Atropine What, Who, How, When… and Why?

Atropine is a naturally occurring alkaloid found in plants of the nightshade family (Solanaceae) including deadly nightshade, mandrake and jimson weed. It was first chemically isolated by German pharmacists in 1824, although its use for medicinal and other purposes has been described for centuries.1 The leaves and roots of jimson weed were burned by ancient Hindu physicians and the smoke used to treat asthma. Deadly nightshade, common throughout Europe and North Africa, was also known as Atropa belladonna; ‘bella donna’ (pretty woman in Italian) because of its historical use to dilate women’s pupils to make them appear more alluring. This practice was described as far back as the last century BCE when Cleopatra was reported to have used it, and, more recently, during the Renaissance and for a brief period in Paris at the turn of the 19th century. In the Roman Empire and during the Middle Ages, Atropa belladonna was also used as an effective poison.

there is evidence to suggest atropine may not be as effective in non-Asian children

PHARMACOLOGY OF ATROPINE

Atropine acts as a non-selective competitive antagonist of muscarinic acetylcholine receptors in the parasympathetic nervous system. It acts on multiple organ systems to exert a clinical effect, which includes increased heart rate, decreased bronchial secretions, dry mouth, pupil dilation, impaired accommodation (causing blurred vision), urinary retention, constipation, and confusion/hallucinations. Clinically, atropine has multiple therapeutic uses including treating bradycardia and heart block, redoing bronchial secretions, and treating poisoning by organophosphates and some nerve gases. In ophthalmology, atropine is routinely used to facilitate refraction and fundus examination, and therapeutically, for example, in malignant glaucoma.

ATROPINE AND MYOPIA

 Using atropine to treat myopia is not new. Franciscus Donders, a Dutch ophthalmologist, described using atropine to treat myopia in his 1864 book, On the Anomalies of Accommodation and Refraction of the Eye. In the book, he theorised myopia was due to excessive accommodation.² In 1916 Inglis Pollack, an ophthalmologist from the Glasgow Eye Infirmary, was the first to describe its prolonged use in treating progressive high myopia in Scottish school-aged children.³ However, its widespread and consistent use was limited, mostly due to the unacceptable side effects of photophobia and blurred near vision.

ATROPINE TRIALS

It was another 50 years before interest in atropine was rekindled. In 1962, Gostin presented his positive experience with atropine for myopia control.⁴ In 1971, Bedrossian et al. presented the first large study on the topic with 90 school-aged myopic children given 1 per cent atropine. In this crossover study, children were given 1 per cent atropine in one eye for one year, and in the subsequent year the atropine was switched to the fellow eye. In the first year myopia progressed -0.20D in the atropine-treated eye compared to -0.85D in the control eye (P<0.01). In the second year, the results were similar with the treated eye progressing at -0.17D compared to -1.05D in the control eye (P<0.01).⁵ In 1984, Brodstein et al. reported their study, which compared 435 children receiving atropine 1 per cent against 146 controls over a median follow-up treatment period of 2.8 years, including 1.8 years after treatment cessation. Myopia progression was -0.12D per year on atropine compared to -0.34D for controls (p<0.001). A large number enrolled in the trial (165/435) were excluded due to non-adherence to treatment. Following cessation of treatment, a rebound effect was associated with atropine treatment whereby progression rates were higher in the atropine group than controls (though not statistically higher).⁶ In 1989, Yen et al. reported results from their comparative trial of atropine 1 per cent, cyclopentolate 1 per cent, and saline eye drops. They found mean myopic progression was -0.219D in the atropine group, -0.578D in the cyclopentolate group, and -0.914D in the saline group.⁷ They did experience a significant drop out rate (151/247) due to eye drop intolerance, mostly in the atropine 1 per cent group.

… is the prolonged use of topical atropine in children safe?

In 2006, the Singapore Atropine for the Treatment of Myopia (ATOM 1) trial was the first randomised, doubleblinded placebo-controlled trial (RCT) to confirm the effectiveness of atropine for progressive myopia in Asian school children. The trial enrolled over 400 school-aged Singaporean children. This trial established 1 per cent atropine was effective in slowing myopia progression by 77 per cent over a two-year period compared to untreated fellow-eye controls (-1.2D versus -0.28D annual progression).⁸ 

Difficulties in achieving long-term tolerance and adherence with atropine 1 per cent treatment motivated researchers to trial lower doses in the 1990s. In Taiwan, Chou et al trialled atropine 0.5 per cent in 20 highly myopic children (<-6.0D) and concluded it was effective in slowing annual myopic progression to -0.48 ± 0.72D from -1.68 ± 0.84D and was reasonably well tolerated.⁹ The same group then examined 0.5 per cent, 0.25 per cent, and 0.1 per cent atropine in 186 myopic school children over two years. They found a dose: response relationship in slowing myopic progression, where mean myopic progression was 0.04 ± 0.63D, 0.45 ± 0.55D, and 0.47 ± 0.91D per year in each group respectively, compared to 1.06 ± 0.61D in the control group (tropicamide 0.5 per cent).¹⁰ Wu et al.¹¹ reported their retrospective case-control study of 117 myopic school children using 0.05 per cent and 0.01 per cent atropine over at least three years’ follow-up. They found low dose atropine had a lower rate of progression than the control group (-0.23D per year vs. -0.86D per year) and was well tolerated. More recently, Polling et al reported the effect of atropine 0.5 per cent in 77 European children with progressive high myopia living in the Netherlands. They found atropine 0.5 per cent to be effective in slowing myopia progression from -1.0 ± 0.7D per year to -0.10 ±0.7D per year. However, side effects were common including photophobia (72 per cent), reading problems (38 per cent), and headaches (22 per cent).¹⁵ 

The Singapore ATOM 2 trial followed the ATOM 1 trial and was designed to explore the effectiveness of lower doses of atropine (0.5 per cent, 0.1 per cent and 0.01 per cent) on myopia progression over five years. Phase 1 was reported at two years in 2012 and showed that mean myopic progression was -0.30D, -0.38D and -0.49D in 0.5 per cent, 0.1 per cent and 0.01 per cent groups respectively.¹² This was significantly lower than the control group from the ATOM 1 trial (-1.20D). Importantly, there was no statistically significant difference in effectiveness between 0.01 per cent atropine and 0.1 per cent and 0.5 per cent. In phase 2, children were untreated for 12 months and those who progressed > -0.50D were restarted on 0.01 per cent atropine for a further two years (phase 3). They reported a significant rebound effect in eyes receiving 1.0 per cent, 0.5 per cent, and 0.1 per cent atropine compared to 0.01 per cent atropine.¹³ In 2016, five-year results were reported and most interestingly, atropine 0.01 per cent was the most effective in slowing progression: -1.38 ± 0.98D compared with -1.83 ± 1.16D, P < 0.003 in 0.1 per cent; and -1.98 ± 1.10D, P < 0.001 in 0.5 per cent groups. This dose was also far better tolerated with minimal pupil dilation, loss of accommodation, and no near visual loss compared with higher doses.¹⁴ One significant criticism of the ATOM 2 trial has been the lack of a placebo control arm since they essentially used the placebo group from ATOM 1 as the control.

MECHANISM OF ACTION 

The exact mechanism whereby atropine slows myopic progression is incompletely understood. The initial theory that it is mediated by impairing accommodation has been disproven in animal models. In chicks, for example, atropine slows progression despite them possessing striated ciliary muscles comprised of nicotinic receptors rather than muscarinic receptors. ¹⁶ The most favoured theories are that atropine affects signalling at the retinal photoreceptor level to impair axial elongation or that it acts directly on scleral fibroblasts to impair scleral growth.

FUTURE OF ATROPINE 

Whatever the mechanism, it is clear from over a century of studies and reports that atropine slows myopic progression. The significant issues with photophobia and visual blur limiting its widespread adoption have been mostly ameliorated with the use of low-dose atropine supported by randomised clinical trial (RCT) data from the Singapore ATOM trials. This has incentivised the widespread uptake of treatment throughout south east Asia, where at least 50 per cent of children with progressive myopia are being treated with low-dose atropine.¹⁷

As compelling as the data may be, there is still no level one evidence from RCTs to support the use of atropine in school children outside of Asia and there is evidence to suggest atropine may not be as effective in non-Asian children.¹⁸ Anecdotally, atropine is being routinely used by ophthalmologists and optometrists as an off-label treatment for myopia in Australian school children despite the lack of evidence for its effectiveness in this population.

Several trials have begun with the aim to evaluate the effectiveness of lowdose atropine in myopic school children compared to placebo in countries outside of Asia including Europe and Australia (ACTRN12617000598381). These trials will hopefully provide the data to confirm its clinical effectiveness and support its use in school children outside of Asia.

Beyond these confirmatory studies, future trials are needed to answer the many remaining questions. These questions include: when should treatment be stopped? What is the effective atropine dose and frequency to minimise side effects, maximise therapeutic effect, and minimise myopic rebound? Does initiating atropine treatment before the onset of myopia in high-risk children prevent the onset of myopia? Who are the most likely to benefit from atropine therapy and who are least likely? And most importantly, is the prolonged use of topical atropine in children safe?

Dr. Antony Clark FRANZCO PhD completed his ophthalmology training in Western Australia before undertaking two years of sub-speciality fellowship training in glaucoma and paediatrics at the University of Toronto and Hospital for Sick Children in Canada. Dr. Clark has a PhD in public health and continues his interests in epidemiology and clinical ophthalmic research. Dr. Clark is a consultant ophthalmologist at the Lions Eye Institute, Sir Charles Gairdner Hospital and Perth Children’s Hospital. 

References 

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2. Donders FC, Moore WD. On the Anomalies of Accommodation and Refraction of the Eye. New Sydenham Society; 1864. 
3. Pollock W. The reduction of myopia in children of school age. Glasgow Med J 1916;86:214–219. 
4. Gostin SB. Prophylatic management of progressive myopia. South Med J 1962;55:916–920. 
5. Bedrossian RH. The effect of atropine on myopia. Ann Ophthalmol 1971;3:891–897. 
6. Brodstein RS, Brodstein DE, Olson RJ, et al. The treatment of myopia with atropine and bifocals. A long-term prospective study. OPHTHA 1984;91: 1373–1379. 
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12. Chia A, Chua W-H, Cheung Y-B, 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;119:347–354. 
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