Not sure you've made the case for this enough in the intro - I know what you mean, but I think to say this you have to guide the reader through the current problems/fragility with the opioid conversion studies before. I don't think it's unreasonable to have one key recommendation (1)

cite the conversion tables used

should

I think this is really nice, and is your key message? Maybe this could go in the letter to the editor in some form?

minimal,

those

del

effect, potentially

*space

del

not sure what this is, and doesn't seem immediately obvious from a quick google - bias from a bilinear operation or interpolation? Or is it bilinear basis as in the mathematical form?

recalculation of point estimate and dose range was attempted using a range of conversion values

vary the magnitude of the induced error (??)

del

*opioid

*the

The mathematical...

I think you can make this more direct:

"Studies of perioperative analgesia commonly report differences in opioid requirements between groups using the arthimetic mean of summed TOB. In many cases this is the primary outcome measure used to determine the effectiveness of the intervention."

I think you are implying the clinical use case came before the research one - is that right and it's not the other way around?

would maybe change "lack of clear methodological assurance" to "without additional methodological quality assurance"

aiming

Does this need another sentence setting the context for why these are used?

..to produce equi-analgesic doses measured in OME or MME depending on the reference. This is commonly conducted to enable effective comparisons within research studies (as an outcome measure), or clinically, to guide opioid switching in acute or chronic pain settings.

I think this is missing a results punchline - TOB is widely used We can observe a bias because of proportions & conversion values And this is important because it does XYZ

Or,

"Given over 4,000 published papers have used TOB metrics in the last decade, and it remains an important quantitative outcome measure for perioperative pain research, the potential implications of this bias are significant"

should we state what these key implications are?

"or where there is"

"different opioids," better?

Still too complex for a lay summary I think

perioperative

prescribing?

calculated

analgesia

Postoperative

del

del

grid

del

I think you need to spell this out more

and this is just a feature of NSHT?

relative proportion of opioid drugs between groups

impact, and the true treatment effect...

del

three

postop

d

conversion value?

if necessary there are sources to cite for "rapid literature review" methodology

del

will probably need to add some more details about the study design into the main manuscript body here so it can be broadly understood without referring to the supp materials, which should give the detail you don't want to read in the main body

why?

I think you could explain this concept of an external "system perturbation" more here - is it simply an external random factor which induces variation in opioid distribution across both groups - could you cite prescriber preference literature here as an example?

should you state what the reference was here?

d

We should consider asking Tim Morris at MRC trials unit to have a look at this?

I might be wrong but shouldn't you describe the literature to define the scale of the problem before the simulations?

I think this needs explaining (at least to me!)

I think this is where I get stuck - the ground truth at the individual level is not known? Therefore the conversion factor is the best pragmatic value we have and becomes the reference standard?

I think this is an important section, it leads you through the derivation of the problem you're addressing. It might need tailoring depending on what journal we select or reframing as just text with the proofs in appendix?

mean?

dependent

Could cite some examples here?

del

pharmacodynamic? pharmacokinetic? clinical end point?

refers to

equipotency (no hyphen)

describes

? Opioid Equivalence Metrics

different proportions of opioid drug combinations within the overall summary metric

Again, this is tagged on to the end of the paragraph, but could be a separate paragraph in it's own right?

del

researchers

which became the standard for...

to whom?

unified

conducted

sampled/reviewed

del

del

"in the last five years 4,031 papers have used OME or MME"

total opioid use has become a commonly used feature and outcome measure.

[Not sure you need the bit about EHR data here, it's pretty common for trials and non-EPR observational studies to report OME metrics]

The use of equi-analgesic conversion tables has enabled the quantification of total opioid burden for patients on multiple opioid medications.

Do we need something here on why these limitations are important - what clinical or research implications do they have?

albeit

maybe clarify here? small sample sizes (maybe state a range), small geographical area etc?

this feels a bit disjointed, like it's the beginning of it's own paragraph?

Also not just limited to the perioperative context

Do you need to link this concept to the previous sentence on calculating equianalgesic doses?

given

del (superfluous)

did not?

del

during

of which 70% deliver morphine and 30% oxycodone.

if a robot-assisted surgical approach for a given procedure is superior to the standard (open or laparoscopic) approach for an outcome of pain in the immediate postoperative period.

to

del

Good start but probably reads a bit too technical in places. Can always send it through to Jenny and Ollie and ask them to get some public peer review of the language. It probably needs something on why this matters beyond "bias" i.e. does it mean we interpret the findings of pain research wrong etc?

should

del

..proportions, finding that only a...

unequal

types of opioid?

unhyphenated perioperative is the mesh term and default in BJA etc.