Monday, February 19, 2018

As a layperson, how do you deconstruct an artificial tear study? (PART 1)

All about a study abstract

At the bottom of this page, I've posted the abstract of a study that was just published a few days ago, which compares three artificial tears and their effect on the "signs, symptoms and inflammatory status" of the patients in the study.

I've spent years looking at abstracts, often digging into the complete studies to the extent they are available online for free, and trying to distill the content into fact bites and language normal people can understand.

I almost always skip the artificial tear ones or "blurbify" them as the meaningless repeats they so often seem to be. This one, though, prompted me to start asking more questions. Somewhere in the process, I reverted to musing on how inaccessible some of these studies are to the casual reader who just wants to know one thing: what works?

So I decided to take the opportunity to pick one apart and lay out all the gory details. I thought it wouldn't take long. I was wrong. Just figuring out which drops were being studied made this a very long blog post, so I'm turning this into a mini-series, because the same study has much, much food for thought and discussion.

PART 1. What are they talking about?

You'd think the products or drugs being studied would be obvious.

Sort of?

Absolutely not.

Study abstracts usually don't reference brand names. For example, studies about Restasis or Xiidra will refer to them as "cyclosporine ophthalmic emulsion 0.05%" and "lifitegrast ophthalmic solution 5%". The brand names don't go in the keywords either, incidentally, so if you're trying to do a broad search, you kind of need to know what you're doing.

So, we have to do a little legwork to figure out which the three products in this study are.

We are told they are:
  1. carboxymethylcellulose-glycerine-castor oil (CGC)
  2. carboxymethylcellulose (CMC)
  3. hydroxypropyl guar (HPG)
Having read a great many of these abstracts over the years, I recognize the pattern:
We are watching a really cheesy stage portrayal of scene CCXLIV of Shakespeare's classic work, "Refresh and Systane". In this scene, the young, vigorous, ambitious scion of the Refresh family uses a blunted sword on stage to disable his elder brother before moving on to inflict would-be fatal wounds in the oldest, tiredest member of the Systane family and, seeing him duly fall to the ground clutching his heart, gloats at his success. 

Alas, no. It's just because I've seen this play out so many times. Now I peek ahead to the conclusion paragraph and realize I could not be more wrong, at least as regards the plot. In fact.... Oooooh. This one might actually be ever so slightly fun and interesting (to nerds like me).

But I'm getting ahead of myself. Back to the homework on the products.

Who ARE these three masked actors, really?

We know they are all artificial tears, a/k/a "tear supplements". Actually, that term may be a little confusing to the layperson because there are so many superfluous nutritional supplements sold to improve tears - and so many dime-a-dozen studies published about them - that it wouldn't be surprising if that's where your head goes the moment you see the word "supplement". (I freely admit mine did, at first glance, and I read these things all the time!) But as soon as you get to the ingredients, it's clear we're not talking about another Omega 3 study. Back up. Oh, yes, tear supplements = artificial tears = "lubricant eye drops", etc.

That should make it very easy to find the products, right? After all, I have a handy ingredient reference list posted at the Dry Eye Shop for all the major brands of artificial tears and even a few minors. However, as always, I'm making a mental note even before I start that we'll have to make some assumptions as we match them up. On the one hand, they could be the major brands, and almost certainly are. I mean, who else but Allergan puts money into studying artificial tears? But if they aren't, we can't assume the results will apply to the name brands. The only things listed in the abstract are the polymer and lipid type ingredients. The abstract doesn't list the concentrations (which are listed on product packaging), let alone any more minor differences, and we certainly don't know what might be lurking in the inactive ingredients.

Sidebar: Speaking of inactive ingredients, and noting castor oil in one drop: because of the archaic and arcane way the FDA regulates artificial tears, if there is castor oil present, you can bet it's listed in the inactives, because it's not allowed to be listed in the actives! Go figure!

So anyway, I'm thinking this will be easy. Then I look them up.

QUESTION #1: What is the drop referred to as"carboxymethylcellulose-glycerine-castor oil"?

Refresh Optive Advanced is the first one on my list that has all three of these ingredients - the first two are listed in actives, the third in inactives, as I said. But it also has polysorbate 80 listed in the actives. So are we talking about a different drop, or do the authors just not care about the polysorbate 80? Furthermore, Refresh Optive Advanced Mega 3 also contains all three of these ingredients; the active ingredients are identical; but Mega 3 also contains more lipids, also listed in the inactives where the FDA regs force them to dwell.
ANSWER: Probably Refresh Optive Advanced? Maybe Refresh Optive Advanced Mega 3? Maybe something different, but what? Mental note that I really have to find out.

QUESTION #2: What is the drop referred to as "carboxymethylcellulose"?

OK this one could be Refresh, or Refresh Plus, or Theratears, or any number of generics. Unfortunately the abstract does not even bother to specify whether they are preserved or preservative free, let alone the polymer concentration. Mental note that the ambiguities may be deliberate - this is obviously just meant to be the middle of the road ubiquitous artificial tear, right?
ANSWER: I really couldn't care less, but probably Refresh Plus.

QUESTION #3: What is the drop referred to as "hydroxypropyl guar"?

Easy peasy. Systane. They are the only major brand using this ingredient. 

Except... HP is in ALL Systane products. So, is this Systane, or is it Systane Balance (which contains a lipid), or is it Systane Ultra (which is a high concentration), or is it Systane Sport? 

Then I read a little more carefully - the abstract says that CGC and HPG are "emulsified lipids", and Systane Balance is the only emulsion drop in the Systane brand, so this pretty much has to be Systane Balance, unless there's a new knockoff somewhere, but then, knockoffs don't spend money conducting studies.

BUT... FOR HEAVEN'S SAKES! Would the real artificial tear please stand up? By this time I'm fuming over the fact that I probably can't find out without forking over $30 to get a copy of the study or hitting up an academic friend to hunt it down at their university, because I seriously doubt that even any of my ophthalmologist friends subscribe to Cytokine, of all the obscure journals! Not to mention that no one really cares all that much about artificial tear studies anyway, so how many people looking at the abstract would have any more doubts than I did that it's really just another round in the Refresh v Systane challenge, and make an assumption about which specific ones? Yawn, move on. 

As a last resort, I google the study, in case it's one of the ones that really IS available online in full text.

Bingo. There it is, in all its glory! Yes, of course it's Refresh v Systane, but I am still in for some surprises.

#1 = "Optive Plus", by Allergan

Optive WHAT?

Oh. I realize for the first time that the study was done in the UK. Optive Plus is sold on prescription in the UK, AND as far as I can tell, considering they don't list the inactive ingredients, it's at least quite close to if not exactly the preserved version of Refresh Optive Advanced. Kinda called it.

#2 = "Refresh Contacts", by Allergan

Seriously? The UK version looks to be identical with the US one, but... but... but... I thought this was a study of tear supplements, not lens wetting drops?

Then I have a look through Allergan's UK product offerings and I see that they do not, in fact, have a CMC drop other than their contact lens one - which, let's be honest, in the US Refresh Contacts is the same thing as Refresh Tears under a different label anyway right? So it really doesn't matter. Fair enough. It's the sweetly smelling ubiquitous preserved CMC artificial tear under any other name. Called it.

#3 = Systane Balance, by Alcon

Called it.

So now we know WHAT they are talking about.

We have several more questions to go, including:

  • What did they find out, and how?
  • Who cares (if anyone), and why?

I really don't usually have this much fun on Mondays. Thank goodness for the Presidents Day holiday.


 2018 Feb 13;105:37-44. doi: 10.1016/j.cyto.2018.02.009. [Epub ahead of print]

Effect of tear supplements on signs, symptoms and inflammatory markers in dry eye.



Three tear supplements were compared for their effects on the signs, symptoms and inflammatory status of subjects with dry eye disease. Assessments were made before and after both 2 and 4 weeks of treatment.


In this masked, randomized, 3-way crossover trial, eighteen dry eye subjects were recruited. At each visit, symptoms, tear evaporation rate, stability and osmolarity were measured and tear samples were analyzed for 7 inflammatory markers, using multiplex immunoassays. The 3 treatments included carboxymethylcellulose-glycerine-castor oil (CGC), carboxymethylcellulose (CMC) and hydroxypropyl guar (HPG). The CGC and HPG drops are emulsified lipids; CGC also contains osmoprotectants. The CMC drop is a standard aqueous polymeric supplement.


Significant improvements were seen in symptoms (OSDI) and tear stability (NITBUT) with all 3 treatments at 4 weeks. At 4 weeks post-CGC, 6 out of 7 biomarkers demonstrated a >25% reduction (in 40% of subjects). The same reduction (>25%) was seen in 10% of the subjects for CMC and in none of the subjects for HPG. No significantly different change to either evaporation rate or tear osmolarity was found following any of the three treatments.


In this study, the CGC treatment resulted in the greatest reduction in ocular biomarkers of inflammation, while all 3 treatments reduced symptoms and improved tear stability. These results indicate that subject-perceived symptomatic improvements are not necessarily associated with a reduction in objective measures of inflammation.

1 comment:

karen whall said...

Rebecca, the conclusion in this study was reflected in the 2-part Harvard survey you forwarded to us "Johns Hopkins / Cochrane Eyes Dry Eye Priorities and Outcomes Survey!"
What is currently measured in dry eye studies does not often reflect what the individual feels/perceives/experiences. There appears to be an effort to better 'measure' variables that reflect not just the surface characteristics of the eye, but also the neural transmission to the brain of this sensory input by the individual that is undergoing treatment. Relief or improvement in problems like itching, scratchiness, blurring, different levels of pain, etc. can indicate additional factors that can be assessed at the time of treatment/product development. Because it is the perception of relief by an individual that is multifaceted, minute differences in products-of which there are MANY on the market- will have a positive end for one person but not another.