Association of Receipt of Opioid Prescription for Acute Post-Delivery Pain Management with Buprenorphine Discontinuation among Postpartum People with Opioid Use Disorder

Round 1

Reviewer 1 Report

I read with interest the paper titled "Association of Receipt of Opioid Prescription for Acute Post Delivery Pain Management with Buprenorphine Discontinuation Among Postpartum People with Opioid Use Disorder"

In overall article use the wording "sex" instead of "gender". 

For sure, there are no need to present a line in the table a line for sex of the postpartum people. Presenting 100% females is not surpresing. 

In each p-value of table 1, present the test used

Table 1 - race (test was significant). Have you excluded not reported for the test? 

Table 1 - incarcerated at time of delivery (test was significant). Have you excluded not reported for the test? 

Table 1 - insured status (test was significant). Have you excluded not reported for the test? 

Why you use Gehan-Breslow-Wilcoxon method to compare the curves instead of a log-rank test? Why give more weight to early timepoints? Please discuss.

Have you tested log-rank (or MH test) which gives equal weights to all timepoints? Whats the difference in results?

Having a psychiatric comorbidity have an adjusted HR of 0.51 with significance. Please discuss. From all the comorbidities identified there are any that contributes more to that? Please check in the regression model. 

I would like to see a better conclusion of the study. What this study adds to clinical practice? In that cases, should the pratitioners prescribe opioids or non-opioids? Whats the reccomendations?

Author Response

RESPONSE TO REVIEWER 1 COMMENTS

1. Summary

I read with interest the paper titled "Association of Receipt of Opioid Prescription for Acute Post Delivery Pain Management with Buprenorphine Discontinuation Among Postpartum People with Opioid Use Disorder"

Thank you very much for taking the time to review this manuscript and for your interest in our research.

3. Point-by-point response to Comments and Suggestions for Authors

Comment 1: In overall article use the wording "sex" instead of "gender". 

 Thank you for your suggestion, we have applied changes accordingly to the manuscript.

Comment 2: For sure, there are no need to present a line in the table a line for sex of the postpartum people. Presenting 100% females is not surpresing. 

This row has been removed from Table 1. 

Comment 3: In each p-value of table 1, present the test used

We have adapted the footnotes of Table 1 to help clarify the statistical tests used. Next to continuous variables (p-value for t-test) of Table 1, we have included footnote 1: “Differences between patients who continued vs. discontinued buprenorphine within the 52-week study period were assessed using a student’s t-test (continuous data)”. Next to categorical variables (p-value for chi-square test) of Table 1, we have included footnote 2: “Differences between patients who continued vs. discontinued buprenorphine within the 52-week study period were assessed using a chi-square test (categorical data)”.

Comment 4: Table 1 - race (test was significant). Have you excluded not reported for the test? 

 Yes, “Not reported” was excluded from the chi-square test.

Comment 5: Table 1 - incarcerated at time of delivery (test was significant). Have you excluded not reported for the test? 

  Yes, “Not reported” was excluded from the chi-square test.

Comment 6: Table 1 - insured status (test was significant). Have you excluded not reported for the test? 

  Yes, “Not reported” was excluded from the chi-square test.

Comment 7: Why you use Gehan-Breslow-Wilcoxon method to compare the curves instead of a log-rank test? Why give more weight to early timepoints? Please discuss.

Thank you for your comment. The decision to use the Gehan-Breslow-Wilcoxon method over the log-rank test was made to enhance the sensitivity of our analysis to potential differences in survival experiences during the crucial early postpartum period. For instance, a previous study (Lo-Ciganic et al., 2018) identified changes in the adherence trajectories of buprenorphine through 12 weeks postpartum, wherein the authors considered this early postpartum period as a ‘clinically reasonable’ period for noting changes in buprenorphine adherence during the first (or first few) postpartum followup visits. Further, another previous study (Shadowen et al., 2022) noted that receiving behavioral health therapy between weeks 9-38 postpartum was associated with a lower risk of buprenorphine discontinuation, further corroborating that these early time points within the postpartum period are crucial to examine to inform timely interventions. Overall, given the limited sized sample (n=142) in our study, the Gehan-Breslow-Wilcoxon method allows for greater sensitivity to differences in survival experiences during the crucial early postpartum period within this sample. A brief sentence describing this rationale has been added to section 4.3.

Comment 8: Have you tested log-rank (or MH test) which gives equal weights to all timepoints? Whats the difference in results?

The log-rank test yields a chi-square test statistic of 1.92, and p-value of 0.1662. Please be reminded that, as described in our response to the last question, the Wilcoxon test is better indicated since it is more sensitive to early survival differences, which is an important consideration given our moderate sample size (n=142) and sharp decline in buprenorphine discontinuation in the early timepoints of our study. This is consistent with the methodology of an earlier paper (Shadowen et al., 2022).

Comment 9: Having a psychiatric comorbidity have an adjusted HR of 0.51 with significance. Please discuss. From all the comorbidities identified, are there any that contributes more to that? Please check in the regression model. 

We have added two sentences to the first paragraph of the discussion (lines 209-217) to address this significant finding.      

Comment 10: I would like to see a better conclusion of the study. What this study adds to clinical practice? In that cases, should the pratitioners prescribe opioids or non-opioids? Whats the reccomendations?

Thank you for this comment. We have revised first paragraph of the discussion to emphasize that while our studies to not show a strong association between receipt of opioid prescriptions and buprenorphine discontinuation, practitioners should consider additional patient factors, such as the patients’ engagement with addiction and mental health treatment services in making a decision to prescribe opioids to postpartum patients with OUD. Additional studies are needed to inform specific clinical recommendations.

4. Itemized, point by point response to the comments of the reviewers and changes that were made in the manuscript.

• Page 1 Line 34 Remove (ACOG)
• Page 1 Line 36 Replace The ACOG-recommended treatment for pregnant individuals with opioid use disorder (OUD) includes medications for OUD[1]. with The American College of Obstetricians and Gynecologists -recommended treatment for pregnant individuals with opioid use disorder includes medications for opioid use disorder(e.g., buprenorphine) during pregnancy, delivery, and postpartum.
• Page 1 Line 41 replace [2] and opioid overdose is the leading cause of postpartum maternal death in individuals with OUD with and opioid overdose is the leading cause of postpartum maternal death in individuals with opioid use disorder [3]
• Page 1 Line 43 replace OUD (MOUD) with medication for opioid use disorder.
• Page 2 Line 46 replace OUD with opioid use disorder
• Page 2 Line 47 insert In one study of over 1500 birthing people diagnosed with opioid use disorder, 42.9% received buprenorphine treatment throughout their pregnancy, however one third experienced a treatment disruption during the postpartum period [5]. after [4].
• Page 2 Line 50 replace MOUD with medication for opioid use disorder
• Page 2 Line 52 replace continuate with adherence
• Page 2 Line 54 replace MOUD with mediation for opioid use disorder
• Page 2 Line 55 replace MOUD with medication for opioid use disorder
• Page 2 Line 57 replace MOUD with medication for opioid use disorder
• Page 2 Line 61 replace [5] with [6]
• Page 2 Line 63 replace MOUD with medication for opioid use disorder
• Page 2 Line 64 replace On the other hand, another. with Another recent study found that opioid refill rates for post-delivery pain were increased in patients with opioid use disorder or chronic pain compared to individuals without these diagnoses [7]. On the other hand, one
• Page 2 Line 68 OUD with opioid use disorder [8]. This literature indicates that there is likely an association between opioid prescription receipt and medication for opioid use disorder treatment adherence during the postpartum period. However, the directionality of this relationship has not yet been determined.
• Page 2 Line 74 replace OUD with opioid use disorder
• Page 2 Line 75 remove Qualitative studies have reported that nurses and obstetric providers are unsure how to address pain management during labor and the postoperative period for individuals with OUD and patients taking MOUD [7].
• Page 2 Line 76 replace [8] with [9]
• Page 2 Line 77 replace [5] with [6]
• Page 2 Line 78 replace MOUD with medication for opioid use disorder
• Page 2 Line 86 replace [8]. However, the association between prescription opioid-managed postpartum pain and MOUD continuation has not yet been determined. Accordingly, this study of pregnant individuals receiving buprenorphine for OUD with with [9,10]. Qualitative studies have reported that nurses and obstetric providers are unsure how to address pain management during labor and the postoperative period for individuals with opioid use disorder and patients taking medication for opioid use disorder [11]. This uncertainty is in part due to the lack of evidence-based recommendations for clinicians regarding how to safely and effectively prescribe opioids postpartum patients with opioid use disorder. Accordingly, this study of opioid use disorder patients maintained on buprenorphine
• Page 2 Line 89 insert while also supporting adherence to recovery after pain management
• Page 2 Line 90 replace MOUD with medication for opioid use disorder
• Page 4-5 see table 1 for changes made
• Page 5 Line 116 remove or chi square test (categorical data)
• Page 5 Line 117 replace patients with ²Differences between patients who continued vs. discontinued buprenorphine within the 52-week study period were assessed using a
• Page 5 Line 119 insert ³patient before could
• Page 6 Line 121 replace ³ with ⁴
• Page 7 Line 207 replace These results with However, the Cox proportional hazards model did indicate that, after adjusting for opioid prescription at delivery, incarceration at delivery, receipt of buprenorphine before delivery, and chronic pain, the presence of a psychiatric comorbidity was associated with a reduced risk of buprenorphine discontinuation. This result is consistent with a previous study [13], which suggested that individuals with a psychiatric comorbidity may be at reduced risk of discontinuing buprenorphine treatment due to multiple factors such as increased engagement in opioid use disorder care and potentially more contact points with various dimensions (e.g., addiction care, mental health, recovery support services) of the integrated care model within the academic center in which this study was conducted. Overall, the results of the current study
• Page 7 Line 217 replace this finding is sensitive to the methods and other factors may be with but it is likely not the main factor leading to buprenorphine discontinuation. There are additional factors, such as engagement with other addiction and mental health care services, that are likely to play a more meaningful role in
• Page 8 Line 220 after influencing this relationship. insert As such, a clinician’s decision to prescribe opioids to postpartum patients with opioid use disorder should take into consideration individualized patient factors
• Page 8 Line 223 replace OUD with opioid use disorder
• Page 8 Line 229 replace OUD with opioid use disorder
• Page 8 Line 230 replace OUD with opioid use disorder
• Page 8 Line 231 replace OUD with opioid use disorder
• Page 8 Line 235 after pregnancy insert Further survey-based and qualitative research is needed to understand the potential intrapersonal, interpersonal, and structural factors that could influence buprenorphine discontinuation during the high-risk postpartum period.
• Page 8 Line 251 replace OUD with opioid use disorder
• Page 8 Line 253 replace OUD with opioid use disorder
• Page 8 Line 254 replace OUD with opioid use disorder
• Page 8 Line 255 replace [10] with [12]
• Page 8 Line 256 replace OUD with opioid use disorder
• Page 8 Line 257 replace OUD with opioid use disorder
• Page 8 Line 260 replace [11] with [13]
• Page 8 Line 261 replace OUD with opioid use disorder
• Page 8 Line 262 replace [7] with [11]
• Page 8 Line 264 replace OUD with opioid use disorder
• Page 8 Line 266 replace OUD with opioid use disorder
• Page 8 Line 270 replace OUD with opioid use disorder
• Page 9 Line 274 replace [12] with [14]
• Page 9 Line 277 replace [13] with [15]
• Page 9 Line 310 This decision to use a statistical test that is sensitive to early differences in the survival curves was informed by prior studies emphasizing that buprenorphine discontinuation at early timepoints (0 – 38 weeks) within the postpartum period are critical for clinicians to make timely interventions [2,16,17].
• Page 9 Line 318 replace [13,14] with [15,18]
• Page 9 Line 319 replace [15,16] with [19,20]
• Page 10 Reference list updated to reflect changes made to the manuscript.

Reviewer 2 Report

The authors have conducted a study to find any association between opioid prescription during post-partum with buprenorphine discontinuation in pregnant patients taking buprenorphine as MOUD. The results report a non-significant association and apart from presence of psychiatric morbidity, no other factor influenced buprenorphine discontinuation.

Few queries from my side are as follows:

1.     Did the authors try to look into various reasons for buprenorphine discontinuation by patients?

2.     The incidence of opioid prescription at hospital discharge was very less and approximately only one-fourth of the patients. What is the protocol for opioid prescription at study site for example which type of cases are prescribed opioids, and any other factors which are taken into consideration for prescribing opioids post delivery?

3.     In introduction, the study rationale is not very clear. I would suggest to rephrase particularly last paragraph of introduction for a better understanding of the readers.

Minor editing required.

Author Response

RESPONSE TO REVIEWER 2 COMMENTS

1. Summary: The authors have conducted a study to find any association between opioid prescription during post-partum with buprenorphine discontinuation in pregnant patients taking buprenorphine as MOUD. The results report a non-significant association and apart from presence of psychiatric morbidity, no other factor influenced buprenorphine discontinuation.

Thank you very much for taking the time to review this manuscript.

3. Point-by-point response to Comments and Suggestions for Authors

Comment 1: Did the authors try to look into various reasons for buprenorphine discontinuation by patients?

We did not specifically assess such reasons, but we certainly agree that further research should conduct an in-depth investigation into the intrapersonal, interpersonal, and structural factors that could influence buprenorphine discontinuation. We added an additional sentence to paragraph 2 (Lines 235-237) in the discussion to highlight this important point.

“Further survey-based and qualitative research is needed to understand the potential intrapersonal, interpersonal, and structural factors that could influence buprenorphine discontinuation during the high-risk postpartum period.”

Comment 2: The incidence of opioid prescription at hospital discharge was very less and approximately only one-fourth of the patients. What is the protocol for opioid prescription at study site for example which type of cases are prescribed opioids, and any other factors which are taken into consideration for prescribing opioids post delivery?

Thank you for your comment, we agree that the incidence of opioid prescription at hospital discharge was lower than those who did not receive an opioid prescription at discharge and that this could have affected our results. We have addressed this in paragraph 3 of the discussion (Line 240-244).  This prevalence of opioid prescription at discharge is expected due to fact that 36% of the sample had Cesarean procedures. It is expected that most, but not all, patients who get a Cesarean typically receive an opioid prescription.

First, receipt of an opioid prescription at hospital discharge was rare, with only 37 patients (26% of total sample) receiving a prescription. The disproportionate sample sizes between individuals who received vs. did not receive an opioid prescription at discharge makes it difficult to draw conclusions about the differences between these two groups.

 The protocol for opioid prescriptions at the current study site follow the CDC recommendations (Line 289-292).

“For clinical context, opioid prescriptions provided at discharge following delivery generally consist of oxycodone 5 mg tablets with amounts protocolized to be in line with CDC recommendations (e.g., 3-7 days of prescription).”

Comment 3: In introduction, the study rationale is not very clear. I would suggest to rephrase particularly last paragraph of introduction for a better understanding of the readers.

Thank you for this comment. The introduction has been revised and two additional citations have been added to help clarify the study rationale.

4. Itemized, point by point response to the comments of the reviewers and changes that were made in the manuscript.

• Page 1 Line 34 Remove (ACOG)
• Page 1 Line 36 Replace The ACOG-recommended treatment for pregnant individuals with opioid use disorder (OUD) includes medications for OUD[1]. with The American College of Obstetricians and Gynecologists -recommended treatment for pregnant individuals with opioid use disorder includes medications for opioid use disorder(e.g., buprenorphine) during pregnancy, delivery, and postpartum.
• Page 1 Line 41 replace [2] and opioid overdose is the leading cause of postpartum maternal death in individuals with OUD with and opioid overdose is the leading cause of postpartum maternal death in individuals with opioid use disorder [3]
• Page 1 Line 43 replace OUD (MOUD) with medication for opioid use disorder.
• Page 2 Line 46 replace OUD with opioid use disorder
• Page 2 Line 47 insert In one study of over 1500 birthing people diagnosed with opioid use disorder, 42.9% received buprenorphine treatment throughout their pregnancy, however one third experienced a treatment disruption during the postpartum period [5]. after [4].
• Page 2 Line 50 replace MOUD with medication for opioid use disorder
• Page 2 Line 52 replace continuate with adherence
• Page 2 Line 54 replace MOUD with mediation for opioid use disorder
• Page 2 Line 55 replace MOUD with medication for opioid use disorder
• Page 2 Line 57 replace MOUD with medication for opioid use disorder
• Page 2 Line 61 replace [5] with [6]
• Page 2 Line 63 replace MOUD with medication for opioid use disorder
• Page 2 Line 64 replace On the other hand, another. with Another recent study found that opioid refill rates for post-delivery pain were increased in patients with opioid use disorder or chronic pain compared to individuals without these diagnoses [7]. On the other hand, one
• Page 2 Line 68 OUD with opioid use disorder [8]. This literature indicates that there is likely an association between opioid prescription receipt and medication for opioid use disorder treatment adherence during the postpartum period. However, the directionality of this relationship has not yet been determined.
• Page 2 Line 74 replace OUD with opioid use disorder
• Page 2 Line 75 remove Qualitative studies have reported that nurses and obstetric providers are unsure how to address pain management during labor and the postoperative period for individuals with OUD and patients taking MOUD [7].
• Page 2 Line 76 replace [8] with [9]
• Page 2 Line 77 replace [5] with [6]
• Page 2 Line 78 replace MOUD with medication for opioid use disorder
• Page 2 Line 86 replace [8]. However, the association between prescription opioid-managed postpartum pain and MOUD continuation has not yet been determined. Accordingly, this study of pregnant individuals receiving buprenorphine for OUD with with [9,10]. Qualitative studies have reported that nurses and obstetric providers are unsure how to address pain management during labor and the postoperative period for individuals with opioid use disorder and patients taking medication for opioid use disorder [11]. This uncertainty is in part due to the lack of evidence-based recommendations for clinicians regarding how to safely and effectively prescribe opioids postpartum patients with opioid use disorder. Accordingly, this study of opioid use disorder patients maintained on buprenorphine
• Page 2 Line 89 insert while also supporting adherence to recovery after pain management
• Page 2 Line 90 replace MOUD with medication for opioid use disorder
• Page 4-5 see table 1 for changes made
• Page 5 Line 116 remove or chi square test (categorical data)
• Page 5 Line 117 replace patients with ²Differences between patients who continued vs. discontinued buprenorphine within the 52-week study period were assessed using a
• Page 5 Line 119 insert ³patient before could
• Page 6 Line 121 replace ³ with ⁴
• Page 7 Line 207 replace These results with However, the Cox proportional hazards model did indicate that, after adjusting for opioid prescription at delivery, incarceration at delivery, receipt of buprenorphine before delivery, and chronic pain, the presence of a psychiatric comorbidity was associated with a reduced risk of buprenorphine discontinuation. This result is consistent with a previous study [13], which suggested that individuals with a psychiatric comorbidity may be at reduced risk of discontinuing buprenorphine treatment due to multiple factors such as increased engagement in opioid use disorder care and potentially more contact points with various dimensions (e.g., addiction care, mental health, recovery support services) of the integrated care model within the academic center in which this study was conducted. Overall, the results of the current study
• Page 7 Line 217 replace this finding is sensitive to the methods and other factors may be with but it is likely not the main factor leading to buprenorphine discontinuation. There are additional factors, such as engagement with other addiction and mental health care services, that are likely to play a more meaningful role in
• Page 8 Line 220 after influencing this relationship. insert As such, a clinician’s decision to prescribe opioids to postpartum patients with opioid use disorder should take into consideration individualized patient factors
• Page 8 Line 223 replace OUD with opioid use disorder
• Page 8 Line 229 replace OUD with opioid use disorder
• Page 8 Line 230 replace OUD with opioid use disorder
• Page 8 Line 231 replace OUD with opioid use disorder
• Page 8 Line 235 after pregnancy insert Further survey-based and qualitative research is needed to understand the potential intrapersonal, interpersonal, and structural factors that could influence buprenorphine discontinuation during the high-risk postpartum period.
• Page 8 Line 251 replace OUD with opioid use disorder
• Page 8 Line 253 replace OUD with opioid use disorder
• Page 8 Line 254 replace OUD with opioid use disorder
• Page 8 Line 255 replace [10] with [12]
• Page 8 Line 256 replace OUD with opioid use disorder
• Page 8 Line 257 replace OUD with opioid use disorder
• Page 8 Line 260 replace [11] with [13]
• Page 8 Line 261 replace OUD with opioid use disorder
• Page 8 Line 262 replace [7] with [11]
• Page 8 Line 264 replace OUD with opioid use disorder
• Page 8 Line 266 replace OUD with opioid use disorder
• Page 8 Line 270 replace OUD with opioid use disorder
• Page 9 Line 274 replace [12] with [14]
• Page 9 Line 277 replace [13] with [15]
• Page 9 Line 310 This decision to use a statistical test that is sensitive to early differences in the survival curves was informed by prior studies emphasizing that buprenorphine discontinuation at early timepoints (0 – 38 weeks) within the postpartum period are critical for clinicians to make timely interventions [2,16,17].
• Page 9 Line 318 replace [13,14] with [15,18]
• Page 9 Line 319 replace [15,16] with [19,20]
• Page 10 Reference list updated to reflect changes made to the manuscript.

Round 2

Reviewer 1 Report

The authors adressed the comments and incorporated in the manuscript. I have no further comments to add. My decision is to accept in the current form. 

Author Response

Thank you, we appreciate your feedback!