Antioxidant Treatments for Fibromyalgia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Fibromyalgia is a complex condition characterized by a wide spectrum of symptoms, a large variability in severity combination and underlying contributing factors. This extreme variability requires a multidisciplinary, patient-centered approach and a tailored treatment. Authors should better discuss this point, in particular with the regard to the possible treatment of the disease with antioxidants.

Moreover, a number of experimental and clinical publications reported that there is an interdependence between the antioxidant and anti- inflammatory systems.For example, relationship between activation and/or inhibition of  NFkB and Nrf2  during fibromyalgia  should be added in the paper and extensively explained.

The role of curcumin, crocus sativus natural extract and quercetin as possible antioxidant therapy should be discussed.

Oxidative stress is cause or consequence of the disease ( in fibromyalgia as well as other similar diseases)? Please discuss this important point.

Author Response

Dear Colleague,

Thank you for your feedback. We have made improvements to our manuscript based on your suggestions as outlined below each item. Your original comments are in bold.

Fibromyalgia is a complex condition characterized by a wide spectrum of symptoms, a large variability in severity combination and underlying contributing factors. This extreme variability requires a multidisciplinary, patient-centered approach and a tailored treatment. Authors should better discuss this point, in particular with the regard to the possible treatment of the disease with antioxidants.

We agree that these factors should be emphasized. We modified the first paragraph of the introduction to include your suggestions, which were also supported by Jurado et al. 2024 (citation #1) and Siracusa et al.2021 (citation #3). Some of the changes that we made are as follows: “Fibromyalgia is a complex syndrome that causes chronic musculoskeletal pain and stiffness [1]. It is characterized by a wide spectrum of symptoms that may include fatigue, sleep disorders, headaches, anxiety, and depression. The severity of these symptoms can vary significantly.” …. “The wide range of risk factors or triggers for fibromyalgia may include genetics, illness, repeated injury, traumatic events, or emotional stress.”…. “The extensive variability of causes, symptoms, and severity requires a multidisciplinary, patient-centered approach with a tailored treatment plan that may include a combination of pharmacological agents, non-pharmacological methods, antioxidants, and diet [1,3–5]”. These changes are highlighted in yellow in the updated manuscript.

Moreover, a number of experimental and clinical publications reported that there is an interdependence between the antioxidant and anti- inflammatory systems. For example, relationship between activation and/or inhibition of  NFkB and Nrf2  during fibromyalgia  should be added in the paper and extensively explained.

Thank you for this suggestion. Although we did mention this briefly under the vitamin D section, we added more information to the third paragraph of the introduction based on your suggestion as follows: “The interplay between antioxidants and anti-inflammatory compounds found in plants is important to note. Oxidative stress can trigger inflammation, and vice versa [29]. Thus, incorporating a variety of plants in the diet with both antioxidant and anti-inflammatory properties is a good strategy for improved health. In some animal models, curcumin was found to reduce oxidative stress and suppress cell signaling pathways such as nuclear factor kappa-light chain enhancer of activated B cells (NF-kB) and nuclear factor erythroid 2-related factor 2 (Nrf2) [30]. The activated NF-kB pathway triggers the release of inflammatory mediators, which in turn cause the sensitization to pain signals, promoting the development of fibromyalgia. Polyphenols in plants, herbs, and spices, such as capsaicin, curcumin, and quercetin have a potential role in pain management due to their combined anti-inflammatory and antioxidant properties”. New citations were also added to support these statements (Antonelli et al 2025 and Biswas et al 2016).

The role of curcumin, crocus sativus natural extract and quercetin as possible antioxidant therapy should be discussed.

Thank you for this suggestion. Originally, we had planned to include bioactive compounds in this paper. However, since most of the articles related to phytochemicals were preclinical, we decided not to pursue this category. We also decided that adding this category was too broad and would make this article too long. However, based on your recommendation, we added a statement about bioactive compounds in the introduction and provided citations to three reviews on this topic. “Bioactive compounds with antioxidant capacity, such as curcumin and quercetin, were not included in our review due to limited clinical studies in fibromyalgia patients. However, for readers interested in this topic, recent reviews related to the potential therapeutic effects of bioactive compounds are available [24,32,33].”  We also mention our literature search for bioactive compounds in the methods section and provide our reasoning for not including the topic in this review.

Oxidative stress is cause or consequence of the disease ( in fibromyalgia as well as other similar diseases)? Please discuss this important point.

Thank you for pointing this out. We have included a statement at the end of the second paragraph of the introduction as follows: “Taken together, these studies provide evidence that oxidative stress may be a key contributing factor of fibromyalgia etiology and pathophysiology.” Since we mentioned earlier in the introduction that there is no known cause for this syndrome, we wanted to be careful about not making conclusions about oxidative stress as a definite cause or consequence. We did not address this question beyond fibromyalgia since that would be beyond the scope of this review.

Overall, we hope that these revisions and new citations based on your feedback provide a stronger foundation for our review article.

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

Dear editor, the manuscript is well written and understandable to the reader.

A point for improvement is the methodology; it is very brief. The selection does not detail why they chose these antioxidants and not others or what narrative method they used. This needs to be addressed and improved to enhance the review.

Otherwise, a good piece of work.

Author Response

Dear Colleague,

Thank you for your valuable feedback. We have made changes to our manuscript based on your suggestions below. Your original comments are also below in bold.

A point for improvement is the methodology; it is very brief. The selection does not detail why they chose these antioxidants and not others or what narrative method they used. This needs to be addressed and improved to enhance the review.

Otherwise, a good piece of work.

Regarding why we chose these antioxidants, we have added a statement at the end of the introduction to explain our selection: “These specific antioxidants were selected based on the available clinical data within the review time frame.” Additionally, in the methods we previously stated that “Based on the results of the overall search and the number of articles within each category, we narrowed our focus of antioxidants to the following: vitamins (mainly vitamin B12 and vitamin D), iron, melatonin, coenzyme Q, alpha-lipoic acid, and palmitoylethanolamide”.  In essence, we selected these antioxidants based on available data within the 10-year time frame. We also mention in the methods that only clinical trials were used, which helped narrow our focus. Originally, we had planned to include bioactive compounds in this paper. However, since most of the articles related to phytochemicals were preclinical, we decided not to pursue this category. We also decided that adding that category would make this article too long. We hope that this is enough information to explain our selection of antioxidants, but we are open to further suggestions.

In terms of our narrative method, we first reviewed other narrative reviews within the journal Oxygen, as well as other narrative reviews within MDPI journals. We noticed that some reviews did not include a methods section, however, we included one for our manuscript. To improve the description of our methodology based on your comment, we included this sentence at the beginning of the methods section and modified the second sentence: “The research question for this narrative review was to determine if new antioxidant treatments had been discovered for patients with fibromyalgia over the last decade. For the literature search, peer-reviewed articles were retrieved from PubMed and Proquest Central in January 2025.” The remaining portion of the methods describes the search terms we used, the specific dates we searched, and the inclusion/exclusion terms. At the end of the methods section, we added the following: “Key results were extracted from each article and summarized into antioxidant categories to provide an organized synopsis of the latest antioxidant treatment strategies for fibromyalgia.” We hope that these additional statements help to clarify our narrative method.

Reviewer 3 Report

Comments and Suggestions for Authors

This narrative review adopts an antioxidant framework to assess the therapeutic potential of various micronutrients and supplements in fibromyalgia. It not only offers clinicians a consolidated reference for selecting agents such as vitamin B12/D, iron, melatonin, coenzyme Q, α-lipoic acid, and palmitoylethanolamide, but also provides mechanistic insights into their antioxidant actions. The manuscript is appropriately focused, highly instructive, and at the cutting edge of current research. However, prior to further consideration, please address the following:

• For each of the micronutrients and supplements listed—namely vitamin B12/D, iron, melatonin, coenzyme Q, α-lipoic acid, and palmitoylethanolamide—compile the available clinical data into a a comparative table to enhance readability and facilitate analysis. Where possible, include but not limit to:
  
  1. Number of patients;
  2. Gender distribution;
  3. Dosage and duration of treatment;
  4. Outcome measures (e.g., FIQR scores, FIQ scores, VAS scores, tender point counts);
  5. Proposed antioxidant pathways underpinning their effects.
  
  Thank you.

Author Response

Dear Colleague,

Thank you for taking the time to review our manuscript. We appreciate your feedback and helpful suggestions. As you recommended, we added a table to compile the clinical data into a more organized and readable format (Table 1). The proposed mechanisms for each study (when provided by the authors) add more depth to our paper and may inspire researchers in this field to design their studies in such a way to investigate these mechanisms.

Through the process of creating the table, we realized that more detail could be added to the text as well. Changes made during this round of revisions are noted in blue within the manuscript. Previous changes are noted in yellow.

Again, we thank you for your time and believe that your suggestions for revision provided a substantial improvement to our manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The revised form of the manuscript briefly answers questions posed by reviewer.

The list of antioxidant therapy in fibromyalgia has been reported from other studies and this minireview does not add important contribution to this topic.

The complexity of the disease suggests the need of an integrated therapy ( antioxidant, antinflammatory, neuro-pharmacological etc...) in the treatment of fibromyalgia; papers able to explore the sequential or simultaneous use of  various therapies are welcome.

 

Author Response

Dear Colleague,

Thank you for taking the time to review our manuscript. We believe that the changes we made based on your previous suggestions and the new changes that we have made based on another reviewer’s suggestions have strengthened our manuscript.