Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have focused on an important topic. 

Line 44, please add a sentence on nociplastic pain. Please provide a reference. 

Line 114, Did you obtain medication history? Were patients taking medications like Duloxetine and Gabapentin? If not, please mention in the limitation section.

Line 338, please add a sentence on treatment of central sensitization pain using medications. 

 

 

 

Author Response

Comment 1: Line 44 – Please add a sentence on nociplastic pain and provide a reference.

Response: We agree with the reviewer and have incorporated an explanatory sentence on nociplastic pain, citing the updated IASP definition.

 

 “CSP is reflected in the term  nociplastic pain , recently included by the IASP, which defines it as pain originating from an alteration of nociception with sensitization as the main underlying mechanism [7].”

 

Comment 2:    Line 114 – Did you obtain medication history? Were patients taking medications such as Duloxetine or Gabapentin? If not, please mention in the limitation section.

 

  Response:   Medication history was not systematically collected. We have now acknowledged this limitation in the revised version.

 

“Fifth, data regarding the use of centrally acting pain-modulating medication was not collected. Medication history, including the use of drugs potentially influencing central sensitization (e.g., duloxetine, pregabalin, gabapentin), was not recorded, which may have influenced CSI scores. We recommend that future investigations include assessment of these pharmacotherapies to clarify their influence on central sensitization and patient outcomes.”

 

Comment 3: Line 338 – Please add a sentence on treatment of central sensitization pain using medications.

 

  Response:   A paragraph on pharmacological approaches for central sensitization has been added to the Discussion section.

Added in Discussion (355-359): 

Regarding the pharmacotherapy on CSI, tricyclic antidepressants (TCAs) such as Duloxetine, have been shown to be effective in controlling pain, depression, anxiety and improving sleeping quality of patients [8]. Another group of drugs that have demonstrated efficacy are the serotonin reuptake inhibitors (SSRIs) and the norepinephrine reuptake inhibitors (SNRIs).

Reviewer 2 Report

Comments and Suggestions for Authors

Respected authors 

The scientific hypothesis for your study is very good 

I would recommend you to refine the conclusion section in abstract 

The conclusion section in the main article body is too lengthy, please reduce it and mention the positive outcomes from your study and any recommendations 

The limitation of the study is also too lengthy,  please shorten it and mention it Cleary highlighting important points.

The study can also come out with any recomendations for improving the outcomes in both foot and low back pain 

Thank you

 

Author Response

Comment 1: Refine the conclusion section in the abstract.

Response: The conclusion of the abstract has been rewritten to highlight the main findings and clinical implications.

 

Revised Abstract Conclusion: 

Patients with low back pain exhibited higher CSI scores and a greater prevalence of central sensitization compared with those with foot and ankle disorders. Recognizing these mechanisms may help clinicians tailor more effective, multidisciplinary treatment strategies.

 

Comment 2:    The conclusion in the main article body is too lengthy. Please reduce it and emphasize positive outcomes and recommendations.

  Response:   We have condensed the main conclusion to focus on key findings and added a practical recommendation.

 

Revised Conclusion:

Patients with low back pain exhibited higher CSI scores and a greater prevalence of central sensitization compared with those with foot and ankle disorders. Central sensitization is linked to greater pain, disability, and comorbidity. Early identification of central sensitization through routine screening is recommended, as multidisciplinary management strategies—combining education, rehabilitation, and pharmacotherapy—can optimize recovery and improve quality of life. These positive outcomes underscore the value of proactive screening and tailored interventions for affected patients.

 

  Comment 3:    The limitation section is too lengthy. Please shorten and highlight main points.

  Response:   The Limitations section has been streamlined to emphasize the most relevant issues, including design, heterogeneity, and the new point about medication history.

 

>   Main limitations now highlighted: 

 Despite its strengths, including prospective data collection and the use of validated outcome measures [15-18,29], this study has several limitations that deserve consideration. First, the cross-sectional design limits the ability to establish causality. We cannot determine whether CS precedes symptom chronicity or arises as a consequence of persistent pain [30].

 

Second, the reliance on self-reported questionnaires introduces potential recall and reporting bias. Although the instruments employed have demonstrated reliability and validity [12, 15-18, 29], subjective measures inevitably involve variability.

 

Third, generalizability is limited by the single-center setting. The sample was drawn from patients consulting at the University of Navarra Clinic, which may not reflect the demographic or clinical characteristics of patients in other institutions or health systems.  Moreover, detailed information regarding the referral source and the pathway by which patients were included was not collected, limiting our ability to analyze clinical pathways and referral patterns.

 

Fourth, due to the lack of specific diagnostic data, we were unable to classify patients according to pain phenotypes, which restricts phenotype-based subgroup analyses. The choice of CSI cut-off remains a source of uncertainty. While we adhered to the widely used threshold of 40 points [13], our exploratory analyses suggest that alternative thresholds may yield different conclusions.

 

Fifth, data regarding the use of centrally acting pain-modulating medication was not collected. Medication history, including the use of drugs potentially influencing central sensitization (e.g., duloxetine, pregabalin, gabapentin), was not recorded, which may have influenced CSI scores. We recommend that future investigations include assessment of these pharmacotherapies to clarify their influence on central sensitization and patient outcomes.

 

Finally, objective physiological or neuroimaging markers of CS, such as quantitative sensory testing or functional imaging were not assessed. Including these could provide complementary evidence of central alterations [4,6,7].

 

 

  Comment 4:    Provide recommendations for improving outcomes in both foot and low back pain.

 

Response: We have added a sentence with clinical recommendations to the end of the Conclusions.

 

Added: 

Early identification of central sensitization through routine screening is recommended, as multidisciplinary management strategies—combining education, rehabilitation, and pharmacotherapy—can optimize recovery and improve quality of life.

 

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors, 

Thank you for submitting the manuscript which is well-written and address an interesting topic about central sensitisation in two different pain conditions - low back pain and limb pain. 

I have some comments on the methodological and result parts.

1. in methodological part you need provide when study started and finished.
2. Did patients come with referrals? Who was the major part referring the patients? For ex primary health care, specialised units, etc. Was the question in the referrals the operative intervention? Were (alla) patients operated after the first visit or recommended some kind conservative treatment /rehabilitation?
3. Could you specify the phenotype of pain types? For ex. how many participants had neuroplastic, neuropathic, nociceptive and mixed pains, both for low back and limb pain. 
4. The questionnaires. What is the reason behind the fact that different questionnaires were used for the entire population? This makes difficult to compare the subgroups or maybe I misunderstood. 
5. Pain intensity is presented in VAS. Was it applied for low back pain or just for the overall pain scoring? This information addresses even Table 1 where you present VAS and then VAS limb. You should indicate the number for each characteristics since VAS Limb seems to be relevant only for low back pain. You should spell abbreviations under the Table 1. 
6. Since Table 1 is unclear, I suggest to present only demographic data for the entire population and for every subgroup, to present the comparisons between the subgroups in the table, indicating N for every parameter. Diagnoses should be omitted from Table 1 since you present them in Figure 1 A and B. Information from Table 2 could be included here.
7. The questionnaires should be presented in a separate table. Table 1 carries too much information and is difficult to read. Indicate N for every parameter for entire population and for subgroups, as well as presenting the differences between the subgroups. In that case the information from Tables 3-4 will be put in this table and will give a better overview of the study results.

Author Response

Comment 1: Specify when the study started and finished.

  Response:   The study period (September–December 2023) is clearly indicated in the Materials and Methods section.

 

Comment 2: Describe patient referral sources (primary care, specialized units, etc.). Were patients operated after the first visit or treated conservatively?

 

Response: Patients attended our center on their own initiative, directly requesting a consultation, as our facility operates as a private center. They were not referred by other physicians, specialized units, or primary care providers.

Data on whether patients received conservative or surgical treatment was not collected, as this was beyond the scope of our study. The primary aim was to assess the prevalence of central sensitization among patients presenting to our clinic. Our approach focuses on identifying potential psychosocial factors that may influence treatment outcomes—whether conservative or surgical. We appreciate the comment, as it highlights an important area for ongoing research and opens a new line of inquiry for future studies.

 

Comment 3:    Specify the phenotype of pain types (nociplastic, neuropathic, nociceptive, mixed).

 

Response:   This has been added as a limitation: Fourth, due to the lack of specific diagnostic data, we were unable to classify patients according to pain phenotypes, which restricts phenotype-based subgroup analyses. The choice of CSI cut-off remains a source of uncertainty. While we adhered to the widely used threshold of 40 points [13], our exploratory analyses suggest that alternative thresholds may yield different conclusions.

 

  Comment 5:    Explain the use of different questionnaires (ODI, FAAM) and the difficulty in comparing groups.

 

  Response:  Different validated questionnaires were used because each is specific to the anatomical region studied, enhancing construct validity, although limiting direct numerical comparison between groups.

 

Comment 6:    Clarify VAS for low back vs. overall pain, define abbreviations under Table 1 and 2.

  Response:   . Abbreviations and distinctions are defined below Table 1 and 2 .

 

 

  Comment 7:    Simplify and reorganize Tables 1–4, avoid duplication of diagnoses.

  Response:   Tables have been reorganized to improve readability and remove redundant information. A separate table now summarizes questionnaire results.

 

 

  Comment 8:    Figures and tables can be improved.

  Response:   Figures were revised for improved clarity and uniform formatting, with consistent color schemes and enhanced label readability.

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors, 

 

Thank you for submitting the article which now is improved. You still have small mistakes left, such as Figure 2b (title given in Spanish), in Table 2 not able to find explanation for "NS/NC". Please, correct when editing. 

Author Response

Comment: Thank you for submitting the article which now is improved. You still have small mistakes left, such as Figure 2b (title given in Spanish), in Table 2 not able to find explanation for "NS/NC". Please, correct when editing.  

Answer: Thank you for your careful review and helpful comments. We have corrected the issues indicated: the title of Figure 2b has been translated into English, and the explanation for the term “NS/NC” has been added in Table 2. These modifications have been incorporated into the revised manuscript.