Combination atropine treatments: when more is more

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

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 wear^5,6 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.

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.

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.

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.

• 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.

• Case study: Combining atropine and orthokeratology for a fast progressing myope

• Atropine - Wonder or Weak Treatment?

• The Latest and Greatest Research on Atropine

• Case study: Atropine eye drops and ocular allergy - what's the cause?