REVIEW ARTICLE

Subconjunctival Triamcinolone Acetonidein the Management of Ocular Inflammatory Disease

Yannis Athanasiadis,1 Michael Tsatsos,2 Anant Sharma,1 and Parwez Hossain2

Abstract

Purpose: To review the existing evidence that supports the subconjunctival use of triamcinolone acetonide (TA)in the treatment of various ophthalmic diseases.Methods: A literature search was performed for published articles about the pharmacokinetic (PK) and phar-macodynamic characteristics of triamcinolone, as well as its potential ophthalmic use, focused mainly in thesubconjunctival mode of delivery. Search terms included corticosteroids, triamcinolone, ocular, subconjunctival,and ophthalmic.Results: Corticosteroids represent the mainstay of treatment of ocular inflammation, exerting their action byaffecting multiple pathways of the inflammatory response, making them particularly effective in the majority ofcases. However, due to the number and severity of the side effects associated with their use, they have to begiven with caution. Corticosteroids can be given topically, subconjunctivally, intraocularly, and systemically totreat a variety of ocular diseases with specific pharmacological and PK characteristics. Triamcinolone is one ofthe most widely used corticosteroids in the treatment of ocular inflammation. This glucocorticoid used sub-conjunctivally was proven to be particularly safe and effective in some common and important inflammatoryophthalmic diseases such as anterior scleritis, uveitis, and corneal graft rejection. Further, there are other indi-cations for its successful use where data exist, but somehow less abundant.Conclusions: This article highlights the potential of TA to complement the treatment armamentarium of anteriorsegment inflammation.

Introduction

Corticosteroids have been used in the treatment ofocular inflammatory disease for more than 40 years, first

used intraocularly in 1974 by Peyman et al.1–4 Glucocorti-coids exhibit their anti-inflammatory effect through inhibi-tion of chemotaxis, phagocytosis, and influx of inflammatorycells, by blocking the synthesis of prostaglandins via inhi-bition of the phospholipase A2 and lipo-oxygenase pathwaysand by reducing the production of chemokines, cytokines, andgrowth factors and suppressing the expression of various ad-hesion molecules and receptors. Additionally, they decreasecellular and fibrinous exudation, restore the permeability of thecapillaries, stabilize the lysosomal membranes of polymor-phonuclear cells, inhibit vascularization, and exert a vasocon-strictive effect. Glucocorticoids also have immunosuppressiveaction, through reduction of the number of circulating T-lymphocytes and inhibition of their proliferation.5–10

The purpose of this article was to review the use ofsubconjunctival triamcinolone acetonide (SCTA). Sub-

conjunctival use of corticosteroids, including SCTA, isnot a novel therapeutic approach. However, like all sub-conjunctival modes of drug delivery, its application has beenin decline since the advent of newer, fortified corticosteroids,formulated to penetrate the eye better. These were consid-ered to be safer and more effective, and their administrationwas much less invasive and traumatic for the patient, al-though they often required high level of compliance.

We performed an extensive literature search in Medlineusing the keywords ocular, subconjunctival, triamcinolone,ophthalmic, and corticosteroids.

Properties of Triamcinolone Acetonide

Triamcinolone in its 2 commercially available forms,acetonide and diacetate, is a moderate-strength corticoste-roid with a relatively long duration of action that can last aminimum of 6 weeks when injected locally (Table 1).11–13

Triamcinolone acetonide (TA) is the most widely used formof the drug. TA for ophthalmic use is administered as an

1Moorfields Eye Hospital NHS Foundation Trust, Bedford, United Kingdom.2NHS Foundation Trust Eye Unit, University Hospital Southampton, Southampton, United Kingdom.

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 29, Number 6, 2013ª Mary Ann Liebert, Inc.DOI: 10.1089/jop.2012.0208

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injectable suspension either periocularly or intraocularly asan off-label medication.2 The most widely used preparationis Kenalog (TA, aqueous suspension 40 mg/mL; Bristol-Myers Squibb), which contains benzyl alcohol as a preser-vative and has been found to be less toxic for the eye in bothhumans and animals than the vehicles of other frequentlyinjectable corticosteroids.2 TA exists in a crystalloid form, thesize of the particles ranging from 1 to more than 20mm, withthe majority of them being in the range of 1–5 mm.14

Apart from its subconjunctival administration, TA is alsoused in the management of various ocular diseases in-travitreally (IVTA) and as a posterior sub-Tenon’s or orbitalfloor injection.2,15–18,19 Anterior-segment surgeons are alsousing TA to visualize and remove the vitreous from the anteriorchamber in cataract surgery complicated with posterior capsulerupture.20,21 Recently, intracameral corticosteroids, includingTA, have been successfully used in the treatment of endothelialimmune reactions after penetrating keratoplasties (PKPs).22,23

TA and its vehicle showed no retinal24,25 or corneal endo-thelial toxicity26 after intravitreal injection and additionallydecreased inflammation after surgery.15 However, one investi-gation showed that IVTA doses of 4 mg or higher caused pro-minent retinal damage, with these contrasting findingssuggesting that other factors may contribute to intravitreal reti-nal toxicity of TA, such as preservatives.27 Finally, sterile, non-infectious endophthalmitis occurring after IVTA is most likelyan inflammatory reaction to TA or its vehicle rather than a resultof ocular toxicity, with a good visual recovery after treatment.28

Recently, new formulations of TA were approved by theFDA in the United States under the commercial names Tri-varis (TA injectable suspension 80 mg/mL; Allergan) andTriesence (TA injectable suspension 40 mg/mL; Alcon). Bothwere approved for intraocular use; they are available in single-use preparations and have the major advantage of a preser-vative-free formulation. In addition, Triesence is terminallysterilized. Thus, the risk of toxicity and sterile or infectiousendophthalmitis is potentially reduced to a great extent.

In ophthalmic practice, TA is used in its injectable form withdoses ranging from 4 to 20 mg. The variable amount used mayresult in a difference in pharmacokinetics; higher doses mayhave the potential benefit of a longer duration of action.29

SCTA in Ophthalmic Disease

Indications

SCTA has been used with success for anterior scleritis30–32

and recalcitrant vernal keratoconjunctivitis,33 and prevent

pterygium recurrence after surgery,34 superior limbic kera-toconjunctivitis,35 uveitis, corneal burns and ulcers, herpetickeratitis, and episcleritis,4 intraocular surgery,4,36,37 as wellas in upper eyelid retraction related to active thyroid eyedisease.38,39 SCTA is mainly used in recurrent and refractorycases, resistant to other medication and when there arecontraindications for conventional treatment. A summary ofthe indications for SCTA is given in Table 2 in order of itsrelative effectiveness, as this is elicited by the number ofstudies referring to its successful use. Clinicians should al-ways seek and obtain informed consent by all patients un-dergoing SCTA.

In anterior scleritis, usually, patients who had experiencedfailure of systemic anti-inflammatory medicines were re-cruited. However, because SCTA was found to be very ef-fective and safe, many patients were given SCTA after theyhad failed local immunomodulatory therapy only (topical orsubconjunctival corticosteroids).30

Recently, SCTA in conjunction with intensive topical cor-ticosteroid treatment has been reported to successfully re-verse corneal endothelial graft rejection after posteriorlamellar corneal transplantation40 and PKPs.41,42 Cornealgraft rejection is a complex immune process in which theimmune-privileged status of the eye is lost by inflammationand neovascularization mediated mainly by cytokines,growth factors, T-lymphocytes, and antigen-presentingcells.7 These elements of the inflammatory cascade are themain target of the anti-inflammatory effect of corticosteroids,as mentioned earlier in the text. Short-acting subconjunctivalsteroids such as betamethasone, for the treatment of cornealtransplant rejection, appear to have a limited role, and theiruse is in decline.43 We suggest that if subconjunctival TA is

Table 1. Steroids: Equivalent Dose and Anti-Inflammatory Potency

Relative anti-inflammatory potency

Equivalentdose (mg)

Half-life after systemicadministration (h)

Duration of action of injectablecorticosteroids (approximate)

Cortisol 1 20 8–12 N/ACortisone 0.8 25 8–12 N/APrednisone 4 5 12–36 N/APrednisolone 4 5 12–36 N/AMethylprednisolone 5 4 12–36 6–12 weeks or moreTriamcinolone 5 4 12–36 3–6 weeks or moreBetamethasone 25 0.75 36–72 1–10 daysDexamethasone 25 0.75 36–72 1–3 days

Goodman & Gilman’s. The Pharmacological Basis of Therapeutics. McGraw-Hill; 2001. The material is reproduced with permission of theMcGraw-Hill companies.

Table 2. Indications for Subconjunctival

Triamcinolone Acetonide

Anterior scleritisCorneal graft rejectionVernal keratoconjunctivitisUveitisEpiscleritisPterygium surgerySuperior limbic keratoconjunctivitisCorneal burns and ulcersHerpetic keratitisIntraocular surgeryThyroid eye diseaseNeovascularization

SUBCONJUNCTIVAL TRIAMCINOLONE ACETONIDE AND OCULAR DISEASE 517

used for corneal graft rejection, it should be placed as close tothe limbus—and thus rejection site and the antigen-presentingcells—as possible in accordance with the suggestions ofprevious authors regarding optimal positioning of sub-conjunctival injections.44

SCTA has also been successfully used to reverse neo-vascularization in rabbits.45 As new vessels can mature over2–3 weeks,46 subconjunctival TA should be considered earlyin the management of corneal new vessel formation, which isresistant to topical steroids.

Pharmacokinetics

A number of reports suggest that subconjunctival steroidsachieve intraocular penetration mainly through the tempo-rary incision leakage into the tear film and then through thecornea into the eye. However, due to the lipophilic barrier ofthe corneal epithelial layer, water-soluble formulations suchas phosphate hydrophilic derivatives do not penetrate thecornea easily.1,11,47,48 There is also a local scleral and vesselabsorption,11,41,47–49 which probably becomes more impor-tant once the incision has healed. Once in the eye, a fourthroute of drug diffusion has been postulated: from aqueousinto the vitreous.48 The local fibrolytic effects of SCTA, re-stricted adjacent to the drug, may play an important role tothe scleral absorption by enhancing diffusion of the drug.50

The penetration of TA after sub-Tenon’s injection 5–6 mmfrom the limbus has been studied in rabbits. It was demon-strated that there are saturable ocular barriers to the trans-scleral delivery of TA into the vitreous with the lymphatics/blood vessels of the conjunctiva being presumably themost important of them. Increasing the amount of the druginjected produced higher levels intraocularly, which was at-tributed to saturation of these barriers. Other barriers pos-tulated in this study were the sclera, choroid, and retina.49

The concentration, vehicle, and formulation of a drug mayplay a much more important role in the degree of intraocularpenetration and overall therapeutic effect than its actualpharmacological strength. TA is a long-acting minimallysoluble corticosteroid, and its absorption rate may consid-erably differ from that of short-acting water-soluble cortico-steroids.47,51 In other nonocular models, it has been shownthat corticosteroids with lower solubility such as TA areabsorbed slower, thus maintaining the drug levels for alonger time and creating lower systemic corticoid levels.52,53

One major advantage of subconjunctival/sub-Tenon’s in-jection of corticosteroids, either posteriorly or anteriorly, isthe delivery of the maximum amount of drug into theeye—whether this is the aqueous, vitreous, or subretinalfluid—than the rest of the body when compared with otherperiocular modes of delivery or oral medication. Systemicabsorption after a subconjunctival injection is nearly equal tothat after a peribulbar injection or oral administration.54

However, a smaller dose is needed to obtain equal intraoc-ular concentrations when the drug is injected subconjunc-tivally compared with peribulbar or oral delivery, and thusthe absolute systemic corticosteroid concentration is lowerwith a reduced risk of systemic adverse events and a moretarget-specific drug application.48 In clinical practice though,this is probably most relevant for children due to their sig-nificantly less body mass.11 Even IVTA is associated withsystemic absorption, but this is not considered pharmaco-logically significant.2 In addition, TA is a moderately potent

corticosteroid that minimizes its systemic effects. Generally,it is preferable to reserve the systemic corticosteroid thera-peutic option for severe, bilateral intraocular inflammationor when an associated systemic inflammatory conditioncoexists.1,47,48,55,56

A study carried out in humans has demonstrated signifi-cant intraocular penetration of short-acting water-solublecorticosteroids (dexamethasone disodium phosphate) aftersubconjunctival injection of 0.5 mL of 5 mg/mL solution,much higher than that achieved with peribulbar injection ororal administration. Up to 858 ng/mL of dexamethasone wasmeasured in the aqueous humor in this study.48 This is muchhigher than the 670 ng/mL of prednisolone acetate and the31 ng/mL of dexamethasone alcohol recorded in the humanaqueous humor after topical administration of 1 droponly.1,47 In addition, another study showed that repeatedtopical application of dexamethasone disodium phosphate0.1% results in a maximum aqueous humor and vitreousconcentration of only 30.5 and 1.1 ng/mL, respectively.54

One other study showed increased intraocular penetration ofprednisolone acetate (Econopred plus; Alcon) with a peakaqueous humor level of 1,130 ng/mL 30–45 min after instil-lation.1 The above discrepancies could be attributed to thedifferent formulations used in each study, as it has beenproven that lipophilic derivatives penetrate the normal cor-nea more than hydrophilic ones. Also, higher concentrationsof any corticosteroid, regardless its relative potency, achievehigher intraocular concentrations.47 The timing of the tissuesample retrieval after instillation could also affect the finaldrug concentration. A major shortcoming is that the intra-ocular concentration of short-acting corticosteroids injectedperiocularly, as well as after topical administration, rapidlydeclines within a 24-h period unless repeated in frequentintervals.1,48

Although subconjunctival or anterior sub-Tenon’s TA in-jections produce a significant anterior segment steroid con-centration that remains detectable in the aqueous humor formonths, the peak vitreous levels are substantially less. Thisdiscrepancy could be attributed to the lack of postequatorialdiffusion of drug following these modes of administra-tion.47,49 A study in rabbits showed that periocular injectionsanterior to the equator (subconjunctival and subtenons) re-sults in the drug tending to remain anterior to the equa-tor, concluding that such an approach is more useful inanterior ocular disease and far superior to systemic drugadministration.57

Studies reviewing the histological and biochemical char-acteristics of subconjunctivally injected corticosteroids andTA are scarce. According to one literature review, the ther-apeutic and diagnostic excision of the drug revealed theeosinophilic material present in the subepithelial connectivetissue that was granular in the case of TA (after 3 weeks) orfoamy and homogeneous in the case of methylprednisoloneacetate (after 7 weeks).58 Quantification of the TA sub-conjunctival depots revealed interestingly enough that TAdepots could be present for as long as 13 months after theinjection.59 This is in accordance with 2 other reports with theTA being present for as long as 7 months51 and 10 months,60

as well as our own anecdotal experience with SCTA depotsbeing present for more than 12 months in some cases. Kali-na’s study revealed that the percentage of the originally in-jected triamcinolone in the excised sample ranged from 4.2%to 44%, with a mean of 20%, and the disappearance rates

518 ATHANASIADIS ET AL.

from depot triamcinolone did not correlate with the timefrom injection to surgical excision.59 In other published re-ports, the amount of residual surgically excised triamcino-lone was 5.9% after 4.5 months61 and 19% after 6.5 months.60

Delivery and Mode of Action of TA

The authors believe that SCTA acts by locally suppressingthe immune response over a period of time, due to thecrystalline nature of the drug. The long-acting and constantpresence of local steroid (up to several months) appear to bean important property, as TA is only a moderate-strengthglucocorticoid, 4 times the strength of hydrocortisone and5 times weaker than betamethasone.11 Recently, antivascularendothelial growth factor (anti-VEGF) agents have been usedto reverse corneal neovascularization and graft rejection inhumans and animals, but their effect was short-lived andlimited.62–64 This is in contrast with the pluripotent cortico-steroid agents and specifically the long-acting TA (Fig. 1).8,11

It is a well-accepted notion that subconjunctival delivery isa safer way to administer drugs periocularly compared withretrobulbar and peribulbar injections, because the needle tip isvisible throughout the procedure, thus minimizing the risks,such as retrobulbar hemorrhage or perforation of the eye.48

The technique we recommend for the most efficient use ofSCTA is to cause precipitation of the white crystals in thesyringe and remove the supernatant before the injection. Thiscan be achieved by positioning a 2-mL or insulin syringe in avertical position and observe the separation of the crystalsfrom the vehicle as a densely white precipitate with anoverlying grayish, turbid fluid. If 1 mL of TA is used, theprecipitate will measure *0.1–0.15 mL and will account forthe larger amount of TA in the solution. Whitening of thesubconjunctival area is observed while injecting with a27-gauge needle, indicating that pure TA is mostly present,and thus a drug depot is created (Fig. 2). In this way, theshort-term absorption of leaking TA via the cornea is re-duced, and absorption for longer may be achieved. The po-tentially toxic vehicle and preservative could also beminimized in this way. Sometimes, resistance may be feltwhile advancing the plunger due to the presence of drugcrystals, and thus a smaller gauge needle may facilitate ad-ministration. A long needle track could also minimize leak-age of the drug from the subconjunctival space. Injectionshould be placed anteriorly to facilitate potential removal inthe future if complications occur. Shaking the vial before useis not affecting the actual dose of TA delivered.65

Complications and Side Effects of SCTA

Intraocular pressure

The most significant and most common adverse reactionof SCTA is the development of increased intraocular pres-

sure (IOP) (Table 3). This a well-known complication of thetopical ophthalmic use of corticosteroids, especially, in in-dividuals with primary open-angle glaucoma or a familyhistory of glaucoma.48,59–61,66,67 Other well-documented riskfactors for steroid-induced IOP rise are increasing age, my-opia, and type I diabetes.68 In general, the higher the steroidpotency the greater the ocular hypertensive effect.69 Thesystemic use of corticosteroids has also been proven to havea similar effect on the IOP, but not as profound as with othermodes of delivery.70

The time for the discovery of IOP elevation after sub-conjunctival injection of triamcinolone varies in differentstudies from 1 week51 to 10 months.60 The duration and se-verity of the steroid-induced IOP response appear to be in-versely related to the solubility of the subconjunctivalcorticosteroid preparation, irrespectively of whether topicalcorticosteroid treatment, before SCTA injection, caused IOPrise or not.51

Baseline measurement of IOP is required before the SCTAinjection. Thereafter, regular monitoring is necessary in morefrequent intervals initially and no longer than 6 months ifIOP is not elevated in the first few months. In case of IOPrise, attempts for normalization include both pharmacologi-cal and surgical methods. Topical beta-blockers, carbonicanhydrase inhibitors, and alpha-agonists are usual first-linetreatments with miotics and prostaglandins being relativelycontraindicated or ineffective.68 The most effective and safe

FIG. 1. Properties of triamcinolone acetonide (TA).

FIG. 2. Subconjunctival triamcinolone acetonide (SCTA)injection inferotemporally, visible as an opaque area of drugdepot (black arrow).

Table 3. Side Effects of Subconjunctival

Triamcinolone Acetonide

Increased intraocular pressureCataractConjunctival ulceration/necrosis/ischemiaBlepharoptosisMydriasisSubconjunctival hemorrhage

SUBCONJUNCTIVAL TRIAMCINOLONE ACETONIDE AND OCULAR DISEASE 519

way to manage the elevation of IOP after subconjunctivalinjection of long-acting corticosteroids is surgical excision ofthe depot,48,68 and this is our own clinical experience as well(Fig. 3), though this may not be feasible for more posteriorlyplaced depots. Thus, as mentioned earlier, depots of triam-cinolone in case of subconjunctival injection should be placedanteriorly to facilitate potential removal in the future ifdeemed necessary. Similarly, vitrectomy may help controlthe IOP in selected cases after intravitreal TA. Trabecu-lectomy remains an effective surgical treatment in thosepatients who have a persistently raised IOP after complete/incomplete removal of the SCTA depot and are refractoryto medical therapy. However, as always, the adverse con-sequences of trabeculectomy or other forms of filtrationsurgery should be considered in relation to the potentialbenefits and alternative treatments.68

Cataract and other less-common side effects

Cataract, well documented with other routes of cortico-steroid administration,71,72 was linked with only one case ofSCTA,41 although concurrent uveitis was also postulated as apossible cause.46 Other reported side effects of SCTA areconjunctival ulceration,73 infectious scleritis,74 blepharoptosisand mydriasis,51 and conjunctival ischemia.75 Potential sideeffects of SCTA such as delayed wound healing or systemicabsorption of TA have not been reported as of yet.

Finally, the SCTA injection should ideally be placed infe-riorly if possible, for cosmetic reasons, as the white deposit iscovered by the lower eyelid. Subconjunctival hemorrhage isalso a well known, but trivial side effect.

Summary

SCTA is a very efficient mode of treatment in ocular an-terior segment disease, especially in the management of an-terior scleritis, where it has been widely used. Excellentoutcomes were also reported in corneal graft rejection andvernal keratoconjunctivitis. Smaller doses are requiredcompared to systemic administration for equivalent or evengreater local corticosteroid concentration, and there is also amore target-specific drug application and reduced risk of

systemic adverse events.1 It is also a generally safer mode ofadministration with higher intraocular penetration, lesspotential toxicity, and fewer complications compared withperibulbar and infraorbital injections or systemic adminis-tration,11,48 particularly beneficial in cases of noncompliance.

We believe that the dosing of TA needs to be adjusted inrelation to the severity of inflammation, with higher doses insevere cases, both for optimal control of inflammation andsaturation of the ocular barriers from the conjunctiva to theretina. Whether anteriorly placed TA injection will be moreeffective if placed in the sub-Tenon’s area is not clear, andthese 2 anatomically distinct spaces are not distinguished inmost studies and in clinical practice.52

Raised IOP appears to be the most important and com-monest side effect. It cannot be predicted with certaintywhich patient will develop steroid-induced high IOP, astopical steroid nonresponsiveness does not preclude IOP riseafter SCTA. The fact that topical corticosteroids are given in apulsed fashion and that repository corticosteroids enter theeye in a continuous pattern may contribute to this undesir-able effect.51 Thus, it is necessary to establish a baseline IOPbefore initiating therapy and closely monitor the IOP for atleast 6 months after periocular TA, especially if risk factorsare present. It seems that surgical excision of the sub-conjunctival depot is an effective way to normalize IOP.

It is important to note that the visibility of triamcinolonecorrelates with its action.32,60 Although TA is not more po-tent than dexamethasone or betamethasone, SCTA seems tohave a more favorable outcome, but also results in morefrequent and severe IOP rise, which could indirectly confirmits effectiveness. The reason is not clear, but it could be at-tributed to the less-soluble form of TA, slow release ofthe drug from the formed depot, and the long duration ofaction.

Some of the substantial studies referred in this reviewhave used short-acting corticosteroids, and some caution isrequired when extrapolating their results to long-acting drugssuch as TA. The difference is that a slower release and moresustained intraocular levels are achieved with long-actingmedication, such as TA, and this in turn may mean lowerlevels into the systemic circulation, as previously shown innonocular models.52 In addition, the majority of the studiesregarding the intraocular delivery of corticosteroids after di-verse modes of administration were done in animals and othernonocular models, for example, joints. Their results can besignificantly different from human and ocular data because ofthe differences in the anatomy and physiology.

The role of SCTA in various ocular diseases and especiallyin corneal graft rejection and corneal new vessel formationneeds to be further investigated. Questions such as optimaldosing and optimal mode of delivery for TA remain to beanswered. We believe that SCTA is a safe, efficacious, andcost–effective adjunct or alternative to currently availabletreatments for the contemporary ophthalmologist.

Author Disclosure Statement

No competing financial interests exist.

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FIG. 3. SCTA depot removed surgically.

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Received: September 12, 2012Accepted: January 29, 2013

Address correspondence to:Dr. Yannis Athanasiadis

Moorfields at Bedford Eye ClinicBedford Hospital NHS Trust

Kempston RoadBedford MK42 9DJ

United Kingdom

E-mail: athana1972@yahoo.com

522 ATHANASIADIS ET AL.