Allergic reactions and adverse effects of glaucoma treatment

Evidence Summaries

Level of Evidence = B
Allergic reactions and adverse effects of glaucoma treatment appear to be common.

The purpose was to examine the incidence of allergic reactions and side effects of glaucoma treatment in asymptomatic individuals with early POAG. The glaucoma treatment studies were identified from MEDLINE, Cochrane Library and from HUCS Skin and allergy Hospital. The database search about possible adverse effects to various glaucoma medications consisted of 224 abstracts and titles from 1998 to 2004.

There are no high quality prospective studies concerning adverse effects and the adverse effects are often told as secondary outcomes in big glaucoma treatment studies.

There are only few studies, where the allergic reactions are verified by allergy tests. Another problem is that we may have an allergic reaction in the eye caused by glaucoma medication but the skin tests used for eye drops are not sensitive enough compared to the eye. Further problems are test medications, which usually are eye drops used by the patients. They are tested in most instances "as is" on the back skin. The back skin 5mm thick and the lid skin 0.5mm. This causes a fundamental difference in sensitivity, which is further amplified by very sensitive cornea and conjunctiva.

The treatment options include topical medications, systemic medications, laser surgery, and incisional surgery, alone or in combination. No data exists about sensitivity and specificity in suspected ocular allergies caused by topical glaucoma medication.

Contact allergy is caused by almost all topical glaucoma medications; pilocarpin, beta blockers: timolol, befunolol, betaxolol, levobunolol, carteol, metipranolol, carboanhydrase inhibitors, adrenergics, prostaglandin analoques, preservatives (BAK, bentsalkon chloride), parabens, thimerosal 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . Our own results in HUCS Skin and allergy Hospital varies from 1.1% to 5.5 %. The suspected allergic reactions to adrenergic apraclonidine and brimonidine are about 50 % among all users 17 .

  • Quality of the study: moderate, most studies are small or only case reports. There are no good controlled studies
  • Comment: The reliability of most allergy tests with eye drops is poor, especially when they are done "as is" epicutan tests on the thick back skin. The eye and lids are much more sensitive, which is the common source of error.

Adverse effects are common. In the Collaborative Normal-Tension Glaucoma Study (CNTGS) 12 23 of 66 treated eyes (35 %) developed cataract, compared with 11 of 79 eyes in the control group (14 %) (p = 0.0011), relative risk (RR) 2.5, CL 1,32-4,75. The highest incidence of cataracts (16 of 33) occurred in surgically treated eyes, RR 3,48, CL 1,82-6,68. The rate of cataract formation in untreated eyes was lower than surgically treated eyes (p=0.0001) but was not different from medically treated eyes (p=0.18). In another study the risk of cataract formation was compared in medically treated vs. untreated eyes. In the EMGT 15 study, cataract development was more likely in the group treated with ALT (Argon Laser Trabeculoplasty) plus betaxolol than in untreated subjects (p=0.002), and the risk of cataracts related to treatment increase over time (p=0.02).

  • Quality of the study: moderate
  • Comment: Surgery increases the risk of cataract formation. The risk of for cataract after laser therapy is less or about same as with topical therapy.

Ocular symptoms, such as dryness, tearing and itching, were frequently reported. In the Ocular Hypertension Treatment Study (OHTS) 13 ocular symptoms occurred in 57 % of treated patients and 47 % of control subjects, NNH (number needed to harm) 10, p<0.001. Other symptoms such as darkening of the eyelids or eyelash growth, were reposted in 23 % of treated patients vs. 18 % of control subjects (NNH 10, p<0.001). Patients were treated by prostaglandinanaloques, most often by latanoprost and betablockers.

  • Quality of the study: moderate
  • Comment: Adverse effects are common. Many patients wonder their red and/or dark eyes after prostaglandin derivatives therapy. The activation of an iridocyclitis is possible.

The CIGTS 14 trial reported intraoperative and postoperative complication for surgical trabeculectomy in 524 participants. Intraoperative complication included bleeding in the anterior chamber (7.1 %) and conjunctival buttonhole defects (1.0 %). Complications within 30 days postoperative were: shallow or flat anterior chamber (14.2 %); failed or encapsulated filtering bleb (11.9 %); ptosis (11.9 %); serous choroidal detachment (11.3%); and anterior chamber bleeding oor hyphema (10.9 %). Over time, the cataract extraction rate in the surgery group remained significantly higher than in the medication group (p=0.0001).

In the Finnish study there were examined complications of Neodymium YAG laser goniopuncture after deep sclerectomy in 31 patients. Three patients had spontaneous iris prolapse but there were no signs of severe hypotension 16 .

  • Quality of the study: high quality
  • Comment: Surgery has also its complications but adverse effects in long term topical therapy may be more long lasting and every day life disturbing.

In the EMGT 15 study there are also reported serious systemic adverse effects. In this study, more participants died in the group treated with topical medication and ALT (15 of 22) than in the untreated control group (7 of 22, p=0.08), RR 2.14, CL 1.09-4.21. Most of these deaths occurred among men in the first 2 years of the study. The patterns of cause specific mortality, primarily cardiovascular events and malignancy, were similar those expected in a population of the same age and gender.

  • Quality of the study: moderate
  • Comment: as a rule glaucoma patients are old and have many diseases besides glaucoma like malignancies and cardiovascular diseases. The beta blockers should be prescribed with caution.

In the OHTS 13 study, there were no observed differences between the treated and untreated participants in total hospitalizations, worsening of pre existing conditions, or mortality. Serious psychiatric adverse effects were reported in 5,5 % (44 of 800) vs. 3.4 % (27 of 802) in the control group (p=0.05), RR 1.63, CL 1.02-2.61. Serious genitourinary adverse effects occurred in 1.5 % (12 of 800) of the treatment group vs. 0.5 % (4 of 802) in the control group (p=0.04), RR 3.01, CL 0.97-9.29.

  • Quality of the study: moderate
  • Comment: Patients with pre existing psychiatric disorders and genitourinary disorders should be given in first line prostaglandin derivatives, laser therapy or surcigal treatment.


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2. Butler P, Mannschreck M, Lin S, Hwang I, Alvarado J. Clinical experience with the long-term use of 1% apraclonidine. Incidence of allergic reactions. Arch Ophthalmol 1995 Mar;113(3):293-6.  [PMID:7887842]
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11. Hätinen A, Teräsvirta M, Fräki JE. Contact allergy to components in topical ophthalmologic preparations. Acta Ophthalmol (Copenh) 1985 Aug;63(4):424-6.  [PMID:4050363]
12. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 1998 Oct;126(4):487-97.  [PMID:9780093]
13. Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Gordon MO. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002 Jun;120(6):701-13; discussion 829-30.  [PMID:12049574]
14. Lichter PR, Musch DC, Gillespie BW, Guire KE, Janz NK, Wren PA, Mills RP, CIGTS Study Group. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001 Nov;108(11):1943-53.  [PMID:11713061]
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16. Vuori ML. Complications of Neodymium:YAG laser goniopuncture after deep sclerectomy. Acta Ophthalmol Scand 2003 Dec;81(6):573-6.  [PMID:14641256]
17. Gross RL, Pinyero A, Orengo-Nania S. Clinical experience with apraclonidine 0.5%. J Glaucoma 1997 Oct;6(5):298-302.  [PMID:9327348]

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