Journal of Refractive Surgery

Review Supplemental Data

Pharmacological Strategies for Presbyopia Correction

Robert Montés-Micó, PhD; W. Neil Charman, PhD, DSc

Abstract

PURPOSE:

To summarize the pharmacological strategies that are being explored for presbyopia correction.

METHODS:

The review concentrates on pharmacologically induced pupillary miosis to increase depth-of-focus and lens softening or other measures to restore active accommodation.

RESULTS:

Several studies suggest that near vision improves and distance vision is unaffected for many hours after either monocular or binocular instillation of any one of several drug combinations that cause miosis. Unfortunately, in most studies, measurements were limited to photopic visual acuity for near and distance vision, whereas it is anticipated that pupil constriction may have adverse effects on mesopic and scotopic vision. It is not clear whether improved near vision was due entirely to increased depth-of-focus, or whether, for example, a drug-induced myopic shift in refraction was also involved. Currently, no study has provided direct evidence for drug-induced restoration/enhancement of true accommodation involving an ocular power change.

CONCLUSIONS:

Although it is possible that, in the future, pharmacological drops may offer a safe and reliable solution for presbyopia correction, more evidence of their effectiveness and limitations is required.

[J Refract Surg. 2019;35(12):803–814.]

Abstract

PURPOSE:

To summarize the pharmacological strategies that are being explored for presbyopia correction.

METHODS:

The review concentrates on pharmacologically induced pupillary miosis to increase depth-of-focus and lens softening or other measures to restore active accommodation.

RESULTS:

Several studies suggest that near vision improves and distance vision is unaffected for many hours after either monocular or binocular instillation of any one of several drug combinations that cause miosis. Unfortunately, in most studies, measurements were limited to photopic visual acuity for near and distance vision, whereas it is anticipated that pupil constriction may have adverse effects on mesopic and scotopic vision. It is not clear whether improved near vision was due entirely to increased depth-of-focus, or whether, for example, a drug-induced myopic shift in refraction was also involved. Currently, no study has provided direct evidence for drug-induced restoration/enhancement of true accommodation involving an ocular power change.

CONCLUSIONS:

Although it is possible that, in the future, pharmacological drops may offer a safe and reliable solution for presbyopia correction, more evidence of their effectiveness and limitations is required.

[J Refract Surg. 2019;35(12):803–814.]

Following the invention of spectacles in the 13th century, the correction of presbyopia became one of the most important challenges faced by those concerned with the optimization of vision. It is estimated that approximately 30% of the whole world population is presbyopic, the proportion rising to nearly 50% in some developed countries.1,2 The inadequate amplitude of accommodation that characterizes uncorrected presbyopia reduces our ability to perform a wide range of daily near visual tasks. This visual disability that we suffer after reaching an age of approximately 40 years affects the whole world population, regardless of sex and race.

To develop new methods for presbyopia correction, we need to fully understand the factors involved in the development of presbyopia and their changes with age.3 Schematic accommodating model eyes have been proposed to describe in detail and mimic the behavior of the human eye.4 Various reviews have discussed the advantages and limitations of different possible ways of correcting presbyopia and restoring our capability to see effectively at near.5–7 Current widely used methods of correction include spectacles, contact lenses, or intraocular lenses and surgical approaches based on the cornea. Although these methods satisfy the needs of many individuals with presbyopia, some find them unsatisfactory. Most of the approaches do not provide real restoration of accommodation (ie, dynamic changes in the power of the corrected eye) but rely on methods such as sequential vision through, for example, differently powered areas of a bifocal lens, pseudoaccommodation using simultaneous images, monovision, or the use of a pinhole or increased aberrations to enhance depth-of-focus (DOF). However, possible dynamic solutions have been proposed. These aim to provide an appropriate temporal change in the power of the corrected eye to create in-focus retinal images of successively observed objects over a range of distances. Suggested approaches include: accommodating intraocular or other lenses; scleral procedures; regeneration, refilling, or photodisruption of the lens; and ciliary muscle electrostimulation. However, as yet, none of these dynamic solutions has proved capable of reliably providing an appropriate change in the power of the “corrected” eye over the desired focal range of a few diopters.

The limitations of current forms of presbyopic correction have brought renewed interest in the possibility of using topically applied pharmacological agents to ease the problems of individuals with presbyopia.8–10 Such an approach has the advantages of being noninvasive and, at least nominally, easily reversible. To date, attention has been focused on aiding those with emmetropic presbyopia. Two main strategies are being studied, involving either a reduction in pupil diameter to increase DOF and hence the quality of photopic near vision in the emmetropic eye or an increase in the amplitude of the patient's accommodation, primarily through a reduction in crystalline lens stiffness. This article reviews currently suggested variants of these strategies and the outcomes reported.

Methods

The following databases were explored for the initial literature review: PubMed and Clinicaltrials (U.S. National Library of Medicine); Web of Science (Clarivate Science); and Scopus (Elsevier). The search was limited to English publications and included both peer-reviewed scientific reports and clinical trials. No date restriction was used in the electronic searches. The date of the last electronic search was March 9, 2019. The literature search included a combination of different keywords: “presbyopia,” “drops,” “eye,” “treatment,” “pharmacological,” and “correction.” In addition, all of the references for those selected studies were also screened to ensure that other relevant studies on this topic were not omitted.

Pharmacological Strategies

As noted earlier, it appears that two broad groups of pharmacological strategies have been proposed to improve near vision in presbyopia: those attempting to increase the DOF of the eye and those aiming to produce a real restoration of accommodation, often in conjunction with an increased DOF. Table A (available in the online version of this article) summarizes the characteristics of the major drugs currently used in the formulation of topically applied drops designed to achieve these objectives.

Topical Drugs Used in the Treatment of Presbyopia

Table A:

Topical Drugs Used in the Treatment of Presbyopia

Increasing DOF

The first miotic agent discovered was derived from the calabar bean, the active agent being the parasympathomimetic alkaloid physostigmine.11 It is interesting to note that, a year later in 1864, Donders12 commented that following its topical application: “The improvement in the acuteness of vision in ordinary ametropia is indeed remarkable.” He rightly attributed this in part to the smaller retinal circles of confusion and increased DOF associated with the induced miosis.12

If the center of the full dioptric DOF corresponds to the image of a distant object being precisely in focus on the retina (ie, the eye is truly emmetropic), the proximal end of the DOF will correspond to the near point. A larger DOF therefore implies that the dioptric vergence of the nearpoint increases (ie, the nearpoint moves closer to the eye), and that the range of object distances over which satisfactorily clear vision can be obtained increases. In a geometrical optical approximation, ocular DOF changes inversely with the pupil diameter, so that it would be expected that, with an emmetropic eye, small pupils would increase DOF and improve near vision. In practice, aberration and the Stiles–Crawford effect mean that an inverse relationship is not strictly followed, particularly at larger pupil diameters, but it is true that DOF is markedly enhanced as the pupil diameter is reduced to approximately 1.5 mm. Figure 1 gives examples of the results of several relevant experimental studies.13–18 Numerical values in different studies vary due to differences in the methods and criteria used to assess the DOF, but it is clear that higher values are indeed achieved with lower pupil diameters. Further reductions in pupil diameter below approximately 1.5 mm have the disadvantages that retinal light levels become excessively low and that diffraction starts to markedly degrade the retinal image, resulting in a loss in acuity across the full focal range. Unlike small pupils placed on the cornea, whose axial separation from the natural pupil introduces vignetting for non-axial ray pencils, a small natural pupil has only minor effects on the extent of the peripheral visual field.19

Results of experimental studies of the total ocular depth-of-focus as a function of pupil diameter (created using data from Campbell,13 Ogle & Schwartz,14 Tucker & Charman,15 Charman & Whitefoot,16 Atchison et al.,17 and Marcos et al.18). D = diopters

Figure 1.

Results of experimental studies of the total ocular depth-of-focus as a function of pupil diameter (created using data from Campbell,13 Ogle & Schwartz,14 Tucker & Charman,15 Charman & Whitefoot,16 Atchison et al.,17 and Marcos et al.18). D = diopters

For an individual with late presbyopia who has no active accommodation, the through-focus acuity peaks when the test chart is placed at a dioptric position corresponding to the individual's refractive error and falls for stimuli above and below this dioptric value. The peak is rarely perfectly symmetrical, due to the effects of higher-order aberrations, particularly spherical aberration. A decrease in pupil diameter widens the peak and, correspondingly, increases the DOF (Figure 2). For emmetropia, the optimal acuity is found for a distant chart and, if the DOF is defined in terms of the dioptric range over which the acuity exceeds some acceptable but lower value (eg, 0.2 logMAR in Figure 2), use can be made of only approximately half of the full available DOF, the effective nearpoint being at the proximal end of the DOF. An individual with low hyperopia will only be able to make use of less than half of the available DOF. To make use of the full DOF, a distant object should be imaged at the distal end of the DOF (ie, the eye should have approximately DOF/2 of myopia) (Figure 2). This implies that the near vision of individuals with presbyopic “emmetropia” who in fact have low hyperopia may benefit less from the use of a small pupil than those with “emmetropia” who have low myopia. Any active accommodation in the earlier individual with presbyopia will asymmetrically extend the through-focus curve toward closer objects, so that the effective DOF increases.

Experimental data for the changes in logMAR acuity as a function of the dioptric stimulus for a non-accommodating emmetropic patient with a 2-mm (black continuous curve) or a 4-mm pupil (dotted curve). Created using data from Tucker & Charman.15

Figure 2.

Experimental data for the changes in logMAR acuity as a function of the dioptric stimulus for a non-accommodating emmetropic patient with a 2-mm (black continuous curve) or a 4-mm pupil (dotted curve). Created using data from Tucker & Charman.15

Substantial use has been made of the small pupil (“pinhole”) principle in the past,20 most recently in the use of KAMRA corneal inlays (Acufocus, Irvine, CA) to improve near vision in presbyopia,21,22 the IC-8 intraocular lens, and the Xtrafocus implant.23 Various drug combinations have been proposed to achieve the required decrease in pupil diameter. Broadly speaking, these combinations aim to optimize the speed, duration, and extent of the miosis without inducing significant refractive changes or adverse short- or long-term side effects. Some combinations that have been used in published studies are discussed below. Available information on compositions is limited or almost non-existent; even when components and their concentrations are identified, their relative proportions are not specified (this also applies to drug combinations that attempt to restore some accommodation).

Carbachol and Brimonidine

In a 2015 study, Abdelkader24 used the combination of a parasympathomimetic drug (2.25% carbachol) with an alpha agonist (0.2% brimonidine), as originally suggested by Kaufman,25 to reduce the effect of presbyopia by creating miosis. The prospective, double-masked, randomized, placebo-controlled clinical trial involved 48 individuals with emmetropic presbyopia with ages ranging from 43 to 56 years (mean: 50.4 ± 4.0 years) and an uncorrected distance visual acuity (UDVA) of at least 20/20 in both eyes. The patient sample was divided into two groups: the treatment group (30 eyes), who received a daily single dose of the eye drops, and the control group (18 eyes), who received placebo drops. Drops were given monocularly in the non-dominant eye of all participants. Scotopic pupil diameter and photopic near and distance visual acuity were evaluated before treatment commenced and on day 1 of treatment at 1, 2, 4, 8, and 10 hours after drop instillation. When evaluating the consistency of the drug effects, practical constraints on participant availability meant that repeated posttreatment measurements at different times after drug instillation were made on different days within the overall trial period (ie, the 2-hour measurements were repeated after 1 week of treatment, 4-hour after 1 month, 8-hour after 2 months, and 10-hour after 3 months). Treatment continued for at least 3 months.

The results revealed that for several hours after drop instillation there was a statistically significant improvement in near visual acuity in all participants who received the carbachol plus brimonidine drops (P < .0001). The changes in uncorrected near visual acuity (UNVA) followed a similar time course to the changes in recorded pupil diameter (Figure 3), although it must be remembered that the pupil measurements were not made under the same observing conditions as the visual acuity measurements. No statistically significant differences were found between any of the parameters as measured later in the trial period and those found on day 1. UDVA showed no change over the trial period. No changes in either distance or near acuity were observed in the placebo group. All individuals with presbyopia who received the drug mixture were satisfied with the quality of their distance and near vision and abandoned their near spectacles. No participant suffered from adverse effects sufficient to cause the abandonment of the treatment.

Time course on day 1 of the trial after instillation of a mixture of carbachol and brimonidine for (top) mean pupil diameter and (bottom) mean near visual acuity (created using data from Abdelkader24). Zero time gives the pretreatment values. Differences between age groups were not significant.

Figure 3.

Time course on day 1 of the trial after instillation of a mixture of carbachol and brimonidine for (top) mean pupil diameter and (bottom) mean near visual acuity (created using data from Abdelkader24). Zero time gives the pretreatment values. Differences between age groups were not significant.

In a related study by Abdelkader and Kaufman,26 10 individuals with emmetropic presbyopia received in turn one of four drug mixtures: 3% carbachol and 0.2% brimonidine in either combined or separate forms; 3% carbachol alone: and 0.2% brimonidine alone (control). The drops were applied to the non-dominant eye in a crossover manner with 1-week washout between tests. Inclusion criteria were ages between 42 and 58 years, emmetropia (cycloplegic spherical equivalent [SE], ±0.25 D; astigmatism of 0.25 D or less), and binocular UDVA of 20/20 or better. Exclusion criteria were myopia, hyperopia and astigmatism of greater than 0.25 D, corneal, lens, and vitreous opacities, pupil irregularities, anisocoria, amblyopia, chronic general pathologies, and medications that would interact unfavorably with carbachol and brimonidine.

The authors found that mean UNVA was significantly better in participants who received the 3% carbachol and 0.2% brimonidine combined in the same formula compared with those who received the two drugs in separate forms or the single drugs (P < .0001), suggesting that the brimonidine usefully enhanced the effects of the carbachol. Pupil diameters achieved were smaller and near acuity values better than in Abdelkader's earlier study,24 perhaps as a result of the higher concentration of carbachol used. Mean UNVA (Jaeger at 40 cm) obtained at 1, 2, 4, and 8 hours after drug instillation was J1.1, J1.1, J1.8, and J2.3, respectively. In relation to adverse events, the authors indicated that a mild burning sensation was reported in one of 10 participants of the combined drops trial compared to 6 participants when carbachol drops alone were instilled. Three participants in both the brimonidine and separate groups reported a mild burning sensation.

As a result of these studies, the authors26 concluded that monocular treatment of the non-dominant eye of individuals with emmetropic presbyopia with one drop a day of this drug combination yielded acceptable reading vision (even in older individuals) while maintaining good distance vision. Any adverse effects were mild and transient. It was therefore proposed that this combination offers an acceptable and safe alternative to corrective lenses and surgical procedures.

PresbiDrops

PresbiDrops (CSF-1; Orasis Pharmaceuticals, Herzliya, Israel) is a combination of a parasympathomimetic agent with a non-steroidal anti-inflammatory drug to prolong the effect of the parasympathetic action, in an oil-based formulation, although its exact formulation has not been released. The stated aim is to increase DOF and reduce higher order aberrations (although reduction of Zernike aberration coefficients would always be expected to accompany a reduction in pupil diameter). The first results were presented at the Nordic Congress of Ophthalmology in 2014,27,28 where 81 and 33 eyes were evaluated and it was concluded that this was a safe treatment providing good outcomes both for distance and near. Specifically, for pseudophakic eyes, both near and distance visual acuity improved after drop instillation. The results showed that the intervention improved near vision from J6 to J3 in some cases, and that a 1-mm reduction in pupil size was associated with an increase in DOF of 1.00 D.

Two clinical trials have been registered, the NCT0274522329 and the NCT02965664.30 The first29 involved 36 participants (aged 40 to 65 years) in a phase 2, double-blind, randomized, placebo-controlled, crossover study to establish safety, tolerability, and efficacy of PresbiDrops (CSF-1) in individuals with presbyopia. One group self-administered PresbiDrops (one drop in each eye each morning for 2 weeks) and the other self-administered a placebo. The main outcome measures were the percentage of participants with an improvement of two or more lines from baseline in UNVA and the mean change from baseline in the number of lines correctly identified in UNVA. In the second trial,30 drops were instilled with the supervision or help of the hospital staff, rather than being self-administered. As yet, no results have been published in clinical trials or peer-reviewed journals.

Aceclidine and Tropicamide

A combination of aceclidine (a muscarinic agonist agent) and tropicamide (an antimuscarinic agent) has been developed by Presbyopia Therapies, LLC (Coronado, CA), under the name Liquid Vision (PRX-100). This combination of agents aims to produce miosis (typically a reduction in pupil diameter of 1.5 to 2 mm) without stimulating accommodation. It is intended to be instilled in both eyes. Two clinical studies have been performed. The first was a phase 2 study (NCT0255439631) based on a 1-day, randomized, double-masked, single-center evaluation of the efficacy and safety of PRX-100 ophthalmic solution compared to a placebo in 20 participants to evaluate the safety of PRX-100 and the magnitude and duration of effects on improving near vision acuity. The inclusion criterion was patient age between 45 and 59 years, and exclusion criteria included previous refractive surgery or sensitivity to the medications used. Binocular assessment of UNVA was done in two groups: PRX-100 and placebo (saline solution). The second, a phase 2 study (NCT0320156232), increased the number of patients to 58, with three arms: PRX-100 (aceclidine + tropicamide), PRX-100 (aceclidine), and a vehicle with no active ingredient. The primary out-come measure was the proportion of individuals showing at least a three-line improvement after treatment in the monocular distance corrected near visual acuity (DCNVA) at 45 cm of the study eye compared to the baseline value, the measurements being continued up to 7 hours after treatment. No results have been published in clinical trials or peer-reviewed journals, although a press release suggests that, 1 hour after instillation, approximately 47% of the PRX group showed an improvement of at least three lines in near vision and 92% improved by at least two lines. There was no loss of distance visual acuity. The effect lasted 7 hours and the solution was well tolerated.33

AGN-199291 and AGN-190584

The AGN-199291 and AGN-190584 (Allergan, Dublin, Ireland) components are currently under investigation by Allergan. No detailed information of these components has been published, but they are presumed to be oxymetazoline and pilocarpine.34 Three phase 2 clinical studies have been conducted to assess the safety and efficacy of the use of both components either alone or combined: NCT0219780635 with 65 participants, NCT0259552836 with 163 participants, and NCT0278011537 with 151 participants.

Only the first study in 2014 showed an outcome, this being the percentage of participants with at least a two-line improvement from baseline in UNVA in the non-dominant eye. The inclusion criterion was that patient age should be between 40 and 55 years and exclusion criteria were the use of topical ophthalmic medications, contact lens use within 14 days or planned use during the study, a history of eye surgery, and diagnosis of any type of glaucoma or ocular hypertension. This was a four-arm study with: AGN-199201 (one drop of AGN-199201 ophthalmic solution followed by one drop of AGN-199201 vehicle in the non-dominant eye and two drops of AGN-199201 vehicle in the dominant eye, once and twice daily for 3 days each), AGN-190584 (one drop of AGN-190584 ophthalmic solution followed by one drop of AGN-199201 vehicle in the non-dominant eye and two drops of AGN-199201 vehicle in the dominant eye, once and twice daily for 3 days each), AGN-199201 + AGN-190584 in one eye (one drop of AGN-199201 ophthalmic solution followed by one drop of AGN-190584 ophthalmic solution in the non-dominant eye and two drops of AGN-199201 vehicle in the dominant eye, once and twice daily for 3 days each), and AGN-199201 + AGN-190584 in both eyes (one drop of AGN-199201 ophthalmic solution followed by one drop of AGN-190584 ophthalmic solution in both eyes, once and twice daily for 3 days each). The percentages of patients with at least a two-line improvement in UNVA in the four groups were: 47%, 71%, 56%, and 69%, respectively, and no serious adverse events were reported. Other adverse events were eyelid retraction in 26% of the AGN-199201 only users and one case each of blurred vision, hyperemia, increased lacrimation and eye irritation in the AGN-190584 only users.

A phase 3 study (NCT0380426838) is planned with the AGN-190584 component. This aims to recruit 300 participants with a two-arm study: one drop bilaterally once daily for 30 days with AGN-190584 for the experimental group and a vehicle for the placebo group. The objective is to evaluate the efficacy, safety, and pharmacokinetics of AGN-190584 when administered bilaterally, once daily for 30 days in participants with presbyopia. The primary outcome measure is the proportion of participants gaining three lines or more in mesopic, high-contrast, binocular DCNVA. A new study (NCT0385754239) will evaluate the AGN-190584 in an expanded participant population to establish efficacy, safety, and tolerability versus the vehicle control when administered bilaterally once a day in participants with presbyopia, over a 30-day study intervention period.

Treatments Intended to Either Slow the Progress of Presbyopic Change or to Partially Restore Active Accommodation

Several studies have used drug combinations that attempt to improve or retain any residual accommodative ability in the presbyopic eye, this attempt sometimes being combined with miosis to increase DOF.

Although a variety of factors contribute to the slow decline in the amplitude of accommodation in earlier life and the development of presbyopia, there is general agreement that increased stiffness of the lens plays an important role,40,41 the lens becoming increasingly more difficult to deform as it ages (Figure 4A). In contrast, the ciliary muscle maintains its strength well beyond the age at which the eye can actively change its power.42–45 This is illustrated in Figure 4B, which shows the age-dependent results of a transverse magnetic resonance imaging study on the diameter of the ciliary ring when a participant views either a distant target or one requiring maximal accommodation.44 It can be seen that the change in ring diameter with accommodative effort remains almost constant with age up to approximately 90 years, even though the actual accommodation change achieved is effectively zero after approximately 55 years. If this is true, the eye's accommodative ability might be restored if the stiffness of the older lens could be reduced or if better use could be made of the forces potentially available from the ciliary muscle to reshape the lens. Several pharmacological treatments have been devised on this basis.

(A) Relative resistance of the crystalline lens to physical deformation as a function of age (created using data from Glasser & Campbell41). (B) Diameter of the ciliary muscle ring when the eye is exerting minimal and maximal accommodation as a function of age (created using data from Strenk et al.44). Only the regression results of the original authors are shown.

Figure 4.

(A) Relative resistance of the crystalline lens to physical deformation as a function of age (created using data from Glasser & Campbell41). (B) Diameter of the ciliary muscle ring when the eye is exerting minimal and maximal accommodation as a function of age (created using data from Strenk et al.44). Only the regression results of the original authors are shown.

However, the ring diameter declines with age (Figure 4B), whereas the lens diameter remains constant.45 The consequent reduction in the gap between the ciliary ring and the lens equator would be expected to reduce the tension applied by the zonule and hence may contribute to the development of presbyopia. This might suggest that reduction in the stiffness of the older lens would not necessarily restore accommodation and has led to alternative attempts to achieve this by surgically modifying the sclera to increase the circumlental space to more youthful levels.46

Pilocarpine and Diclofenac

In 2012, Benozzi et al.47 suggested that the near vision of individuals with emmetropic presbyopia could be improved with a pharmacological treatment that induced miosis and change in the ciliary muscle by using a cholinergic agent combined with an non-steroidal anti-inflammatory drug. Over a 5-year period, a combination of pilocarpine 1% and diclofenac 0.1% was applied at 6-hour intervals during the day to both eyes of 100 participants, with ages ranging from 45 to 50 years. It was reported that all of them achieved near vision of J1 and distance visual acuity of 20/20. However, 20 patients felt ocular burning and discomfort directly after drop instillation. One abandoned the treatment for this reason and 4 preferred treatment with spectacles. The authors concluded that accommodation in patients with presbyopia could be restored using their drug combination, claiming: “The restoration of accommodation can be achieved by stimulating the ciliary muscle contractions with parasympathetic drug administration to modify the shape and position of the lens.” However, their study offers no evidence that true accommodation was occurring. It seems possible that the enhanced near vision was simply associated with pupil contraction and enhanced DOF, although the study did not measure pupil diameter.

FOV Tears (PresbV)

This more complex composition, patented by Luis Felipe Vejarano, consists of pilocarpine (0.247%), phenylephrine (0.78%), polyethyleneglycol (0.09%), nepafenac (0.023%), pheniramine (0.034%), and naphazoline (0.003%). Renna et al.48 and Vejarano et al.49 evaluated the effectiveness of binocular instillation of this combination. In an explanation of the composition, Renna et al. indicated that, as is well known, pilocarpine produces ciliary body contraction and stimulates accommodation, also inducing miosis that increases the DOF. Naphazoline intensifies the relaxing effect of pilocarpine on the dilator pupillae. Nepafenac, pheniramine, and phenylephrine counteract any ciliary muscle spasm, hyperemia, and excessive pupil constriction induced by the pilocarpine. Polyethyleneglycol lubricates the eye and stops the burning sensation caused by the other drugs. The authors suggest that the synergistic effect between these compounds permits improved near vision and preserves distance vision.

In the pilot study,48,49 both eyes of 14 participants with presbyopia (28 eyes) were treated, with 9 natural emmetropes and 5 emmetropes after LASIK surgery; their ages ranged from 41 to 55 years. Although in the pilot study a single drop was applied to each eye, the topical formulation is intended for twice daily use. The results, with a follow-up of 1 month, showed that UNVA improved by approximately two to three lines from baseline in each eye alone and binocularly. Monocular and binocular UDVA were not degraded. There was a maximum early myopic shift of 0.50 D that progressively reduced and disappeared at 4 hours. A claimed advantage over simpler miotic formulations was that the pupil remained active and that its diameter was only slightly reduced, so that vision under mesopic and scotopic conditions was little affected.

In a more recent study, Vargas et al.50 applied this composition in 117 patients with presbyopia and evaluated the outcomes at 2 hours after instillation. This was a consecutive, non-randomized, interventional, non-comparative clinical study with patient ages ranging from 41 to 65 years. Inclusion criteria were binocular distance visual acuity of 0.0 logMAR, spherical refractive error of between +1.50 and −0.50 D, and astigmatism of less than 1.50 D. Exclusion criteria included previous refractive surgery, pseudophakia, and significant comorbidities (eg, dry eye or glaucoma). Each patient received one drop in each eye. Patients were divided into two age groups: 41 to 50 years and 51 to 65 years. Visual acuities at distance and near were evaluated before and 2 hours after drop instillation. The authors reported a mean UNVA before instillation of 0.35 logMAR, which improved significantly to 0.16 logMAR at 2 hours after instillation. No UNVA improvement was found in 9 patients but no patients showed a loss of lines. It seems possible that these intersubject differences might be related to the relatively wide range of refractive errors in the patient population. Fourteen patients (11.9%) reported headaches as a side effect of the therapy.

Pupil size changed significantly in both groups after the use of the eye drops. Despite this, the authors state that a dynamic pupil was maintained, which was still able to change its diameter under different light stimuli (referred to by them as “dynamic pseudoaccommodation”). The authors suggest that the enhanced near acuity observed was attributable partly to a small increase in DOF associated with modest amounts of pupil constriction and partly to stimulation of contraction of the ciliary body. No formally published information has been offered to support this, but informal reports claim the existence of an increase of 0.75 D after drug instillation in the objective amplitude of accommodation.51

Choline Ester of Lipoic Acid (LACE)

There is evidence that one reason why the older lens becomes stiffer is because disulfides increase protein cross-linking. LACE (EV06, LACE, UNR844, Novartis, Basel, Switzerland) is used with the aim of reducing these protein disulfides and making the lens more elastic, hence restoring some accommodation. The first evidence for the utility of LACE was reported in 2014 by Crawford et al.52 and Garner et al.53 using rabbit eyes, and in 2016 by Garner and Garner54 using mouse eyes. The rabbit eye study showed that this formation was well tolerated: no systemic or adverse events were reported. The mouse study showed that the lenses of treated eyes were more elastic and that the increase of lens elasticity was dependent on the concentration of the lipoic acid applied. The authors therefore suggested a topical ocular treatment for presbyopic humans to increase lens elasticity through reduction of disulfides to restore accommodative amplitude. This solution was covered in a patent55 by Encore Health, LLC. Encore Vision started with phase 1 and 2 to determine whether the ophthalmic solution (namely EV06) was safe and effective to improve DCNVA in patients with presbyopia.

In the first clinical trial (NCT02516306),56 75 patients aged 45 to 55 years were recruited with a CDVA of 20/20 or better and DCNVA of worse than 20/40 in each eye. Exclusion criteria included certain pupillary conditions, significant astigmatism, glaucoma, diabetes mellitus, cataract, eye surgery, ocular trauma, or accommodative issues. This was a prospective, randomized, double-masked, placebo-controlled, multicenter study where the primary outcome was to assess the ocular comfort. The experimental EV06 ophthalmic solution was administered one drop twice per day in one eye from days 1 to 7, and one drop twice per day in both eyes from days 8 to 91. The placebo was administered in a similar way. Forty-nine patients completed the two periods of treatment for the EV06 ophthalmic solution and 23 for the placebo. The study concluded that during the 3 months of study there were no clinically significant changes in ocular comfort comparing the treatment groups.57

A later report presented at the Association for Research in Vision and Ophthalmology annual meeting in 201758 showed a cohort of this study with a 7-month follow-up after cessation of their assigned treatment to assess the duration of the effect; 52 of 72 patients who originally participated were enrolled in the new study (34 who received the EV06 and 18 who received the placebo solution). At the end of the initial 3-month dosing period, a statistically significant difference in bilateral DCNVA between the EV06 and placebo groups was found (mean logMAR ± standard error of the mean: EV06 0.201 ± 0.036 vs placebo 0.311 ± 0.022; P = .011). A significant difference remained at 210 days after the last drug exposure (EV06 0.245 ± 0.037 logMAR vs placebo 0.348 ± 0.032 logMAR; P = .042). Novartis, which acquired Encore Vision, has started a phase 2 clinical study of EV06, now named UNR844-CI, in 120 participants (NCT03809611).59 The primary outcome is to measure the change from baseline in binocular DCNVA in individuals aged 45 to 55 years at month 3 after UNR844-Cl or placebo treatment (randomized, placebo-controlled, double-masked, multicenter study).

It is important in future studies that the amplitude of accommodation be monitored objectively after drug use to confirm the claimed primary lenticular softening effect of the lipoic acid. Such measurements would clarify whether residual amplitude is merely preserved against normal decline or whether it is enhanced in the younger individual with presbyopia (younger than 55 years). Similarly, they would establish whether accommodation can be restored in older individuals with presbyopia (older than 55 years) whose accommodative ability had previously been completely lost. The possible effect of the pharmacological treatment on other ocular structures containing protein disulphides, such as the lens zonules, also needs to be monitored.

Pirenoxine

Pirenoxine, a pyridophenoxazine compound resembling xanthommatin, has been shown to prevent visual acuity from decreasing in patients with senile cataracts.60 This encouraged Tsuneyoshi et al.61 to search for anti-presbyopic activity of pirenoxine in rats and humans. They found that pirenoxine eye drops significantly (P < .001) suppressed lens hardening in rats. In humans, they analyzed two groups, treatment (0.005% pirenoxine) and control (artificial tears). In both cases, patients were divided by age: those in the fifth decade of life (40s) and those in the sixth decade of life (50s). Patients (all male) had ages ranging from 40 to 54 years, had 20/20 corrected distance visual acuity, and showed no history of refractive surgery or ophthalmic diseases. The 19 right eyes of 19 patients were assigned randomly to the treatment or the control group. One patient was excluded due to a small pupil diameter that did not allow objective accommodative amplitude to be measured with the Nidek ARK-1s autorefractor (Nidek, Gamagori, Japan) used. Eye drops were instilled four times daily for 6 months, and accommodative amplitude, DCNVA, functional visual acuity, and pupil diameter were evaluated.

After a 6-month treatment period, the results for patients in their fifth decade of life were analyzed. The objective accommodative amplitude decreased significantly by 0.16 D in the control group (P < .01), but there was no detectable change in the treatment group. This suggested to the authors that pirenoxine eye drops might prevent progression of presbyopia in patients with early presbyopia. The patients in their sixth decade of life, in whom the accommodative amplitude was already close to 0.00 D, showed no change in accommodative amplitude, so there was no evidence that pirenoxine could restore accommodation once it was lost. The authors noted some limitations of their study, such as the small patient sample and the limited period over which the patients were observed, and suggested that future studies should consider different concentrations of pirenoxine. It would obviously also be desirable to explore the effects of intervention at an earlier age, which might yield better results, but currently any benefits of this drug treatment seem to be too small to be clinically useful, even after a relatively long period (6 months) of fairly intensive treatment (four drug instillations each day).

Discussion

The studies described above have largely involved phakic individuals with near-emmetropic presbyopia. However, it is clear that pseudophakic individuals can benefit from the same miotic approaches as those used in phakic individuals and that, in principle, individuals with myopic or hyperopic presbyopia can first be made emmetropic by laser surgery or other methods before undergoing any pharmacological treatment.

The studies summarized above suggest there is little doubt that several drug combinations that include a miotic agent can improve photopic near acuity for individuals with emmetropic presbyopia as a result of the larger DOF associated with smaller pupils, while maintaining distance acuity. In many cases, a single application of the drop early in the morning can give distance and near photopic visual acuities that remain adequate throughout the working day. This is not surprising because Xu et al.62 found that individuals with emmetropic presbyopia who were given small artificial pupils (2 to 3 mm in diameter) could read proficiently at both distance and near, even at the lowest text luminances found in normal photopic interior lighting environments (approximately 2 cd/m2). However, if the pupil diameter was reduced to 1 mm, reading proficiency was notably worse under all conditions as a result of low retinal illuminance and large diffractive effects.

Other problems may arise under mesopic and scotopic conditions with drug-induced small pupils, because retinal illuminances will inevitably be much lower than would be the case with natural pupils. Koch et al.63 found that under night driving conditions (illuminance 5 lux) the typical natural pupil diameter was approximately 5.2 mm for those 40 to 49 years old and 4.6 mm for those 50 to 59 years old. If the miotic pupil was only 2 mm in diameter, the corresponding retinal illuminances in the miotic case would be only approximately 15% and 19% of their natural values in the younger and older age groups, respectively. In cases where miosis is present in both eyes, such a reduction is likely to significantly affect the quality of vision achieved under low lighting conditions and, in situations like night driving, might adversely affect safety.

Where the miosis is unilateral,24,26 the normal eye maintains better vision at lower light levels, so that overall vision remains acceptable. However, some of the advantages of binocular vision may be lost and problems may arise under some circumstances, due to the Pulfrich effect caused by the interocular differences in retinal illuminance inducing distortions of the perceived path of moving objects.64 Nevertheless, patients treated monocularly by Abdelkar and Kaufman26 reported that they could drive safely by day and night without any distortion in the perception of movement.

The effectiveness of pharmacological treatments to improve near vision through their action on elements of the accommodation system (principally the lens) remains less certain. With some drug formulations, it appears more likely that the improvements in near vision that are observed are due to miosis or perhaps a myopic refractive shift, rather than to any enhancement of the objective amplitude of accommodation. Dynamic measurements using objective optometers and other instruments are urgently needed to confirm that any improvements in near vision after drug instillation are caused by an enhanced accommodation response rather than increased DOF or a refractive shift.

Rather than concentrating on increasing lens elasticity or suppressing its hardening to improve accommodation and hence near vision, which is important and perhaps effective, it might also be worth considering the roles of other elements of the accommodation system and whether their effect could be enhanced. Restoration of the capability to modify the lens's shape is important, but the roles of, for example, the zonule and how the fibers transmit forces to the lens, together with effect of the gradient refractive index change during accommodation, should be analyzed in detail. Non-invasive and high-resolution visualization techniques should be used to help us to better understand whether achievable changes in other elements of the accommodation system might help to restore accommodation in presbyopic eyes.

It is encouraging that relatively few pharmacological adverse events were encountered in any of the studies. None were serious. However, the number of patients involved in any study remains small and more work is required on this aspect. It may be, however, that pharmacological treatments prove to be more useful as a temporary supplement or short-term alternative to other methods, so that possible long-term adverse effects become less important. It must be remembered that natural pupil diameter under any specific set of illumination conditions declines with age65–67 (senile miosis). As an example, Figure A (available in the online version of this article) shows the age course of the pupil diameter under fully dark-adapted conditions.67 This reduction with increasing age may imply that the greatest benefits from drug-induced increases in DOF occur in early presbyopia, when the natural pupil is larger and the natural DOF smaller. In more advanced presbyopia, a drug-induced reduction in an already small pupil diameter, allied to age-dependent increase in optical density of the eye media,68 would lead to low retinal illuminances. It might be better to use higher levels of task illumination, which would give the benefits of smaller pupils and enhanced DOFs while also yielding higher retinal illuminance.69,70

Mean pupil diameters after 15 minutes of dark adaptation as a function of patient age (created using data from Kadlekova et al.67). The decrease in diameter with age occurs under any fixed illumination condition.65

Figure A.

Mean pupil diameters after 15 minutes of dark adaptation as a function of patient age (created using data from Kadlekova et al.67). The decrease in diameter with age occurs under any fixed illumination condition.65

In general, comparison of the relative effectiveness of the compositions of the drugs used in different studies is difficult. This is due partly to the heterogeneous nature of the populations of “emmetropic presbyopes” used and partly to differences in the way acuities are measured and expressed. Some studies include individuals in their 40s, who, although having presbyopia, might be expected to retain some measure of active accommodation. Others include individuals with high levels of spherical or cylindrical refractive error, or simply say “naturally emmetropic” (Table B, available in the online version of this article).

Ranges of Refractive Error and Age of Presbyopic Patients Used in Different Studies With Drugs Primarily Intended to Produce Miosis and Increased Depth of Focus

Table B:

Ranges of Refractive Error and Age of Presbyopic Patients Used in Different Studies With Drugs Primarily Intended to Produce Miosis and Increased Depth of Focus

Both of these factors might be expected to influence comparisons before and after drug administration and it would be helpful if future studies were to follow the changes in visual performance of individual patients of more precisely defined age, iris color, and refraction, rather than relying on averages and their standard deviations for broad age groups. It seems likely, for example, that those with early presbyopia, who possess significant residual accommodation, are likely to receive different visual benefits as compared to those enjoyed by the older presbyope. As already noted, through-focus measurements of acuity are preferable to measurements restricted to distance and near acuities because the former give a better insight as to why the drug treatment is or is not effective in giving good distance and near vision. It would also be more helpful if absolute measures of acuity were always presented rather than “lines of improvement,” because vision after treatment may still be poor even if it is improved. The widespread use of Jaeger charts for near acuity assessment is also unfortunate, because letter sizes in charts produced by different manufacturers are poorly standardized71,72; the near testing distance also ought to be standardized. In general, data are lacking on the time course of any visual improvements and their variation with the individual: the question of time delays between drug instillation and the onset of beneficial visual effects is particularly important, as is the time period over which visual benefits continue. As yet, there appears to be no general consensus as to what should be the required outcome of any pharmacological strategy for presbyopia correction.

Finally, this review considered only reviewed scientific reports and clinical trials. Other treatments using different active pharmacological agents have been suggested in conferences and registered in different patents, but unfortunately because no published studies or registered clinical trials are available they have not been covered in this review. We hope that authors publish their outcomes soon to properly assess the benefits of their treatments.

Conclusions

The concept of improving the near vision of individuals with presbyopia by the topical application of pharmacological agents is an attractive one because such methods are non-invasive and reversible. Few relevant research publications have appeared in the peer-reviewed literature, although numerous brief abstracts or news reports can be found in conference programs or ophthalmological tabloids. The information available to date suggests that several drug mixtures that increase DOF through pupil miosis can usefully improve near acuity while preserving satisfactory distance acuity. However, such treatments may adversely affect mesopic and scotopic vision. As yet, treatments designed to enhance the available objective amplitude of accommodation have, at best, produced only small improvements in near vision and no evidence for clinically significant enhancement of objective accommodative amplitude has been presented.

Current registered clinical trials, most of them in phase 2, are expected to clarify which, if any, of the pharmacological approaches have the potential to provide a realistic, tested, and practical solution for the loss of accommodation with age. Further research must include objective measurement of accommodation to assess in detail whether drugs and/or their combinations provide a real change in power to allow an improvement in near visual capabilities in presbyopic patients. High-resolution visualization techniques may aid understanding of the effects of the various treatment options.

The ideal pharmacological approach to presbyopia correction would restore the ability of the eye to make a smooth, fast, and appropriate change in dioptric power in response to changing target distance. Such a method might be applicable to already presbyopic eyes, but we also have to consider possible pharmacological solutions that, rather than being used after the onset of presbyopia, are applied earlier to younger patients before presbyopia to interrupt or reduce the normal age-dependent decline in the decline of the accommodation.

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Topical Drugs Used in the Treatment of Presbyopia

DrugCategoryEffect
PilocarpineParasympathomimetic agonistMiosis and ciliary muscle contraction
CarbacholParasympathomimetic agonistMiosis and ciliary muscle contraction
AceclidineParasympathomimetic, muscarinic agonist agentMiosis and ciliary muscle contraction
TropicamideAntimuscarinic agentMydriasis and paralysis of ciliary muscle
PhenylephrineSympathomimetic, alpha agonistMydriasis without paralysis of ciliary muscle
BrimonidineSympathomimetic, alpha adrenergic agonistReduced intraocular pressure
DiclofenacNonsteroidal anti-inflammatoryReduced inflammation
NepafenacNonsteroidal anti-inflammatoryReduced inflammation
PheniramineAntihistamine anticholinergicDecongestant
NaphazolineSympathomimetic, alpha adrenergicVasoconstriction, decongestant
OxymetazolineAlpha adrenergic agonistVasoconstriction, decongestant
LACECholine ester of lipoid acidIncreased lens elasticity
AGN-199291 and AGN-190584Presumed to be oxymetazoline and pilocarpineSee oxymetazoline and pilocarpine
PirenoxinePyridophenoxazineDecreased cloudiness and hardening of the lens

Ranges of Refractive Error and Age of Presbyopic Patients Used in Different Studies With Drugs Primarily Intended to Produce Miosis and Increased Depth of Focus

AuthorDrugBest Sphere Limits (D)Equivalent Sphere Limits (D)Cylinder Limit (D)Age Range (y)
Abdelkader24Carbachol/brimonidine±0.250.2543 to 56
Abdelkader & Kaufman26Carbachol/brimonidine±0.250.2552 to 58
Feinbaum27PresbiDrops±0.75−2.0040 to 80
Rajan33LiquidVision/PRX-100UnknownUnknownUnknown48 to 63
Renna et al.48FOV Tears±1.00±0.5040 to 65
Vargas et al.50FOV Tears−0.50 to +1.50< 1.5041 to 65
Authors

From Optics and Optometry and Vision Sciences Department, Faculty of Physics, University of Valencia, Spain (RM-M); and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (WNC).

The authors have no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (RM-M, WNC); writing the manuscript (RM-M, WNC)

Correspondence: Robert Montés-Micó, PhD, Optics and Optometry and Vision Sciences Department, Faculty of Physics, University of Valencia, C/Dr Moliner 50, 46100 Burjassot, Spain. E-mail: robert.montes@uv.es

Received: July 16, 2019
Accepted: October 10, 2019

10.3928/1081597X-20191010-04

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