Prescription Trends in Complex Regional Pain Syndrome: A Retrospective Case–Control Study

Round 1

Reviewer 1 Report

Comment:

This paper discusses " Prescription Trends in Complex Regional Pain Syndrome: A retrospective case-control study". The main contribution of the paper is " it o evaluate discrepancies in prescription trends for analgesic medications in CRPS patients based on recommendations in the literature, using Retrospective case-control study Subjects. The study provided evidence that  there is a divergence between some published recommendations and actual practice."

This is an interesting study and is generally well written and structured. However, in my opinion the paper has some shortcomings in regards to signaling of GPCRs receptors and mechanism of these receptors with relation to pain, in particular cannabinoid and opioids. Indeed, short paragraph about receptors in general (possibly cannabinoids and adenosine) and its relation to pain or signaling in peripheral tissue is recommended to be added. This is important to highlight the significance of adenosine receptors. Moreover, cite more references are recommended.

In several instances I also suggested to cite more relevant and recent literature.

Important papers

Cannabinoids

Haddad, Mansour^a; Alsalem, Mohammad^b; Saleh, Tareq^c; Jaffal, Sahar M.^d; Barakat, Noor A.^b; El-Salem, Khalid^e. Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model. NeuroReport 34(8):p 441-448, May 17, 2023. | DOI: 10.1097/WNR.0000000000001910

https://pubmed.ncbi.nlm.nih.gov/37096753/

Adenosine

Haddad, M., Alsalem, M., Aldossary, S.A. et al. The role of adenosine receptor ligands on inflammatory pain: possible modulation of TRPV1 receptor function. Inflammopharmacology (2022). https://doi.org/10.1007/s10787-022-01127-3

https://pubmed.ncbi.nlm.nih.gov/36580157/

Minor comments:

·         Well written except in some situations. I advise recheck it again.

·         The introduction should be advised to be re-written to be in more logical flow. And introduce GPCRs and combination with opioids

·         I prefer to divide the results from discussion

·         What about the GPCRs/ligands in this paper? (cannabinoids, adenosine,…)

·         Cite more recent papers in peripheral tissue /inflammation. (above is suggested)

·         What about cannabinoid/adenosine receptors in pain?

·         Please, Suggest future experiments in details

·         Please, try to add general paragraph about GPCRs cannabinids and adenosine receptors and discuss it importance to pain and inflammation. (Above references are suggested)

·         Please, discuss the role of NR4A in pain

·         Please, discuss the role of inflammation and it relation pain. (Short paragraph)

·          There are Too many tables. suggest that you make a summary for them as figures.

·          Table 2 are not obvious to me. It is not understandable.

·         Although it needs to be in more logical flow, the introduction provides a good, generalized background of the topic. However, why not cite more literature papers (above).

·         I think the motivations for this study need to be made clearer. In particular, the connection between pain and inflammation.

·         Regarding the figures: I recommend make figures to be illustrative rather than only table with only numbers.

·         Conclusion is too general/vague. It should be more precise.

none

Author Response

1. Well written except in some situations. I advise recheck it again.
2. I think the motivations for this study need to be made clearer. In particular, the connection between pain and inflammation.
3. The introduction should be advised to be re-written to be in more logical flow. And introduce GPCRs and combination with opioids
4. What about the GPCRs/ligands in this paper? (cannabinoids, adenosine,…)-
5. Cite more recent papers in peripheral tissue /inflammation. (above is suggested)
6. What about cannabinoid/adenosine receptors in pain?
7. Please, try to add general paragraph about GPCRs cannabinids and adenosine receptors and discuss it importance to pain and inflammation. (Above references are suggested)
8. Please, discuss the role of NR4A in pain
9. Please, discuss the role of inflammation and it relation pain. (Short paragraph)
10. Although it needs to be in more logical flow, the introduction provides a good, generalized background of the topic. However, why not cite more literature papers (above).
    1. Response to 2-10: Introduction was edited and made more concise. A paragraph on GPCRs/ligands and their relation to pain/inflammation pathways was added to the introduction. The two suggested references were utilized in the introduction and more references were added in general.
11. Please, Suggest future experiments in details
    1. Response to 11: Suggestions for future experiments were added to the end of the limitations section
12. Regarding the figures: I recommend make figures to be illustrative rather than only table with only numbers.
    1. Response to 12: Two figures created and added to supplemental material at the end of the article. The figures are visual representations of the new tables 2a and 2b.
13. Table 2 are not obvious to me. It is not understandable.
14. There are Too many tables. suggest that you make a summary for them as figures.
    1. Response to 13-14: Addressed by removal of table 2b and 2d – now in “supplemental data” for reference of specific medications if readers are interestedTables 1-5 are now moved to results section and referenced in more chronological order. Figures created as visual representations of tables 2a and 2b, also in supplemental material.
15. I prefer to divide the results from discussion
    1. Response to 15: Results and discussion have been reworded and made more concise so that there is minimal discussion in the results section and minimal results in the discussion section.
16. Conclusion is too general/vague. It should be more precise.
    1. Response to 16: Reworded conclusion

Reviewer 2 Report

: The objective of this study was to evaluate discrepancies in prescription trends  for analgesic medications in CRPS patients based on recommendations in the literature.  The authors findrs  there is a divergence between some published  recommendations and actual practice

The title and the abstract of the article are informative

The introduction too detailed and required to make it concise, the introduction should not be like a review but a brief explanation of this study.

There are several limitations to this study. It was difficult to ensure that CRPS was properly diagnosed with Budapest criteria .

It was also difficult to ascertain the true percentage of each medication that was specifically prescribed for CRPS.

Another limitation is not knowing which specific conditions these medications were prescribed for in both the cases and control

 Methods   PubMed and Google Scholar were used for all literature review pertaining to this  manuscript should be removed

Results  Should indicate statistical significance  p value  ( no p>0.09)

The results are repetitive

the discussion should be shortenedthe tables should appear in the results section, not in methods tables are excessive they should be merged or deleted

Author Response

1. The objective of this study was to evaluate discrepancies in prescription trends  for analgesic medications in CRPS patients based on recommendations in the literature.  The authors findrs  there is a divergence between some published  recommendations and actual practice
2. The title and the abstract of the article are informative
3. The introduction too detailed and required to make it concise, the introduction should not be like a review but a brief explanation of this study.
   1. Response to 3: The introduction was reworded and made more concise. Information regarding pain and inflammatory pathways was added (as requested by reviewer 1.
4. There are several limitations to this study. It was difficult to ensure that CRPS was properly diagnosed with Budapest criteria .
5. It was also difficult to ascertain the true percentage of each medication that was specifically prescribed for CRPS.
6. Another limitation is not knowing which specific conditions these medications were prescribed for in both the cases and control
7. Methods   PubMed and Google Scholar were used for all literature review pertaining to this  manuscript should be removed
   1. Response to 7: Completed
8. Results  Should indicate statistical significance  p value  ( no p>0.09)
   1. Response to 8: P values in the demographic table were removed as they are not applicable in this case (no significant difference since controls were age/gender/and race matched to the cases). Any non-significant results were removed from Results section and not discussed.
9. The results are repetitive
   1. Response to 9: Results section was shortened and made more concise. Any non-significant results were removed from this section and parts of this section were reworded to be less repetitive. Tables 2b and 2d were moved to “supplemental data” at the end of the manuscript and not discussed in the results section.
10. the discussion should be shortened the tables should appear in the results section, not in methods tables are excessive they should be merged or deleted
    1. Response to 10: Tables 2b and 2d were moved to “supplemental data” at the end of the manuscript. All tables were moved from methods section to the results section and are now in chronological order. Discussion was shortened and all repetitive discussion of results was removed from this section.

Round 2

Reviewer 2 Report

The authors have made the following major changes