Dexamethasone tachyphylaxis in the treatment of macular oedema

Abstract

Tachyphylaxis is characterized by a rapid decrease in response to an administered drug (Von Zastrow 2012). In ophthalmic practice, beta-blockers, brimonidine and anti-VEGF compounds (Gasperini et al. 2012) have been related to this phenomenon. Intravitreal dexamethasone implant (Ozurdex®; Allergan Inc., Irvine, CA, USA) is currently employed for treatment of macular oedema (ME) associated with retinal vein occlusions, diabetic retinopathy (DR) and uveitis and its effects lasting from 3 to 6 months (Haller et al. 2011). Early ME recurrence or partial ME resolution following Ozurdex® may be interpreted as a reduced therapeutic response subsequent to tachyphylaxis. This report provides evidence of tachyphylaxis following Ozurdex® administration and discusses its possible management. Data of patients receiving Ozurdex® for ME secondary to central retinal vein occlusion (CRVO) and DR with a minimum 12-month follow-up were retrospectively analysed. Main inclusion criteria before treatment were the following: central foveal thickness (CFT) >250 μm and best-corrected visual acuity (BCVA) between 1.30 and 0.30 logMAR. Eyes with any additional disorders were excluded. Additional Ozurdex® was administered when a BCVA deterioration of five letters associated with CFT >250 μm occurred after a positive initial response (defined as BCVA improvement >5 letters and CFT reduction >20%). Tachyphylaxis was defined as evidence of initial positive morphological response, characterized by reduction in or absence of intraretinal fluid for at least 3 months, followed by subsequent poor response to the same treatment (either a rapid ME recurrence or only a partial ME resolution). Twenty subjects (mean age: 61.4 ± 6.8; F/M: 8/12) with ME secondary to CRVO (16 eyes) and DR (four eyes) were considered. Mean baseline BCVA improved from 1.2 ± 0.25 to 0.87 ± 0.27 logMAR (p: 0.001, t-test) at the 12-month examination, whereas mean CFT changed from 621 ± 239 μm SD to 312 ± 203 μm (p: 0.001, t-test). All patients positively responded to the first treatment. Tachyphylaxis was identified in four eyes (20%), two with CRVO and DR, respectively. In all these four cases, the complete ME resolution lasted 3–5 months after the first implant. Three eyes showed early recurrence between 1 and 3 months, whereas one eye showed persistent intraretinal cysts following the second implants. A parallel BCVA worsening was registered in all cases. Neither the mean ME duration before the first implant nor the mean previous number of anti-VEGF injections was different in the eyes showing tachyphylaxis (13 ± 2 months, 3 ± 3 injections), compared with the remaining 16 patients (14 ± 3 months, 3 ± 3 injections). Owing to the absence of response to a single therapy, the four patients received a combined therapy (Ozurdex® plus intravitreal bevacizumab). One month later, BCVA improved by 2–4 lines and ME resolved in all the cases with persistent resolution lasting 4 months. Laboratory studies show that dexamethasone concentrations after OZURDEX implant are maximum up to 60 days, gradually decreasing up to 180 days (Chang-Lin et al. 2011). In clinical practice, a corresponding reduction in the efficacy is usually noted after 3 months, and frequent retreatments are necessary. The unexpected early loss of drug efficacy observed in 20% of cases may be ascribed to tachyphylaxis. Increased metabolic degradation of biochemical substances participating to the drug's action and loss of, or changes to, receptors are all potential causative factors responsible for tachyphylaxis. Moreover, drug holidays, drug-free intervals, increased drug dosage or combination therapy with different drug classes may counteract the loss of efficacy due to tachyphylaxis (Hoffman & Taylor 2001), as registered in our four cases receiving a combination therapy. In conclusion, tachyphylaxis should be considered a cause of reduced efficacy of dexamethasone implants. Further studies are warranted to elucidate characteristics and mechanisms involved in this phenomenon.