ATROPINE EYE DROPS are employed by eyecare practitioners to curb myopic progression and the development of pathological myopia. Results of early clinical trials conducted from the 1980s into the 2000s led to the wide use of high concentrations of atropine (≥ 0.5%) by clinicians in East Asian countries like Taiwan and Singapore.^1,2 However, high concentrations of atropine are typically poorly tolerated by patients due to its adverse ocular effects, including light sensitivity (due to pupil dilation) and near vision blur (due to reduced ability to accommodate).

Atropine is a known antimuscarinic agent that selectively binds to each muscarinic receptor subtype (M1 to M5) as a nonselective antagonist.³ While atropine can vary the optics of the eye through increased pupil size and altered higher-order aberrations,⁴ its mechanism of action is generally thought to be via therapeutic targeting of muscarinic and non-muscarinic receptors in the retina and sclera, mediating scleral remodeling and slowing eye elongation.³

Despite atropine’s adverse effects, it has several benefits for patients and clinicians when compared to other myopia control treatments:

• The treatment paradigm is simple, with nightly instillation that parents can oversee and administer, if necessary, particularly for young children.

• Atropine treatment is lower in cost compared to other myopia management modalities, including orthokeratology and myopia control contact lenses and spectacle lenses. However, it is important to note that patients who use low-dose atropine will still require refractive correction, as atropine does not contribute to the refractive component of myopia.

• Atropine can be used as a foundational myopia control treatment, while allowing clinicians to correct a patient’s vision by whatever means necessary. Atropine treatment is particularly useful for patients who have low levels of myopia and who are not reliant on a refractive correction for clear vision, or those with significant astigmatism or other complex refractive requirements.

• Myopia onset can be delayed in children who are pre-myopic using low-concentration atropine eye drops.⁵

• Optical treatments (contact lenses and/or spectacles) can be augmented by using atropine to further reduce myopia progression and eye growth.^6-8

In 2015, atropine accounted for 1.6% of myopia control treatments prescribed globally,⁹ and the percentage has increased in subsequent years to ~13% in certain regions, likely due to availability and regulatory considerations.¹⁰ In this article, we have curated five recommendations based on the current evidence regarding the use of atropine for myopia control, to assist eyecare practitioners in making clinical decisions in 2024 with respect to low-concentration atropine eye drops (Figure 1).

CLINICAL GUIDELINE 1: PRESCRIBE 0.05% AS FIRST-LINE ATROPINE CONCENTRATION (0.025% AT A MINIMUM).

The optimal atropine concentration for myopia control is one that offers an acceptable balance between treatment effectiveness in reducing myopia progression and eye growth with minimal side effects. The Atropine Treatment of Myopia (ATOM) 2 study was the first to demonstrate the potential of low-concentration atropine eye drops for effective myopia control.¹¹ However, despite its reported considerable effect of slowing myopic refractive error progression by ~50% over five years,¹² subsequent critical analysis of these results indicated that 0.01% atropine had a negligible effect on axial growth.^13,14

Since then, several large, randomized-controlled clinical trials across a range of ethnicities and geographic locations have demonstrated that 0.01% atropine eye drops do not reduce myopia progression by a clinically significant amount over two to three years compared to single-vision spectacle-wearing controls.^15-20

More recently, the Low-concentration Atropine for Myopia Progression (LAMP) study reported greater efficacy for 0.025% and 0.05% atropine eye drops, with a mean reduction in myopia progression and axial elongation of ~0.54D and 0.21mm using 0.05%, and a reduction of ~0.35D and 0.12mm using 0.025% over the first year compared to placebo, respectively.¹⁵ This dose dependency continues through three years of treatment,²¹ indicating the superiority of higher concentrations of low-dose atropine (> 0.01%), particularly 0.05%, for effective myopia control in children.

Notably, age has also been highlighted as a significant factor with respect to initial concentration selection.²² Higher concentrations are necessary to achieve a similar treatment effect for a younger child compared to an older child, likely due to the innate slowing of myopia progression and axial elongation with age.²³

Therefore, if commencing atropine for myopia control for a child younger than 12 years, the authors advise a more aggressive approach—prescribing 0.05%—while clinicians could consider prescribing 0.025% for those 12 years and older, depending on the child’s individual level of risk. Additionally, clinicians should consider prescribing higher concentrations if requiring greater treatment effects, given the dose dependence of atropine and greater efficacy of ≥ 0.1% atropine, and balance or manage the side effect profile.

Atropine binds to the melanin within pigmented intraocular structures, which may act as an atropine reservoir and provide slower diffusion to the target tissues in more heavily pigmented eyes.²⁵ Based on this, pigment-binding has the potential to influence atropine users based on ethnic background through both treatment efficacy and side effect profiles. A 2014 meta-analysis suggested greater atropine efficacy in Asian compared to Caucasian children;²⁵ however, subsequent studies^17-19 and meta-analyses²⁶ have reported either no ethnic differences or, instead, superior efficacy of 0.01% in Caucasian children compared to non-Caucasian children.²⁰

It should be noted that until recently, very few studies of atropine were conducted on non-Asian children or compared the effects on children of different ethnicities. Further research is required to clarify the effect of atropine efficacy and side effects for patients with eyes of differing levels of pigmentation.

There are a few adverse ocular effects of atropine, including photophobia and blurred near vision most commonly, with an increase in frequency and intensity with increasing concentrations.²⁶ There is some anecdotal and limited literature evidence^26,27 that these adverse effects may be greater in children of fairer complexion; however, further research is required to confirm the presence and magnitude of any such differences in side effect profiles.

For low-concentration atropine eye drops, a significant proportion (≥ 20%) of children report photophobia with 0.05% and 0.025% in the first two weeks of use; however, this percentage fell to < 8% for all doses by the end of the first year¹⁵ and third year,²¹ suggesting that adaptation over time persists with longer duration. While blurred near vision may also be reported, < 2% of LAMP study participants required progressive addition lenses in the first year,¹⁵ and although this increased to ~10% by the end of the third year,²¹ in general, all low concentrations were well tolerated.

Less common side effects of low-concentration atropine eye drops include allergic conjunctivitis, with a frequency of < 7% and no significant dose-dependent differences.^11,15,21 Hypersensitivity reactions, which can range from mild itching to follicular reactions with erythema and watery discharge has occurred less frequently (< 5%).^11,18,19 Stinging on instillation has been reported rarely and is likely associated with the acidic component of the drug.²⁸

Although atropine’s long-term ocular and systemic adverse effects are of great concern, these effects are rarely reported. Signs of systemic atropine toxicity include fever, facial flushing, dryness of the skin and mouth, irritability, insomnia, drowsiness, tachycardia, disorientation, and delirium.²⁹

Thankfully, these systemic effects are rare, even with 1% atropine, and none of the clinical trials using low-concentration atropine eye drops have reported them.^11,15,19,21 In the decades since atropine use for myopia control started being used routinely in Taiwan and Singapore, no known long-term side effects have been reported.^11,30

Note regarding compounded atropine: Commercial preparations of 0.5% and 1% atropine are readily available worldwide. However, only a select few countries, including Singapore, Japan, India, and Australia, have access to commercially available low-dose atropine products, and these are only available in a 0.01% concentration. Until commercial preparations of low-dose atropine become more readily available, eyecare providers across the globe must rely on prescribing ophthalmic atropine eye drops supplied by compounding pharmacies.

It is important to recognize the potential for inconsistencies in low-concentration atropine formulations.³¹ For example, some compounding pharmacies dilute commercially available 0.5% or 1% atropine eye drops to lower concentrations, while others use a solvation process to dissolve atropine sulfate powder into solution.²⁸

The variation in preparation method can lead to inconsistencies in concentration, pH, viscosity, chemical impurities or atropine byproducts, and potential solution instability or non-sterility.³¹ It is imperative that clinicians are cognizant of the potential issues that can arise with compounded atropine products in the case of poor treatment outcomes or greater-than-expected adverse effects.

CLINICAL GUIDELINE 2: PRESCRIBE NIGHTLY DOSING AND REVIEW REGULARLY. ENCOURAGE AND MONITOR COMPLIANCE BUT ACCEPT SOME FLEXIBILITY.

Success with any myopia control treatment, including atropine, is highly dependent on compliance. Often, patients will report deviations from their nightly drop regimens. For example, the patient may have regularly missed one to two nights per week, ceased using the drops for a short duration while they attended a school camp, or run out of eye drops and delayed refilling their prescription for weeks or months.

There is emerging animal model evidence that suggests that less frequent dosing may be as effective as daily dosing,³²which is not surprising, given the extended duration of action of atropine.²⁹ While there is not yet similar evidence in humans, this provides clinicians with reassurance that the occasional missed dose is unlikely to substantially impact treatment outcomes. However, compliance with the prescribed regimen should be strongly encouraged for patients who regularly miss doses, particularly for prolonged periods, due to the potential for rebound progression associated with sudden discontinuation.^21,33,34

Review examinations are important for patients using atropine to ensure efficacy and tolerance of treatment and patient compliance. Irrespective of concentration, it is advisable for patients using atropine to be reviewed approximately one to two weeks after commencement to evaluate the side effects and adherence to the prescribed regimen, ensure that pupil size and accommodation amplitudes have been affected by an expected amount, assess the ocular surface, measure intraocular pressure, and ensure tolerance of the drops. Following this, there should be a review of these clinical assessments and measurements of myopia progression and axial elongation every three to six months to monitor treatment outcomes.

Treatment adherence should be monitored closely in children who administer the drops themselves without parental oversight or supervision as, anecdotally, they are more likely to be noncompliant.

CLINICAL GUIDELINE 3: CONSIDER ATROPINE AS A COMBINATION TREATMENT FOR HIGH-RISK INDIVIDUALS OR THOSE PROGRESSING RAPIDLY ON A MONOTHERAPY.

Combination treatments typically involve atropine in combination with an optical (spectacle- or contact lens-based) treatment. A recent meta-analysis broadly indicates that combination treatments augment and slow myopia progression and axial elongation more than either treatment individually;⁶ however, the mechanism of action behind the enhanced effect with combination treatment, and the specific combinations that offer greater efficacy, remain unclear.

The most likely conclusion is that atropine and optical treatments act on different pathways, resulting in synergistic treatment outcomes. Assuming this is the case, it is likely that atropine needs to be prescribed at concentrations similar to those for monotherapy (i.e., 0.025% or 0.05%). While clinicians report anecdotal evidence of success using combination treatments in this manner, further research is required to support their use across a broader range of possible treatment combinations.

If combining optical treatments with pharmacological treatments, there are both practical and efficacy considerations. For spectacle treatments, it is inconsequential when the drop is instilled, but for contact lens wearers the timing of the instillation must be such that contact time between the atropine, the ocular surface, and the lens are minimized.

Soft contact lenses absorb the medication; therefore, it is advisable to instill atropine after lens removal.³⁵ During overnight ortho-k lens wear the post-lens reservoir may retain some of the medication; so, atropine should be instilled at least 15 to 20 minutes before lens application. This may be argued as a benefit, as more atropine may be available for ocular absorption rather than being lost to systemic absorption, but further study is required to confirm this.

CLINICAL GUIDELINE 4: DISCONTINUATION OF ATROPINE SHOULD INVOLVE A TAPER AND CLOSE MONITORING IF USING CONCENTRATIONS OF ≥ 0.025%.

Sudden atropine cessation results in a dose-dependent rebound effect, and higher concentrations resulting in a period of faster refractive and axial length progression. While the ATOM 1,³³ ATOM 2,³⁴ and LAMP²¹ studies demonstrated that rebound progression over a one-year washout period does not negate the beneficial effects of atropine over the preceding two years of treatment, continuing treatment will prevent these gains from being lost.

For concentrations ≥ 0.1%, the rebound effect is significant;^33,34 however, the rebound for low concentrations (≤ 0.05%) is less impactful.²¹ For low-concentration atropine, a dose-dependent rebound effect was still observed. The data suggests that clinically significant progression is likely to occur in those who suddenly cease 0.05% and 0.025%, but is less likely for those using 0.01%. Therefore, it seems reasonable that sudden cessation of 0.01% atropine may be acceptable, but not for higher concentrations.

Any tapering strategy should be undertaken with caution and patients should be informed that tapering may result in significant myopia or axial length progression, which may require them to recommence treatment. The recommendation of Chia and Tay³⁶ based on the results of the ATOM 2 study¹² was to reduce the frequency of atropine eye drop instillation to every second or third day.

However, this could result in poor treatment adherence due to the less frequent and irregular dosing and thus potentially greater rebound effect. Hence, continuing with the regular daily dosing routine but reducing concentration over time is likely to maximize compliance with the tapering strategy,³⁷ with the added benefit of improving any of the patient’s adverse effects.

When a clinical decision is made to discontinue atropine for a child—whether ceasing treatment or switching to an optical treatment—a stepwise tapering approach from higher to lower concentrations with close monitoring is advisable to minimize potential rebound effects (Figure 2). For example, a child using 0.05% could be tapered to 0.025% for three to six months, followed by a review of his or her refraction and/or axial length to determine whether continued cessation or reinitiation of treatment is appropriate. If these measurements are acceptable, a further reduction to 0.01% for three to six months could be considered, after which time 0.01% atropine could be stopped.

If clinically significant myopia or axial length progression was observed at any stage, the initial treatment could be recommenced. Furthermore, if a child is switching from atropine to an optical treatment, it is possible that rebound from atropine tapering or cessation may be misidentified as a poor response to the optical treatment. Therefore, continuing with atropine until the optical treatment has been successfully worn for three to six months before commencing a similar atropine tapering strategy will allow the clinician to better understand a child’s response to each treatment individually.

CLINICAL GUIDELINE 5: TAKE AN INDIVIDUALIZED APPROACH TO TREATMENT DURATION, BUT CONTINUE TREATMENT UNTIL LATE TEENAGE YEARS, WITH AT LEAST 12 MONTHS OF MYOPIA STABILIZATION OR SLOW PROGRESSION.

The Correction of Myopia Evaluation Trial (COMET) reported that approximately 50% of young-onset myopes (< 12 years old) stabilized by 15 years of age, ~75% by 18 years of age, ~90% by 21 years of age, and ~96% by 24 years of age (Figure 3).³⁸ Hence, while the majority of myopes are stable by 18 years, a significant proportion may still progress. Therefore, it is advisable to continue treatment until a patient is 15 to 18 years of age and has been stable for at least 12 months.

An alternative treatment duration for myopia control using atropine that was suggested by the LAMP study authors was a “weaning” strategy based on patient age, as there was a reduced rebound effect associated with older age and lower atropine concentration.²¹ They recommended tapering from higher to successively lower concentrations as children become older, with the data suggesting that 0.05% could be tapered to 0.025% around 12 years and tapered again to 0.01% at around 14 years, with treatment cessation when appropriate after a prolonged duration of stabilization (e.g., 12 months).

While both of these approaches have some validity, the most appropriate strategy remains unclear. Therefore, the most important factor when considering treatment duration is to ensure that clinical decisions to cease a myopia control treatment are made on a case-by-case basis, with patient understanding and consent, and include careful monitoring (reviews every six months at a minimum), with treatment recommencement if progression is observed.

CONCLUSION

Although questions remain regarding the optimal atropine concentration and treatment protocols, low-concentration atropine eye drops are a safe, effective, simple, and versatile myopia control treatment available to eyecare practitioners for slowing childhood myopia progression.

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