The association of gender and persistent opioid use following an acute pain event: A retrospective population based study of renal colic.

INTRODUCTION: This study aims to explore gender-related differences in persistent opioid use following an acute pain episode and evaluate potential explanatory variables.
METHODS: This retrospective population-based study using administrative databases included all opioid-naïve patients in Ontario with renal colic between 2013 and 2017. The primary outcome was to assess any association between persistent opioid use at 3-6 months by gender. Key confounding covariates and explanatory variables examined included both care- and patient-related factors, specifically past evidence of mental health diagnoses.
RESULTS: The dataset of 64,240 males and 37,656 females demonstrated that 8.7% of males and 9.6% of females had evidence of persistent opioid use 3-6 months after presentation (OR 1.11, 95% CI 1.05, 1.17). Females had a higher incidence of mental health services utilization [44.5% vs 29.6% (p<0.001)] and were more likely to be on a provincial disability program [5.1% vs 3.8% (p<0.001)]. Age, income quintile, mental health diagnoses and dose of opioid prescribed were associated with the primary outcome in both genders. On adjusted analysis for multiple confounding and explanatory variables, females were still more likely than males to demonstrate persistent opioid use (OR 1.07, 95% CI 1.01, 1.13) with even more pronounced associations at 1-2 years.
INTERPRETATION: After controlling for key covariates, females are at slightly higher risk of demonstrating long term opioid use following an episode of renal colic. Evidence of prior mental health service utilization and acute colic care did not appear to significantly explain these observations.

Introduction

Our knowledge of sex- and gender-related differences in the pathogenesis, care delivery and response to treatment is relatively nascent. Pain management represents one field that has generated significant interest in recent years [1-4]. The majority of this research demonstrates that females report more pain and are at increased risk for chronic pain. Furthermore, there is some evidence suggesting that females may experience more severe acute pain with greater pain sensitivity, enhanced pain facilitation and reduced pain inhibition [5]. Any relationship between sex, gender and pain is complex and biases in pain management are well described: influenced by both the patient and health care providers [6]. Additional research is required to elucidate mechanisms driving these differences, better understand clinical ramifications and develop strategies to address these disparities.

One critical implication of any gender-related differences in pain would appear to relate to opioid use, misuse and addiction in the general public. The opioid crisis has serious social and economic repercussions leading to multiple countries declaring public health emergencies [7, 8]. The role of the physician in the opioid crisis is acknowledged with a significant incidence of persistent opioid use following management of an acute pain event [9-13]. In addition, certain vulnerable populations have been described to be at risk for persistent opioid use including patients of lower socioeconomic status (SES) and those with mental illness [3, 14, 15]. Investigating gender-related differences in continued opioid utilization after acute pain management appears critical given that from 1990 to 2010, deaths from prescription opioid overdose in the US increased 400% for women compared to 237% for men [16].

In a previous population-based study of patients presenting with renal colic in Ontario, we demonstrated that a majority of patients were prescribed opioids at diagnosis and of those, 9% had evidence of persistent use beyond three months [16]. Urolithiasis is an extremely painful, but limited, condition and resolution of the stone does not result in any lasting tissue damage or require rehabilitation. For these reasons, it is a useful model to further study the gender-related differences following a short course of opioids. The objective of this present study is to perform a secondary analysis of this dataset to determine if opioid-naïve female patients have unique risks of persistent opioid use. We hypothesize that females are more susceptible to persistent opioid use after an acute pain event given an increased incidence of mental health related comorbidity.

Methods

Study design

This population-based, retrospective cohort study explores gender-related differences in persistent opioid use in previously opioid naïve patients presenting with renal colic. The present study expands on a parent study of linked administrative databases describing all opioid-naïve patients diagnosed with renal colic between July 1, 2013 and September 30, 2017 in Ontario [16]. As of 2012, all opioid prescriptions that are dispensed in Ontario are captured in the Narcotic Monitoring System (NMS). Administrative databases utilized were all linked through Institute of Clinical Evaluative Sciences (ICES) as previously described [16]. The accuracy of these databases in terms of quality and coding has been previously discussed [17]. Codes utilized in this study have been summarized in S1 Table and the team accessed the dataset between August 2019 and March 2020.

Exclusion criteria were patients that had been dispensed an opioid in the year prior to their renal colic presentation, those who had a renal colic episode in the year prior, and any patient who had received palliative care services either the year before or the year after their index presentation. This study was approved by the Queen’s University Health Sciences and Affiliated Hospitals Research Ethics Board. All data were fully anonymized before accessing them and requirement for informed consent was waived.

Outcomes

Persistent opioid use after renal colic by documented gender was the primary outcome. Persistent opioid use was defined by one or more opioid prescription(s) dispensed between 0 and 90 days following the index renal colic visit that subsequently resulted in one or more prescription(s) for opioids that was dispensed between 91 and 180 days following the index visit. These definitions are similar to that of other comparable studies [10, 11] although we also determined dispensed opioids 6–12 months and 1–2 years after index diagnosis. Secondary outcomes included any subsequent diagnosis of opioid overdose, opioid addiction, hyperalgesia, and opioid-related death [17, 18].

Covariates

Covariates were determined a priori and conceptualized as confounding variables such as age, income quintiles, geographic location, patient comorbidities (Charlson index) [19], and enrollment with a primary care practitioner (PCP). The majority of these explanatory factors were conceived, documented on a Dataset Creation Plan, for the parent study [16] including clinical care-related covariates such as number of emergency department (ED) visits, gender of prescriber, number of PCP visits, and total oral morphine equivalents (OMEs) [20] dispensed during the index presentation. Given past literature focusing on sex and gender on pain perception, experience and management [3, 14, 15] we also included new covariates: mental health utilization, substance abuse and disability program registration (ODSP). The most important covariates not available in this dataset are the kidney stone details (size and location).

Statistics

Descriptive statistics (ratios) were used for demographic and baseline characteristics and to compare proportions between groups the Chi-square test was used. To identify the factors associated with the primary outcome, both univariate and multivariable logistic regression models were used. All patient-related and care-related variables were included in the original models and then subsequent iterative models were performed with groupings of covariates as described. Given the previous literature around gender, mental health diagnoses and pain outcomes we performed a test of interaction terms of gender and any mental health services utilization with the primary outcome of persistent opioid use. Missing data was included in the analyses as unknown indicator variable. A two-sided p-value of <0.05 was considered statistically significant. As per institutional policy, cells with <6 patients were not reported due to privacy concerns. Data were analysed using SAS Stat 14.3.

Results

The dataset was comprised of 64,240 males and 37,656 females who presented with renal colic. The characteristics of males and females presenting with renal colic in Ontario are described in Table 1 with some differences in baseline demographic data. Males tended to be slightly older compared to females with further minor differences in SES, comorbidity and enrollment in a PCP practice. Females however, had a significantly higher incidence of mental health services utilization [44.5% vs 29.6% (p<0.001)]. There was also a higher proportion of female patients on the Ontario Disability Support Program (ODSP) in the 3 years prior to presentation [5.1% vs 3.8% (p<0.001)]. Although females appeared to have slightly earlier resolution of their renal colic event and more likely to have earlier stone related surgery, there was more documentation of primary care visits compared to males during the initial presentation (Table 2).

Table 1

Patient characteristics of male and female patients with renal colic in Ontario during 2013–2017.

Characteristic	Male	Female	P Valuea
	n = 64,240	n = 37,656
Age at index, year, n (%)b			< .001
0–18	754 (1.2)	938 (2.5)
19–39	13,969 (21.7)	10,867 (28.9)
40–59	29,988 (46.7)	15,640 (41.5)
60–79	17,403 (27.1)	8,827 (23.4)
80 +	2,126 (3.3)	1,384 (3.7)
Neighborhood income, n (%)b			< .001
1 –Lowest quintile	11,474 (17.9)	7,471 (19.8)
2	12,572 (19.6)	7,836 (20.8)
3	13,032 (20.3)	7,530 (20.0)
4	13,531 (21.1)	7,587 (20.1)
5- Highest quintile	13,492 (21.0)	7,161 (19.0)
ODSP record, n (%)b			< .001
No	61,793 (96.2)	35,739 (94.9)
Yes	2,447 (3.8)	1,917 (5.1)
Geographic, n (%)b			< .001
Urban	57,072 (88.8)	32,948 (87.5)
Rural	7,070 (11.0)	4,668 (12.4)
Any mental health utilization, n (%)	18,987 (29.6)	16,770 (44.5)	< .001
Anxiety by primary care, n (%)	12,736 (19.8)	11,808 (31.4)	< .001
Anxiety by psychiatrist, n (%)	3,184 (5.0)	2,928 (7.8)	< .001
Mood disorder by primary care, n (%)	2,523 (3.9)	2,806 (7.5)	< .001
Mood disorder by psychiatrist, n (%)	1,621 (2.5)	1,478 (3.9)	< .001
Substance abuse, n (%)	2,429 (3.8)	1,239 (3.3)	< .001
Self-harm, n (%)	182 (0.3)	213 (0.6)	< .001
Charlson Index, n (%)b			0.03
0	60,463 (94.1)	35,486 (94.2)
1–2	2,797 (4.4)	1,672 (4.4)
3 +	980 (1.5)	498 (1.3)
Enrolled with a Family Practice, n (%)	52,336 (81.5)	31,912 (84.7)	< .001

ODSP = Ontario Disability Support Program.

a Chi-square test.

b Column percentages, may not add to 100% due to missing or unrepresented data.

Table 2

Clinical care characteristics of male and female patients with renal colic in Ontario during 2013–2017.

Characteristic	Male	Female	P Valuea
	n = 64,240	n = 37,656
Months in renal colic, n (%)b			< .001
< 2	48,042 (74.8)	28,902 (76.8)
≥2	16,198 (25.2)	8,754 (23.2)
ED visits during renal colic, n (%)b			0.09
0	45,882 (71.4)	26,633 (70.7)
1	12,976 (20.2)	7,843 (20.8)
2	3,596 (5.6)	2,136 (5.7)
> 2	1,786 (2.8)	1,044 (2.8)
PCP visits during renal colic, n (%)b			< .001
0	33,733 (52.5)	18,027 (47.9)
1	17,896 (27.9)	11,219 (29.8)
2	7,150 (11.1)	4,648 (12.3)
> 2	5,461 (8.5)	3,762 (10.0)
Surgery within 6 months, n (%)	14,920 (23.2)	9,803 (26.0)	< .001
Time to surgery n (%)b			< .001
No surgery	49,320 (76.8)	27,853 (74.0)
< 1 month	10,021 (15.6)	6,900 (18.3)
≥1 month	4,899 (7.6)	2,903 (7.7)
Any opioid dispensed 0–90 days, n (%)	43,625 (67.9)	23,373 (62.1)	< .001
Sum of opioid days supplied, n (%)b			< .001
1–2	10,346 (16.1)	5,378 (14.3)
3–4	14,545 (22.6)	7,763 (20.6)
5–7	10,220 (15.9)	5,671 (15.1)
> 7	8,289 (12.9)	4,308 (11.4)
Total oral morphine equivalents, n (%)b			< .001
1 - <100	7,334 (11.4)	4,495 (11.9)
100 - <150	8,155 (12.7)	4,895 (13.0)
150 - <200	9,406 (14.6)	4,727 (12.6)
200 - <300	9,058 (14.1)	4,523 (12.0)
300 +	9,410 (14.6)	4,453 (11.8)

ED = Emergency department.

PCP = Primary care practitioner.

a Chi-square test.

b Column percentages, may not add to 100% due to missing or unrepresented data.

Of those previously opioid naïve patients prescribed an opioid during their colic event, 3,794 (8.7%) males and 2,236 (9.6%) females continued to fill at least one opioid prescription 3–6 months after the initial presentation. Consequential outcomes secondary to opioid use such as addiction (0.4%), overdose (0.3% males, 0.4% females) and hyperalgesia (0.4% males, 0.6% females) were similar for both genders. However, longer follow-up of those opioid naïve patients filling a prescription at 3–6 months demonstrated higher rates of further continued use 6–12 months after the initial stone presentation in females (31.8% vs. 26% males). At 1–2 years, 38.1% of females compared with 31.4% of males continued to fill at least one opioid prescription.

The dataset demonstrated that 8.7% of males and 9.6% of females had evidence of persistent opioid use 3–6 months after presentation (OR 1.11, 95% CI 1.05, 1.17). The factors associated with persistent opioid use on unadjusted analyses were similar for both males and females (S2 Table). Age was associated with continued opioid use in both genders. Evidence of any mental health services utilization appeared to be associated with the primary outcome in both males (OR 1.30 95% CI 1.21, 1.39) and females (OR 1.32 95% CI 1.21, 1.44). Evidence of substance abuse and self-harm were similarly associated with persistent opioid use in unadjusted analyses. As a direct comparison, Fig 1 describes the odds ratios from multivariable models incorporating all covariates for each gender separately. In these adjusted models, mental health utilization, substance abuse and enrollment in a disability program were associated with long term opioid use to a similar degree in both genders although substance abuse was not significant in females. A test of interaction terms of gender and any mental health services utilization with the primary outcome was not significant.

Fig 1

A and B. Odds ratios for the associations between characteristics and persistent opioid use by gender. Controlled in logistic regression for all covariates listed as well as enrollment in primary care practice, geographic region (urban, rural), specialty and gender of initial opioid prescriber as well as sum of opioid days supplied. OME = Oral morphine equivalents, ED = Emergency Department, ODSP = Ontario Disability Support Program, SES = Socio-economic status.

On multivariable analysis of all covariates including gender, females were associated with persistent opioid use 3–6 months after initial presentation (OR 1.07, 95% CI 1.01, 1.13, p = 0.03) despite controlling for all key covariates investigated in this cohort (S2 Table). Both the duration and total amount of OME prescribed was strongly associated with persistent use. Female gender continued to be associated with the primary outcome after adjusting for each of these individual covariates. In subsequent iterative sensitivity models, incorporating confounding variables of age, SES and comorbidity and then more explanatory variables such as mental health services utilization, renal colic care and total OME originally prescribed, gender continued to be associated with persistent use (Fig 2). These results were similar if not more pronounced when extending these observations out to those filling an opioid prescription 1–2 years after the index renal colic episode (Fig 3). Unadjusted risk between genders for the primary outcome was OR 1.35 (95% CI 1.21, 1.50) and in the fully adjusted model: 1.28 (95% CI 1.14, 1.43).

Fig 2

Odds ratios for the associations between gender and persistent opioid use at 3–6 months after index.

a Adjusted in logistic regression for age, socio-economic status, comorbidity bFurther adjusted for mental health utilization, substance abuse and Ontario Disability Support Program cFurther adjusted for time of renal colic episode, subsequent need for stone surgery, number of Emergency Department visits dFurther adjusted for total oral morphine equivalents prescribed during renal colic management.

Fig 3

Odds ratios for the associations between characteristics and persistent opioid use by gender at 1–2 years after index.

a Adjusted in logistic regression.

Interpretation

In this population-based study, we demonstrate gender-related differences in persistent opioid use beyond 3 months after an intended short-term course required for renal colic, independent of multiple key confounders or explanatory variables. Of the 2,236 (9.6%) previously opioid naïve females that continued to fill opioid prescriptions after an acute pain event, more than a third had evidence of persistent opioid use 1–2 years later. Females were more likely to have documented utilization of mental health services compared to males in this cohort and given the strength of its association with persistent opioid use, it could be hypothesized as an explanatory factor although gender continued to be significant even after adjusting for this covariate. Key treatment-related factors associated with persistent opioid use including need for surgical intervention and the amount of opioids dispensed appeared to be similarly associated in both males and females.

Female patients in this cohort, representing all those diagnosed with renal colic during the study period, differed in several parameters compared to their male counterparts, some of which have been previously associated with continued opioid utilization. Female patients tended to be somewhat younger with some evidence of lower SES, although other statistically significant variances in baseline characteristics such as rurality, comorbidity and previous stone surgery were likely not clinically different. Nonetheless, previous studies exploring associations of persistent opioid use and patient-related factors would suggest many of these variables such as age, SES and comorbidity may confound these findings [10, 11]. Female patients were less likely to be prescribed an opioid during their renal colic presentation (62.1% vs. 67.9% for men) and the total OME prescribed to women was significantly less (23.8% females prescribed >200 OME vs. 28.7% for males) which is consistent with previous studies. This finding is interesting given the strength of the association of dose and duration of original opioid prescriptions and persistent use in otherwise unselected patients with acute or chronic non-cancer pain [21]. As well, females appeared to have slightly earlier resolution of their renal colic event and more likely to have earlier stone related surgery. Despite these findings that might predict less ongoing opioid utilization, females still demonstrated more opioid use 3–6 months after the acute pain event in both unadjusted and adjusted analysis.

There were other apparent gender-related differences in the management of patients with renal colic which may have contributed to the primary outcome including more surgical interventions (23.2% for males vs. 26% for females) and more health provider visits during the initial renal colic event which may have been associated with repeated access to opioid prescriptions. We have previously reported several kidney stone surgery specific risk factors for persistent opioid use [16] including an increased number of interventions as well as surgical type. These factors appeared to be similarly associated with the primary outcome in both males and females in this present study (S3 Table).

Multiple studies have investigated differences in opioid prescribing and opioid use between genders with consistent findings that characteristics such as mental health diagnoses and post-traumatic stress are strongly associated with opioid utilization in the chronic pain setting [2, 3, 14]. Similarly, a limited number of recent studies exploring persistent opioid use following acute pain events in previously opioid-naïve patients have found similar results in terms of gender-related risk factors [21, 22]. Involvement in a disability program, such as the ODSP in this present study, has been also been shown to be associated with long term opioid use [23], but few have included such programs in their analyses of persistent opioid use after short-term acute opioid prescriptions. In this current study, mental health services utilization appeared to be strongly associated with continued opioid use in both males and females in adjusted analysis. However, the incidence of such diagnoses was significantly higher in females than their male counterparts.

Given the millions of low-complexity procedures that are performed every day, in addition to the various acutely painful conditions that present to primary care and urgent care clinics, these significant rates of persistent opioid use are concerning. The strong association of previous mental health services utilization and continued opioid use is consistent for both males and females, however the increased incidence of a mental health diagnosis in females in this large population-based cohort emphasizes their vulnerability. The specific etiological basis underlying any gender differences in pain experiences are complex and multi-factorial, and emerging evidence suggests endogenous opioid functioning may play a causal role in these disparities, including sex hormones as factors influencing pain sensitivity [1]. Psychosocial processes, stereotypical gender roles manifesting in differences in pain expression and sex differences in responses to analgesic medications have been implicated [1, 5]. Despite adjusting for multiple key factors associated with persistent opioid use in this present study, the fact that female gender remained an independent variable associated with persistent opioid use underscores the need to consider gender when identifying vulnerable populations with regard to opioid prescribing.

This study is limited by the retrospective nature as well as the accuracy of the data used, including diagnostic codes, procedure codes and opioid prescription capture, leading to potential misclassification bias. Furthermore, it is not possible to determine potential additional diagnoses for which ongoing opioid management would be considered, or the severity of the diagnoses that were coded. In addition, the NMS only tracks opioids dispensed, not necessarily those actually utilized by patients, or opioids utilized by a patient from a non-physician source (e.g. friend/relative’s prescription, street). Importantly, information around the size and location of urolithiasis was not captured in the current study. Finally, there remains the potential threat of residual confounding. Strengths of the study however include the large population-based cohort size and the ability to determine opioid utilization prior to the urolithiasis diagnosis as the NMS captures opioid prescriptions for patients of all ages in this mandatory, province-wide reporting system.

In conclusion, the majority of patients diagnosed with renal colic in this real-world study were prescribed opioids, despite increasing awareness of risks and documented efficacy of non-opioid medications. Females were at slightly higher risk to fill prescriptions beyond 3 months after the acute pain event and this remained significant even after adjustment for key confounders. The data support and highlight the urgent need for opioid reduction strategies, including opioid-reduced prescriptions and multimodal non-opioid analgesia strategies with a focus on provider education to identify vulnerable populations.

(DOCX)

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Codes utilized.

(DOCX)

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Odds ratios for the association between characteristic and persistent opioid use.

(DOCX)

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Odds ratios for the association between surgical factors and persistent opioid use by gender.

(DOCX)

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25 May 2021

PONE-D-21-08670

The Association of Gender and Persistent Opioid Use Following an Acute Pain Event: A Retrospective Population Based Study of Renal Colic

PLOS ONE

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Additional Editor Comments:

Overall comment: the manuscript entitled “The Association of Gender and Persistent Opioid Use Following an Acute Pain Event: A Retrospective Population Based Study of Renal Colic” assessed gender-related differences in persistent opioid use following an acute pain episode and evaluated potential explanatory variables. Using administrative databases including a large cohort of opioid-naïve patients in Ontario with renal colic between 2013 and 2017, the authors found that females were at higher risk of demonstrating long term opioid use following an episode of renal colic. I have the following comments for editor’s and authors’ consideration:

1. Methods: page 7, please justify the selected covariates to briefly explain the rationale of the selections.

2. Methods: in the statistics section, please describe the individual interaction terms that were tested in the multivariable logistic regression model and the rationale.

3. Results: page 10, the authors mentioned “Age was associated with continued opioid use in both genders, however females aged 0-18 had a higher odds ratio (OR) (1.14, 95% confidence interval (CI) 0.82, 1.58) whereas males aged 0-18 had a lower OR (0.77, 95% CI 0.48, 1.25).” when describing results from the unadjusted analyses. However, given that these 95% CIs indicated statistical non-significance, please modify the description to avoid presenting “higher” or “lower” odds ratios for females and males. Similarly, please also revise the corresponding content in the Interpretation section on page 13 (first paragraph).

4. Results: in Tables 1 and 2, all patient level and clinical level covariates were statistically different between females and males. An alternative (potentially better) approach is to use propensity score matching or weighting to balance these covariates before assess the association between gender and persistent opioid use following an acute pain episode. Please discuss why propensity score was not used for your analysis and if it might show different findings from your results.

5. Results: there are a few places where the authors indicated "data not shown" instead of adding corresponding results in the supplemental materials. Please make your data/results fully available to the audience.

6. Interpretation: based on the authors’ main finding of “females were associated with persistent opioid use 3-6 months after initial presentation (OR 1.07, 95% CI 1.01, 1.13, p=0.03)”, please discuss clinical significance (instead of statistical significance) of the marginal difference (less than 4% in difference based on the adjusted OR) in persistent opioid use 3-6 months between females and males.

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Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

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Reviewer #1: Yes

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Reviewer #1: This manuscript is technically sound and overall easy to read. The authors should be congratulated. I have no concerns regarding the conduct of the study. Some specific recommendations regarding the write-up are included below.

Title:

-For clarity, consider revising to, "The association between gender and persistent opioid use..."

Ethics statement:

-There is no explicit statement that the Queen's IRB approved the research or what type of consent was obtained.

Data availability section:

-Please supply details regarding where/how all raw study data can be obtained (even though it seems it is publicly available).

Abstract:

-In the first sentence of the results, please indicate some statistical measure (with error term) regarding whether the unadjusted proportion of males and females with persistent opioid use are different. (Please make the same clarification in the main Results section.)

-In the conclusion, consider adding a term such as, "females are at a 'slightly' higher risk..." since the prevalences of 8.7% and 9.6% (and the OR of 1.07) are, arguably, fairly similar from a clinical standpoint.

Results:

-When discussing the prevalence of longer term opioid use, please provide statistical metrics for the comparisons of proportions.

Figure 1:

-The text in the figures is quite small. Consider splitting the figure across two pages for easier readability. Or, if color-coded, you could potentially put the male and female data on the same plot.

Figure 2:

-This is a great figure. Very digestable and informative.

Figure 3:

-Also a great figure. Consider adding an adjustment for prescription of opioids 3-6 months after index.

Other:

-Both gender and sex are mentioned in the Intro, but then the manuscript seems to focus on only gender. What was the rationale behind focusing on gender as opposed to sex (since they are not interchangeable variables)? Does the administrative database truly capture gender, sex, or both?

**********

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8 Jun 2021

Editors and Reviewers Comments:

Overall comment: the manuscript entitled “The Association of Gender and Persistent Opioid Use Following an Acute Pain Event: A Retrospective Population Based Study of Renal Colic” assessed gender-related differences in persistent opioid use following an acute pain episode and evaluated potential explanatory variables. Using administrative databases including a large cohort of opioid-naïve patients in Ontario with renal colic between 2013 and 2017, the authors found that females were at higher risk of demonstrating long term opioid use following an episode of renal colic. I have the following comments for editor’s and authors’ consideration:

1. Methods: page 7, please justify the selected covariates to briefly explain the rationale of the selections.

Thank you for this comment around the covariates chosen. The selected covariates and explanatory factors described herein were conceived a priori by the research team, and are documented on a Dataset Creation Plan, for the parent study which is listed as reference 16. Given past literature focusing on sex and gender on pain perception, experience and management we also included the new covariates such as mental health utilization, substance abuse and disability program registration (ODSP). The most important covariates not available in this dataset are the kidney stone details (size and location) and a limitation of the observations.

2. Methods: in the statistics section, please describe the individual interaction terms that were tested in the multivariable logistic regression model and the rationale.

We have added this wording to the methodology: Given the previous literature around gender, mental health diagnoses and pain outcomes we performed a test of interaction terms of gender and any mental health services utilization with the primary outcome of persistent opioid use.

3. Results: page 10, the authors mentioned “Age was associated with continued opioid use in both genders, however females aged 0-18 had a higher odds ratio (OR) (1.14, 95% confidence interval (CI) 0.82, 1.58) whereas males aged 0-18 had a lower OR (0.77, 95% CI 0.48, 1.25).” when describing results from the unadjusted analyses. However, given that these 95% CIs indicated statistical non-significance, please modify the description to avoid presenting “higher” or “lower” odds ratios for females and males. Similarly, please also revise the corresponding content in the Interpretation section on page 13 (first paragraph).

This is an excellent point and we simply removed from the manuscript as the point around direction was a minor observation from Supplementary Table 2 and not additive given the CIs with respect to the younger age groups.

4. Results: in Tables 1 and 2, all patient level and clinical level covariates were statistically different between females and males. An alternative (potentially better) approach is to use propensity score matching or weighting to balance these covariates before assess the association between gender and persistent opioid use following an acute pain episode. Please discuss why propensity score was not used for your analysis and if it might show different findings from your results.

Thank you for this question about the adjusted models. We appreciate the academic discussions around the differences and potential benefits (and drawbacks) of PSM compared to regression analyses employed herein. In this present study, we wanted to identify potential explanatory factors for any observed differences between the genders and any association with the primary outcome and therefore utilized univariate and multivariable logistic regression models as informative for the clinical reader. It is a formidable tool to appraise multivariate predictors of dichotomous events and evaluate the independent predictive role of more than one independent variable of interest. However, we recognize that these models may not perfectly guide the strength of the confounders.

As mentioned above, there is some imbalance between the covariates between the genders (Table 1) although we felt these were in general not clinically remarkable and only significant because of the large number of patients presenting with renal colic in the dataset (n=101,978). The benefit of PSM to control for overt, measurable biases did not resonate for us as the exposure in this study was gender (male/female) and we simply didn’t conceptualize any propensity score as the conditional probability of receiving the exposure given a vector of measured covariates. However, as conceived as a balancing variable to achieve “balance” between the two groups (male/female), especially given the potential complexity of the methodology (different propensity score matching techniques), PSM are likely superior to standard MVA methods only in small datasets (which of course is not the case in this study). It is our understanding the literature would suggest that PSM performance in larger datasets is similar or less precise than logistic regression.

5. Results: there are a few places where the authors indicated "data not shown" instead of adding corresponding results in the supplemental materials. Please make your data/results fully available to the audience.

Thank you. We have removed that commentary in the Results as it was actually a mistake as it is included in the Supplementary Table 2. Further, we have added Supplementary Table 3 to reference the statement in the Interpretation.

6. Interpretation: based on the authors’ main finding of “females were associated with persistent opioid use 3-6 months after initial presentation (OR 1.07, 95% CI 1.01, 1.13, p=0.03)”, please discuss clinical significance (instead of statistical significance) of the marginal difference (less than 4% in difference based on the adjusted OR) in persistent opioid use 3-6 months between females and males.

Thank you for this comment as it was important as we put this manuscript together: not just to confirm the gender differences in persistent opioid use but to dissect the “explanatory” variables associated with the outcome. Hence the reason for the different iterative (sensitivity) regression analyses rather than PSM as described above.

Within the Interpretation we do comment on the significance of these observed differences between the genders and this addition to the literature. Although the main outcome was persistent opioid use in previously opioid naïve patients at 3-6 months we also observed more stark differences later on within the NMS data (1-2 years): 38.1% of females compared with 31.4% of males. Further, although only a small difference based on the adjusted OR, this was adjusted for really key confounders (baseline, mental health utilization, opioids prescribed, surgical variables and interactions with health professionals) and yet we still see a difference between the genders. Our interpretation was that despite controlling for these variables, females still demonstrated more opioid use 3-6 months after an acute pain event in adjusted analysis (OR 1.07 at 3-6 months and 1.28 at 1-2 years later) suggesting there may be other unmeasured confounding variables to explain the ORs or “true” differences in other bio-psycho-social determinants of pain and opioid prescription filling. In fact, we discuss in the Interpretation that females appeared to have slightly earlier resolution of their renal colic event and more likely to have earlier stone related surgery. “Despite these findings that might predict less ongoing opioid utilization, females still demonstrated more opioid use 3-6 months after the acute pain event in both unadjusted and adjusted analysis”.

Our interpretation around the clinical relevance was that “Despite adjusting for multiple key factors associated with persistent opioid use in this present study, the fact that female gender remained an independent variable associated with persistent opioid use underscores the need to consider gender when identifying vulnerable populations with regard to opioid prescribing.”

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Added these captions to the end of the manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may reply upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

Reviewer #1: Yes

________________________________________

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Reviewer #1: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript is technically sound and overall easy to read. The authors should be congratulated. I have no concerns regarding the conduct of the study. Some specific recommendations regarding the write-up are included below.

Title:

-For clarity, consider revising to, "The association between gender and persistent opioid use..."

Done

Ethics statement:

-There is no explicit statement that the Queen's IRB approved the research or what type of consent was obtained.

Changed in the Methods

Data availability section:

-Please supply details regarding where/how all raw study data can be obtained (even though it seems it is publicly available).

The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may reply upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

Abstract:

-In the first sentence of the results, please indicate some statistical measure (with error term) regarding whether the unadjusted proportion of males and females with persistent opioid use are different. (Please make the same clarification in the main Results section.)

The unadjusted OR between males and females can be found in Figure 1 3-6 months (1.11 95% CI 1.05-1.17) and has been added to the results of the Abstract and in the Results section.

-In the conclusion, consider adding a term such as, "females are at a 'slightly' higher risk..." since the prevalences of 8.7% and 9.6% (and the OR of 1.07) are, arguably, fairly similar from a clinical standpoint.

As above, although these ORs after controlling for key confounders are low, the relevance of these observations is pointed out in the Interpretation. We have qualified the conclusions as suggested as it is true that the remaining effect size is small at least in the 3-6 month timeframe.

Results:

-When discussing the prevalence of longer term opioid use, please provide statistical metrics for the comparisons of proportions.

The ORs for the 1-2 year time frame were found in Figure 3: unadjusted 1.35 (95% CI 1.21, 1.50) and in the fully adjusted model 1.28 (95% CI 1.14, 1.43). This has been added to the Results section as well as the Figure.

Figure 1:

-The text in the figures is quite small. Consider splitting the figure across two pages for easier readability. Or, if color-coded, you could potentially put the male and female data on the same plot.

We are hoping the quality of the figure is sufficient as we were specifically wanting to exhibit the data one on top of the other to help the reader assess the effect size for the covariates and make “comparisons” between males and females. We tried combining on the same plot but we felt this was more complicated than the larger figure with two plots on top of each other. We do have examples of this in the literature which we felt represented the observations quite well and wanted to re-capitulate.

Figure 2:

-This is a great figure. Very digestable and informative.

Figure 3:

-Also a great figure. Consider adding an adjustment for prescription of opioids 3-6 months after index.

We have of course stratified only to those that were prescribed opioids initially and we are not sure (given the dwindling numbers of cases) if adjusting for those that received opioids in early time points (3-6 months) will be additive to the observations we are trying to convey.

Other:

-Both gender and sex are mentioned in the Intro, but then the manuscript seems to focus on only gender. What was the rationale behind focusing on gender as opposed to sex (since they are not interchangeable variables)? Does the administrative database truly capture gender, sex, or both?

Thank you for this comment and we are quite cognizant of the difference between the terminology and agree with the SAGER guidelines. With the recent additions of gender identity and gender expression to the Canadian Human Rights Act and the Criminal Code as well as some sources of administrative data changing from sex to gender, it is of course necessary to distinguish the concepts of sex, gender identity and gender expression. Statistics Canada has revised the variable 'sex of person' as well as creating a new variable, 'gender of person'.

Unfortunately, the dataset utilized through ICES would be self-reported in general and different options to capture gender identity other than binary (male/female) is not possible. However it would also be true that biological sex would not be specifically captured within the administrative data. Although both sex (biological) and gender (socially constructed roles, behaviours, expressions) may play a role in in the primary outcome of this study we felt that as the data point is self-reported, and as some of the covariates/concepts more align with socially determined health care utilization/interactions, that gender would be the preferred term for this study. As mentioned we did discuss this briefly in the Introduction and were conscientious to use the term gender as well as male/female throughout.

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Submitted filename: Reviewer responses.June1.docx

Click here for additional data file.

9 Jul 2021

PONE-D-21-08670R1

The Association of Gender and Persistent Opioid Use Following an Acute Pain Event: A Retrospective Population Based Study of Renal Colic

PLOS ONE

Dear Dr. Siemens,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Jingjing Qian

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Thanks for addressing majority of comments. Due to the small/modest adjusted difference between male and female found in the study, we would like the authors to take additional edits before we can accept your paper. Specifically:

1. Abstract:"Interpretation: After controlling for key covariates, females are at higher risk of demonstrating long term opioid use following an episode of renal colic. Evidence of prior mental health service utilization and acute colic care did not appear to significantly explain these observations." Please add "slightly" before "higher risk of demonstrating long term opioid use following an episode of renal colic" as you did in the conclusion section.

2. Methods: page 7, covariates -- the authors provided appropriate explanation in the responses to comments document, but did not incorporate corresponding edits in this section to justify selection of covariates. Please make the edits and cite relevant studies.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

**********

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5 Aug 2021

May 26, 2021

Jingjing Qian

Academic Editor

PLOS ONE

Dear Dr. Qian:

Please find enclosed our manuscript re-submission (revision 2) entitled “The Association of Gender and Persistent Opioid Use Following an Acute Pain Event: A Population Based Study of Renal Colic”. Thank you for the opportunity to re-submit a revised version of this manuscript for consideration of publication in your journal.

Sincerely,

D. Robert Siemens

Professor and Chair

Department of Urology

Queen's University

Editors and Reviewers Comments:

Thanks for addressing majority of comments. Due to the small/modest adjusted difference between male and female found in the study, we would like the authors to take additional edits before we can accept your paper. Specifically:

1. Abstract:"Interpretation: After controlling for key covariates, females are at higher risk of demonstrating long term opioid use following an episode of renal colic. Evidence of prior mental health service utilization and acute colic care did not appear to significantly explain these observations." Please add "slightly" before "higher risk of demonstrating long term opioid use following an episode of renal colic" as you did in the conclusion section.

This is very much appropriate and done (page 3)

2. Methods: page 7, covariates -- the authors provided appropriate explanation in the responses to comments document, but did not incorporate corresponding edits in this section to justify selection of covariates. Please make the edits and cite relevant studies.

Thank you. We have added a few sentences in the Methods explaining what we discussed in the rebuttal letter (with references).

Journal Requirements:

Further there was this one comment by a reviewer and we previously have addressed giving the ICES privacy policy. We are happy to add this as some supplementary comment or in “Acknowledgements”?

4. Have the authors made all data underlying the findings in their manuscript fully available?

No

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may reply upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

Submitted filename: PLOS rebuttal letter.aug3.docx

Click here for additional data file.

11 Aug 2021

The Association of Gender and Persistent Opioid Use Following an Acute Pain Event: A Retrospective Population Based Study of Renal Colic

PONE-D-21-08670R2

Dear Dr. Siemens,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Jingjing Qian

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thanks for addressing all comments and making edits as suggested.

Reviewers' comments:

19 Aug 2021

PONE-D-21-08670R2

The Association of Gender and Persistent Opioid Use Following an Acute Pain Event: A Retrospective Population Based Study of Renal Colic

Dear Dr. Siemens:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Jingjing Qian

Academic Editor

PLOS ONE