.
Histopathological changes
Reduction of goblet cells
Epithelial keratinization
Squamous metaplasia
Loss of microvilli
Increased number of desmosomes
Bullous dystrophy of the epithelium
Increased number of subepithelial broblasts
Subepithelial brosis
Reduction of intravascular spaces
Increased number of subepithelial
lymphocytes and plasma cells
Thickening of basal membrane
Basement membrane staining for
immunoglobulin

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

antiglaucoma therapy (Levrat et al.

1999; Pisella et al. 2002; Jaenen et al.
2007). In a recent study involving 9658
patients (Jaenen et al. 2007), all
recorded symptoms and signs were signicantly more frequent in patients
taking preserved medications compared with those taking preservativefree formulations (p < 0.0001 for all).
For example, foreign body sensation
was experienced by 42% of the preservative recipients compared with 15%
of those taking non-preserved medication, and stinging or burning was noted
in 48% versus 20% of recipients,
respectively, and dry eye sensation in
35% versus 16%, respectively. Jaenen
et al. (2007) concluded that preservative-free eyedrops are signicantly less
likely to be associated with ocular
symptoms and signs of irritation.
These ndings were similar to those
seen in observational studies reported
by Pisella et al. (2002) and Levrat
et al. (1999). A signicantly higher
proportion of patients receiving preserved therapies experienced discomfort or pain during therapy compared
with those treated with preservativefree formulations (58% versus 30%;
p < 0.001) (Levrat et al. 1999). All
signs and symptoms were signicantly
more prevalent in patients using preserved drops compared with those
using preservative-free drops (p <
0.001) (Figs 1 and 2) (Jaenen et al.
2007). Furthermore, the effect was
dose-dependent (Pisella et al. 2002).
Preliminary short-term studies with
preserved and preservative-free tauprost, a novel prostaglandin analogue
in development, have shown similar
safety results (Hamacher et al. 2007;
Uusitalo et al. 2007). In one of these
studies, ocular hyperaemia was classied as predominantly moderate with
preserved tauprost and predominantly mild with preservative-free
tauprost (Uusitalo et al. 2007).
Some studies have even demonstrated a direct correlation between
the degree of damage to eye structures
and clinical symptoms. Indirectly,
Nuzzi et al. (1998) showed that the
treatment groups associated with the
greatest reductions in tear lm (timolol plus pilocarpine and BAK) also
displayed the highest frequencies of
subjective symptoms. In more direct
analyses, patients complaints have
been correlated with objective signs of
conjunctival damage (e.g. conjunctival

Acta Ophthalmologica 2008

redness) and corneal damage (supercial punctuate keratitis) (Levrat et al.

1999; Jaenen et al. 2007).
Furthermore, switching from a
preservative-containing to a preservative-free formulation leads to a
reduction of complaints regarding
burning or dry eye sensation, reduces
all signs of structural eye damage and
objective clinical symptoms, and
improves tolerance (Levrat et al. 1999;
Albietz & Bruce 2001; Pisella et al.
2002; Dogan et al. 2004; Jaenen et al.
2007).

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-

its of tolerance ) by improving the

tolerability of medications ) should
become one of the key objectives of
glaucoma therapy.
Overall, the provision of preservative-free formulations would offer
clinically relevant benets to patients
who are highly sensitive to preservatives because of pre-existing or concomitant ocular surface diseases, as
well as to patients who use combinations of two or more drugs, those at
risk of undergoing surgery, and all
patients who will need treatment over
several decades. Preservative-free formulations should therefore become
the gold standard for glaucoma therapy in the near future.

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.

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Received on October 18th, 2007.

Accepted on February 7th, 2008.
Correspondence:
Christophe Baudouin
Department of Ophthalmology III
Quinze-Vingts National Ophthalmology
Hospital
28 rue de Charenton
75012 Paris
France
Tel: + 33 1 40 02 13 01
Fax: + 33 1 40 02 13 99
E-mail: baudouin@quinze-vingts.fr