Dear Editor,
thank you for your request to review the manuscript “WWOM VII : Effectiveness of Systemic Pharmacotherapeutic Interventions in the Management of BMS: a systematic review and meta- analysis
The conceptualization of the paper is good, in addition the paper is well-written and the authors have completely evaluated the pharmacological treatment of BMS in the last 25 years. Unfortunately the topic is not new because this is the third systematic review about the treatment of BMS (in 2020).
Despite this consideration , the paper should be accepted after making some changes.
I have several comments:
- in the second part of the introduction section (page 6) the Authors should better specify the definition of BMS according with the ICOP 2020, highlighting the differences with the previous definition
- in page 7, line 15-16, the Authors should modify the sentence “relieving symptom and changing quality” because they have written about oral symptoms, quality of life and after about oral symptoms again. In addition, during the time, BMS symptoms have became more complex so, in my opinion, in this part of the manuscript the Authors should specify additional oral symptoms and the effectiveness of the treatment on them.
- In the inclusion and exclusion criteria (page 9) the Authors included all the studies on patients reporting symptoms regarding BMS for a minimum of 1 month (not in line with ICOP 2020). Therefore they better specified this as a bias in the discussion section.
- in the page 10 (line 20/ 25) the Authors have considered only the first period of intervention in cross over RCT; in my opinion this is a great bias in the evaluation of the treatment in chronic diseases because the majority of pharmacological treatment begin to work at least after six weeks. Therefore the Authors should clarify this point and better specify the possible carry-over effects that may skew the outcomes.
- In many sections the Authors should better specify in detail “ the long term effect” (not only 10+ weeks) of the treatment for every intervention considering that only 14 RCTS were included
- In the section “changes in pain intensity” the Authors should better specify which articles they have used as validated test (such as VAS scale) and which used as not validated test.
- The Authors should better explain the lack of validated test such as Mc Gill pain questionnaire in the RCT studies not only in 3.4.2.1 section but also in the discussion section
- in the section 3.4.2.2 line 46 the Authors should modify the sentence because VAS scale can not evaluate the quality of sleep.
- In addition the Authors regarding “Change in Physical functioning” should include the importance of validated test in this field, because they couldn’t use simply questions in order to evaluate this aspect
- In the section 3.4.2.3 The Authors should explain the lack of evaluation of patients’ psychological profile with BMS because in the majority of studies the Authors evaluated or anxiety or depression but not together and specifically in this field it is not possible to consider studies that not used validated psychometric tests.
- Regarding 3.4.2.4 The authors should better specify the concept of patients’ global improvement (only subjective improvement or objective improvement using validated test) and to explain this concept in the discussion section
- in the section of 3.4.2.5 The Authors should explicate that there were not studies which included tests that evaluated side effects of the therapy (they are commonly used in studies that include pharmacological treatment in many fields).
- The Authors should improve the discussion considering previous comments and possibly divide in sections
- in the page 33 The Authors should give an opinion about the longer intervention periods for BMS and on the lack of side effects using clonazepam and gapabentin
- in the page 34 (line 52-53) the authors should probably modify the sentence considering more recent papers in which the pharmacological treatment of BMS continue for at least 6-12 months in line with psychological comorbidity and the clinical response or remission of the disease
- in conclusion, in my opinion it is important to highlight the lack of original research articles in the treatment of BMS and the necessity to perform this type of studies in the future.

the Authors correctly addressed all my suggestion.
Congratulation to the Authors for this excellent contribution