Use of topical 1% atropine for slowing childhood myopia progression was initially cited more than 40 years ago (Bedrossian, 1971; Brodstein et al, 1984), and the first randomized controlled trial (the Atropine for the Treatment of Myopia 1 [ATOM1] Study) was published in 2006 (Chua et al, 2006). Atropine only gained clinical traction in the past decade, though, as evidence emerged on lower concentrations.

The ATOM2 study showed concentration-dependent efficacy of 0.5%, 0.1%, and 0.01% atropine over two years (Chia et al, 2012). This study was then continued for another three years; a rebound effect was observed on cessation for a year, and then all participants were re-treated for another two years with 0.01% atropine. The resulting ATOM2 five-year study concluded that 0.01% was most effective (Chia et al, 2016).

The Twist Away from 0.01%

On reflection, there are some notable flaws in the “0.01% is best” conclusion of the ATOM2 five-year study (Chia et al, 2016). First, the final axial lengths were no different between the groups, even though the 0.01% group was around 0.50D less myopic after five years than the 0.1% and 0.5% groups. Second, there was no control group. And third, ceasing treatment for a year in children aged 8 to 14 years would not be usual practice. This confuses the clinical application of the results.

In 2018, Bullimore and Berntsen highlighted that axial length data tends to tell a more modest story of atropine’s efficacy than does refractive data. A historical comparison (Chua et al, 2006) indicated that 0.01% actually had minimal impact on axial length control (Bullimore and Berntsen, 2018). Subsequent placebo-controlled randomized trials have confirmed this, with 0.02% (Cui et al, 2021) and 0.025% to 0.05% (Yam et al, 2019) showing stronger efficacy to slow eye growth with minimal side effects.

The Plot Compounds

The formulation of atropine could influence its efficacy. With few commercially manufactured preparations of low-concentration atropine available, most research studies use compounded versions (and most of what is done is off-label). These are either diluted from commercially available 1% atropine or prepared from raw materials, such as by dissolving a powder. While both methods could produce an accurate product, dilution alters the concentration of preservatives and other constituents, which can influence the final product’s stability and consistency (Haywood et al, 2020).

Compounded medications are formulated individually by pharmacists when a commercially prepared product is unavailable or doesn’t fit patient needs. By virtue of being individually compounded, these medications are not regulatory approved and cannot be verified for their consistent stability and efficacy as can be done for manufactured drugs (Donovan et al, 2018).

When prescribing compounded atropine, it is beneficial for prescribers to talk to pharmacists to confirm whether the medication will be prepared in sterile conditions (required by most countries for topical ocular preparations), how it will be prepared (diluted or from raw materials), what preservatives will be used, and to gain advice about storage and shelf life (Haywood et al, 2020).

A Twist Back to 0.01%?

Clinical myopia trials are underway utilizing commercially prepared, non-preserved atropine in 0.01% and 0.02% concentrations.These studies—with initial results expected this year—may provide answers on how the formulation of atropine influences efficacy, and 0.01% may even emerge back into favor as a monotherapy, depending on outcomes.

An emerging benefit of 0.01% atropine could be combining it with an optical intervention to boost myopia control efficacy. So far, this has only been demonstrated with orthokeratology wear in 1.0D-to-4.0D myopes for the first six to 12 months of combination treatment (Tan et al, 2020; Kinoshita et al, 2020).

Lots to Learn

The twists and turns in the atropine story have been intriguing but can lead to clinical uncertainty. For now, 0.05% appears to provide the best balance of efficacy with minimal side effects, 0.01% provides some effective combination treatments, and there is more to learn. CLS

References

1. Bedrossian RH. The effect of atropine on myopia. Ann Ophthalmol. 1971 Aug;3:891-897.
2. Brodstein RS, Brodstein DE, Olson RJ, Hunt SC, Williams RR. The treatment of myopia with atropine and bifocals. A long-term prospective study. Ophthalmology. 1984 Nov;91:1373-1379.
3. Chua WH, Balakrishnan V, Chan YH, et al. Atropine for the treatment of childhood myopia. Ophthalmology. 2006 Dec;113:2285-2291.
4. 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 Feb;119:347-354.
5. Chia A, Lu QS, Tan D. Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. Ophthalmology. 2016 Feb;123:391-399.
6. World Health Organization. The Impact of Myopia and High Myopia. Report of the Joint World Health Organization-Brien Holden Vision Institute Global Scientific Meeting on Myopia. Sydney, 2016. Available at https://www.who.int/blindness/causes/MyopiaReportforWeb.pdf . Accessed Mar. 2, 2022.
7. Bullimore MA, Berntsen DA. Low-Dose Atropine for Myopia Control: Considering All the Data. JAMA Ophthalmol. 2018 Mar;136:303.
8. Cui C, Li X, Lyu et al. Safety and efficacy of 0.02% and 0.01% atropine on controlling myopia progression: a 2-year clinical trial. Sci Rep. 2021 Nov;11:22267.
9. 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 Jan;126:113-124.
10. Haywood A, Testa C, Glass B. Personalised medicines for eye care. Pharma (Optometry Australia magazine). 2020;3:22-24.
11. Donovan G, Parkin L, Brierley-Jones L, Wilkes S. Unlicensed medicines use: a UK guideline analysis using AGREE II. Int J Pharm Pract. 2018 Dec;26:515-525.
12. Tan Q, Ng AL, Choy BN, Cheng GP, Woo VC, Cho P. One-year results of 0.01% atropine with orthokeratology (AOK) study: a randomised clinical trial. Ophthalmic Physiol Opt. 2020 Sep;40:557-566.
13. Kinoshita N, Konno Y, Hamada N, et al. Efficacy of combined orthokeratology and 0.01% atropine solution for slowing axial elongation in children with myopia: a 2-year randomised trial. Sci Rep. 2020 Jul 29;10:12750.
14. Huang J, Mutti DO, Jones-Jordan LA, Walline JJ. Bifocal & Atropine in Myopia Study: Baseline Data and Methods. Optom Vis Sci. 2019 May;96:335-344.