How do we visualize a 3-dimensional world on a 2-dimensional surface called the retina? For the most part, we use the mechanism called accommodation. Accommodation allows us to see clear images at different depths from us. But, unfortunately, it does not last forever. With time, accommodation diminishes. This process of losing accommodation is called presbyopia. There are many treatment strategies for this process. The newest category of these treatment strategies is pharmacologic.
Key points
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Most presbyopia drugs work by increasing depth of focus through miosis.
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Pilocarpine is the most common presbyopia drug.
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Safety concerns include retinal and vitreous detachment.
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Patient selection is the key to success with presbyopia drugs.
Introduction
Presbyopia is estimated to impact almost 2 billion people globally and more than 120 million people in the US. It was mentioned by Aristotle as early as the fourth century BC. [ ].
Presbyopia is a normal part of the aging process and is primarily caused by the loss of elasticity in the crystalline lens. Several factors contribute to the development of presbyopia. The most significant factor is the aging of the lens. Over time, the lens thickens and stiffens with age, which reduces its ability to change shape. This contributes to reduced accommodation.
Environmental factors can play a role. Prolonged exposure to ultraviolet light, smoking, and certain medications can accelerate the onset and progression of presbyopia. Miranda [ ] showed countries with higher ambient temperatures have an average earlier onset of presbyopia. Some systemic health conditions, such as diabetes and cardiovascular diseases, can potentially influence the onset and severity of presbyopia [ , ].
Non-pharmacologic treatments
The primary treatment for presbyopia is the use of corrective lenses, such as reading glasses, bifocal or multifocal glasses, multifocal contact lenses, and surgical options, like corneal inlays.
Bifocal lenses
Most of the traditional treatments for presbyopia are refractive or surgical. Spectacles are the most common choice. Benjamin Franklin has been credited as the inventor of bifocal lenses.
In 1784, Franklin wrote a letter to his friend George Whatley in which he described his invention of bifocal glasses. He mentioned that he had 2 pairs of glasses cut in half with the top half for distance vision and the bottom half for reading. Franklin’s motivation for creating bifocals was because he wanted to read the lips of French speakers at court. This was the only way he could understand them. Inventors before Franklin had played with similar ideas, but it was his practical design that gained widespread recognition and popularity. Benjamin Franklin commonly is associated with the invention of bifocals due to his description of the concept in the letter [ ].
After Franklin’s invention, lens makers began producing bifocal lenses as a single piece with a clear line dividing the 2 sections. Segmented or lined bifocal lenses have been largely replaced by progressive multifocal lenses in clinical practice. Progressive multifocal lenses, commonly referred to as “progressives,” are a type of eyeglass lens that provides a seamless transition from distance vision at the top of the lens to intermediate and near vision at the bottom. All visible lines found in traditional bifocals and trifocals are eliminated. The first patent for a progressive addition lens was British Patent 15,735, granted to Owen Aves with a 1907 priority date. These earlier lenses were not widely adopted and had limited success [ ].
Varilux in 1959 changed all of that. Developed by Bernard Maitenaz, a French optical engineer, he created the first commercially successful progressive lens. Maitenaz used computer-aided design and manufacturing techniques to produce a lens with a smooth and continuous progression of prescription powers from top to bottom [ ].
After Varilux, various manufacturers began developing their own designs. These new designs aimed to improve the lenses, minimize distortion, and provide a broader field of view for wearers. Digital technology and freeform manufacturing techniques have vastly improved the production of progressive lenses. Progressive lenses have become the standard for people with presbyopia and have largely replaced traditional bifocals and trifocals [ ].
Contact lenses for presbyopia
Contact lenses were originally designed to incorporate 1 prescription power. Combining 2 prescriptions into 1 lens became a challenge from a design standpoint and a fitting standpoint. Contact lenses for presbyopia usually require a more complex fitting process. Often, contact lens fitting for a presbyope takes more time and effort on the part of the patient and practitioner. Compromise is the rule of thumb.
Multifocal contact lenses: The concept of multifocal contact lenses dates to the 1970s and 1980s. The early designs had a limited success rate, were uncomfortable, and did not provide clear vision at different distances. It was not until the 1980s and 1990s that rigid bifocal contact lenses became available with 2 distinct prescription powers. Simultaneous vision multifocal lenses came about in the 1990s to 2000s. Simultaneous vision allows both distance and near vision at the same time. Most of the designs today are now center-near soft lenses.
Monovision contact lenses: Monovision involves fitting 1 eye with a contact lens for distance vision and the other eye with a contact lens for near vision. While this approach can work for some people, it may not be suitable for everyone, as it can lead to issues with depth perception and adaptation [ , ].
Modified monovision: In this approach, 1 eye is fitted with a multifocal contact lens, and the other eye is fitted with a contact lens for distance vision. It offers some of the benefits of multifocal contacts while maintaining better depth perception.
Hybrid contact lenses: Hybrid lenses combine the comfort of soft contact lenses with the optical quality of rigid gas permeable lenses. Some hybrid lenses are designed for presbyopia and offer multifocal optics for clear vision at different distances.
Custom-made multifocal lenses: Customized soft lens designs are offered by some manufacturers.
Extended depth of focus lenses: These lenses are designed to provide a broader range of clear vision by extending the depth of focus. They may not have distinct near and far zones. The effect is like a small aperture; only the aperture is formed by rapid increases in plus power. Because of the small aperture effect, peripheral vision may be compromised. Exact centering over the line of sight also may be required to give optimal vision [ ].
Corneal inlays for presbyopia
Corneal inlays are inserted into or under a pocket or flap made by a laser. The pocket or flap is usually in the middle of the nondominant eye’s cornea. They are normally smaller than the width of an eraser tip. The inlay reshapes the cornea and corrects near vision by increasing the depth of focus of the center of the cornea. Currently, 2 main types of corneal inlays exist: refractive corneal inlays and small aperture inlays [ , ]. Just like contact lenses for presbyopia, the effectiveness may vary from person to person, and some individuals may still need reading glasses for very fine print.
Pharmacologic treatment
Most of the pharmaceutical treatments for presbyopia depend on small-aperture optics, or the pinhole effect.
Pinhole effect
The pinhole effect refers to the phenomenon where a small aperture, such as a pinhole, can improve vision at different distances without the aid of lenses. Pinhole optics refers to the principles and applications associated with the use of a pinhole or small aperture to control the passage of light in optical systems.
While pinhole optics can be useful for certain applications, they also have limitations. For instance, the images produced by pinhole cameras may be dim due to the limited amount of light entering through the small aperture. Also, the peripheral visual field is compromised. Despite these shortcomings, the objects at different distances can be seen clearly [ ].
Depth of field versus depth of focus
“Depth of field” and “depth of focus” are terms sometimes used interchangeably when referring to small aperture or pinhole optics. Depth of field refers to the range of distances that appears acceptably sharp in an image. In other words, it is the zone of focus that extends in front of and behind the subject that is actually focused on. Depth of focus refers to the range of distances along the optical axis within which an image is formed to be acceptably sharp. It is related to the ability of an optical system to maintain focus on an object placed at a certain distance from the lens. Depth of focus is influenced by the refractive properties of the optical system like the crystalline lens [ ]. When dealing with presbyopia drugs, depth of focus is the preferred term.
The near triad
Currently, miosis is the main mechanism of action (MOA) for most of the pharmaceutical treatments of presbyopia. It depends on one of the components of the “near triad.”
The “near triad” refers to a set of 3 coordinated physiologic adjustments that occur when looking from a distant object to a near object. The near triad consists of 3 components: accommodation, convergence, and miosis. Accommodation is the adjustment of the crystalline lens to focus at near. The ciliary muscle contracts, causing the lens to change power.
Convergence is the inward turning of the eyes toward each other when focusing on a close object. The greater the nearness of the object, the greater the degree of convergence required.
Miosis is the third component. When looking at a near object, the pupils constrict (miosis). Pupillary constriction helps to increase the depth of focus and sharpen the image [ , ].
Pupillary sizes
The effectiveness of presbyopia drugs can largely depend on pupillary size. Depth of focus is influenced by the size of the aperture, or, for our purposes, the pupil. Depth of focus is inversely related to aperture size. In other words, the smaller the aperture, the greater the depth of focus. Too large of a pupil, the depth of focus can be drastically decreased. Too small of a pupil may compromise distance vision.
Xu and colleagues [ ] looked at optimum pupil diameters for presbyopic eyes when environmental light levels vary from high photopic to low mesopic. They studied the effects on optical image quality for pupil diameters ranging from 1 to 7 mm over a wide range of photopic and mesopic target luminances. They concluded that a 2-mm to 3-mm small pupil or a 30% pupil miosis can both produce near-visual acuity gains without significant losses to distance acuity. This can be considered as optimal pupil size for a presbyope in mesopic and photopic conditions [ ]. ( Figs. 1 and 2 ).
Pharmaceutical options, mechanisms, and side effects
Pilocarpine
Pilocarpine is a member of the drug class cholinergic agonists. It is commonly used to treat conditions such as glaucoma and to induce miosis (constriction of the pupil). Pilocarpine acts by stimulating the muscarinic receptors in the eye, leading to the contraction of the iris sphincter muscle and the ciliary muscles [ , ].
Abbvie/Allergan’s Vuity is 1.25% pilocarpine that can be prescribed twice a day. The efficacy of Vuity was demonstrated in 2 30-day, phase 3, randomized, double-masked, vehicle-controlled studies, named Gemini 1 and 2. Seven hundred fifty subjects aged 40 to 55 year old were randomized in the 2 studies. In both studies, the proportion of participants gaining 3 lines or more in mesopic, high-contrast, binocular distance–corrected near-visual acuity was statistically significantly greater in the Vuity group compared to the vehicle group at day 30, hour 3.
The most common adverse reactions were headache and conjunctival hyperemia. Adverse events reported in 1% to 5% of patients were blurred vision, eye pain, visual impairment, eye irritation, and increased lacrimation [ ].
Aceclidine
Aceclidine is a cholinergic agonist that activates receptors responsive to acetylcholine. It stimulates muscarinic M3 receptors, which leads to the contraction of the iris sphincter muscle and results in miosis. Aceclidine’s MOA can create a pinhole pupil effect while avoiding a myopic shift. It has negligible side effects on myopisation.
Some reported systemic side effects include those associated with muscarinic stimulation, such as increased salivation, sweating, and gastrointestinal effects [ ].
Lenz Therapeutics’ LNZ100 (aceclidine), and LNZ101 (aceclidine + brimonidine) achieved the primary endpoint of 3-line or greater improvement in near-visual acuity without losing 1-line or more in distance-visual acuity at 1 hour in 71% and 56% of treated subjects, respectively, compared to 6% of vehicle-treated subjects. Both LNZ100 and LNZ101 maintained statistical significance of 3-line or greater improvement compared to vehicle-treated subjects for all timepoints including the last measured at 10 hours, 37% and 48%, respectively. Both formulations maintained an average pupil size of 1.5 to 2 mm for 10 hours [ ].
Brimonidine
Brimonidine is a medication that belongs to the class of drugs known as alpha-2 adrenergic agonists. It is commonly used to lower intraocular pressure and to treat glaucoma. By stimulating alpha-2 adrenergic receptors, a decrease in the production of aqueous humor occurs along with an increase in its outflow [ ]. Reported adverse events of brimonidine around (∼10%–20%) are allergic conjunctivitis, conjunctival hyperemia, and eye pruritis [ ].
Brimonidine tartrate 0.2% has been shown to have a significant effect in decreasing pupil size under scotopic conditions [ ]. This occurs most likely from its alpha-2 adrenergic effect. Brimonidine binds to alpha-2 receptors that are located on the presynaptic nerve endings of the dilator muscle. The b inding inhibits further release of the neurotransmitter into the synaptic cleft. The reduced activity of the dilator muscle produces a miotic pupil [ ].
One study showed that before brimonidine tartrate administration, the mean scotopic pupil size was 6.22 mm. After administration, there was significant miosis to 4.57 mm that continued for at least 6 hours [ ]. When compared to aceclidine 0.02% and dapiprazole 0.25%, brimonidine had the best miotic effect [ ].
Carbachol
Carbachol stimulates the muscarinic and nicotinic receptors on the iris sphincter muscle to create miosis. Carbachol, which is formed by substituting a terminal amino group in the acetylcholine molecule, is a quaternary ammonium compound, and so has the pharmacologic characteristics of being lipid insoluble, surface inactive, and hydrophilic. Carbachol, by itself, penetrates the cornea very poorly. Corneal penetration by carbachol may be enhanced either by reducing the surface tension using benzalkonium chloride as a wetting agent or by administering it in a petrolatum-based ointment and massaging the cornea through closed lids [ ].
Ocular side effects including corneal clouding, persistent bullous keratopathy, retinal detachment, and postoperative iritis following cataract extraction have been reported.
Systemic side effects include flushing, sweating, epigastric distress, abdominal cramps, tightness in urinary bladder, and headache have been reported [ ].
Brimonidine and carbachol
Brimochol PF is a once a day fixed-dose combination product with brimonidine and carbachol developed by Visus Therapeutics Inc. They report a greater than 15-letter (3 lines) gain at near up to 6 hours without a loss of ≥5 letters at distance. Significant reductions in pupil size lasted as much as 10 hours ( P < .001) Less than 10% was the reported headache rate [ , ].
Phentolamine
Phentolamine is an alpha-adrenergic blocker, which means it inhibits the action of certain neurotransmitters called catecholamines (such as norepinephrine) at alpha receptors [ ]. This action leads to vasodilation (widening of blood vessels) and decreased vascular resistance. Phentolamine has been used for various medical purposes, including the treatment of hypertension and erectile dysfunction [ , ]. Common side effects may include dizziness, lightheadedness, nasal congestion, and changes in heart rate.
Ocuphire’s phentolamine ophthalmic solution 0.75% is a preservative-free ophthalmic solution containing 0.75% phentolamine (or 1% phentolamine mesylate), a nonselective alpha-adrenergic antagonist that inhibits the contraction of smooth muscle of the iris and reduces the pupil diameter. Phentolamine ophthalmic solution 0.75% is being developed for reversal of pharmacologically induced mydriasis and night (or dim light) vision disturbances. The combination of phentolamine ophthalmic solution 0.75% + low-dose 0.4% pilocarpine is being studied for presbyopia [ ].
Lipoic acid choline ester (UNR844)
Lipoic acid (LA) is an antioxidant shown to chemically reduce lens disulfide bonds. Topical LA increased lens elasticity in vitro [ ]. LA is produced in the mitochondria of all cells. UNR844 (formerly known as EV06) is a LA choline ester developed by Novartis. Linking LA to choline increases its corneal penetration and is taken up into lens fiber cells. It is metabolized by oxidoreductases to the active species, dihydrolipoic acid, which reduces disulfide bonds between lens proteins [ ]. Novartis has since discontinued its development in quarter 3 of 2022 [ ].
Ursodeoxycholic acid
Ursodeoxycholic acid (UDCA) is an antioxidant bile acid formed by bacterial action in the intestine [ ]. Bile acids play a crucial role in the emulsification and absorption of dietary fats [ ]. UDCA is used in the treatment of primary biliary cirrhosis and dissolution of cholesterol gallstones [ ]. Mild side effects include diarrhea, constipation, or stomach discomfort [ ].
In 1 animal study, UDCA prevented oxidative stress and cleared up cataract formation. Also, UDCA has been shown to reduce disulfide bonds in the lens and improve elasticity [ ]. Santen is developing UDCA for presbyopia.
Adverse events specific to pilocarpine
Retinal detachment and vitreous conditions
Several cases of retinal and vitreous conditions have been reported in the literature with pilocarpine indicated for presbyopia. Three cases of retinal detachments were reported in 2 cases. Both were men in their 40s; one had flashes and floaters after 3 days and retinal detachment and retinal tear in both eyes. The other case took place after 5 weeks on the medication resulting in retinal detachment and subretinal fluid in the macula. Other cases described immediate vitreomacular traction and retinal detachment after 10 days of use. Risk factors seem to be with high myopia, lattice degeneration, and prior retinal detachment [ ]. In 2022, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) Public Dashboard reported retinal detachment, vitreous floaters, and vitreous detachment at less than 7% for each adverse event [ ].
Myopic shift
Since pilocarpine is a common active ingredient for many presbyopia drops, a myopic shift has been reported. Pilocarpine acts by stimulating the muscarinic receptors in the eye, leading to the contraction of the iris sphincter muscle and the ciliary muscle. When pilocarpine causes the ciliary muscle to contract, it may lead to an increase in the crystalline lens optical power, resulting in a myopic shift [ ].
Headache
Headache and browache was the most reported adverse event with pilocarpine. FAERS reported 25% rate: 106 out of 424 reported cases. 85% of the Vuity subjects did not report headaches. Out of the 15% that did have headaches, 13% were mild [ ].
Discussion
One of the main unwritten goals of a clinical study for FDA approval is to include patients who will be successful with the drug tested. By looking at the inclusion and exclusion criteria of a study, one can surmise which patient population for which the drug would be the most efficacious.
For presbyopia drug studies, the population targeted in the early studies was emmetropes with low to moderate add powers. Age was about 40 to 50 year old. As far as safety was concerned, no history of retinal problems was allowed. A thorough retinal examination was required before randomization and enrollment. Some studies exclude any medications that may have any whiff of pupillary effects [ ].
For miotics, the “slam dunk” patient has zero refractive error at distance as evidenced by inclusion and exclusion criteria. I remember a conversation years ago with the “presbyopia contact lens guru,” Dr Pete Kollbaum from Indiana University. He helped design presbyopia contact lenses for a major manufacturer. I asked him why the lens system that he designed only had about +1.50D difference between the eyes (one distance-biased, the other near-biased). Essentially, there was a total of +1.50D add power in his system. What about the presbyope who needed a +2.50 add? Pete went on to explain that the pupil size gets smaller with age, and the depth of focus makes up the difference. In other words, for a +2.50D add, the contact lens picks up +1.00D to +1.50D, and miosis picks up another +1.00D to +1.50D. Another consideration is that there is variability in the contact lens add because the lens is aspheric.
Based on this, miosis is worth about +1.50D add, nicely working for a low to moderate presbyope. The early clinical studies also had an age requirement, about 40 to 50 years old. Again, this falls nicely into the low to moderate add power category.
I have found success in patients beyond 50 years old. It depends on visual demand or, in clinical parlance, working distance. Therefore, if the “older” presbyopic patient looks at an 18-inch to 20-inch distance from the screen, simple math says all you need is about a +1.50D add. This includes those patients that hold their phones about 20 inches away.
One aspect of the early clinical studies was establishing how long the drop lasts. In those early studies, patients were kept in an office for 10 to 12 hours, sometimes referred to as “subject imprisonment.” The current rule of thumb with pilocarpine is about 4 hours of efficacy. The newer drops might establish longer times or go to twice-a-day dosing.
Presbyopia studies have a pupil-size guardrail. Large pupils were not allowed in the studies. Pupil size makes a huge difference between success and failure in the real world. As stated before, the optimum pupil size was 2 to 3 mm for near vision. This is where the guardrail worked in the clinical trials. If the patient had a large, say 9-mm, pupil, the drops would probably not be able to bring the pupil size into the optimal range. The patient would probably be left with a pupil that was too large so that the near effect would be diminished. Conversely, a small pupil may not be optimal either; a too-small pupil can affect distance vision [ ].
Summary
Pharmaceutical treatments for presbyopia do work. In some cases, the effects are profoundly successful. Patient selection is the key. The inventors of the drops knew this and designed the earlier studies to reflect it. Greater refractive errors, larger or smaller pupils, the working distance of the patient, how many hours the patient needs near vision, and so forth, are all factors that influence the success rate.
Finally, you may have patients who have all of these factors going against them, they are well outside the profile of the perfect patient, but yet they succeed. Taking a cue from contact lenses, patient motivation is the X factor. High motivation can push everything into the success category. An example is a patient not wanting to wear reading glasses on a date. I have had patients, despite all the factors stated before going against them, succeed because they were extremely motivated. The X factor was at work [ ].
Clinics care points
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Nothing tops a highly motivated patient.
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Do not get stuck on 40-cm vision; many patients do well with good intermediate “digital device” vision.
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A miotic presbyopic drug will provide about +1.50 add.
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