Opioid Use, Pain, Pregnancy Related
Conditions
Brief summary
Non-inferiority randomized trial of 5,500 women with a cesarean delivery randomized prior to discharge to either an individualized opioid prescription protocol (IOPP) that includes shared decision making or to a fixed opioid prescription of 20 tablets of oxycodone 5mg.
Detailed description
This was a non-inferiority multi-center unblinded randomized trial of 5,500 women undergoing a cesarean delivery who were randomized before discharge to either an individualized opioid prescription protocol (IOPP) that includes shared decision making or to a fixed opioid prescription of 20 tablets of oxycodone 5mg. The primary endpoint was the presence/absence of moderate to severe pain at 1 week after discharge. Moderate to severe pain was defined as a value of 4 or higher on the Brief Pain Inventory worst pain scale (0 to 10) in the last 24 hours. Consenting women were assigned in a 1:1 ratio to one of the two arms using a secure internet based randomization system maintained centrally by the Data Coordinating Center (DCC). Randomization was stratified by site. Women were followed through 90 days postpartum.
Interventions
DRUG0 to 20 tablets of oxycodone 5mg
Individualized opioid prescription protocol (IOPP) that includes shared decision making
DRUGFixed opioid prescription
20 tablets of oxycodone 5mg
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The George Washington University Biostatistics Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Participants were randomized to either an individualized opioid prescription protocol (IOPP) that includes shared decision making or to a fixed opioid prescription of 20 tablets of oxycodone 5mg.
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
* Post cesarean delivery (combined vaginal/cesarean deliveries are not eligible) * Singleton, twin or triplet gestation
Exclusion criteria
* An opioid prescription filled during the current pregnancy * Known history of opioid use disorder, by medical record review * Contraindication to opioids (oxycodone) * Contraindications to both acetaminophen and ibuprofen * Significant surgical procedures (e.g., hysterectomy) prior to randomization as pain trajectory will be completely different * Fetal or neonatal death prior to randomization * Inability to randomize within 1 day before planned discharge from the hospital * Inability to participate in shared decision making as assessed by research staff * Language barrier (non-English or Spanish speaking) * Participation in this trial in a previous pregnancy * Participation in another intervention study that influences the primary outcome in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Worst Pain Score of Moderate to Severe on the Brief Pain Inventory | 1 week post hospital discharge | Number of participants with moderate to severe pain at 1 week post-discharge; moderate to severe pain is defined as a value of 4 or higher on the Worst Pain question of the Brief Pain Inventory (BPI) in the last 24 hours. The BPI measures pain severity on a numeric scale of 0 to 10, with 0 being no pain and 10 being the highest level of pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Opioid Prescriptions Filled | 90 days postpartum | Number of opioid prescriptions filled by ninety days postpartum |
| Number of Opioid Tablets Unused Since Discharge | 90 days postpartum | Number of opioid tablets unused from discharge to 90 days postpartum |
| Number of Morphine Milligram Equivalents Used at 2 Weeks Post Discharge | 2 weeks post discharge | Total morphine milligram equivalents (MME) used from discharge to 2 weeks post-discharge. MME is the amount of milligrams of morphine an opioid dose is equal to when prescribed. Calculating MME accounts for differences in opioid drug type and strength. |
| Worst Pain Severity Score at 2 Weeks Post Discharge | 2 weeks post discharge | Pain severity scores assessed on the Brief Pain Inventory numeric scale from 0 to 10 at 2 weeks post-discharge. The BPI measures pain severity on a numeric scale of 0 to 10, with 0 being no pain and 10 being the highest level of pain. |
| Number of Participants Who Filled One or More Opioid Prescriptions Beyond the Amount Prescribed at Discharge | After hospital discharge and up to 90 days postpartum | Number of participants who filled one or more opioid prescriptions beyond what was prescribed to them at discharge - measured at ninety days postpartum |
| Number of Participants Who Indicated an Improved Global Impression of Change | 2 weeks post discharge | Number of participants who indicated an improved global impression of change in overall pain at 2 weeks post-discharge. This represents a selection on a multiple choice survey question with the response options: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. |
| Infant Hospital Readmissions | 6 weeks postpartum | Proportion of infants readmitted to the hospital |
| Maternal Depression Score ≥ 13 | 6 weeks postpartum | The proportion of participants with a score of 13 or higher on the Edinburgh Postnatal Depression Scale. The minimum score is 0 and the maximum score is 30. Higher scores indicate worse outcomes, where persons scoring about 13 are likely to be suffering from a depressive illness. The scale indicates how the respondent has felt during the previous week. |
| Pain Interference Score ≥ 4 at 2 Weeks Post Discharge | 2 weeks post discharge | Pain interference scores ≥ 4 on the Brief Pain Inventory (numeric scale from 0 to 10) at 2 weeks post-discharge. The BPI measures pain severity on a numeric scale of 0 to 10, with 0 being no pain and 10 being the highest level of pain. This outcome asks participants to indicate their pain scores for the week prior to completing the inventory. |
Countries
United States
Participant flow
Recruitment details
We conducted this multicenter, randomized, controlled, double blinded trial at 31 hospitals. From September 2020 through March 2022, a total of 18,990 patients underwent screening for randomization. Of the 9,963 eligible patients, 5,521 provided informed consent and were randomized
Pre-assignment details
1 participant in the Fixed Opioid Prescription Arm/Group was reenrolled in the study for a second pregnancy
Participants by arm
| Arm | Count |
|---|---|
| Individualized Opioid Prescription Individualized opioid prescription protocol (IOPP) with shared decision making
IOPP will be based on inpatient oral opioid intake during the 24 hour period prior to randomization and should not include the 12 hours immediately after the cesarean. | 2,748 |
| Fixed Opioid Prescription Fixed amount of opioids (20 tablets of oxycodone 5mg) | 2,772 |
| Total | 5,520 |
Baseline characteristics
| Characteristic | Individualized Opioid Prescription | Fixed Opioid Prescription | Total |
|---|---|---|---|
| Age, Continuous | 30.5 years STANDARD_DEVIATION 5.7 | 30.3 years STANDARD_DEVIATION 5.8 | 30.4 years STANDARD_DEVIATION 5.7 |
| Number of cesarean deliveries One | 1623 Participants | 1630 Participants | 3253 Participants |
| Number of cesarean deliveries Three or more | 394 Participants | 406 Participants | 800 Participants |
| Number of cesarean deliveries Two | 730 Participants | 735 Participants | 1465 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized American Indian/Alaskan Native | 24 Participants | 17 Participants | 41 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized Asian | 118 Participants | 119 Participants | 237 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized Hispanic | 574 Participants | 589 Participants | 1163 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized More than one race | 72 Participants | 78 Participants | 150 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized Native Hawaiian/Pacific Islander | 9 Participants | 7 Participants | 16 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized Non-Hispanic Black | 759 Participants | 746 Participants | 1505 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized Non-Hispanic White | 1158 Participants | 1194 Participants | 2352 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Customized Unknown/Not Reported | 34 Participants | 22 Participants | 56 Participants |
| Sex: Female, Male Female | 2748 Participants | 2772 Participants | 5520 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Type of labor Induced | 778 Participants | 805 Participants | 1583 Participants |
| Type of labor No labor | 1411 Participants | 1392 Participants | 2803 Participants |
| Type of labor Spontaneous | 558 Participants | 574 Participants | 1132 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2,748 | 0 / 2,772 | 11 / 2,856 | 8 / 2,889 |
| other Total, other adverse events | 166 / 2,748 | 186 / 2,772 | 0 / 2,856 | 0 / 2,889 |
| serious Total, serious adverse events | 133 / 2,748 | 96 / 2,772 | 37 / 2,856 | 30 / 2,889 |
Outcome results
Primary
Number of Participants With Worst Pain Score of Moderate to Severe on the Brief Pain Inventory
Number of participants with moderate to severe pain at 1 week post-discharge; moderate to severe pain is defined as a value of 4 or higher on the Worst Pain question of the Brief Pain Inventory (BPI) in the last 24 hours. The BPI measures pain severity on a numeric scale of 0 to 10, with 0 being no pain and 10 being the highest level of pain.
Time frame: 1 week post hospital discharge
Population: Of 2273 participants in the fixed group, 1 was enrolled in the study for a second pregnancy. Only the first pregnancy was included in the analysis. The primary analysis included participants who completed the highest pain in the last 24 hours on the Brief Pain Inventory at 1 week post-discharge. This data was missing for 230 participants in the individualized opioid prescription group and 219 participants in the fixed group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Opioid Prescription | Number of Participants With Worst Pain Score of Moderate to Severe on the Brief Pain Inventory | 1497 Participants |
| Fixed Opioid Prescription | Number of Participants With Worst Pain Score of Moderate to Severe on the Brief Pain Inventory | 1535 Participants |
95% CI: [-2.03, 3.37]
Secondary
Infant Hospital Readmissions
Proportion of infants readmitted to the hospital
Time frame: 6 weeks postpartum
Population: 2856 and 2889. Data is missing for 102 neonates in the IOPP group and 92 neonates in the fixed opioid group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Opioid Prescription | Infant Hospital Readmissions | 59 Participants |
| Fixed Opioid Prescription | Infant Hospital Readmissions | 63 Participants |
Secondary
Maternal Depression Score ≥ 13
The proportion of participants with a score of 13 or higher on the Edinburgh Postnatal Depression Scale. The minimum score is 0 and the maximum score is 30. Higher scores indicate worse outcomes, where persons scoring about 13 are likely to be suffering from a depressive illness. The scale indicates how the respondent has felt during the previous week.
Time frame: 6 weeks postpartum
Population: data is missing for 252 participants in the IOPP group and 276 participants in the fixed prescription group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Opioid Prescription | Maternal Depression Score ≥ 13 | 185 Participants |
| Fixed Opioid Prescription | Maternal Depression Score ≥ 13 | 191 Participants |
Secondary
Number of Morphine Milligram Equivalents Used at 2 Weeks Post Discharge
Total morphine milligram equivalents (MME) used from discharge to 2 weeks post-discharge. MME is the amount of milligrams of morphine an opioid dose is equal to when prescribed. Calculating MME accounts for differences in opioid drug type and strength.
Time frame: 2 weeks post discharge
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Individualized Opioid Prescription | Number of Morphine Milligram Equivalents Used at 2 Weeks Post Discharge | 22.5 morphine milligram equivalent |
| Fixed Opioid Prescription | Number of Morphine Milligram Equivalents Used at 2 Weeks Post Discharge | 37.5 morphine milligram equivalent |
p-value: <0.00198.75% CI: [-19.2, -10.8]quartile regression
Secondary
Number of Opioid Prescriptions Filled
Number of opioid prescriptions filled by ninety days postpartum
Time frame: 90 days postpartum
Population: 94 missing in the IOPP group. 75 missing in the fixed group
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Individualized Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled one prescription | 1873 Participants |
| Individualized Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled 3 prescriptions | 12 Participants |
| Individualized Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled 2 prescriptions | 163 Participants |
| Individualized Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled 4 prescriptions | 5 Participants |
| Individualized Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled zero prescriptions | 601 Participants |
| Fixed Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled 4 prescriptions | 3 Participants |
| Fixed Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled zero prescriptions | 452 Participants |
| Fixed Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled one prescription | 2086 Participants |
| Fixed Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled 2 prescriptions | 140 Participants |
| Fixed Opioid Prescription | Number of Opioid Prescriptions Filled | Number of participants who filled 3 prescriptions | 16 Participants |
p-value: <0.001Chi-squared
Secondary
Number of Opioid Tablets Unused Since Discharge
Number of opioid tablets unused from discharge to 90 days postpartum
Time frame: 90 days postpartum
Population: Data were missing for 207 participants in the IOPP group and for 180 in the fixed group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Individualized Opioid Prescription | Number of Opioid Tablets Unused Since Discharge | 2 tablets |
| Fixed Opioid Prescription | Number of Opioid Tablets Unused Since Discharge | 7 tablets |
p-value: <0.00197.5% CI: [-6.6, -3.5]quantile regression
Secondary
Number of Participants Who Filled One or More Opioid Prescriptions Beyond the Amount Prescribed at Discharge
Number of participants who filled one or more opioid prescriptions beyond what was prescribed to them at discharge - measured at ninety days postpartum
Time frame: After hospital discharge and up to 90 days postpartum
Population: Of 2273 participants in the fixed group, 1 was enrolled in the study for a second pregnancy. Only the first pregnancy was included in the analysis. This data was missing for 94 participants in the individualized opioid prescription group and 76 participants in the fixed group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Opioid Prescription | Number of Participants Who Filled One or More Opioid Prescriptions Beyond the Amount Prescribed at Discharge | 200 Participants |
| Fixed Opioid Prescription | Number of Participants Who Filled One or More Opioid Prescriptions Beyond the Amount Prescribed at Discharge | 166 Participants |
p-value: 0.04696.25% CI: [0.99, 1.51]Chi-squared
Secondary
Number of Participants Who Indicated an Improved Global Impression of Change
Number of participants who indicated an improved global impression of change in overall pain at 2 weeks post-discharge. This represents a selection on a multiple choice survey question with the response options: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse.
Time frame: 2 weeks post discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Opioid Prescription | Number of Participants Who Indicated an Improved Global Impression of Change | 2436 Participants |
| Fixed Opioid Prescription | Number of Participants Who Indicated an Improved Global Impression of Change | 2436 Participants |
p-value: 0.1595% CI: [0.98, 1]Regression, Linear
Secondary
Pain Interference Score ≥ 4 at 2 Weeks Post Discharge
Pain interference scores ≥ 4 on the Brief Pain Inventory (numeric scale from 0 to 10) at 2 weeks post-discharge. The BPI measures pain severity on a numeric scale of 0 to 10, with 0 being no pain and 10 being the highest level of pain. This outcome asks participants to indicate their pain scores for the week prior to completing the inventory.
Time frame: 2 weeks post discharge
Population: Data were missing for 234 participants in the IOPP group and for 286 in the fixed group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Opioid Prescription | Pain Interference Score ≥ 4 at 2 Weeks Post Discharge | 415 Participants |
| Fixed Opioid Prescription | Pain Interference Score ≥ 4 at 2 Weeks Post Discharge | 427 Participants |
p-value: 0.5295% CI: [0.85, 1.09]Chi-squared
Secondary
Worst Pain Severity Score at 2 Weeks Post Discharge
Pain severity scores assessed on the Brief Pain Inventory numeric scale from 0 to 10 at 2 weeks post-discharge. The BPI measures pain severity on a numeric scale of 0 to 10, with 0 being no pain and 10 being the highest level of pain.
Time frame: 2 weeks post discharge
Population: Data were missing for 234 participants in the IOPP group and for 286 in the fixed group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Individualized Opioid Prescription | Worst Pain Severity Score at 2 Weeks Post Discharge | 2.0 score on a scale |
| Fixed Opioid Prescription | Worst Pain Severity Score at 2 Weeks Post Discharge | 2.0 score on a scale |
p-value: 195% CI: [0, 0]quantile regression