At the completion of this CPD activity, optometrists will have developed their knowledge of atropine as a treatment for myopia management. Including:
- Understand the clinical rationale for the use of low-concentration atropine in the treatment of myopia
- Understand the clinical safety and efficacy profiles of atropine
- Explain to parents and patients the value of atropine intervention
- Understand the clinical treatment protocols of atropine
NOTE: Optomery Australia members can enter their details at the bottom of this article to have it automatically added to their Learning Plan.
In the second part of an educational feature on myopia management, CASSANDRA HAINES and DR KATE GIFFORD summarise atropine’s clinical efficacy and delve into data surrounding optimal concentrations.
Cassandra Haines
B Vis Sci M Optom CO
Associate lecturer – Flinders University
Clinical educator – Myopia Profile Pty Ltd
Policy and advocacy advisor – Optometry Australia
Dr Kate Gifford
PhD BAppSc(Optom)Hons, GradCertOcTher, FBCLA, FIACLE, FCCLSA, FAAO
Optometrist, professional educator and clinician-scientist
Co-founder and lead educator – Myopia Profile Pty Ltd
Visiting Research Fellow – Queensland University of Technology
When considering atropine for myopia management, it’s important to start with the fundamentals.
Known to eyecare practitioners for its mydriatic and cycloplegic effects, atropine is also a systemic medication used in cardiovascular management.1 Originally derived from Belladonna,2 the antimuscarinic agent (or muscarinic antagonist) inhibits postganglionic muscarinic receptors. When used systemically, this affects the autonomic nervous system, and increases cardiac output.1
Scientists are still unravelling the full mechanism for the myopia-controlling effect of atropine. However, it is known that acetylcholine, a neurotransmitter, is involved in retinal growth and signalling. Atropine blocks the action of acetylcholine at the muscarinic receptors, which may present a mechanism for slowing eye growth.
Atropine’s action as a mydriatic with associated relaxed accommodation tone may also play a role; it was previously thought myopia growth was due to excessive accommodation tone, but this has recently been refuted in animal models.3
History of atropine evidence
Atropine has been a possible contender on the myopia-management scene for longer than most may realise, with published literature as early as 1979 and 1984 reporting the effects of 1.0% atropine on fast myopia progressors.4,5 In 2006, the landmark paper ‘Atropine for the Treatment of Childhood Myopia (ATOM)’ was published, which evaluated 1% atropine against a placebo, demonstrating for the first time in a large-scale, randomised controlled trial that atropine could become a key player in myopia management.6
Despite its effectiveness, with 1% atropine demonstrating an almost halt (100% control effect) to axial length growth, the considerable side effects made it an unappealing treatment option,6 and the race began to find the ideal lower concentration of atropine, to achieve efficacy with minimal side effects.
Twist
The ATOM2 study in 2012 investigated 0.5%, 0.1% and 0.01% (as the intended placebo) for two years and found a concentration-dependent response in myopia control efficacy.7 From here, the scientific twist in the story occurred. These same participants then underwent a 12-month washout period before fast progressors (more than 0.50D myopia progression over the year) were resumed on 0.01% atropine treatment for another two years. While there was a concentration-dependent response in the first part of the study, there was also a concentration-dependent rebound effect noted in the washout year. At the conclusion of the five years, children treated with the 0.01% atropine for two years, discontinued for a year, then recommenced for another two years had the lowest final level of myopic refraction compared to children who had commenced on a higher concentration and then been shifted to 0.01% atropine.7
Given its low rate of side effects, minimal rebound and overall appearance of effective myopia-control, 0.01% atropine then rapidly gained popularity in the myopia-management landscape. The 2016 World Health Organisation (WHO) landmark myopia paper entitled: ‘The Impact of Myopia and High Myopia’ listed atropine 0.01% as a key treatment option for progressing myopes.8 This spurred further clinical trials such as the CHAMP study in the UK and the PEDIG group in America.9
Twist (again)
The next scientific twist away from 0.01% atropine occurred only recently, as researchers highlighted in 2018 that the ATOM2 study did not have a placebo control group, and that a historical control group comparison showed the actual impact on axial length control was minimal.10 This was affirmed with the 2019 publication of the ‘Low-concentration Atropine for Myopia Progression (LAMP)’ study, comparing 0.01%, 0.025% and 0.05% atropine directly to a placebo.
After 12 months, it was found that there was a statistically-significant slowing of eye growth in the 0.025% and 0.05% group, both in axial length and refractive change, however, there was a limited effect in the 0.01% group. The overall effect of 0.05% was almost double that of the 0.01%; leading to the conclusion that there is a concentration-dependent response to atropine and 0.01% may simply not be enough. This is the case for both regular and fast progressors, further backed by studies since.11,12
Side effects and safety
Side effect profiles reflect that higher concentrations (<0.1%) suffer higher rates of adverse effects;7,12 low-concentration atropine is reported to have very few side effects.13,14 Only 2.2% of the LAMP participants needed progressive glasses and 5% reported photophobia, with no differences noted between the various concentration and placebo groups. Patient preference, however, saw around one-third of the study participants prescribed photochromic glasses, including in the placebo group.13 Since these were offered at the study outset to parents concerned about side effects or pupil dilation, the authors suggested that this may have been taken up for protection against potential instead of realised side effects.15
Compounding
Almost all published atropine studies use compounded atropine, made from diluted 1% atropine drops with little reference to the method of compounding, stability of end product, or independent testing of concentration to ensure accuracy.
Complex compounding, required to produce sterile eye drop formulations, is a complicated process requiring specialist pharmacy skills and in some countries, may suffer reports of contamination, error and adverse outcomes.16
This doesn’t appear to be as much the case in Australia, where strong regulation on complex compounding is in place.17 Compounded atropine is frequently preserved with benzalkonium chloride (BAK), which is a known ocular surface irritant and hence not ideal for long-term use in children. Atropine itself does not appear to be a significant ocular irritant, with low rates of allergic conjunctivitis in studies being consistent across all participants, indicating BAK as the more likely culprit.13
Commercially-prepared formulations
Studies on commercially-prepared, non-preserved solutions are currently under way, which may provide some answers on how the formulation of atropine influences efficacy and side effects and also may potentially lead to another scientific shift back towards 0.01% if it proves effective.
Safety and contraindications
Atropine safety and tolerance as a topical ocular preparation appears to be high, but there have been isolated case reports of fatality in a child18 and poisoning in an adult19 from oral ingestion of 1% atropine eye drops. Systemic absorption through topical application, (to avoid anticholinergic side effects such as mouth and eye dryness, delirium or restlessness, tachycardia and flushed skin and face) and risks of allergy can be minimised through punctal occlusion.20 The majority of reported systemic complications from ocular use of atropine have occurred from children or young adults with pre-existing heart conditions, such a congenital rubella syndrome and developmental delays.18,21
This means that topical atropine may be contraindicated in children with heart conditions, and caution must be exercised in congenital syndromes, history of asthma or other anticholinergic medicine use.2,18,21 In these cases, communication and co-management with the patient’s healthcare team, especially paediatric ophthalmology, is essential to discuss risks and benefits – strict instruction and close supervision of patients in a risk category is a must.21
Choosing the ideal patient
For parents who may cite concerns with cost or logistics of myopia management spectacles or contact lenses, atropine can potentially provide a lower-cost alternative, with simple night-time dosing. However, atropine doesn’t correct refractive error, which places it at significant disadvantage to spectacle or contact lens myopia management strategies.
Parents must understand that this treatment will not reduce myopia, nor correct it, and spectacles or contact lenses will still be required. Providing children with progressive addition spectacle lenses will resolve any difficulties with near vision, if they arise. Encouraging children to wear sunglasses or recommending photochromic lenses will reduce any symptoms of photophobia and protect children from any potentially increased risk of UV exposure due to dilated pupils.
Children as young as four with documented myopia progression have been included in major landmark atropine trials such as the LAMP study,15 with the majority of studies including children from six years of age.6,9,22 This does not preclude the treatment from being effective on older populations; extrapolation that atropine is still effective in progressing teenagers is reasonable.
With all parents, ensuring informed consent is essential, including a discussion of the evidence for treating each individual child. In very young children, referral or co-management with ophthalmology may be prudent, especially when the degree of myopia exceeds the years of age, indicating high potential for systemic associations alongside the high myopia.23
Despite the fact that extended treatment with 1% atropine for amblyopia penalisation does not result in long-term side effects, and that the short-term cycloplegic effects of atropine are demonstrated to return to pre-treatment levels, there must still be consideration to potential long-term effects of atropine treatment.24
Before commencing any treatment, it is important to take thorough pupil and binocular vision measurements to help monitor for side effects, and to have a discussion with parents regarding the current evidence and likely long-term treatment protocol of atropine.
The LAMP study found that 0.05% was the most effective concentration for controlling axial length growth, achieving a balance of effectively slowing myopia progression with minimal side effects.15
Recent analysis of the ATOM2 data10 showed that 0.1% and 0.5% likely didn’t have a stronger impact on controlling axial elongation than the 0.05% outcomes in the LAMP study, although a direct comparison has not yet been undertaken. Furthermore, a 2020 analysis of all myopia control studies published to that date concluded that: “No single method of treatment shows clear superiority with the best of orthokeratology, soft multifocal contact lenses (SMCLs), spectacles and atropine showing similar effect.”25
Considering the dual correction-and-control benefits of spectacle or contact lens interventions, it makes clinical sense to prescribe these as first line treatments, and consider atropine a first line treatment where the ideal optical intervention is not suitable to that patient or available in your practice.
Figure 1 presents a flow chart for the prescription of atropine based on current evidence.
Combination treatments
Atropine 0.01% combined with orthokeratology has been shown to have an additive myopia control effect over orthokeratology alone. Two randomised clinical trials have shown that the increased efficacy was evident only in 1-4D myopes, and only for the first six to 12 months of combination treatment.26,27 A study on combining 0.01% atropine with centre-distance +2.50 Add multifocal contact lenses is under way, with outcomes expected to be reported in 2022.28 There are no other investigations of combining atropine with optical interventions.
Tapering and cessation of treatment
The question of tapering is yet to be fully addressed, given the rebound effects noted with 0.5% and 0.1% in the ATOM2 study7 and the current lack of investigation of rebound in lower concentrations.
The WHO recommendations from 2015 suggest a taper, however provide no instructions on reducing concentration or lowering dose frequency as the ideal approach.29 Zhu et al published a study in 2020 where a single monthly dose of atropine 1.0% for two years was reduced to every second month for a further year and then ceased, with no further myopia management intervention and no reported ‘rebound’ effects;30 but the side effect profile of 1.0% in this novel dosing approach raises questions regarding the best prescribing practices.
It has been demonstrated that half of myopic children stop progressing by 16 years of age, but this leaves 50% of children still with escalating myopia, so long-term treatment throughout the teenage years should be discussed with families.31 The 2015 WHO Myopia report8 suggested only two years of 0.01% atropine treatment based on the current evidence at that time. It would appear that if atropine is to be used as a primary myopia management strategy throughout childhood, treatment would likely need to continue for longer than this. While efficacy and safety appears robust with low-concentration topical atropine, longer-term treatment data beyond five years is not yet available.
Prescribing atropine in practice
Axial length control data in atropine studies has helped to reveal the true story of the ideal concentration, and will continue to be the key outcome measure for research trials.32 In the clinical setting, while axial length measurement is likely the ideal way to monitor for treatment efficacy, lack of access to such instrumentation should not be a barrier to practitioners offering myopia control treatment to their young patients.33
If you do wish to include this data in your practice consider working with your colleagues or interprofessional referral for axial length measurement. Co-management can also be important in providing the best possible treatments and outcomes for all patients.
In Australia, the only commercially-available topical atropine concentration is 1%, with any lower concentrations requiring compounding. The tide is shifting however, with the Therapeutic Goods Administration recently listing Eikance, a preservative-free, single use formulation of 0.01%, as an ‘extended use’ of atropine for children 4 to 14 years of age who have experienced a progression in myopia of -1.00D or more per year.34
Multiple clinical trials are under way in the United States and Europe, investigating commercially-prepared, preservative free low-concentration formulations – 2022 may see yet another exciting twist in the scientific story of atropine for myopia management.
References
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15. 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.
16. FDA. Compounding and the FDA: Questions and Answers. Guidance, Compliance, & Regulatory Information 2018.
17. Pharmacy Board of Australia. Frequently asked questions for pharmacists on the compounding of medications, 2020.
18. North RV, Kelly ME. A review of the uses and adverse effects of topical administration of atropine. Ophthalmic Physiol Opt. 1987; 7 (2): 109-14.
19. Stellpflug SJ, Cole JB, Isaacson BA, Lintner CP, Bilden EF. Massive atropine eye drop ingestion treated with high-dose physostigmine to avoid intubation. West J Emerg Med. 2012 Feb; 13 (1): 77-9.
20. Kothari M, Jain R, Khadse N, Rathod V, Mutha S. Allergic reactions to atropine eye drops for retardation of progressive myopia in children. Indian J Ophthalmol. 2018 Oct; 66 (10): 1446-1450.
21. Hirsbein D, Genevois O, Proust N, Calenda E. Are eye drops of atropine completely safe for heart? BJA: British Journal of Anaesthesia. 2006; 97 (eLetters Supplement).
22. McCrann S, Flitcroft I, Strang NC, Saunders KJ, Logan NS, Lee SS, Mackey DA, Butler JS, Loughman J. Myopia Outcome Study of Atropine in Children (MOSAIC): an investigator-led, double-masked, placebo-controlled, randomised clinical trial protocol. HRB Open Res. 2019 Jul 23; 2:15.
23. Marr JE, Halliwell-Ewen J, Fisher B, Soler L, Ainsworth JR. Associations of high myopia in childhood. Eye (Lond). 2001 Feb; 15 (Pt 1): 70-4.
24. Tong L, Huang XL, Koh AL, Zhang X, Tan DT, Chua WH. Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology. 2009 Mar; 116 (3): 572-9.
25. Brennan NA, Toubouti YM, Cheng X, Bullimore MA. Efficacy in myopia control. Prog Retin Eye Res. 2021 Jul; 83: 100923.
26. 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 (5): 557-566.
27. 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.
28. 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.
29. Holden BA, Fricke TR, Wilson DA, Jong M, Naidoo KS, Sankaridurg P, Wong TY, Naduvilath TJ, Resnikoff S. Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050. Ophthalmology. 2016 May; 123 (5): 1036-42.
30. Zhu Q, Tang Y, Guo L, Tighe S, Zhou Y, Zhang X, Zhang J, Zhu Y, Hu M. Efficacy and Safety of 1% Atropine on Retardation of Moderate Myopia Progression in Chinese School Children. Int J Med Sci. 2020 Jan 1; 17(2):176-181.
31. COMET Group. Myopia stabilization and associated factors among participants in the Correction of Myopia Evaluation Trial (COMET). Invest Ophthalmol Vis Sci. 2013 Dec 3; 54 (13): 7871-84.
32. Wolffsohn JS, Kollbaum PS, Berntsen DA, Atchison DA, Benavente A, Bradley A, Buckhurst H, Collins M, Fujikado T, Hiraoka T, Hirota M, Jones D, Logan NS, Lundström L, Torii H, Read SA, Naidoo K. IMI – Clinical Myopia Control Trials and Instrumentation Report. Invest Ophthalmol Vis Sci. 2019 Feb 28; 60 (3): M132-M160.
33. Gifford KL, Richdale K, Kang P, Aller TA, Lam CS, Liu YM, Michaud L, Mulder J, Orr JB, Rose KA, Saunders KJ, Seidel D, Tideman JWL, Sankaridurg P. IMI – Clinical Management Guidelines Report. Invest Ophthalmol Vis Sci. 2019 Feb 28; 60 (3): M184-M203.
34. The Therapeutic Goods Administration. Prescription medicines: new or extended uses, or new combinations of registered medicines. https://www.tga.gov.au/prescription-medicines-new-or-extended-uses-registered-medicines. Accessed 30.01.2022, 2022.
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