Does the Use of Two Major Opioids Have an Impact on Improving Pain Treatment and Quality of Life in Cancer Patients?—A Literature Review
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors present a narrative review that aims to evaluate if combining two major opioids can improve pain management and quality of life in cancer patients, while considering their pharmacodynamic and pharmacokinetic properties and the impact on side effects. The article is well-structured, with clear objectives and methods. However, there is only minor concern.
Although the article explains that cancer pain can result from various causes, a more thorough discussion of why opioids are necessary. For instance, it would be interesting to specify why alternative treatments are insufficient for cancer pain, the role of opioid receptors, and which are the mail limitations of non-opioid analgesics. This would also help readers unfamiliar with the topic understand why cancer pain management is so complex.
Author Response
Thanks for your comment. We added 3 paragraphs (lines 102-115) in the introduction section to explore all these issues. We explained why opioids are so important to treat cancer pain, why they are so effective, and we address other therapies that have proven synergistic effects with opioids, reinforcing the need for multimodal therapy.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsThe review manuscript titled "Does the use of two major opioids have an impact on improving pain treatment and quality of life in cancer patients?—a literature review" contains some basic information that could be considered for publication after addressing some major revisions.
1. Based on the methodology of selecting articles for this review, the authors are using the approach of a systematic review, but the writing style of the current is more like a narrative review. Please choose one style and adopt it for your review.
2. In Table 1, what is the meaning of "level of evidence" and how is it obtained? Additionally, this table should be revised to include parameters such as mode of administrations, dosages, exposure time, mode of action and key findings.
3. The mechanism of action of combined opioids should be represented with figures that summarize what is described in the text.
4. The doses of opioids used in combination are sometimes not mentioned by the authors, and this is a serious issue that can make the study not scientifically valid. In addition, I think there is not enough evidence in some cases to support the benefit of combination therapy between major opioids.
Author Response
- Based on the methodology of selecting articles for this review, the authors are using the approach of a systematic review, but the writing style of the current is more like a narrative review. Please choose one style and adopt it for your review.
Answer: Thanks for your comment. This is a narrative review of literature as we did not follow the guidelines and steps necessary to be considered a systematic review. However, we believe that the inclusion of a flowchart explaining article selection reinforces the scientific evidence found to answer the main research question: the use of two opioids can add value in treating pain and mitigating possible adverse effects in patients with cancer pain?
- In Table 1, what is the meaning of "level of evidence" and how is it obtained? Additionally, this table should be revised to include parameters such as mode of administrations, dosages, exposure time, mode of action and key findings.
Answer: Thank you for your question and suggestions. We considered SORT to recognize levels of evidence, and we add this information in lines 181-182. In the table caption we also add the information that we are considering the levels of evidence according to SORT. We also had this information in line 215. This table has already the key findings. As we were unable to include all the remaining information that you advised, we chose to include in the table the names of the opioids combined and mode of administration, because dosages and exposure time were explored in the text below.
- The mechanism of action of combined opioids should be represented with figures that summarize what is described in the text.
Answer: Thank you for you suggestion. We add figure 2 (lines 211-227) to reinforce the premise that different opioids will have different binding strengths on opioid receptors on the nerve cell.
- The doses of opioids used in combination are sometimes not mentioned by the authors, and this is a serious issue that can make the study not scientifically valid. In addition, I think there is not enough evidence in some cases to support the benefit of combination therapy between major opioids.
Answer: Thank you for your attention to this issue. In fact, we have inconsistency in data regarding dosages used, and we clearly introduce this limitation in the article. However, we believe that this article highlights the need to carry out studies with consistent methodologies, and following the same line of reasoning regarding the dosages used among opioids, including calculations for equivalent dosages of morphine.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsDear Editor,
The manuscript “Does the use of two major opioids have an impact on improving pain treatment and quality of life in cancer patients? – a literature review” by Shirley Duarte et al., represents an interesting review on synergistic effects of combination of two major opioids in pain relief in cancer patients. The topic is very valuable and the study design and the papers reviewed look fine, however the manuscript need to get a deeper focus on the opioid functions and their interactions. The introduction can be improved by inclusion of a very brief overview on opioid receptors and their priorities, mechanisms and importance maybe using some diagram(s) of figure(s) in pains in cancer patients. The results section should be carefully rewritten to classify the different combinations of the two major opioids. Lines 260-267 can be moved to immediately after line 243, and the rest of the results section may get a separate title for combination of fentanyl and oxycodone. Lines 264-267 are not clear enough. The important findings of the study are not well discussed.
Best regards,
Comments on the Quality of English LanguageThe manuscript needs a brief language check for several typos and spelling errors.
Author Response
- The manuscript need to get a deeper focus on the opioid functions and their interactions. The introduction can be improved by inclusion of a very brief overview on opioid receptors and their priorities, mechanisms and importance maybe using some diagram(s) of figure(s) in pains in cancer patients.
Answer: Thank you for your comment and suggestion. We wanted to respond to your suggestion but not move away from the topic of pain and the function that we are primarily evaluating, which is the ability of opioids to interact with pain pathways and pain inhibitory pathways. We explored this information and the potential of other therapies in cancer pain in lines 102-115. In line 98 to 101 we already explored which receptors are stimulated by opioids and which opioids are nonspecific. We also added figure 2 (lines 211-226), which represents the ability of different opioids to have more affinity with different receptors on the nerve cell.
- The results section should be carefully rewritten to classify the different combinations of the two major opioids. Lines 260-267 can be moved to immediately after line 243, and the rest of the results section may get a separate title for combination of fentanyl and oxycodone. Lines 264-267 are not clear enough.
Answer: Thank you for your comments and suggestions. We rearrange the results so that they would be more in line with what you suggested.
- The important findings of the study are not well discussed.
Answer: Thank you for your comments and suggestions. We reflected on this section and rewrote a part to make it clearer.
Author Response File: Author Response.docx
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsDear Editor,
The manuscript "Does the use of two major opioids have an impact on improving pain treatment and quality of life in cancer patients? – a literature review" by Shirely Duarte et al. has been properly revised and can now be considered for publication.
Best regards,
