EXH%§ET §
`
`137
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`137
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`“\\\.\‘\\ 9 <3-‘\
`
`-
`
`. .
`
`‘
`
`1%
`
`Marfragerriem and "iireragy Gf Ery Eye Eisaasaz
`Repart af the Management and Therayy Submrnmiiteg
`0f the Irriematiainai Ery Eye Warirfiaap (24%?)
`
`‘firs rmmbers rs? the fifianagsrraant and Therapy
`ABS‘i’RAC‘i'
`suhwmmittee ESSQSSGG cumm fly eye rhea.-395$. Each man»
`her wrute a auccinei evidarrea-hi review an an maimed
`wpeect ref fire tepid, and fins finai report was wrirten after
`review by and with consensus of an ssaheemresiitae smmbers
`and rinse write my Eye werksimp membership. in adriirjan ta
`3% main review :3? the lltsratum, the Suheammrttae reviewed
`the Dry Eye Preferred Practice Pattezm of the American
`Asaaismy oi Qphthaimsiogv and the intematienai ‘Eask Farce
`(STE Daphl Pami on my Eye. The Suhersmrrsittsd hwomd fies
`spgreaeh taken by we WE whws reaozrsmanded treatments
`were ham an Save! at disem savarity. ‘me rmmmendd
`titans af the mnbeammittaa are mm an as: madifiaafinrs er
`and 3?? severity gazing scheme, and saggested ireatmarafi
`wars chasm: mm a menu 9%‘ tiaarapias for which svidanca ref
`flrarapreutic effaet had ban prmnted.
`
`KEVWQRDS DEWS, dry eya disease, my Eye Worifihasn,
`management, therayy
`
`E. iNTR6DE3£?i9N
`
`his report summarizes the management and thera-
`\. peutic options for treating dry eye disease. The level
`. of evidence for supporting data from the literature
`is evaluated according to the modified American Academy
`of Ophthalmology Preferred Practices guidelines {Table 1).
`
`ii. GUALS GF 'E'HE MANAGEMEFET AME THERAPY
`SUBCQMMSWEE
`
`Goals of this committee were to identify appropriate
`therapeutic me-thcds for the management of dry eye disease
`and recommend a sequence or strategy for their app}i<:ation.,
`based cm evidence-based review of the literature.
`
`The quality of the evidence in the iitaraiure was graded
`according is ea mod.i&<:ation of the scheme used in the
`American Academy of Ophthaimciiogy Preferred Practice
`Patterns series. ‘When possible, pe:er—1“::viewed full publica-
`timis, not abstracts, were used. The repair: was rgviewed
`
`Accepted for publication January 2007.
`Management and Therapy Subcnmmitiee members: Stzpiszn C. Filnngeldzr,
`ME3 (Chair); Gard Geeriing, MD; Shigero Kinoshita, MD;Mir;haeEA.1.emp,
`MD; James McCul1ey, MD; Daniel Nzison, MD; Gary N, Novack, F310; jun
`Shimazz-.E{i, MD; Clive V-fiisom Phi).
`Proprietary imcrcsi.-3 cf Subccmmitzec members are disclosed on pages 202
`and 204.
`
`Reprints are 1101 available. Articles can be accessed at:www.:earfiim.o:g.
`Correspondence in regard to ma: this ciiapzzr should be addressed in Stephm
`C. Pflugfcider MD, Ophtbaimoiogy-Ocular Surf Ctr, Culicn Eye instirmer
`6565 Farmin Street NC 205. Houston, TX 77035. "Fri: 713-798-4732. Fax:
`?'13—.798~i45'.7. Email: 5t.eve:1p@hcm..trm:.edu
`
`wm
`3 @200? Ems Communications. inc. The GcwarSurface ESSN: 1542-
`§
`0124. (No answers listed). Management and therapy cf dry eye
`;
`disease: remrt an‘ the Management and iherapy Subcommittee of
`.
`5
`the intematicna! Dry Eye works-nap (29073. 2oe7;5{2):1se.17s.
`i
`i...W...WN”m.._..m......._...._......,._....,_..._._.N _
`
`THE OCULAR SURFACE / APRIL 2007, VOL 5, NO. 2 / www.iheocu1arsur‘face.ca)m
`
`138
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`
`DEWS MANAGEMENT AND THERAFY
`
`Ell. AS$§$ME*§"§ GF CURRENT ER? EYE ‘ll-l$APlE5
`‘Fear fiunplerneotation: Lubricants
`A.
`E. Qeneral Cliaraeteristiszs and Efiects
`
`The term “artificial tears” is a misnomer for most prod»
`ucts that identify themselves as such, because they do not
`mimic the composition of human tears. Most function as
`lubricants, although some more recent formulations mimic
`the electrolyte composition of human tears {1”hera"fears®
`{Advanced Vision Research, Wobum, MAD.” Tlie ocular
`lubricants presently available in the United States are ap-
`proved based on the US Food and Drug Administration
`(Fall) monograph on ovetzthe-counter (GTO products
`(21 CFR 349) and are not based on clinical efileacy. The
`monograph specifies permitted active ingredients (eg,
`demulcents, emulsifiers, surfactants, and viscosity agents)
`and concentrations, but gives only limited guidance on
`inactive additives and solution parameters. Certain inac-
`tive ingredients that are used in artificial tears sold in the
`US (eg, Castor oil in Endura" [Allergart, inc, Irvine, CA}
`and guar in Systanew l_Alcon, Ft Worth, TXD are not listed
`in the monograph.
`It is difficult to prove that any ingredient in an ocular
`lubricant acts as an active agent. If there is an active in-
`gredient, it is the polymeric base or viscosity agent, but
`this has proved difficult to demonstrate. This is either
`because it is not possible to detect the effects or dillerences
`in clinical trials with presently available clinical tests or
`because the currently available agents do not have any
`dlscernahle clinical activity beyond a lubrication effect.
`Although certain artificial tears have demonstrated more
`success than others in reducing syrnptonts of imitation
`or decreasing ocular surface dye staining in head-to-head
`comparisons, there have been no large scale, masked,
`comparative clinical trials to evaluate the wide variety of
`ocular lubricants.
`What is the clinical effect of ocular lubricants or artificial
`tears? Do they lubricate, replace missing tear constituents,
`reduce elevated tear film osrnolarity, dilute or wash out
`inllarnrnatory or inflainrnation-inducing agents? Do they,
`in some instances, actually wash out essential substances
`found in normal human tears? These questions remain to
`be answered as more sensitive clinical tests become avail-
`able to detect changes in the ocular surface.
`The foremost objectives in caring for patients with dry
`eye disease are to improve the patients ocular comfort and
`quality of life, and to return the ocular surface and tear film
`to the normal homeostatic state. Although symptoms can
`rarely be eliminated, they can often be improved, leading
`to an improvement in the quality of life. It is more difficult
`to demonstrate that topical lubricants improve the ocular
`surface and the tear film abnormalities associated with dry
`eye. Most clinical studies fail to demonstrate significant
`correlation between syrnpterns and clinical test values
`or between the clinical test values thernselves.3‘5 it is not
`unusual for a dry eye with only mild symptoms to show
`significant rose bengal staining. Until agenm are developed
`that can restore the ocular surface and tear film to their
`
`by all subcommittee members and by the entire Dry Eye
`'Worl<Shop membership. Comments and suggested reviu
`sions were discussed by the subcommittee members and
`incorporated into the report where deemed appropriate
`by consensus,
`
`164
`
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`139
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`DEWS MANAGEMENT AND THERAPY
`
`nonnal homeostatic state, the symptoms and signs of dry
`eye disease will continue.
`Ocular lubricants are characterized by hypotonic or
`isotonic buffered solutions containing electrolytes, surfac-
`tants, and various types of viscosity agents. in theory, the
`ideal artificial luliricant slioulcl lie pres;s:rvative~frec, contain
`potassium, bicarbonate, and other electrolytes and have 8
`polymeric sysizern to increase its retention time. l ‘*3 Physical
`properties should include a neutral to slightly alltaline pit.
`Osmolarities of artificial tears have been measured to range
`from about l 81 to 354 mOsm/L." The main variables in the
`formulatic-n of ocular lubricants regard the concentration
`of and choice of electrolytes, the osmolatity and the type
`of viscosity/polymeric system, the presence or al:2se:n.ce oi’
`preservative, and, if present, the type of preservative.
`
`2. Presexviitivm
`
`The single most critical advance in the treatment of dry
`eye carne with the eliinirration ofpreservatives, such as l:er1zal--
`konium chlcrirlc (BAX), from OTC lubricants. Because
`of the risk of contamination of rnulti-close products, most
`ei=.;h.er contain a preservative or employ some me<:harai:sr>:i
`for minimizing contamination. The FDA has required that
`multidose artificial tears contain preservatives to prevent
`miczrobial grovv:h.‘° lilresetvativesz are not required. in unit
`close vials. that are discarded alter a single use. The W'l(.l€-
`spread availability of nortpreservetl pre*,oara1:ions allows
`patients to acltninister lulzzrlizantzs more frequently without
`concern about the toxic effects or" preservatives. For patients
`with anoderate~to—severe dry eye disease, the absence of
`preservatives is ofniorc critical irnportatice than the particu
`lar polymeric agent used in ocular lubricants. The ocular
`surface inflzirrirrazition associated with dry eye is exacer‘-.*)ated
`by preserved ltibricants; however, nonprescrvccl solutions
`are inaclequate in tlieniselves to improve the surface inilarm
`mation and epithelial pathology seen
`-dry eye disea.=;e.“
`Bermalleonlum chloride is the most frequently used
`preservative in topical ophthalmic preparations, as well as
`in topical lub-ric:zan:s. lu; epitlielial toxic effects have been
`well establishetlfiml The toxicity of BAK is related to its
`concentration, the frequency of dosing, the level or amount
`f tear secretion, and the severity of the ocular surface
`disease. in the patient with mild dry eye, BAK~pieserved
`drops are usually well tolerated when used 4-5 times a clay
`or less. in patients with morleratexto-severe dry eye, the
`potential for BAK toxicity is high, due to decreased tear
`secretion and decreased turnover. 57 Some patients may be
`using other topical prepariations (cg, glaucoma medications)
`that contain BAK, increasing their exposure to the toxic.
`effects of BAR. Also, the potential for toxicity exists with
`patient abuse of other OTC products that contain BAK,
`such as vasoc<instricl.ors.
`
`BAK can damage the corneal and conjunctival epithe—
`liurn, affecting cell~to—eell junctions and cell shape and
`microvilli, eventually leacling to cell necrosis with slmighing
`of l~2 layers of epithelial cells. 17 P’reservative—iree formula-
`tions. are absolutely necessary for patients with severe dry
`
`eye with ocular surface disease and impairment of lticrimal
`gland setzretlon, or for patients; on multiple, pretervecl.
`topical medications for chronic eye disease. Patients with
`severe dry eye, greatly reduced tear secretion, and punetal
`oc::l.ussior1a.i'e at ‘pan'.i::ular risk lot‘ preservflive toxicity. In
`such patients, the instilled agent cannot be washed out; if
`this
`has not been appreciated by the clinician, preserved
`drops might be usecl at high frequency.
`Another additive used in OTC formulations is clisotlium
`(BETA). it augments the preservative efficacy of EAK and
`other preservatives, ‘out, by itself, it is not a sufficient pre-
`servative. Used in some nortpreserved solutions, it may
`help limit microbial growth in opened unit—dose vials.
`Although use of EDTA may allow at lower concentration of
`preservative, EDTA may itselfbe toxic to the ocular surface
`epithelium. A study comparing two preserva-tive— free solu-
`tions, I-Iypotears PW (Novartis Ophthalmics, East Hanover,
`NJ) containing EDTA and Refresh@ (Allergen, inc, lrvine,
`CA) without EDIA, showed that both formulat.i0n.s2 had
`identical safety profiles and were completely nontoidc to
`the rabbit corneal epitlielium.“’ Other studies found that
`l?.D7l1’-‘i-containing preparatiotis increased. ccimeal epithelial
`permeability 193“ The potential exists that patients with
`severe dry eye will find that ElC3”lfis—containiiig preparations
`increase irritation.
`
`Nonpreserved, single unit—dose tear substitiites are
`more costly for the rtiatxmacturer to ‘pro-:luce, more
`costly for the patients to purchase, and less convenient
`to use than bottled ocular lubricants. For these reasons,
`recloszilole unit close vials (cg, Refresh Free {Allergen inc,
`irvine, CAl; Tears Natural Free@ EAlcon, Fort Worth,
`TXED were introduced. Less toxic preservatives-, such as;
`polyquatl (polyquaternium-1), sodium clilotite {i’urite®),
`and sodium perhorate were developed to allow the use
`of rtiultidose lzvottlecl lularicants and to avoid the lrnown
`toxicity of BAK-contzaitairag solutioris.3l>23 The “vanishing”
`preservatives were sodium perborate and sodium ehlorize
`(Tl‘iera'fears°5° Erldvariced Vision Research, 'W-Dlzuru, lvlAl,
`Gentealfl lNovartis, East 1-ianover, Nil . and Refresh Tears®
`{Allergen inc, Irvine, CAD.
`Sodium chlorite degrades to czliloricle ions and water
`upon exposure to UV light after instillation. Sodium perl3o~
`rate is converted to water and oxygen on contact with the
`tear film. For patients with severe dry eye, even vanishing
`preservatives may not totally degrade, due to a decrease in
`rear volume, and may lie irritating. llatients prefer bottled
`preparations for reasons of both cost and ease of use. The
`ideal lubricant would come in a tnultidose, easy--to-use
`bottle that contains a preservative that completely dissipates
`before reaching, the tear film, or is completely nontoxic and
`tionirritating and tiiaintains absolute sterility with frequent
`use. One such multi-use, preservative-free product has
`been introduced to the market (‘Value l’ure-'.l‘cars‘3’ ll’fizer,
`l1’1C, Nll).
`Ocular ointment; and gels are also used in treatment of
`dry eye disease. Ointments are formulated with :3 specific
`tnizuure of ruitieral oil and petrolatuin. Some contaui lanolin,
`
`THE OCULAR S’Ui{FA.Cl‘;‘ I APRIE. 2007, VOL. 5, NC). 2 I ww:v.theocularsurface.corn
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`
`DEWS MAl\lAGl7.MEN"l' AND THERAPY
`
`wliich can be irritating to the eye and delay corneal wound
`healing.” Individuals with sensitivity to wool may also be
`sensitive to lanolin.” Some ointniems ctmtairi paralaens as
`preservettives, ztml these ointments are not well tolerated
`by patients witli severe dry eye. in general, ointments do
`not support bacterial growth and, tlicrefore, do not require
`presenratives. Gels containing high molecular weight cross-
`llnked polymers of acrylic acid (carljotnersl have longer
`retention times than artificial tear soltttinrts, lzint have
`visual laltrrnng eflecrt than petroliaturn ointrnents.
`
`3. Elecwolytc Composition
`Solutions containing electrolytes and or ions have been
`shown to be beneficial in treating ocular surface damage
`due to dry e},'c.lt5»3°~Z”5 To date, potassium and bicarbon-
`ate seem to be the most ::rtt.ical. Potassium is important to
`maintain corneal thickness.’ ln a drywcye rabbit model, a
`hypotortic te:ar—mat«: ted electrolyte solution (”l"l1era'.i"ears®
`ljldvanced Vision Research, Wobum, MAE) increased con~
`junctival goblet cell density and corneal glycogen content,
`and recluctecl. tear osmolarity and rose ‘oertgal staining after 2
`weeks of treatrncnt.” The restoration of conjunctival goblet
`cells seen in the dry—eyc rabbit model has been cc2‘rrol:3omte<l
`in patients with dry eye after l_A£ilKtZ5
`Bicarbonate-containing solutions promote the recovery
`of epithelial barrier function in damaged corneal szpitlicliurn
`and aid in rn.aint2ti.ning rtorrnal epithelial ultrastructurc.
`They may also be important for maintaining the mucitr layer
`of the tear film.“ Ocular lnbriearzts are available that mimic
`the electrolyte corn.position. of human tears, cg, Thcralcarsa’
`{Advanced Vision Research, Woburn, MA.) and BIDN Tears“
`(Alcoti, Fort \M>r1;h., 'l"X.}.‘~2 'l‘hcse also contain bicarbonate,
`which is critical for forming and maintaining the protec~
`rive mucin gel in the stomach.“ Bicarbonate may play a
`similar role for gel-~l'orrni.ng mticlns on the ocular surface.
`Because bicarbonate is convened to carbon dioxide when
`
`in contact with air and can tlilluse through the plastic unit
`dose vials, foil ‘packaging oi the plastic vials is required to
`maintain stability
`
`4.
`
`flsmolztiritry
`Tears of patients with dry eye have a higher tear film
`(PS!'Ki()l:aEiIy(:C1’)r'Sl.8llt)l(.l (ssrnolarityl than do those. of normal
`patient5.33-Z9 Elevated tear film osmolarity causes mor-
`phological and lriochcmical changes to the cortical and
`ccsnjnnctival epitliel‘iurn‘35"‘ and is pro-inflammatory“ This
`knowledge influenced the development of hypo-osmotic
`artificial tears such as i—lypoi.ears@ (2363 mOsm/L llflovartis
`Ophtlialmics, East Hanover, N31) and subsequently Theta»
`Tears?“ (181 rnOsmfl_ {Advance Vision Resear<:lx, Wolaum,
`MAD}:
`Colloidal osmolality is another factor that varies in
`artificial tear formulations. ‘While crystalloicl osmolazity
`is related to the prcsencze of ions, colloidal osrnolality is
`dependent largely on macrornolcculc content. Colloidal
`osmolarity, also known as oncutic pressure, is involved in the
`control oi water transport in tissues. Differences in colloidal
`
`osrnolality affect the net water flow across membranes, and
`water llow is elimlnatecl by applying hydrostatic pressure
`to the downside of the water flow. The magnitude of this
`osmotic pressure is determined by osrrrolality differences
`on tlte two sides; of the mcmbranc. Epithelial cells swell
`clue to damage to their cellular membranes or clue to a
`dysfunction in the punipirag 1‘E1€Cll;8.l.‘ElSm. Following the
`adnition of a flnitl with a liigh colloidal osmolality to the
`clarnagctl cell surface, clctnrgesccncc occurs, leading to at
`return of nortnal cell physiology. Theoretically, an artificial
`tear fc>rrrtulatiort with a high colloidal osmolality may be of
`value. Holly and Esq‘-nivcl cvaluatccl many different artificial
`tear formulations and showed that llypotears“‘° (Novartis
`Oplrtltalrnics, East. l-iariovcr, Nj) had the highest colloidal
`osmolality oi all of the formulations tested.” Formulations
`with higher colloidal osmnlality have since been marltcteti
`(l)welle“" llfiry Eye Company, Silverclalc, WAD.
`Protection against the adverse ellects of increased os~
`molarity losmoprotecztionl has led to development of OTC
`drops incorporating compatible solutes (such as glycerin,
`erytluitol, and lcvoczrnitinc ffiptiveg [Allergart Inc, Irvine,
`CAD. it is thought that the compatible solutes distribute be-
`tween the tears and the intracellular fluids to protect against
`potential cellular damage from liyperosmtslar tezars.“
`
`5. Viscosity Agents
`The stability of the tear film siepentls on the cl1cm,ical~
`physical cliaractt=.risttt;=. of that film interacting with the
`conjttnctival and corneal erzitlieliurrt via the mern‘omne-
`spanning rnnciris (ic, MUG l6 and MUC-4}. In the classical
`tlircmliiyered tear film model, the mucin layer is usually
`thought of as a surfactant or wetting agent, acting to lower
`the surface tension of the relatively hydrophobic ocular
`surface, rendering the corneal and conjunctival cells “wet-
`t:ablc.”33 Currently, the tear
`is prolctalfly best described
`as a ltiyrlrated, mucin gel whose rnttcin concentration
`decreases with distance from the epithelial cell sufliace. it
`may have a protective. role s;lmilar1.ca that of trmcin in the
`stornacli.-‘S It may also serve
`a “sink” or storage velrlclt-2
`for substances secreted by the main and accessory lscrirnal
`glands and the ocular surface cells. lltis may cxplain why
`roost of the available water-containing lubncants are only
`minimally cifcctivc in restoring the normal homeostasis
`of the ocular surface. ln addition to washing away and
`diluting out irritating or toxic substances in the tear film,
`artificial lubricarits hydrate gel--fomiing rnuciri. While some
`patients with dry eye have decreased aqueous lacritnal gland
`secretion. alterations or deficiencies involving rmtcin also
`cause dry eye.
`Macromolecular complexes added to artificial lubricants
`act as viscosity agents. ’l"he acldltiort of El viscosity agent in-
`resi<lenc:c time, providing a longer interval of patient
`comfort. For example, when a viscous, anionic charged
`carboxymetliylncellulnse (CMC, 100,000 mw) solution was
`comparccl with a neutral liyclroxyrnetliylccllulose (llPl.‘»/EC}
`solution, CMC was shown to have a sigriillc.artt.ly slower rate
`of clearance from the eye.” Viscous agents in active. drug;
`
`16:’;
`
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`141
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`
`DEWS lVlAl\l.Af3El\/IENT AND Tl-lERAl?Y
`
`formulations may also prolong ocular surface contact, in-
`creasing the rluzation of action and penetration of the drug.
`Viscous agents may also pml.ect the ocular surface
`epithelium. it is lmowri that rose bengal stains abnormal
`cortical and conjurtctival epithelial cells expressing er: al»
`tered niuein glycoaalyx. 37 Agents such as liyclroxyrnetlty<:el--
`lulose (HMC), which decrease rose bengetl staining in dry
`eye: sub;le.cts,33 may either “coat and protect” the surface
`epithelium or help restore the prczlzcctive effect of mucins.
`In the US, carboxyittetliyl cellulose is the most com-
`monly used polymeric viscosity agent (iRl lvlarl—tet Slisre
`Data, Clticzago, ll..), typically in concentratioris l’2‘orn 0.23%
`to 1%, with differences in molecular weight also eontrib~
`uting to final product viscosity Carboxymetliyl cellulose
`has been found to lnirid to and be retains-.<l liy liumaan epi-~
`thelial cells?“ Other viscosity agents included in the FDA
`trionograpli (iii various concentrations) include polyvinyl
`alcohol, polyethylene glycol, glycol 400, propylene glycol
`liyclroxymethyl cellulose and hyriroxypropyl cellulose.
`Tlie blurring ofvision and esthetic disadvantages ol cak-
`ing and drying on eyelashes are drawbacl<s of highly viscous
`agents that patients with mild to moderate dry eye will
`not tolerate. Lower molecularaweight viscous agents lielp
`to minimize these problems. Because patient compliance,
`comfort, and coiivcriicnce are important considerations, a
`range of tear substitute lomiulatioris with varying viscosi~
`ties are needed.
`
`l-lydroxypropyl-g‘-.1ar (HP~guar) has been used as a gel
`ling agent in a solution conl.alnln.g glycol 400 and propyl~
`ezie. glycol {$ysta1ie®, Alcou, Port Wortli, TX). it has been
`suggested that HP--gum,’ ‘pl‘E‘3f€.‘E’CIilIlEil.ly
`l)ll1ClSE to the more
`hydrophobic, desiccated or damaged areas of the surface
`epithelial cells, providing temporary protection for these
`cells.‘”l’”'l ;.I‘~£':\/erzil commercial preparatiorizs containing oil in
`the form of castor oil (Euduram lzillergan irie, iwine, CAB
`or mineral oil (Sootlie@ lB3‘i;L‘.SCl'1 cc: Lomla, Rochester,
`are purported to aid in restoring or increasing the lipid layer
`of the tear filial.“-‘*3 l-lyaluronic acid is a viscosity agent that
`l‘li3..’5 been investigated for years as an “active” compound
`added to tear subs‘i'imt.c icu“rnulati.oi1s lot the treatrxrent of
`
`dry eye. llyalutoriic acid (0.3%) lies significantly longer
`ocular surface resiclericc times than 0.3 percent l*l'PlviC
`or 1.4 percent polyvinyl alcohol.“ Some clinical studies
`reported imgsrovemerit in ‘M45 dry eye in patients treated
`widi soclitim lryaluronate--containing solutions compared
`to other lubricant solutions, whereas others did not.“
`Although lubricant preparations zzoritaining sodium ltyal--
`uronate have not been. approved for use in the US, tliey are
`frequently uwd in some countries.
`
`6.. Summary
`Although many topical lubricants, with various viscos-
`ity agents, may improve symptoms and obj active findings,
`there is no evidence that any agent is superior to another.
`Most clinical trials involving topical lubricant preparations
`will document tSO'EIl'.8 improvement (but not rcssolutionl of
`subjective syrnptorris and improvement in some objective
`
`parameters.‘ However, t re improvements noted are not
`necessarily any better than those seen with the vehicle or
`other uonpre.sc3.'ved artificial lul3ric2mt.s. The elimination
`of preservatives and the development of newer, less toxic:
`preservatives have made ocular lubricants better tolerated
`by dry eye patients. ‘However’, ocular lularlcasits, which
`have been shown to provide some protection of tlie ocular
`surface epithelium and some improvenient in patient symp-
`toms and obje.t::.ivc fimliriggs, have not been demonstrated
`in controlled clinical trials to be suffieieut to resolve the
`ocular‘ surface disorder and inflauniuailori seen in most dry
`eye sufferers.
`
`3.. ‘rear Retention
`1. Pmnetal {Exclusion
`as. Rationale
`
`W’l*1ile the concept of permanently occluding the lacti~
`mal ptmcta with cautcry to treat dry eye. extends l)aCl( 7'9
`years,"5’ and, although the first dissolvable implants were
`used 4:5 years ago,” the modern era of punctal plug use
`‘began in 1975 with the report by Freeman.“ Freeman clc~
`scribed the use of a dumbbell-shaped silicone plug, which
`rests on the operiirig of the ptmcmm, and extends into the
`caualiculus. His report established a concept of punctal oc-
`clusion, which opened the field for development of a variety
`of removable, lorigulasting plugs to retard tear <:lear2rnc:c
`in an attempt to treat the ocular surface of patients with
`deficient aqueous tear production. The Freeman style plug
`remains the prototype for most st.yl<=s of punctzil plugs.
`
`ls.
`
`Ifyym
`Puncial plugs are divided into two main types: absorb-
`alsle and nonalasorbable.
`former are made of collagen.
`or polymers and last for vzrriable periods of time (3 days
`to 6 months). The latter nouabsorlzaable “perrnanerit” plugs
`include the Freeman style. which consists of a surface collar
`te'si:irtg on the ptinclal opening, 2;: neclt, and at wider base, in
`contrast, the I-ierriclr plug (Lacrirncdics lEae<;tsound,\7y’Al)
`is shaped like :3: golf tee and is clesignecl to reside witliizi
`the czmaliculus. lt is blue for V‘l$l.EEil2lZ2£l.'.l(3K'l; Oll.'1('i!'V2£3,’l8Il€)IiS
`are radiopaque. A newly designed cylindrical Sniartplugm
`{Medezmiurra lric Eirvine, CAD expaaitls and ittcreases in
`diameter in situ following insertion into the czmaliculus
`due to therirtodynarnic properties of its lrydrophilic acrylic
`composition.
`
`£3. Clinical Studies
`
`A variety of clinical studies evaluating the efficacy of
`purictal plugs have been reported.53‘5“ These series generally
`fall into level II eviderzce. Their use lies been associated
`with objective and subjective improvement in patients
`with both Sjogrert and non-Sjogren aqueous tear deficient:
`dry eye, filamentary l:e‘rati.tis, conta(:t lens in,tole.ran.ce,
`Stevetis-johrisori disease, severe michoma, neurotrophic
`keratopathy, post—perietrating lceratoplasty, diabetic l<era--
`topatliy, and post-pliotorelractivc keratectomy or laser in
`situ keratomileusis. Several studies have been performed
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`l)li'WS MANAGEl\/ll3N'1' AND THERAPY
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`to evaluate the effects of punctal plugs on the efficacy of
`glaucoma medications in recluczlng intraoczulzar pressure,
`and these studies have reported conflicting results.“-59
`Beneficial outczome in dry eye symptoms has been reported
`in 7°‘.-—85% of patients treated with punctal plugs. Objective
`mclices of improvement reported with the use oi pnnctttl
`plugs; incliicle improved corneal staining, prolonged tear
`film breakup time ('.E‘l<'I8't'.3'i'), decrease in tear osrnolarity,
`and increase in goblet cell density Overall‘ the clinical util-
`ity of pimctal
`in the management of dry eye disease
`has been well cloonmentecl,
`
`ti,
`
`Imlimtiozss and Ctmirrtitadiwtiotas
`in a recent review on pimctal plugs, it was reported
`that in a major eye clinic, punctal plugs are considered
`inrlicatied in patients who are syriipiornatie of dry eyes,
`have a Scliirmer test (with sinwthegsial result less than 5
`mm at 5 minutes._ and show evidence of ocular surface
`dye sl;a:in:ing.55
`Contraindications to the use of punctal plugs include
`allergy to the materials used in the plugs to be implanted,
`punctal ectropion, aocl preexistirig nasolacrimai duct. ob-
`struction, which would, presumably, negate the need for
`punctal occlusion. lt has been suggested that plugs may
`be contrain.dicate:d in dry eye patients with (“.lllTilC53,l ocular
`surface inflammation, because occlusion of tear outflow
`would prolong Contact of the abnormal tears oontainn
`ing proinllammatory cytokines with the ocular surface.
`‘Treatment of the ocular surface inflammation prior to
`plug insertion has been reazotnmended. Acute or (Il’lX'(}E).l(I
`infection of the lactimal canalieulus; or laczrirnal sac is also
`
`a stontraindication to use of a plug.
`
`a. Complications
`The most common complication of punctal plugs is
`spontaneous plug egnttmion, which is particularly -common
`with the Freemamstyle plugs. Over time, an extrusion rate
`of 50% has been reported, but many of these extrusions
`took place after extensive pe.‘E’l0{l5é of plug re.-;i<lene:¢:. Most
`extrusions are of small consequence, except for incon-
`veniemrr and expense. More troulalessonie CO1‘[l}3llC;3li.ClEl.'S
`inclttde internal migration of a plug, lsiofilm formation and
`irilection ,5” and pyogenlc grariulorna formation. Removal of
`inigratecl t:anali::ular plugs can be clilfioult. and may require
`surgery to the nasolacrirnal duct system.5°»‘”
`
`f. Summmy
`The extensive literature on the use of punctal plugs in
`the rnanagemt-:nt of dry eye disease has doourrtented their
`utility. Several recent reports, however, have suggested
`that absorption of tears by the nasolacrirrial duets into 5ur—
`roimcling tissues and blood vessels may provide a feedback
`mechanism to the lacrimal gland regulating tear prod‘-.ic«
`lion.“ In one study, placement of pnnctal plugs in patients
`with normal tear production caused. a sigriificaritz decrease
`in tear production. for up to 2 weeks after plug insertior:-1.53
`This oautionary note should be considered when deciding
`
`wliether to incorporate ptmetal (3-i‘.Cl1lSi0l’1 into a dry eye
`disease management plan.
`
`2. Moistnm Chamber Spectacles
`The wearing of moisture-conserving spectacles has for
`many years been advocated to alleviate ocular discomfort
`associated with dry eye. However, the level of evldenoe sup»
`porting its eificaty for dry eye t1‘(€zti.1'l1§‘:t‘3t has been relatively
`limited. Tsubota et al, using a sensitive moisture sensor,
`reported mi increase in periocular liuiniciity in subjects
`wearing such specmcles.“ Aclditiori of side panels to the
`spectacles was shown to further increase
`llllillitilltjfifi
`The clinical elficacy of moisture chamber spectacles has
`been reported in case reports.“-57 Kuriliashi proposecl a
`related treatment for dry eye patients, in the lorrn of a wet
`gauze eye masltfil Conversely, Nichols et 31 recently report-
`ecl in their epidemiologic study that spectacle wearers were
`twice as lilozly as emmettopes to report dry eye clisease.‘7”‘—’
`The reason for this observation was not explained.
`There have been several reports with relatively high
`level of evidence describing the relationship between
`environrnemal humidity and dry eye. Korh er al reported
`that increases in periocular humidity causecl a significant
`increase in thickness of the tear film lipid layer.” Dry eye
`stihlects wearing spectacles showecl significantly longer
`interblink intervals than those who did not wear spectacles,
`and duration of blink (blinking time) was significan.tly
`longer in the latter s-.1bjec.ts.7° lnstillation of artificial tears
`caused a significant increase in the interhlink interval and
`a decrease in the blink rate.“ Nlsrnya.-ma et al reported that
`dry eye symptoms worsened in soft contact lens wearers
`when environmental humidity decreased. ‘'2
`
`3. Contact lenses
`
`Contact lenses may help to protect and hydrate the
`corneal surface in severe. dry eye contlitions. Several differ»
`ent Contact lens materials and designs have been evaluated,
`including silicone rubber lenses and gas perrneable seismi-
`‘oearing hard coritzact lenses with or without ieriestr2ation.73“77
`Improved visual acuity and comfort, decreased corneal
`epitheliotzathy, and healing of persistent cc-meal epithelial
`defects have been repoi“tetl.73‘77 Highly o3tygen—penneal3le:
`materials ezialzle overnight wear in appropriate
`stances.” There is a small.
`of corneal vssezularization
`and possible corneal infection associated with the use of
`contact lenses by dry eye patients.
`
`3. ‘fear stimulation: iteorotogogaos
`Several potential topizzal pharrr1:acol.ogi<: agents may
`stimulate aqueous secretion, mucous secretion, or both.
`The agents currently under investigation by }3ll31’!1'l2EC€l1[l."
`cal cornpanies are ciiquafosol (one of the PZEYE receptor
`agonists), rebetmipicle, gefamate, eczibet sodium (mucous
`secretion stimulants), and l5(S)~I~{ETE {ix/lUCl stimulant).
`Among them, 3 cliqualosol eye drop has been favorably
`evaluated in clinical trials. 2% diqnafosol GNS365, DE—i)£l9
`léianien, Osakmjapan}; Inspire llilurham, NED proved to
`
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`DEWS MANAGEMENT AND THERAPY
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`be ellective in the treatrnem of dry eye in it randomized,
`double--znasked trial in humans to reduce ocular surface
`
`staining.“ A similar study demonstrated the ocular safety
`and tolerability of tliquaiosol in 3 <:loul)le~rn:isl<ed, placel)o-
`controlled, randomized study” This agent is capable of
`stimulating l’)(3l.li aqueous and mucous secretion in