Low-Dose Atropine Eye Drops (Myopia Progression Control)
1. What is low-dose atropine eye drops (myopia progression control)?
Section titled “1. What is low-dose atropine eye drops (myopia progression control)?”Low-dose atropine (LDA) eye drops are a pharmacotherapy that uses a low concentration (0.01–0.05%) of the non-selective muscarinic receptor antagonist atropine to suppress myopia progression in children. Atropine 1% preparations have been used in ophthalmology for mydriasis and cycloplegia since the 1970s, but in recent years, it has become clear that low concentrations can achieve myopia progression control while minimizing side effects and rebound.
Rijusea® Mini Ophthalmic Solution 0.025% (Santen Pharmaceutical) received the first domestic approval in Japan on December 27, 2024, for the efficacy and effect of “suppression of myopia progression” 1). With the advent of this drug, myopia progression suppression treatment has been established as an option covered by health insurance.
Current Status of Myopia and Risk of Complications
Section titled “Current Status of Myopia and Risk of Complications”In recent years, the proportion of elementary, junior high, and high school students with uncorrected visual acuity less than 1.0 has been increasing. According to the Ministry of Education, Culture, Sports, Science and Technology’s School Health Statistics, the proportion of high school students with uncorrected visual acuity less than 1.0 reached approximately 63% (fiscal year 2014) 1). Myopia is not just a refractive error; when it becomes high, it can cause serious complications.
The Hisayama Study has confirmed an increase in the prevalence of myopic maculopathy 8)9), indicating that preventing progression is essential for improving long-term visual prognosis.
The main risks of complications associated with myopia are shown below. The risk increases with each 1D increase in myopia, and the incidence of complications is significantly higher in high myopia 5)7).
- Glaucoma: Increased risk of open-angle glaucoma
- Cataract: Increased risk of posterior subcapsular cataract
- Retinal detachment: Significantly increased risk
- Myopic macular degeneration: Complication that most affects visual prognosis
- Myopic traction maculopathy: Macular deformation occurring in high myopia
The purpose of myopia progression suppression treatment is to suppress excessive progression of myopia and maintain vision and eye health throughout life.
Low-concentration atropine eye drops are a myopia progression suppression treatment that suppresses axial elongation via muscarinic receptor antagonism. Low-concentration (0.01–0.05%) formulations that minimize the side effects of atropine (mydriasis and cycloplegia) are used, and only one drop is instilled before bedtime. Rijusea® Mini Ophthalmic Solution 0.025% is the first domestically approved insurance-covered drug in December 2024 1).
2. Indications and Treatment Targets
Section titled “2. Indications and Treatment Targets”Diagnostic Criteria
Section titled “Diagnostic Criteria”To determine the indication for low-concentration atropine eye drops to slow myopia progression, an objective diagnosis of myopia is first necessary. According to the treatment guidelines of the Japanese Society of Myopia, the diagnostic criteria for myopia are as follows1).
A myopic refractive error of −0.5 D or greater in spherical equivalent under cycloplegic refraction
Without cycloplegic examination, excessive myopic refractive error may be calculated in children with strong accommodation, so it is indispensable as a basis for diagnosis.
Recommended Treatment Candidates
Section titled “Recommended Treatment Candidates”Treatment is desirable to start early after the onset of myopia. The main characteristics of recommended candidates are shown below1)13).
- Age: The main treatment candidates are those up to early adolescence with rapid myopia progression. Early-onset myopia carries a particularly high risk of future high myopia
- Presence of myopia risk factors: Both parents are myopic, little outdoor activity time, long near work time
- Patients under 5 years of age: Since clinical trials have not been conducted, prescription should be considered carefully
- Exclusion of secondary myopia: Secondary myopia such as congenital night blindness or retinitis pigmentosa is not indicated
It has been reported that the onset of myopia at a young age significantly increases the risk of future high myopia (over −6 D)13).
Evidence from Major RCTs
Section titled “Evidence from Major RCTs”The effect of low-concentration atropine in slowing myopia progression in major trials is shown.
| Trial name | Concentration | Duration | SE progression (treatment group) | SE progression (control group) |
|---|---|---|---|---|
| ATOM2 (Chia 2012) 2) | 0.01% | 2 years | −0.49 D | −1.20 D |
| LAMP (Yam 2022) 3) | 0.025% | 3 years | −0.55 D | — |
| LAMP (Yam 2022) 3) | 0.05% | 3 years | −0.38 D | — |
In the ATOM2 study, the 0.01% group showed a significant suppression effect with a spherical equivalent change of −0.49 D over 2 years (placebo group −1.20 D)2). In the LAMP study, 0.05% was the most effective, and the 3-year report confirmed continuous myopia progression suppression3).
Children diagnosed with myopia of spherical equivalent −0.5 D or more under cycloplegic refraction are eligible for treatment1). Early initiation of treatment is recommended especially for those with multiple risk factors such as early teens with rapid myopia progression, myopic parents, less outdoor activity, and more near work. For children under 5 years old, careful consideration is needed due to insufficient clinical trial data1).
3. Prescription Procedure and Follow-up
Section titled “3. Prescription Procedure and Follow-up”Required Examinations Before Starting Treatment
Section titled “Required Examinations Before Starting Treatment”Before prescribing, perform the following examinations to confirm indications1)11).
- Cycloplegic refraction: Instill 1% cyclopentolate eye drops twice at 10-minute intervals, and measure with an autorefractometer 45–60 minutes after the first instillation. Confirm the spherical equivalent value.
- Axial length measurement: Measurement using an optical biometer is recommended. Record as a baseline value for monitoring myopia progression.
- Exclusion of amblyopia: Check for concomitant amblyopia and manage appropriately.
- Exclusion of secondary myopia: Rule out organic diseases such as congenital stationary night blindness and retinitis pigmentosa in advance.
Follow-up Schedule
Section titled “Follow-up Schedule”The follow-up schedule after prescription is shown below1).
| Timing | Visit Interval | Items to Check |
|---|---|---|
| After initial prescription | 1 week to 1 month later | Check adherence and side effects |
| During continued treatment | Every 3 to 6 months | Regular assessment of myopia progression and side effects |
| Cycloplegic refraction | Approximately once a year | Objective measurement of refractive error |
| Axial length measurement | Performed regularly | Quantitative assessment of axial elongation |
Methods of progression management
Section titled “Methods of progression management”There are two approaches to managing myopia progression1).
- Annual progression rate comparison method: Compare the annual progression rate without treatment with that during treatment to evaluate treatment efficacy
- Management using axial length percentile curves: A method using age-specific axial length percentile curves (including emmetropic eyes) as an indicator.
Tools such as software attached to axial length measurement devices, myopia management notebooks, and smartphone apps can be used as management tools.
When treatment intensification is needed
Section titled “When treatment intensification is needed”If myopia progression is not sufficiently controlled during treatment, respond with the following steps1).
- Check instillation compliance: Reconfirm adherence and support the formation of habits to ensure regular instillation.
- Strengthen lifestyle guidance: Instruct to increase outdoor activities (aim for 2 hours per day) and limit near work time.
- Consider switching or combining treatments: Consider combination with orthokeratology (a RCT by Kinoshita 2020 confirmed significant suppression of axial elongation6)) or combination with DIMS spectacles (Nucci 2023, Kaymak 2022 confirmed safety and efficacy12)).
As of April 2025, myopia progression suppression treatments other than low-concentration atropine (orthokeratology, myopia management spectacle lenses, etc.) are not approved in Japan, and sufficient explanation to patients and guardians is necessary when prescribing1).
4. Side effects and safety
Section titled “4. Side effects and safety”Main side effects
Section titled “Main side effects”The main side effects of low-concentration atropine eye drops are those associated with mydriasis. Instillation before bedtime can minimize the impact on daytime activities1).
- Photophobia and blurred vision due to mydriasis: Instillation before bedtime reduces daytime photophobia. Use sunglasses, photochromic lenses, or tinted glasses as needed.
- Near vision impairment due to cycloplegia: Often improves after several weeks of continued instillation.
- Effects on binocular vision: If accommodative dysfunction persists, consider prescribing progressive addition lenses.
- Allergic conjunctivitis: Occurs in 3–7% with low-concentration formulations, but similar incidence in placebo groups suggests preservatives as the cause5).
- Systemic side effects: No significant reports in many RCTs5)
Side effect profile by concentration
Section titled “Side effect profile by concentration”Higher concentrations tend to increase side effects, so the concentration should be selected considering the balance between efficacy and side effects.
| Concentration | Proportion requiring photochromic glasses (ATOM2)5) | Near vision impairment |
|---|---|---|
| 0.01% | Approximately 6% | Mild |
| 0.1% | Approximately 33% | Moderate |
| 0.5% | Approximately 70% | Severe |
Theoretical Risks
Section titled “Theoretical Risks”Increased light exposure to the retina due to mydriasis is considered a theoretical risk for age-related macular degeneration (AMD), but this may be offset by the fact that myopia itself is a protective factor for AMD 5). To date, there have been no reports of this risk becoming a clinical problem.
Rebound Effect
Section titled “Rebound Effect”If treatment is discontinued before myopia progression stabilizes, accelerated progression (rebound) has been reported 3).
- Discontinuation at a young age carries a particularly high risk of rebound (LAMP study: accelerated progression observed after discontinuation of 0.025% atropine following 2 years of treatment).
- Some opinions suggest that rebound is less clinically problematic with low-concentration formulations of 0.025% or lower.
- After discontinuation, continue refraction and axial length measurements every 6 months, and consider resuming treatment if progression is observed.
The main side effects are photophobia and blurred vision due to mydriasis, and decreased near vision due to cycloplegia. Administering drops before bedtime can significantly reduce daytime side effects. Photochromic lenses or sunglasses may be helpful in some cases. No systemic side effects have been reported in numerous RCTs 5). Symptoms often diminish after a few weeks of continued use 1).
5. Treatment Termination and Combination Therapy
Section titled “5. Treatment Termination and Combination Therapy”Duration of Treatment
Section titled “Duration of Treatment”It is recommended to continue treatment until myopia progression stabilizes. Since myopia progression generally stabilizes in the late teens, it is desirable to continue at least until that age 1)3).
Process of Treatment Termination
Section titled “Process of Treatment Termination”- Consider tapering or discontinuing only after confirming stabilization of myopia progression.
- After discontinuation, continue refraction and axial length measurements every 6 months.
- If progression is observed again, consider resuming treatment early.
Combination Therapy
Section titled “Combination Therapy”If low-concentration atropine alone does not provide sufficient effect, combination with other myopia progression control interventions is an option.
- Orthokeratology (OK) + Atropine 0.01%: A 2-year RCT showed significant axial elongation suppression (Kinoshita 2020)6). This is the combination therapy with the most accumulated evidence.
- DIMS spectacles (MiYOSMART®) + Atropine: Safety and efficacy have been confirmed (Nucci 2023, Kaymak 2022)12).
- Encouragement of outdoor activities: Combination with at least 2 hours of outdoor activity per day is recommended. Even alone, it significantly reduces the risk of myopia onset4).
It is recommended to continue until myopia progression stabilizes, generally until the late teens1). In the LAMP study, rebound was observed after discontinuation following 2 years of treatment3), so self-discontinuation before stabilization should be avoided. After discontinuation, monitor with refraction and axial length measurements every 6 months, and consider resuming if progression is observed.
6. Pathophysiology and Mechanism of Action
Section titled “6. Pathophysiology and Mechanism of Action”Basic Pharmacology of Atropine
Section titled “Basic Pharmacology of Atropine”Atropine is a non-selective muscarinic receptor antagonist that binds to all subtypes M1 through M5 10). In ophthalmology, a 1% formulation has traditionally been used as a mydriatic and cycloplegic agent.
Multiple hypotheses have been proposed regarding the target of action of the active ingredient in suppressing myopia progression, and research is still ongoing 10).
Mechanism of Axial Elongation Suppression
Section titled “Mechanism of Axial Elongation Suppression”After atropine enters the eye, it is thought to modify scleral remodeling via muscarinic receptors (mainly M1 and M3 candidates) in the retina and sclera, thereby suppressing axial elongation 10).
- Involvement in scleral remodeling: Regulates the balance of collagen production and degradation in scleral fibroblasts, suppressing axial elongation.
- Interaction with dopamine pathway: Effects on retinal dopamine release may partly contribute to myopia progression suppression.
- Detailed mechanism unknown: An independent mechanism of axial elongation suppression apart from cycloplegia is thought to exist, but the full picture is not clear.
Significance of Low Concentration
Section titled “Significance of Low Concentration”High-concentration (1%) atropine causes marked mydriasis and cycloplegia, and a strong rebound after discontinuation was confirmed in the ATOM1 study. In contrast, low concentrations (0.01–0.05%) only partially antagonize receptors, thereby maintaining suppression of axial elongation while reducing side effects and rebound 2).
Low-concentration atropine (0.01–0.05%) minimizes mydriasis and cycloplegia while achieving suppression of axial elongation comparable to high-concentration formulations.
Overall Mechanism of Myopia Progression and Role of Atropine
Section titled “Overall Mechanism of Myopia Progression and Role of Atropine”Myopia progression is a biological process in which axial length is regulated by optical signals from the retina.
- Peripheral hyperopic defocus: Hyperopic blur in the peripheral retina is a major signal that elongates the eye posteriorly.
- Dopamine hypothesis: High-intensity outdoor light promotes retinal dopamine secretion and suppresses axial elongation.
- Atropine’s site of action: Intervenes in the above signaling pathways via muscarinic receptors, suppressing excessive scleral elongation.
As an overall picture of myopia progression suppression, atropine functions as a “pharmacological braking of axial elongation” and is considered to have a complementary role with the “optical defocus correction” of optical interventions (orthokeratology, myopia control spectacle lenses)4).
7. Latest Research and Future Perspectives
Section titled “7. Latest Research and Future Perspectives”Exploration of Optimal Concentration
Section titled “Exploration of Optimal Concentration”The balance between efficacy and side effects of 0.01%, 0.025%, and 0.05% is under continuous investigation. The LAMP study showed that 0.05% was the most effective3), but the optimal concentration may vary among individual patients. Standardization of dose escalation criteria when efficacy is insufficient and dose reduction protocols when side effects occur are future challenges.
Long-term Efficacy and Safety Data
Section titled “Long-term Efficacy and Safety Data”Current RCTs have observation periods of approximately 2–3 years, and long-term data over 5 years are limited. With the domestic approval of Ryjusea® Mini Ophthalmic Solution, long-term follow-up studies in Japanese children are expected1).
Optimization of Combination Therapy
Section titled “Optimization of Combination Therapy”RCTs are ongoing for several combinations, including orthokeratology + atropine6), multifocal contact lenses + atropine, and DIMS spectacles + atropine12). The superiority over monotherapy and long-term safety are being verified.
Perspectives on Personalized Treatment
Section titled “Perspectives on Personalized Treatment”Personalization of treatment selection according to myopia progression rate, age of onset, and risk factor profile is being studied4). A future vision is being drawn in which AI-based myopia progression prediction models can propose optimal concentrations and therapy combinations for each patient.
8. References
Section titled “8. References”- 低濃度アトロピン点眼液を用いた近視進行抑制治療の治療指針作成委員会. 低濃度アトロピン点眼液を用いた近視進行抑制治療の手引き. 日眼会誌. 2025;129(10):851-854.
- Chia A, Chua WH, Cheung YB, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (ATOM2). Ophthalmology. 2012;119:347-354.
- Yam JC, Zhang XJ, Zhang Y, et al. Three-year clinical trial of Low-Concentration Atropine for Myopia Progression (LAMP) Study: phase 3 report. Ophthalmology. 2022;129:308-321.
- Yam JC, et al. Interventions to reduce incidence and progression of myopia in children and adults. Prog Retin Eye Res. 2025.
- Bullimore MA, et al. The risks and benefits of myopia control. Ophthalmology. 2021;128:1561-1579.
- Kinoshita N, et al. Efficacy of combined orthokeratology and 0.01% atropine for slowing axial elongation: a 2-year RCT. Sci Rep. 2020;10:12750.
- Haarman AEG, et al. The complications of myopia: a review and meta-analysis. Invest Ophthalmol Vis Sci. 2020;61:49.
- Ueda E, et al. Trends in the prevalence of myopia and myopic maculopathy in a Japanese population: the Hisayama Study. Invest Ophthalmol Vis Sci. 2019;60:2781-2786.
- Ueda E, et al. Five-year incidence of myopic maculopathy: the Hisayama Study. JAMA Ophthalmol. 2020;138:887-893.
- Upadhyay A, Beuerman RW. Biological mechanisms of atropine control of myopia. Eye Contact Lens. 2020;46:129-135.
- 小児眼鏡処方手引き作成委員会. 小児の眼鏡処方に関する手引き. 日眼会誌. 2024;128:730-768.
- Nucci P, et al. Comparison of myopia control with DIMS spectacles, atropine, and combined. PLoS One. 2023;18:e0281816.
- Chua SY, et al. Age of onset of myopia predicts risk of high myopia in later childhood. Ophthalmic Physiol Opt. 2016;36:388-394.