The Atropine Conundrum: Decoding Conflicting Research Results

Amidst the rising tide of global myopia rates, atropine has emerged as a promising new treatment modality, aiming to wrestle control over the axial length growth that marks myopia’s relentless march. Sort of. 

Foundational studies like 2006’s Atropine for the Treatment of Myopia (ATOM)¹ and its longer-term 2016 successor, ATOM2², established atropine, and especially low-dose atropine (generally regarded as concentrations of 0.01-0.05%) as a much-needed tool in the myopia specialist’s toolkit. But other studies have told a much different tale.

Most recently, data out of the United States from a landmark 2023 National Eye Institute-funded Pediatric Eye Disease Investigator Group (PEDIG) study have called into question low-dose atropine’s efficacy, concluding that low-dose atropine (.01%) provided no benefit over placebo.³

This bombshell assertion has brought a long-simmering controversy surrounding atropine for myopia to a full boil. Nuances from concentration to treatment duration and even race have produced wildly different efficacy results, leaving many eye care practitioners scratching their heads.

So what’s behind this minefield of mismatches, and how can the modern practitioner make actionable decisions based on these seemingly irreconcilable findings? 

Methodology matters

A lot, according to pediatric myopia expert Dr. Sun Chen-Hsin, a clinician-engineer at Singapore’s National University Hospital. With Singapore possessing one of the world’s highest myopia rates, his clinic sits at a critical hotspot in the myopia epidemic.

As a proponent of the promise of atropine, Dr. Sun was alarmed by the PEDIG group’s disappointing verdict on the drug. He believes, however, that a closer look at the existing research presents a skewed reflection of real-world atropine results. 

For him, treatment methodology plays a significant role in explaining the mismatch between the research and the real-world results seen in his clinic and those of his colleagues. 

Dr. Sun pointed out that many of the previous studies, including the PEDIG and ATOM studies, involved an abrupt halt in treatment of the drops. “That’s not what we do in real life—we continue to follow up,” Dr. Sun said.

“We never stop the atropine, like in the clinical studies, because we know they are going to rebound. The higher the concentration, the more the rebound,” he noted, referring to the seeming myopic increase observed in some clinical trial patients following abrupt cessation of the drug. 

According to Dr. Sun, practical clinicians opt for a more gradual tapering approach to mitigate these rebound effects and ensure the slowing of myopia progression. Atropine levels are decreased or increased and treatment intervals lengthened over long periods according to individual patient responses. 

These time scales, however, are not practical in clinical trials like the PEDIG study. “It’s a very long, drawn-out process,” he explained. “It’s really difficult to design this kind of trial to run for five or seven years.” 

ATOM2 and its 5-year clinical trial length corroborate this statement by more closely (though not perfectly) reflecting real-world use of atropine. The study lasted five years, with the treatment phase spanning 24 months, followed by a 12-month cessation period.Those exhibiting myopia progression during this break were subsequently reintroduced to atropine 0.01% for an additional 24 months. ATOM2 revealed that this 0.01% concentration, when reintroduced to prevent rebound, exhibited the highest efficacy in myopia control with fewer side effects.²

Formulation domination

Dr. Sun also believes that variations in the formulation of atropine have wrought havoc on the consistency of results between the many studies.

He referenced the work of Dr. Greg Ostrow, a former chemist turned pediatric ophthalmologist, whose presentation at the Brazilian Academy of Myopia Control and Orthokeratology’s World Congress on Myopia Control revealed the chemistry behind atropine drops as a potentially significant variable.

In his presentation, Dr. Ostrow scrutinized the formulation of atropine drops and found that the compound’s bioavailability is inversely proportional to its acidity. However, stability and shelf life also play a crucial role—more stable solutions have a longer shelf life. 

This duality poses a quandary. To achieve FDA approval, atropine solutions must maintain stability for two years, necessitating an acidic pH of four, which, in turn, hinders optimal absorption into the eye. 

The effects this has on children may be another source of study variability. “Firstly, this stings the eye. Children will have more tearing and will squeeze more drops out of the eye as they put them in,” commented Dr. Sun on Dr. Ostrow’s findings.

“Secondly, lower pH reduces the absorption of atropine into the eye itself,” he said. “When you have more acidity it just doesn’t penetrate into the eye.”

Standardizing studies

For Dr. Sun, the crux of the matter lies in the challenge of comparing atropine strength across diverse studies. Each study employs atropine manufactured differently, leading to variations in bioavailability and effectiveness. As such, it is inherently difficult to draw concrete conclusions due to these disparities in atropine formulations.

Dr. Sun looked underneath the hood of these studies, however, and found a possible way of evaluating the absorption of atropine. “One thing that can give you a surrogate marker of how much atropine there is—it’s the pupil size of the children,” Dr. Sun said. 

For Dr. Sun, change in pupil size could thus indicate atropine absorption, as it is also a mydriatic agent. He observed that critically, in studies with positive efficacy data like ATOM2 and 2019’s LAMP, a notable increase in pupil size was observed.^2,4

In the PEDIG study, Dr. Sun noted that although pupillary size was not measured, there were no complaints about increases in photophobia—a telltale sign of an atropine-induced increase in pupil size. For him, this all suggests poor absorption of the drug. 

Dr. Sun also recalled his observation about formulation acidity’s potentially inverse relationship to efficacy in the PEDIG trial. “In PEDIG, both the placebo group and the treated group had eye irritation, perhaps from the higher acidic carrier vehicle,” he said.³

Though these inferences from the studies are far from concrete, they could suggest further avenues for research. “This is, of course, all speculative,” Dr. Sun noted. “But this could be an answer to the question of why there is so much variability in these studies.”

“The number outside the bottle might not be a consistent measure of how much of the drug is getting into the eye. I think in order for there to be standardization, there should be a standardization of pupil change across studies to see how much of the atropine actually went into the eye,” he concluded.

Race’s role 

Besides stoppage-related rebounds, methodology discrepancies, and formulation variation, differences in testing populations—and specifically, race—also play a role. And one of the leading voices putting forth this explanation comes from a perhaps unexpected source. 

Reflecting on the negative PEDIG study results, which found that low-dose atropine did not impede myopia progression, lead co-author Dr. Michael X. Repka emphasized these potential racial differences in treatment response. 

“The absence of a treatment benefit in our U.S.-based study, compared with East Asian studies, may reflect racial differences in atropine response,” Dr. Repka said in a statement on the study results. 

“The study enrolled fewer Asian children, whose myopia progresses more quickly, and included Black children, whose myopia progresses less quickly compared with other races,” he said.

The 2023 study Myopia Outcome Study of Atropine in Children (MOSAIC), echoed these comments on race’s role. This study was the first performed on a primarily white European population, with previous studies having predominantly Asian populations.⁵

MOSAIC saw mixed results for atropine in spherical equivalent refraction (SER), but positive results for slowing axial elongation in this population. In the conclusion of the study, the authors noted issues with the generalizability of previous studies due to their relatively ethnically homogenous patient populations.⁵

About age

This unexpected result could potentially point to another factor influencing the inconsistency in the big atropine studies—the age range of the participants. 

Myopia exhibits a unique trajectory. At around age 15, approximately half of children experience stabilization in their myopia, and this trend continues, with more achieving stability as they transition into their early twenties.⁶

As myopia progression typically slows with age, the age range of research participants has emerged as a crucial factor in assessing atropine’s effectiveness. This was another key observation of MOSAIC, which involved European children with an age range extending up to 16. The study authors noted that many Asian studies have limited participant age to 12, introducing a potential influencing factor on research outcomes.

Dr. Repka, lead author in the PEDIG study, concurred. In recent public comments on the PEDIG study, he underscoring the probable impact of age on the outcome and stressing the importance of administering treatment during the phase of peak progression to optimize its benefits for patients.

From conundrum to clarity

Atropine began as a beacon of hope for myopia control, but now it stands as a multifaceted puzzle, instigating a quest for answers. 

The once-clear path has become a complex web of considerations, from study duration and ethnicity differentials to age nuances and atropine formulations. Each facet introduces layers of intricacy, teasing researchers and clinicians with more questions than answers.

“The overall mixed results on low-dose atropine show us we need more research.  Would a different dose be more effective in a US population? Would combining atropine with other strategies have a synergistic effect?” asked Dr. Michael Chiang, director of the NEI, when commenting on the PEDIG results. 

“Could we develop other approaches to treatment or prevention based on a better understanding of what causes myopia progression?” 

In the end, though potential explanations are coming into focus, uncertainty still abounds. Yet with this uncertainty, lies the heartbeat of progress. These conflicting results are not roadblocks but rather signposts, urging the community to delve deeper, question assumptions, and refine hypotheses. 

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