Title: Loneliness and analgesic overuse among low-dose estrogen-progestin users in Japan
Version: 3 Date: 10 Apr 2025
Reviewer:  Elena Toffol
Reviewer's report:
I would like to thank the authors for revising the article and addressing my comments and
questions. Although the quality of the manuscript has improved, I think there are still some
points that need to be addressed:
1. In general, I think the manuscript would benefit from a language revision.
2. Introduction, page 2, lines 49-50, “Prior loneliness predicts contemporaneous regular use
of depression/anxiety prescription medications [8]”. I think there is also more direct evidence
of a relationship between loneliness and depression and/or anxiety (rather than an indirect
relationship, as the one with medications); I suggest adding some references on this.
3. Introduction, pages 2-3, lines 50-56, “The Three-Item Loneliness Scale (TIL) has been
widely used to measure loneliness in a simplified format [9,10]. TIL was established based on
the 20-item Revised UCLA Loneliness Scale (R-UCLA) to mitigate the response burden and
was validated by the associations with several indicators, such as R-UCLA scores, depressive
symptoms, marital status, and living arrangements. The TIL scale represents feelings of lack of
companionship, feeling left out and feeling isolated from others [9]. The Japanese translated TIL
Scale showed essential unidimensionality and characteristics to differentiate among respondents
at different levels of loneliness [10].” This description of the instruments is very detailed and
perhaps more appropriate for the methods section than for the introduction; please, consider
moving it.
4. Introduction, page 3, lines 58-59, “There were bidirectional longitudinal relationships between
pain and loneliness in the representative sample of older men and women.”. It is not clear to
which representative sample and to which study the authors refer to.
5. Introduction, page 3, lines 58-66: I have the feeling that this paragraph is somehow misplaced,
and in general that the whole introduction would need to be reorganized. How about, after the
first introductory paragraph, first describe the relationship between loneliness and menstrual
problems, then the need to use LEP + analgesics for menstrual symptoms, and thereafter the
problems related to analgesic overuse, including headache and MOH?
6. Methods, page 4, lines 84-85. “The survey was closed when the number of valid responses
reached 258 in age 20s and 258 in age 30s.” How was the target size determined? Just arbitrary,
based on power calculation, or what else? Please, clarify.
7. Methods, page 5, lines 116-117, “There is a relationship between women's health literacy and
work productivity. Women's health literacy may contribute to decreased presenteeism” While
this point could be mentioned in the discussion, I don’t think it is of any relevance in this
paragraph in the Methods section.
8. Methods, page 5, lines 132-136, “The main items investigated were age, TIL score,
HLS-14 score, PSQI score, PMS mental symptoms, PMS physical symptoms, menstrual pain,
endometriosis, frequency of headache per month, LEP patient card use, menstrual app use, LEP
dose recording, self-recording of menstrual symptoms, kampo medicine use, consultation about
LEP with pharmacists, analgesic use, frequency of analgesic use per month, analgesic use for
menstrual pain, headache, low back pain, or prophylaxis, and analgesic dose recording.” Here the
authors need to provide more details on how these variables were assessed and what they mean.
For example, how were PMS symptoms assessed? Alternatively, I suggest clearly referring here
to the supplementary material including the online questionnaire. However, the authors need to
clearly describe here what is meant by “analgesic use”, as this is one of the key variables in
the study: does the variable include any use (from one time up to, let’s say, daily use)? Was it
regular use, or specifically during the past month? This information is quite important for result
interpretation.
9. Methods, page 6, lines 148-150, “The explanatory variables were selected on the basis that the
number of events per explanatory variable should be at least 10 [44]. Based on these criterions,
appropriate selection of explanatory variables was made.” This does not provide information on
the criteria for variable selection, just on the maximum number of variables that can be included
in a model.
10. Methods, page 6, lines 154-155, “Explanatory variables in the logistic regression model
included analgesic use, headache #10 days per month, endometriosis, PMS physical symptoms,
HLS-14 #53, PSQI #6, age 30-39 years.” Why did the authors choose to include in the model
analgesic use, but not frequent analgesic use (i.e., >= 10)? Was headache >= 10 considered
as a proxy of frequent analgesic use? If so, please clarify (I have to say I was not able to
follow the next few sentences “High headache frequency was thought to influence loneliness.
More frequent headaches were also associated with greater use of analgesics. Analgesic use
#10 days per month is included in the criteria for MOH in the third edition of the International
Classification of Headache Disorders [14]. The frequency of this analgesic was set with
reference to at least 10 days per month of headache.” Maybe here is the answer to my question,
but please, reformulate). Testing the association between loneliness and analgesic overuse would
have been of interest and probably more meaningful than the association with analgesic use,
which, in my opinion, is a quite vague informant (please, see also my previous comment #8).
11. Results, page 7, line 187, “LEP users for contraceptive purpose was 20.0% (N=103).” Now
I am a bit confused, as in the Introduction, page 3 lines 83-84, it is stated that “The use of LEP
mainly for contraception, rather than for treatment of menstrual pain, is not authorized in Japan.”
Do the authors mean here that 20% of users used LEP also/mainly for contraception? Or what
else? Please, clarify.
12. Results/Tables: I am not sure if, for the purpose of this study, it is relevant to (statistically)
compare the groups based on age. If so, the authors need to provide a rationale in the
Introduction, and discuss the findings in the Discussion section. Alternatively, p-values of age
group comparisons could be removed.
13. In Table 2: why some p-values are marked as “NA”? Please, clarify.
14. In Table 3: I am a bit confused with the numbers reported in the first raw: as they are, it
seems that 258 women in the 20s and 258 in the 30s age groups (i.e., all women!) were analgesic
users, which is not the case.
15. Results: I am also wondering why variables reported in Table 4 were analysed as such, and
not included in the previous regression models.
16. Discussion, page 9, lines 220-222, “We also clarified the factors associated with loneliness
and analgesic overuse in LEP users. High TIL score indicating high loneliness was significantly
associated with analgesic use (Fig. 2).” Here, I suggest reporting also the rather high prevalence
of loneliness among the study population, which in my opinion is one of the main findings of
the study.
17. Discussion, page 10, lines 239-240, “In a previous study, it was shown that increased
loneliness and the severity of the perceived social isolation is associated with the prevalence/
incidence of pain [47].” I suggest emphasizing here that this is in line with the findings of the
current study, i.e., that loneliness was associated with analgesic use. On this regard, I think
it would have been of interest, and it would add to the study findings, to test the association
between loneliness and analgesic overuse.
18. The Discussion, in particular from line 239 to line 319, is too long, and reports details that
are too far from the current study. While I appreciate the authors trying to contextualize their
findings, and the reported arguments are valid, the suggested hypotheses and mechanisms are
reported too much in detail and cannot be supported, or are extremely far from the current study
findings and available data. I suggest importantly shortening this section and report the suggested
hypotheses in a much more concise way.
Minor:
1. Introduction, page 3, lines 67-68, “The female reproductive system is very sensitive to
physical and physiological stress.” Do the authors mean “physical and psychological” instead?
2. Introduction, page 3, lines 84-85, “In addition, over-the-counter (OTC) drug for LEP is not
authorized in Japan.” The meaning of this sentence is not clear: do the authors mean that LEP
are not OTC medications (i.e., that a prescription is required)? Please, reformulate.