Combination atropine treatments: when more is more

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Originally published August 17, 2021
Updated March 1, 2022

Are combination treatments, like atropine and orthokeratology, more effective than monotherapy? Atropine is considered a first line treatment for myopia control, and we now know thanks to the Low-Concentration Atropine for Myopia Control (LAMP) Study and further analysis of the Atropine for the Treatment of childhood Myopia 2 (ATOM2) Study that the efficacy of atropine appears to be concentration-dependent.1,2

There is interesting evidence that atropine, when combined with orthokeratology, may have improved efficacy than either treatment used separately. A meta-analysis published in 2020 analyzed data from 341 children from two studies and three RCTs, and found a statistically significant reduction in axial elongation of 0.09mm over one year in combination treatment compared to orthokeratology alone.3

What's the mechanism?

There have been a few theories that try to understand why the combined effect is more than the treatments individually. A logical approach is that we know atropine does have a small impact on pupil dilation which could enhance the optical effects of orthokeratology on the central and peripheral retina. Tan et al4 found that larger pupils correlated with increased efficacy in atropine 0.01% + orthokeratology treatment, but this only explained 20% of the effect and there was no such relationship in the OK monotherapy group.

Larger pupils increase higher order aberrations. Some authors have reported an association between the large increase in aberrations in OK wear5,6 and the myopia control effect,5-7 while some have not.8

There is also an interaction between higher order aberrations and accommodation. One study has shown a greater myopia control effect of OK in children with lower baseline amplitude of accommodation.9 Perhaps a small reduction in the amplitude of accommodation (eg. around 2D with 0.025% or 0.05% atropine)2 interacts with the OK-induced aberrations to increase efficacy.

In summary, we don't know the exact mechanism, but this is the case for most myopia control treatments whether monotherapy or combined. Let's take a deep dive into the studies which have been published on combining atropine with orthokeratology or other myopia controlling contact lenses.

The evidence for combination treatments

There's a lot of information in this table, so here's some guidance on how to read it. Essentially we're saving you the time of reading these five papers by collating all of the main findings in one place! This table shows the four currently published papers of 12 months or longer duration on atropine plus orthokeratology.4,10-12 There are no other longitudinal studies published on atropine plus other optical treatments, aside from one on atropine plus the CooperVision centre distance multifocal with +2.50 Add,13 which is shown in the final column. The results were published in February 2022 showing no significant effect of the combination - see the highlighted text under the table.

AOK summary table with shadow

2022 update: The Bifocal and Atropine in Myopia (BAM) Study, described in the last column, was published in online pre-print in February 2022. Over the three year study, there was unfortunately no significant additive effect of combining 0.01% atropine with a centre distance soft multifocal contact lens (SMCL) with a +2.50 Add. The 3-year adjusted axial elongation was 0.31 mm for children treated with SMCL + atropine, 0.39 mm for SMCL alone, and 0.68 mm for the single vision soft contact lens control group. The difference between the SMCL and SMCL+atropine groups of 0.08mm was not statistically significant.

What about side effects?

Ocular surface exposure to preservatives in the atropine drop, such as BAK, is more likely the larger concern of combination treatment than the cycloplegic and mydriatic side effects of atropine interacting with OK treatment. Here's what's been reported in the studies cited above.

  • Kinoshita et al11 utilized a diluted 1% atropine with BAK preservative in their two year 0.01% + OK study. They found 2/43 in the combination group and 1/37 in the monotherapy group developed SPK which worsened over time, such that all three were discontinued out of OK and prescribed spectacles. The SPK resolved within a month. No participants in the combination group dropped out due to photophobia, near vision issues, allergic reaction or other adverse event.
  • Tan et al4 utilized a preservative free 0.01% single use atropine formulation in their one year study. They found 1/29 in the combination group and 1/30 in the monotherapy group developed bacterial conjunctivitis after two weeks, which both resolved with a week of no lens wear and topical antibiotics. There were no other adverse events related to lens wear or atropine.

Preservative free atropine should minimize the potential increased side effects of a combination treatment.

What does this mean for your practice?

  • Which concentration of atropine is best? The likely answer is 0.01%. Combining atropine 0.01% with orthokeratology appears to increase myopia control efficacy with minimal side effects on pupil size or acuity. One study investigating stronger concentrations found that 0.125% wasn't effective and 0.025% greatly impacted pupil size and reduced accommodation amplitude - curiously much more than the LAMP study2 - but 0.025% in this single study appeared to have a similar absolute effect than 0.01% in other studies. Even though 0.01% atropine doesn't have much impact as a monotherapy,1,2 at least in current formulations, it appears to provide benefit in a combination treatment with orthokeratology.
  • Who are the best targets? This is harder to say. Across the studies, there appears to be no relationship between younger age and a better combined effect. Kinoshita et al11 found a significant effect only for 1-3D myopes and not for 3-6D myopes - this wasn't found by Tan et al4 although only 1-4D myopes were included. Wan et al10 found no influence of age or refraction but included myopes up to 17 years of age, who are more likely to be stable than children under age 12 as included in the other studies.
  • Should you try orthokeratology first and then add atropine? The only example of this is Chen et al,12 who took 'poor responders' to OK (defined as progression of 0.30mm or more in a year) and added 0.01% atropine. They found no benefit of the combined treatment. This would seem to indicate that these fast progressors simply didn't get a benefit, more so than that waiting a year led to a 'missed chance' for combination treatment. To balance side effect risk and efficacy, it could make sense to start with orthokeratology alone, which appears to have similar efficacy to atropine 0.05% based on study comparisons.2,14
  • How long should you combine the treatments? The two studies which have investigated this found the greater effect was achieved in the first 6-12 months, with no difference in progression rates between combination and OK-only groups thereafter.

We still have more to learn, but the small volume of studies so far indicate that atropine 0.01% plus orthokeratology appears to have an additive efficacy for myopia control. Conversely, one three-year study has recently shown that atropine 0.01% does not have additive efficacy with soft multifocal contact lenses. As always, your clinical judgement and the level of concern of both you and the parent will likely lead towards combining treatments to increase efficacy.

Further reading on atropine and combination treatment

Cassandra Haines BIO image 2019_white background

About Cassandra

Cassandra Haines is a clinical optometrist, researcher and writer with a background in policy and advocacy from Adelaide, Australia. She has a keen interest in children's vision and myopia control.

Kate profile thumbnail

About Kate

Dr Kate Gifford is a clinical optometrist, researcher, peer educator and professional leader from Brisbane, Australia, and a co-founder of Myopia Profile.

References

  1. Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, Quah BL, Tan D. Atropine for the treatment of childhood myopia. Ophthalmology. 2006 Dec;113(12):2285-91. (link)
  2. Yam JC, Jiang Y, Tang SM, Law AKP, Chan JJ, Wong E, Ko ST, Young AL, Tham CC, Chen LJ, Pang CP. 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(1):113-124. (link)
  3. Gao C, Wan S, Zhang Y, Han J. The efficacy of atropine combined with orthokeratology in slowing axial elongation of myopia children: a meta-analysis. Eye & Contact Lens. 2021 Feb 1;47(2):98-103. (link)
  4. 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 and Physiological Optics. 2020 Sep;40(5):557-66. (link)
  5. Hiraoka T, Kakita T, Okamoto F, Oshika T. Influence of ocular wavefront aberrations on axial length elongation in myopic children treated with overnight orthokeratology. Ophthalmology. 2015 Jan;122(1):93-100. (link)
  6. Kim J, Lim DH, Han SH, Chung T-Y (2019) Predictive factors associated with axial length growth and myopia progression in orthokeratology. PLoS ONE 14(6): e0218140. (link)
  7. Lau JK, Vincent SJ, Cheung SW, Cho P. Higher-Order Aberrations and Axial Elongation in Myopic Children Treated With Orthokeratology. Invest Ophthalmol Vis Sci. 2020 Feb 7;61(2):22. doi: 10.1167/iovs.61.2.22. (link)
  8. Santodomingo-Rubido J, Villa-Collar C, Gilmartin B, Gutiérrez-Ortega R, Suzaki A. Short- and Long-Term Changes in Corneal Aberrations and Axial Length Induced by Orthokeratology in Children Are Not Correlated. Eye Contact Lens. 2017 Nov;43(6):358-363. (link)
  9. Zhu M, Feng H, Zhu J, Qu X. The impact of amplitude of accommodation on controlling the development of myopia in orthokeratology. Chinese J Ophthalmol. 2014;50:14-9. (link)
  10. Wan L, Wei C-C, Chen C, Chang C-Y, Lin C-J, Chen J, et al. The Synergistic Effects of Orthokeratology and Atropine in Slowing the Progression of Myopia. Journal of Clinical Medicine. 2018;(7):259. (link)
  11. Kinoshita N, Konno Y, Hamada N, Kanda Y, Shimmura-Tomita M, Kaburaki T, Kakehashi A. 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(1):12750. (link)
  12. Chen Z, Zhou J, Xue F, Qu X, Zhou X. Two-year add-on effect of using low concentration atropine in poor responders of orthokeratology in myopic children. British Journal of Ophthalmology. 2021 Mar 11. (link)
  13. Huang J, Mutti DO, Jones-Jordan LA, Walline JJ. Bifocal & Atropine in Myopia Study: Baseline Data and Methods. Optom Vis Sci. 2019 May;96(5):335-344. (link)
  14. Sun Y, Xu F, Zhang T, Liu M, Wang D, Chen Y, Liu Q. Orthokeratology to control myopia progression: a meta-analysis. PloS one. 2015 Apr 9;10(4):e0124535. (link)

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