Advances in the Pathophysiology and Management of Cancer Pain: A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In abstract objective is not clear, add a graphical abstract.

Introduction can be little descriptive , divide in sub sections by adding available option with advantages, disadvantages mechanism.

Figure 1. PRISMA flowchart, should be part of method.

Redraw fig 2 as it is not clear.

Include a table/fig with various type of cancer and treatment.

In discussion authorshould able to point out major resons for cancer pain and why its difficult to treat with comaparison to other pain. 

 

Author Response

Reviewer 1

In abstract objective is not clear, add a graphical abstract.

We thank the reviewer for this valuable comment. We have revised and clarified the Objective section of the abstract to explicitly state the aims of the scoping review, including the focus on cancer pain pathophysiology, emerging therapeutic approaches, and identification of knowledge gaps to inform precision-based pain management strategies. In addition, we have added a graphical abstract to visually summarize the scope, methodology, and key conceptual domains of the review, thereby improving clarity and accessibility for readers.

Introduction can be little descriptive , divide in sub sections by adding available option with advantages, disadvantages mechanism.

To improve clarity, readability, and logical flow, we have restructured the Introduction into dedicated subsections.

Figure 1. PRISMA flowchart, should be part of method.

The PRISMA flowchart has been moved into the method 

Redraw fig 2 as it is not clear.

Figure 2 has been redrawn to improve clarity and readability. Specifically, we added short, descriptive titles within each panel and directional arrows to enhance visual flow and guide the reader through the figure. 

Include a table/fig with various type of cancer and treatment.

As requested also by reviewer 3, a dedicated table was added into the manuscript. 

In discussion author should able to point out major reasons for cancer pain and why its difficult to treat with comparison to other pain. 

We thank the reviewer for this important comment. In response, we have added a dedicated paragraph in the Discussion explicitly outlining the major biological and clinical determinants of cancer pain and explaining why it is particularly challenging to manage compared with other pain conditions.

Reviewer 2 Report

Comments and Suggestions for Authors

This is a nice overview of the mechanisms underlying cancer pain and current and ongoing developing approaches for treatment. The manuscripit is well organized with  sections devoted to biological mechanisms, pharmacological management, neuromodulation, radiotherapy and digital health, remote monitoring, and AI-enabled tools. This last section is important as it gets to the future use of AI and underscores the need for personalized and mechanism-based treatments. The section of biological mechanisms points appropriately to the tumor environment and neural-immune interactions leading to sensitization of nociceptors and central neurons.There are only a couple of suggstions for improvement.

1.  In discussing the tumor microenvironment and tumor cell - neuron interactions, there is no mention of the possible role of small extracellular vesicles, or exosomes, released from the cancer cells that may excite nociceptors and contribute to cancer pain. The authors are referred to preclinical studies by Brian Schmidt for oral cancer and Iryna Khasabova for bone cancer pain.

2.  The pharmacology section should include information on the potential of cannabinoids to treat cancer pain.

Author Response

This is a nice overview of the mechanisms underlying cancer pain and current and ongoing developing approaches for treatment. The manuscripit is well organized with  sections devoted to biological mechanisms, pharmacological management, neuromodulation, radiotherapy and digital health, remote monitoring, and AI-enabled tools. This last section is important as it gets to the future use of AI and underscores the need for personalized and mechanism-based treatments. The section of biological mechanisms points appropriately to the tumor environment and neural-immune interactions leading to sensitization of nociceptors and central neurons.There are only a couple of suggstions for improvement.

1. In discussing the tumor microenvironment and tumor cell - neuron interactions, there is no mention of the possible role of small extracellular vesicles, or exosomes, released from the cancer cells that may excite nociceptors and contribute to cancer pain. The authors are referred to preclinical studies by Brian Schmidt for oral cancer and Iryna Khasabova for bone cancer pain.

We thank the reviewer for this insightful and important suggestion. In response, we have added a dedicated paragraph in the revised manuscript explicitly addressing the role of small extracellular vesicles (sEVs/exosomes) in tumor cell–neuron communication and cancer pain.

2. The pharmacology section should include information on the potential of cannabinoids to treat cancer pain. 

We thank the reviewer for this valuable suggestion. In response, we have expanded the pharmacology section by adding a dedicated paragraph addressing the potential role of cannabinoids in cancer pain management.

Reviewer 3 Report

Comments and Suggestions for Authors

Abstract: no issue

Introduction: no issue

Materials and methods: no issue

Results:

• Figure 1 is missing the number of studies included. Authors need to create the last box in the PRSIMA flowchart.
• Missing is the tables of Findings/Outcomes to summarize the results of the included studies.
• Section 3.1 A
• Authors made general assertions without supporting evidence. For example, “Hypermethylation of genes regulating endogenous opioid production or inhibitory neuro- 230 transmission may diminish descending pain modulation, while histone deacetylase activity influences transcription of pro-nociceptive mediators [28]”. Authors need to highlight which genes are hypermethylated. Same goes for changes in micro-RNA and DNA methylation. Need specific examples.
• Authors mentioned transition from acute to chronic pain. They need to make it clear that inflammation is the driving force behind this transition. What is written is very vague and does not add much value to the current understanding. Since this is a review, the authors have to support their general statements with specific evidence.
• Section 3.2. What did the authors learn from the included studies? This section is frustrating to read because it adds no value to the already existing WHO analgesic ladder. Again, general statements without specific evidence.
• Section 3.3.
• “For example, recent work indicates meaningful pain relief and improved functional outcomes in cancer-pain cohorts treated with SCS/DRGS”
• What types of cancer were beneficial with SCS/DRGS therapy? What is “meaningful pain relief and improved functional outcomes”?
• “In contrast, neuroablative neurosurgery remains a niche yet important component when pain is overwhelmingly refractory and life expectancy limited. In this regard, interventions such as cordotomy, cingulotomy, and DREZ lesioning have demonstrated analgesic benefit in case series of end-stage malignancy pain [46].”
• Only one study is cited. Authors need to include all the studies for each intervention. This is repeated mistake throughout the manuscript.
• Section 3.4. This is by far the best section in this review. This is the level of details that are needed throughout this review article.
• Section 3.5. is another good section.

Discussion:

• Cancer-related pain is due to the cancer itself and treatment of the cancer. The authors failed to address the latter. The Discussion section is an opportunity to address this, which the authors did not.
• Line 447 to 450. “Cancer pain management is progressively evolving toward a multi-specialty precision-medicine model”- Disagree with the authors. The treatment of cancer pain is already a multi-specialty precision medicine approach. This has been ongoing for decades. AI-based technology has enhanced this collaborative approach.

Author Response

Abstract: no issue

Introduction: no issue

Materials and methods: no issue

Results:

Figure 1 is missing the number of studies included. Authors need to create the last box in the PRSIMA flowchart.

We thank the reviewer for highlighting this issue. The omission of the final box indicating the number of included studies in Figure 1 was due to an error during the transfer of the figure from the original file to the formatted manuscript. This has now been corrected, and the complete PRISMA flowchart, including the final box reporting the number of studies included, has been uploaded in the revised version of the manuscript.

Missing is the tables of Findings/Outcomes to summarize the results of the included studies.

We have added a table to the manuscript summarizing the main findings and outcomes of the included studies, organized by key thematic areas. Given the breadth of the literature and the resulting length of the table, we also created an additional Supplementary Table, which provides a more detailed overview of the included articles and has been submitted as supplementary material.

Section 3.1 A

Authors made general assertions without supporting evidence. For example, “Hypermethylation of genes regulating endogenous opioid production or inhibitory neuro- 230 transmission may diminish descending pain modulation, while histone deacetylase activity influences transcription of pro-nociceptive mediators [28]”. Authors need to highlight which genes are hypermethylated. Same goes for changes in micro-RNA and DNA methylation. Need specific examples.

We thank the reviewer for this important observation. We have revised these sections to provide specific molecular examples supporting these statements. In particular, we now explicitly cite hypermethylation of genes involved in endogenous opioid signaling and inhibitory neurotransmission (e.g., OPRM1, GAD1/GAD2), as well as histone deacetylase–mediated regulation of pro-nociceptive mediators (e.g., BDNF, NGF, TRPV1). In addition, we have expanded the discussion of epigenetic regulation via microRNAs and DNA methylation, including concrete examples of pain-relevant microRNAs (e.g., miR-21, miR-155, miR-124) and methylation changes affecting neuroinflammatory and nociceptive pathways.

Authors mentioned transition from acute to chronic pain. They need to make it clear that inflammation is the driving force behind this transition. What is written is very vague and does not add much value to the current understanding. Since this is a review, the authors have to support their general statements with specific evidence.

We thank the reviewer for this insightful comment. To address this concern, we have substantially expanded Section 3.1. In the revised section, we provide a detailed, evidence-based discussion of the central role of inflammation as the key driver of pain chronification, integrating peripheral and central mechanisms. In particular, we now describe how persistent inflammatory signaling induces peripheral sensitization, central sensitization, and long-term neuroplastic changes that sustain chronic pain states. 

Section 3.2. What did the authors learn from the included studies? This section is frustrating to read because it adds no value to the already existing WHO analgesic ladder. Again, general statements without specific evidence.

We thank the reviewer for this important and constructive comment. In response, Section 3.2 has been completely rewritten to move beyond a descriptive reiteration of the WHO analgesic ladder and to explicitly articulate the key messages emerging from the included studies. The revised section now synthesizes specific evidence on mechanisms, treatment optimization strategies, and emerging approaches that extend or challenge traditional stepwise analgesic paradigms. In addition, we have incorporated dedicated elements to discussion the critical evidence gaps and unresolved issues. 

Section 3.3.

“For example, recent work indicates meaningful pain relief and improved functional outcomes in cancer-pain cohorts treated with SCS/DRGS”

What types of cancer were beneficial with SCS/DRGS therapy? What is “meaningful pain relief and improved functional outcomes”?

“In contrast, neuroablative neurosurgery remains a niche yet important component when pain is overwhelmingly refractory and life expectancy limited. In this regard, interventions such as cordotomy, cingulotomy, and DREZ lesioning have demonstrated analgesic benefit in case series of end-stage malignancy pain [46].”

Only one study is cited. Authors need to include all the studies for each intervention. This is repeated mistake throughout the manuscript.

We thank the reviewer for this important and constructive comment. In response, Section 3.3 has been completely restructured. The revised section now explicitly reports the types of cancer pain syndromes in which spinal cord stimulation and dorsal root ganglion stimulation have been investigated, including the underlying oncological conditions and pain mechanisms addressed. In addition, we have clarified what is meant by “meaningful pain relief” and “improved functional outcomes” by reporting quantitative outcomes (e.g., reductions in pain intensity scales, improvements in functional or quality-of-life measures) as described in the included studies. Furthermore, we have addressed the reviewer’s concern regarding incomplete citation by systematically incorporating all relevant studies for each neuromodulative and neurolesioning intervention, including spinal cord stimulation, dorsal root ganglion stimulation, cordotomy, cingulotomy, and DREZ lesioning. For each technique, the revised text now summarizes the main findings, clinical indications, and key limitations. We hope that these substantial revisions address the reviewer’s concern and enhance the clarity of the manuscript. 

Section 3.4. This is by far the best section in this review. This is the level of details that are needed throughout this review article.

Section 3.5. is another good section.

We sincerely thank the reviewer for this positive and encouraging feedback.

Discussion:

Cancer-related pain is due to the cancer itself and treatment of the cancer. The authors failed to address the latter. The Discussion section is an opportunity to address this, which the authors did not.

We thank the reviewer for highlighting this important point. In response, we have revised the "Discussion" section to explicitly address treatment-related cancer pain, acknowledging that cancer pain arises not only from tumor burden but also from anticancer therapies, including chemotherapy, radiotherapy, and surgery. 

Line 447 to 450. “Cancer pain management is progressively evolving toward a multi-specialty precision-medicine model”- Disagree with the authors. The treatment of cancer pain is already a multi-specialty precision medicine approach. This has been ongoing for decades. AI-based technology has enhanced this collaborative approach.

We thank the reviewer for this important clarification and fully agree that cancer pain management is fundamentally a multidisciplinary, precision-medicine approach that has been established at specialized centers for decades. Our intention was not to suggest this model is newly emerging, but rather to emphasize that universal implementation of this collaborative paradigm remains incomplete, particularly in resource-limited settings, community hospitals, and healthcare systems with fragmented infrastructure. We have revised the manuscript to acknowledge that this is an established multidisciplinary model while emphasizing the critical challenge of ensuring its implementation across all healthcare settings where barriers persist. We have also clarified that AI-enabled technologies enhance this well-established collaborative approach rather than creating a new paradigm. We believe this revision better reflects the reviewer's accurate assessment while maintaining our emphasis on implementation equity.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

I would like to applaud the authors for their hard work to improve the manuscript. The followings need to be addressed.

• Figure 1. Include the total number for the records identified from the databases prior to the screening. Please add an arrow from the "records screened (n=2398)" box to the next box in the screening. Please add an arrow from the last screening box to the "studies included" box.
• 3.2.5. Opioid optimization strategies. Please include two sentences about the possibility/potential use of Suzetrigine to treat acute cancer pain, especially in patients that require surgery.
• 3.3. Interventional and neuromodulatory approaches. Intrathecal drug delivery systems is one of the mainstays of cancer pain treatment, especially in patients requiring high doses of opioids or refractory to conventional pain therapy. The authors need to have a section covering this treatment in detail.
• In the discussion section, the authors mentioned CIPN. They need to add that the global prevalence of chronic painful neuropathy and moderate-to-severe neuropathy in patients diagnosed with CIPN was estimated at 47.76% (cite this reference PMID: 39880412).

Author Response

I would like to applaud the authors for their hard work to improve the manuscript. The followings need to be addressed.

• Figure 1. Include the total number for the records identified from the databases prior to the screening. Please add an arrow from the "records screened (n=2398)" box to the next box in the screening. Please add an arrow from the last screening box to the "studies included" box.

We sincerely apologize for this oversight, which resulted from the copy-and-paste process of the original PRISMA flow diagram that inadvertently disrupted the continuity of the arrows in the formatted version of the manuscript. The PRISMA flowchart has now been fully revised, including the addition of the total number of records identified prior to screening and the correct directional arrows linking all screening stages through to the final “studies included” box. The figure has been re-exported as a single, complete image. 

• 3.2.5. Opioid optimization strategies. Please include two sentences about the possibility/potential use of Suzetrigine to treat acute cancer pain, especially in patients that require surgery.

We thank the Reviewer for this valuable suggestion. In response, we have expanded Section 3.2.5 (Opioid optimization strategies) by adding a brief paragraph describing suzetrigine. We believe this addition improves the completeness and clinical relevance of the section, and thank the reviewer for the wise suggestion.

• 3.3. Interventional and neuromodulatory approaches. Intrathecal drug delivery systems is one of the mainstays of cancer pain treatment, especially in patients requiring high doses of opioids or refractory to conventional pain therapy. The authors need to have a section covering this treatment in detail.

We thank the Reviewer for this important and constructive comment. In response, we have substantially expanded Section 3.3 by adding a dedicated subsection on intrathecal drug delivery systems (IDDS). This new section provides a detailed overview of the mechanistic rationale, patient selection criteria, FDA-approved and off-label intrathecal agents, clinical efficacy, safety profile and current guideline recommendations, with specific reference to the most recent Polyanalgesic Consensus Conference (PACC) guidelines.

• In the discussion section, the authors mentioned CIPN. They need to add that the global prevalence of chronic painful neuropathy and moderate-to-severe neuropathy in patients diagnosed with CIPN was estimated at 47.76% (cite this reference PMID: 39880412

We sincerely thank the Reviewer for highlighting this recently published and highly relevant study. We have now incorporated the reported global prevalence of chronic painful neuropathy and moderate-to-severe neuropathy in patients with CIPN into the Discussion section and cited the suggested reference (PMID: 39880412).

All changes made during this second round of revision are highlighted in green in the manuscript.

Round 3

Reviewer 3 Report

Comments and Suggestions for Authors

1. Lines 439, 444, and 449 look weird with the numbering and indentation. Consider removing the numbering.
2. Line 633. Please double check to make sure that it is 6 months and not 3 months.
3. Consider adding indentation to the new paragraphs to be consistent.
4. Table 1. Please add the new studies that are cited in the manuscript to the table.

Author Response

1. Lines 439, 444, and 449 look weird with the numbering and indentation. Consider removing the numbering.

We thank the Reviewer for this observation. The numbering and indentation have been removed to improve readability and formatting consistency.

2. Line 633. Please double check to make sure that it is 6 months and not 3 months.

We thank the Reviewer for this important consideration. Indeed, the cited guidelines do not specify an explicit time-based cut-off for intrathecal drug delivery system implantation, but rather emphasize an evolution toward patient-specific selection factors, including overall prognosis. From a clinical perspective, anticipated survival of approximately three months or, in some centers, six months, is often considered a practical threshold for implantation. However, to remain strictly adherent to the cited guidelines, we have revised the manuscript to state that candidates should have an anticipated prognosis sufficient to derive meaningful benefit from an invasive implant, appropriately balancing expected benefit against procedural risks.

3. Consider adding indentation to the new paragraphs to be consistent.

An indentation was added to separate the new paragraph.

4. Table 1. Please add the new studies that are cited in the manuscript to the table.

The new cited studies were added to the table, as appropriately and kindly suggested by the reviewer.

All changes made during this round of revision are highlighted in orange in the manuscript.