Title: Loneliness and analgesic overuse among low-dose estrogen-progestin users in Japan
Version: 4 Date: 01 Jul 2025
Reviewer:  Elena Toffol
Reviewer's report:
I thank the authors for revising the article and addressing my comments and questions. The
manuscript has improved in its readability; however, I would still suggest some possible
changes:
1. The Introduction sections appears now more logically built. However, there are still some
points that could be amended: in the first paragraph, lines 55-57, the authors state that “A recent
network analysis among Chinese university students further clarified the complex interrelations
between loneliness, anxiety, and depression [8].” I think more details about these findings have
to be provided; as such, this sentence is not informative, as it does not offer any insight on what
the cited study actually clarified.
2. Introduction, lines 60-61, “The current results reinforce the strong link between social
support and loneliness, highlighting the critical role of social support in alleviating loneliness
[11].”. Because the study focus is not on social support, I think this sentence overcomplicates
the reading flow, and could be removed. Similarly, in my opinion the final sentence of the
first paragraph (lines 63-64, “However, evidence on the association between loneliness and
medication use remains limited.”) could be removed, as this is stated again in the final sections
of the introduction.
3. Introduction, lines 61-63, “Furthermore, a longitudinal study using a nationally representative
sample of older adults in the United States found that prior loneliness predicted regular,
contemporaneous use of prescription medications for depression and anxiety [12].” To improve
logical flow, I suggest moving this sentence a few lines above (line 57, “after A recent network
analysis among Chinese university students further clarified the complex interrelations between
loneliness, anxiety, and depression [8]. “).
4. Introduction, paragraph at lines 96-102: While this paragraph is important to introduce the
study of sleep quality in relation to loneliness/analgesic use, it is not well connected to the rest
of the text, and it is too long and detailed. I suggest shortening it and better logically connecting
it to the rest of the Introduction.
5. Methods, lines 131-132. “It is difficult to obtain a sample size to analyze such an influence
of healthcare professionals.” In my opinion this sentence could be removed.
6. Methods, lines 162-165, “The TIL score ranges from 3 to 9, with a higher score indicating
greater loneliness [9, 10]. The TIL cut-off value is 6 [39]. The HLS-14 ranges from 14 to 70,
with a higher score indicating better health literacy [40]. The PSQL score ranges from 0 to 21,
with a higher score indicating worse sleep quality [42]. The PSQL cut-off value is 6 [42].” I
somehow feel that this part belongs more properly to the previous chapter, where the utilized
tools are listed, than to the statistical analysis section.
7. Methods, line 181, “sleep quality of life”. I am wondering if there is a typo here: do the authors
mean “sleep quality”, or “sleep, quality of life,….”?
8. Results, lines 212-216, “The median score was 52 for HLS-14 and 5 for TIL. The
percentage with PSQI#6, which indicates low quality of sleep disorder [42], was 56.6% (N=292).
Concomitant analgesic use (#1 day per month) was reported by 64.1% (N=331) of LEP users
(N=516). Of the LEP users, 20.0% (N = 103) reported concomitant use for contraceptive
purposes.”. I suggest moving this part, describing the entire sample, at the beginning of the
paragraph, and thereafter describing differences by age group.
9. Results, lines 228-229, “Loneliness was associated with concomitant analgesic use (#1 day
per month), low health literacy and poor sleep quality.”, and lines 236-237, “Higher use of
concomitant analgesics was associated with higher headache frequency, endometriosis and low
back pain”: these sentences should be removed, as they are only repetition of what stated in
more details in the following sentences.