Title: Loneliness and analgesic overuse among low-dose estrogen-progestin users in Japan
Version: 2 Date: 25 Jul 2024
Reviewer:  Elena Toffol
Reviewer's report:
In this study the authors examine the relationships between loneliness and analgesic use (and
overuse) in a sample of over 500 young women using low-dose estrogen-progestin pills in
Japan. The main findings are those of an association between loneliness and analgesic use in
this population, as well as between analgesic overuse and menstrual-related factors, such as
endometriosis and low back pain. The study findings are of interest; some comments to improve
and clarify the meaning of the manuscript are reported below:
1. Introduction, page 2, line 49, “Loneliness is also associated with medication use”. I think this
claim should be opened a bit more: with which medications? In which way? With higher use,
lower use, overuse, or what else? Please, clarify.
2. Introduction, page 2, lines 51-52: “Using TIL to examine the relationship between loneliness
and medication use is expected to clarify the impact on quality of life.” The impact of what?
Please, reformulate and clarify.
3. Introduction, page 3, lines 71-74: “Clarifying loneliness and analgesic overuse among women
who use LEP may enable effective medication follow-up. Thus, the aim of this study was to
investigate the prevalence of analgesic use and overuse among women who are LEP users and to
clarify factors associated with loneliness and analgesic overuse.” Is the aim of the study to focus
on women who use LEP for alleviating dysmenorrhea and other menstrual symptoms, or does
the study include women who are using LEP for any (main) reason (including contraception)?
If LEP are prescribed for alleviating menstrual pain, the population may be rather different,
especially in terms of analgesic use, compared to women who use LEP only for contraception.
I think this point should be clarified in the introduction and in the results section, as it may have
important implications in terms of results interpretation and generalizability.
4. Methods, page 4, lines 95-96, “LEP patient card use”. Please, note that not all readers are
familiar with this: what is meant with “LEP patient card use”?
5. Methods, section statistical analysis, page 5, lines 105-112: please, clarify how (explanatory)
variables for the regression models were selected or chosen.
6. Results, page 5, line 117: in Fig 1 it is shown that almost 12,000 women were excluded due
to “eligibility criteria”. It is not clear what the eligibility criteria are: was this based exclusively
on LEP use? Were women using other types of OC excluded? Were any other exclusion criteria
applied? Please, clarify.
7. Results, page 6, lines 133-136: the information on associations between high loneliness and
poor health literacy and high risk of sleep problems is reported twice (“High TIL score was
significantly associated with … HLS-14#53 (OR 0.54, 95% CI 0.37-0.78, p=0.001), and PSQI#6
(OR 2.71, 95% CI 1.86-3.94, p<0.001)” and “Low health literacy was significantly associated
with high loneliness. Risk of sleep disorder was significantly associated with high loneliness.“
Please, combine the information in one sentence.
8. Results, Table 4: please, clarify in the footnote what is indicated with “(a)”.
9. Discussion, page 7, line 151: “This study aimed to investigate the prevalence of analgesic
use and overuse.” Please, clarify the study setting: e.g., “This study aimed to investigate the
prevalence of analgesic use and overuse among young LEP users in Japan”.
10. Discussion, page 8, limitations section: In my opinion there are two main limitations of the
study that need to be acknowledged and addressed: 1) the limited generalizability, given that
the study focuses on young women who are using LEP (and not other types of contraceptives).
In this sense, it would be important to know which proportion of these women are using LEP
(mainly) for contraception purposes, and how many for alleviating menstrual symptoms. 2) the
other limitation is related to the lack of a comparison group of non-users of LEP. If loneliness
is associated with menstrual symptoms and analgesic (over)use, how are these associations
among women who have menstrual symptoms but are not taking hormonal (LEP) medications
to alleviate such symptoms?
11. Abstract, Purpose, line 20: to better introduce the rationale of the study I suggest clarifying
that “Loneliness is related to menstrual disorders and medication use”.
12.  Abstract, Purpose, lines 20-21: I think mentioning MOH in the abstract (“Analgesic overuse
is associated with medication overuse headache (MOH)”) is not relevant and could be omitted.
Minor:
1. Table 2, Table 3, Table 4: These are not properly demographic characteristics. Maybe
background or basic characteristics? Please, reformulate.
2. Abstract, Purpose, lines 22-2: “and to clarify factors ASSOCIATED with loneliness and
analgesic overuse among women who are low-dose estrogen-progestin (LEP) users”.