August 9, 2019
By Jianfeng Zhu, MD, Consultant Pediatric Ophthalmologist, Shanghai Eye Disease Prevention and Treatment Center, Visiting Research Scientist, Brien Holden Vision Institute
A network meta-analysis on myopia control found that use of atropine at different concentrations was significantly superior to other interventions (for example, progressive addition spectacle lenses, multifocal soft contact lenses, orthokeratology, more outdoor activities, etc.)1 Other reviews and meta-analysis similarly concluded that there was less myopic progression with atropine and that both the efficacy and adverse effects were dose-dependent.2, 3
Atropine is a non-selective muscarinic acetylcholine receptor antagonist (mAchR), and the underlying mechanisms by which it controls myopia progression remain unclear. Initially, it was thought that the drug acted via accommodative mechanisms. Later evidence suggested that the mechanism was via non-accommodative pathways,4 with some reports suggesting that atropine exerted its action via retinal amacrine cells and dopamine; when atropine binds to mAchR on the cells, they could release dopamine, which is considered to play a role in slowing myopia.5-7 Other studies reported that atropine could be directly acting on sclera8 and might play a role in inhibiting glycosaminoglycan production and, thus, eye growth. 9, 10
Of all the concentrations assessed, 1% (the highest concentration assessed) atropine used daily has the best efficacy for slowing myopia. However, the concentration is also associated with severe side effects that include photophobia, blurred near vision and worse vision-related quality of life. Additionally, on discontinuation of the drug, the magnitude of rebound observed was greatest with this concentration. Lower concentrations of atropine notably 0.01% was considered to be an effective concentration as there was still a significant slowing of myopia with respect to spherical equivalent, adverse effects were minimal, and there was less rebound after cessation. However, both ATOM2 and LAMP studies showed that while 0.01% atropine was beneficial over placebo as determined by change in spherical equivalent (SE), there was no benefit observed with the change in mean axial length (AL) 11,12. Therefore, 0.01% might not be the ideal dose of atropine for controlling axial myopia.
So, should we attempt a higher concentration? Shih et al. reported 0.5% atropine was the most effective for controlling myopia progression (-0.04±0.63D per year) compared with 0.25% (-0.45±0.55D per year) and 0.1% atropine (-0.47±0.91D per year), but they had not considered adverse effects with the various doses.13 In comparison, ATOM2 study confirmed the efficacy of 0.5% and 0.1% atropine to be superior to 0.01% but reported more severe adverse effects with higher concentrations.11 More recently, the LAMP study reported 0.05% to be the most effective dose for slowing myopia compared with 0.025% and 0.01% while not affecting vision-related quality of life.12 Lee et al. found similar efficacy of 0.05% atropine.14 In conclusion, based on these reported data, low concentration atropine (0.05% to 0.1%) atropine might be a desirable starting concentration. It should be noted that the frequency of atropine use in most clinical trials is once per day and this respect, the use of high-dose atropine at a reduced frequency might be an alternative way to lower the adverse effects while maintaining efficacy, but it remains to be explored.
When should one start atropine treatment for myopes? Most clinical trials showed atropine to exert a satisfactory effect for participants aged 4 to 16 years old. In control eyes, slowest myopia progression was observed in older children (>18 years) and the fastest progression occurred between 8 to 12 years.15 Thus it is advisable to commence at an age when progression is faster. However, younger age was also found to be a risk factor for poor atropine response,16 and additionally, early use of atropine on infant monkeys had an impact on anterior segment eye growth and emmetropization.17 Thus, caution should be exercised in very young children (possibly <4 years) with atropine. Although the majority of studies with atropine were aimed at children with moderate myopia (mean baseline SE ranging from -3.0D to -5.0D) a study found 0.5% atropine to be equally effective for low myopia (-0.5D to -2.0D).18 Additionally, 1% atropine was found to show better myopia control with low myopia (-0.5D to-2.0D) (SE change: 0.32±0.22D per year; AL change: -0.03±0.07mm)19 than moderate-high myopia (≥-3D) (SE change: 0.06±0.79D; AL change: 0.09±0.19mm).20 Thus, it appears that it would be beneficial to start a person on atropine at the onset of myopia. In terms of duration of treatment, the optimal length of treatment is not clear, although most recommend one to two years of active treatment. In Taiwan, use of atropine is continuous till late adolescence (around 15–18 years old), as myopia progression is considered to stabilize around this period.21
Is atropine useful for preventing the onset of myopia? Atropine at 0.025% atropine was effective in preventing myopia onset in pre-myopes (<+1.0D) (change of -0.14D ± 0.24D per year) compared with the control group (-0.58D ± 0.34D per year)22. However, this finding needs to be validated with further studies, and, clearly, the concentration should be as low as possible without the risk of adverse effects. At the other end of the spectrum, there have been very few studies that have assessed the efficacy of atropine in high myopia (worse than -6.0D). However, these found atropine to be efficacious in highly myopic eyes. Atropine at 0.5 % was effective in slowing high myopia in a small group of children compared to tropicamide,23 and in another study, high myopia patients benefited more from 0.125% atropine than low to moderate myopia.24 Thus, the use of atropine in high myopia might have been underestimated but requires further work.
In summary, in terms of benefit versus risk, atropine at concentrations ranging from 0.05 % to 0.1% might be a desirable starting point to initiate treatment. Although these concentrations are not free of side effects, they appear to be less severe and additionally show lesser rebound on discontinuation. Initiating therapy at the onset of myopia may provide greater control and therefore reduce the risk of the eye reaching higher levels of myopia. Although the optimal length of treatment is not clear, continuing treatment until after myopia is stabilized may be a useful strategy to reduce the risk of rebound. In addition, atropine appears to have a role in preventing or delaying the onset of myopia as well as controlling progression in high myopes, but this remains to be explored further.
- Huang J, Wen D, Wang Q, et al. Efficacy Comparison of 16 Interventions for Myopia Control in Children: A Network Meta-analysis. Ophthalmology 2016;123(4):697-708.
- Pineles SL, Kraker RT, VanderVeen DK, et al. Atropine for the Prevention of Myopia Progression in Children: A Report by the American Academy of Ophthalmology. Ophthalmology 2017;124(12):1857-66.
- Gong Q, Janowski M, Luo M, et al. Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis. JAMA Ophthalmol. 2017;135(6):624-30.
- McBrien NA, Moghaddam HO, Reeder AP. Atropine reduces experimental myopia and eye enlargement via a nonaccommodative mechanism. Invest Ophthalmol Vis Sci. 1993;34(1):205-15.
- Ashby R, McCarthy CS, Maleszka R, et al. A muscarinic cholinergic antagonist and a dopamine agonist rapidly increase ZENK mRNA expression in the form-deprived chicken retina. Exp Eye Res. 2007;85(1):15-22.
- Schwahn HN, Kaymak H, Schaeffel F. Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick. Vis Neurosci. 2000;17(2):165-76.
- Iuvone PM, Tigges M, Fernandes A, Tigges J. Dopamine synthesis and metabolism in rhesus monkey retina: development, aging, and the effects of monocular visual deprivation. Vis Neurosci. 1989;2(5):465-71.
- Wang LZ, Syn N, Li S, et al. The penetration and distribution of topical atropine in animal ocular tissues. Acta Ophthalmol. 2019;97(2):e238-e47.
- Lind GJ, Chew SJ, Marzani D, Wallman J. Muscarinic acetylcholine receptor antagonists inhibit chick scleral chondrocytes. Invest Ophthalmol Vis Sci. 1998;39(12):2217-31.
- Gallego P, Martinez-Garcia C, Perez-Merino P, et al. Scleral changes induced by atropine in chicks as an experimental model of myopia. Ophthalmic Physiol Opt. 2012;32(6):478-84.
- 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 (Atropine for the Treatment of Myopia 2). Ophthalmology 2012;119(2):347-54.
- Yam JC, Jiang Y, Tang SM, et al. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology 2019;126(1):113-24.
- Shih YF, Chen CH, Chou AC, et al. Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocul Pharmacol Ther. 1999;15(1):85-90.
- Lee JJ, Fang PC, Yang IH, et al. Prevention of myopia progression with 0.05% atropine solution. J Ocul Pharmacol Ther. 2006;22(1):41-6.
- Brodstein RS, Brodstein DE, Olson RJ, et al. The treatment of myopia with atropine and bifocals. A long-term prospective study. Ophthalmology 1984;91(11):1373-9.
- Loh KL, Lu Q, Tan D, Chia A. Risk factors for progressive myopia in the atropine therapy for myopia study. Am J Ophthalmol. 2015;159(5):945-9.
- Whatham AR, Lunn D, Judge SJ. Effects of Monocular Atropinization on Refractive Error and Eye Growth in Infant New World Monkeys. Invest Ophthalmol Vis Sci. 2019;60(7):2623-30.
- Wang YR, Bian HL, Wang Q. Atropine 0.5% eyedrops for the treatment of children with low myopia: A randomized controlled trial. Medicine (Baltimore) 2017;96(27):e7371.
- Yi S, Huang Y, Yu SZ, et al. Therapeutic effect of atropine 1% in children with low myopia. J AAPOS 2015;19(5):426-9.
- Fan DS, Lam DS, Chan CK, et al. Topical atropine in retarding myopic progression and axial length growth in children with moderate to severe myopia: a pilot study. Jpn J Ophthalmol. 2007;51(1):27-33.
- Wu PC, Chuang MN, Choi J, Chen H, Wu G, Ohno-Matsui K, Jonas JB, Cheung CMG. Update in myopia and treatment strategy of atropine use in myopia control. Eye (Lond). 2019 ;33(1):3-13.
- Fang PC, Chung MY, Yu HJ, Wu PC. Prevention of myopia onset with 0.025% atropine in premyopic children. J Ocul Pharmacol Ther. 2010;26(4):341-5.
- Chou AC, Shih YF, Ho TC, Lin LL. The effectiveness of 0.5% atropine in controlling high myopia in children. J Ocul Pharmacol Ther. 1997;13(1):61-7.
- Lin HJ, Wan L, Tsai FJ, et al. Overnight orthokeratology is comparable with atropine in controlling myopia. BMC Ophthalmol. 2014;14:40.