Clinical trial NCT03472521
Conditions: Opioid Use Postpartum Disorder Chronic Pain Syndrome
Sponsor: Stanford University
Start date: 2018-09-17; Completion date: 2021-04-10
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Our previous work has identified the group of women at risk for prolonged pain, opioid use and poor functional recovery after childbirth. The optimal intervention to mitigate this risk is unknown. We propose to test an analgesic adjutant that is commonly used for post-operative pain compared to placebo to improve post-partum recovery.

Detailed description:
A small percent of the large population of women who give birth have difficulty with prolonged pain, opioid use and poor functional recovery. This may be the first opiate exposure and significant health challenge in a young woman's life.

In our previous work, we have identified 20% who are at highest risk for prolonged pain and delayed opioid cessation and functional recovery with usual care. Moderate to severe pain on postpartum day 1 is a significant predictor of being in the risk group. The optimal intervention to mitigate this risk is unknown.

We plan to test an intervention of low dose gabapentin or placebo to be escalated by a pain medicine doctor as needed. We hypothesize that additional care of women predicted to be higher need by virtue of their postoperative day one pain score (\> 6 x2) despite usual multimodal analgesic care will lead to reduced need for opioid, less pain and more rapid functional recovery.

Arms: arm 1: Gabapentin 300 mg capsules will be prescribed at a starting dose of 1 capsule three times a day and titrated on the recommendation of a chronic pain specialist. arm 2: Matched placebo capsules will be prescribed at a starting dose of 1 capsule three times a day and titrated on the recommendation of a chronic pain specialist.
Interventions: intervention 1: Gabapentin intervention 2: Placebo
Intervention descriptions: intervention 1: Treatment with analgesic adjutant commonly used for post-operative pain, titrated to effect by chronic pain specialist compared to placebo titration. intervention 2: Placebo to match gabapentin

Protocol documents:
Prot_000.pdf: 
 
Prevention of Persistent Pain and Opioid Use in Mothers – POMS 
NCT03472521 
February 11, 2020 
Pamela Flood, Principal Investigator 
Stanford University 
Stanford, California 94305 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
While most women have uneventful recovery after childbirth, we have identified 20% 
who are at risk for prolonged pain and delayed opioid cessation and functional recovery 
with usual care in our previous work. Moderate to severe pain on postpartum day 1-2 is a 
significant predictor of being in the risk group. We plan to test an intervention of low 
dose gabapentin or placebo on the time that women require opioid analgesia. We 
hypothesize that outpatient treatment with gabapentin in high risk women (postoperative 
day one pain score (NRS > 6 x 2) despite usual multimodal analgesia) will lead to 
reduced need for opioid, less pain and more rapid functional recovery. 
b. 
Objectives 
We will determine whether treatment of high risk women with gabapentin in the 
outpatient setting will reduce time to opioid cessation.  
c. 
Rationale for Research in Humans 
Pain during the postpartum period is unique in humans and cannot be studied in animals.  
2. 
STUDY PROCEDURES 
a. 
Procedures 
Patients who deliver at Lucille Packard Hospital who report at least 2 NRS pain scores of 
6-10 despite receiving the normally prescribed multimodal analgesic protocol will be 
approached for enrollment. They will be offered gabapentin starting at 300 mg tid or 
placebo tablets in addition to their usual multimodal pain regimen (scheduled 
acetaminophen, a non-steroidal anti-inflammatory and prn oxycodone). Assignment to 
treatment group will be according to a randomization table available only to the research 
pharmacist. All patients will have access to Dr. Flood by email or text for optimal 
titration of study drug or any significant problems. They will be advised to titrate off their 
opioid first, followed by study drug, followed by non-steroidal anti-inflammatory 
medications and acetaminophen. 


February 11, 2020 
 
Page 2 of 7 
 
All study subjects will receive a weekly survey with pain report, medication use and side 
effects for a maximum of 12 weeks or until pain report they report that they have 
recovered to their usual state of health. In addition the weekly survey will include 
PROMIS questionnaires for sleep, fatigue, depression, anxiety and physical. The subject 
will receive a $10 gift card by email when each weekly questionnaire is completed. The 
primary outcome variable will be time to opioid cessation. Secondary outcomes will be 
pain report, functional recovery  PROMIS questionnaire responses, breast feeding, and 
anticipated side effects of opioids including nausea, constipation, and fatigue. 
 
Subjects will be offered the opportunity to wear a wrist worn fitness tracking device. The 
device will track their daily steps taken and sleep efficacy. The results will be compared 
between the active and placebo groups at the end of the study. Baseline expectations for 
mobility and sleep efficacy will also be recorded and published as this information is 
scant in the literature. The device will be theirs to keep at the end of the study. 
 
To evaluate the effect of the intervention on the participant's longer-term wellbeing, those 
who have agreed to be contacted for future studies on the original consent will be 
contacted with an email/text script that is attached one year after delivery. If they consent, 
the questionnaire that that had completed weekly during the 12 week study will be sent to 
them through Redcap. 
b. 
Procedure Risks 
Gabapentin is a medication that is commonly used for breakthrough pain in women 
immediately post-partum at LPCH and in the treatment of epilepsy throughout 
pregnancy. It is a commonly used analgesic for post-operative pain and chronic 
neuropathic pain and fibromyalgia outside of pregnancy. There are mixed data on its 
immediate inpatient post partum analgesic efficacy but has not been studied for longer 
term outpatient recovery benefit for opioid cessation or pain management in this high risk 
group.. 
 
Gabapentin has a low molecular weight and minimal protein-binding in plasma. It has 
penetration into breast milk, with an M/P ratio of 1.1 (range 0.5–2.0) [1-3]. Maternal 
gabapentin doses up to 2100 mg daily produced low infant serum concentrations between 
1 and 6% of the mother's levels, and with no adverse effects in the neonates [1-3]. 
 
1. Kristensen JH, Ilett KF, Hackett LP, et al. Gabapentin and breastfeeding: a case report. 
J Hum Lact 2006;22(4):426–8. 
2. Hovinga CA, Pennell PB. Antiepileptic drug therapy in pregnancy II: fetal and 
neonatal exposure. Int Rev Neurobiol 2008;83:241–58. 
3. Ilett K, Kristensen J. Drug use and breastfeeding. Expert Opin Drug Saf 
2005;4(4):745–68.  
c. 
Use of Deception in the Study 
Deception will not be used. 
d. 
Use of Audio and Video Recordings 


February 11, 2020 
 
Page 3 of 7 
There will be no audio or video recording. 
e. 
Alternative Procedures or Courses of Treatment 
This study drug (gabapentin or placebo) will be added in addition to the usual standard of 
care. In addition, all subjects will be under the supervision of a pain management 
specialist who will provide an enhanced level of care. There is no other routine treatment 
that will be prevented by virtue of the study. If the patient's pain is not well maintained, 
they will be referred to the pain management clinic for further evaluation where they 
would be offered any care deemed necessary regardless of study enrollment. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
If the patient wishes to continue active treatment, they will be referred to pain 
management for further care. 
g. 
Study Endpoint(s) 
The study endpoint will be the day on which there is a report of pain no different than 
baseline, no analgesic requirement and patient reported functional recovery. The 
participant will be recontacted at 12 - 18 months for their permission to receive another 
survey. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
Our previous work has used daily follow-up after delivery to determine norms for pain 
and opioid cessation with functional recovery (2). After cesarean delivery, 27 [19 to 40] 
days are required for pain and opioid-free functional recovery, 9 [5 to 12] for opioid 
cessation, 16 [11 to 24] for pain resolution, and 21 [14 to 27] days for functional 
recovery, respectively in the general population (median [interquartile range (IQR)]).[1] 
 
Two factors allowed for identification of pain burden, post-operative day 1 NRS score > 
6 and labor induction prior to cesarean delivery. High reports of labor pain immediately 
cesarean delivery has previously been found to be predictive of poorer outcome. NIH 
PROMIS anxiety score and Rand (36) item Health Survey SF36 score was predictive of 
delayed opioid cessation in addition.[2] 
 
1. Komatsu R, Carvalho B, Flood PD. Recovery after Nulliparous Birth: A Detailed 
Analysis of Pain Analgesia and Recovery of Function. Anesthesiology. 2017 
Oct;127(4):684-694.  
2. Komatso R, Carvalho B, Flood P. Prediction of pain, analgesia requirement and 
recovery of function after childbirth. Br J Anaesth 2018; 121:417-26. 
b. 
Findings from Past Animal Experiments 
N/A 
4. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 


February 11, 2020 
 
Page 4 of 7 
a. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
Gabapentin 
Dosage: 
300-1200 mg tid 
Administration Route 
Oral 
New and different use? (Y/N) 
No 
5. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
N/A 
 
6. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
78 patients will be enrolled, 39 in active and 39 in placebo arm  
b. 
Age, Gender, and Ethnic Background 
All subjects will be women who have given birth by cesarean section within on week, age 
>18 years with any ethnic background who can understand English well enough to give 
consent and answer written questionnaires administered in English.  
c. 
Vulnerable Populations 
N/A 
d. 
Rationale for Exclusion of Certain Populations 
All subjects will be women after childbearing which is most common in adults.  
e. 
Stanford Populations 
Laboratory personnel, employees, and/or students will not be specifically targeted for 
enrollment but will not be excluded if the meet entry criteria. They will be treated the 
same as any other subject.  
f. 
Healthy Volunteers 
No healthy volunteers  
g. 
Recruitment Details 
Subjects will be identified by review of Epic dashboard post cesarean section for at least 
2 NRS scores > 6 and will be approached by study investigators to discuss interest in the 
study in the post-partum unit at Stanford Hospital. At that time, the prospective patient 
will be provided a handout with information on the purpose of the study, eligibility for 
the study, safety of gabapentin, and participant responsibilities should they enroll. The 
prospective patient can then review this material on their own time and consider whether 
they would like to discuss the study further.  


February 11, 2020 
 
Page 5 of 7 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
Recent delivery, NRS > 6 on 2 occasions  
ii. 
Exclusion Criteria 
Allergy or intolerance to gabapentin. Age <18 years. Inability to complete study 
questionnaires and provide consent in English. Prepartum use of analgesics within 
one month. History of epilepsy.  
i. 
Screening Procedures 
Screening for NRS score will be using EPIC. Other criteria will be evaluated by 
investigator prior to consent.  
j. 
Participation in Multiple Protocols 
Subjects can be enrolled in more than one protocol if it does not require additional study 
drugs post partum. The subject will be asked if they are participating in any other studies.  
k. 
Payments to Participants 
Because the weekly questionnaire will take some time to complete, the subject will be 
paid a token $10 as an amazon gift card on completion of each weekly study 
questionnaire completed at home. They will be allowed to keep the fitness tracker at the 
completion of the 12 week study.  
l. 
Costs to Participants 
There will be no costs to the participant. Study drug will be provided free of charge.  
m. 
Planned Duration of the Study 
In our previous study, the range of days to study completion was 3-85 days. As such, we 
expect the maximal duration to be 12 weeks.  
7. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
None 
ii. 
Investigational drugs 
None 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
Withdrawal precipitated seizure: will not be used in patients with epilepsy 
 


February 11, 2020 
 
Page 6 of 7 
Tumorigenic Potential- In epilepsy trials, with 2085 patient years of exposure, 10 new 
tumors were reported. It is unknown what the baseline incidence of these tumors would 
be in untreated patients and thus it is unknown whether this is above baseline. 
 
Nursing mothers: Gabapentin is secreted into human milk following oral administration. 
A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of 
gabapentin. Because the effect on the nursing infant is unknown, Neurontin should be 
used in women who are nursing only if the benefits clearly outweigh the risks. (package 
insert) 
 
Gabapentin has a low molecular weight and minimal protein binding in plasma. It has 
penetration into breast milk, with an M/P ratio of 1.1 (range 0.5–2.0). Maternal 
gabapentin doses up to 2100 mg daily produced low infant serum concentrations between 
1 and 6% of the mother’s levels, and with no adverse effects in the neonates (1-3). 
 
Hale’s Medications and Mother’s Milk lists Gabapentin in the “Safer” category out of 
categories of “Safer”, “Moderately Safe”, “Possibly Hazardous” and “Contraindicated 
 
1. Kristensen JH, Ilett KF, Hackett LP, et al. Gabapentin and breastfeeding: a case report. 
J Hum Lact 2006;22(4):426–8. 
2. Hovinga CA, Pennell PB. Antiepileptic drug therapy in pregnancy II: fetal and 
neonatal exposure. Int Rev Neurobiol 2008;83:241–58. 
3. Ilett K, Kristensen J. Drug use and breastfeeding. Expert Opin Drug Saf 
2005;4(4):745–68. 
4. Thomas Hale and Hilary Rowe, Medications in Mother's Milk.Copyright © 2017 
Springer Publishing Company, LLC  
iv. 
Procedures 
None 
v. 
Radioisotopes/radiation-producing machines 
N/A 
vi. 
Physical well-being 
Physical well being will be assessed regularly by the patient's obstetrician and through 
the study instruments.  
vii. 
Psychological well-being 
See above. Physical well being will be assessed regularly by the patient's obstetrician and 
by the pain management specialist through the study instruments and contact by patients 
if necessary.  
viii. 
Economic well-being 
There should be no economic cost.  
ix. 
Social well-being 


February 11, 2020 
 
Page 7 of 7 
There should be no social cost.  
x. 
Overall evaluation of risk 
Low - innocuous procedures such as phlebotomy, urine or stool collection, no therapeutic 
agent, or safe therapeutic agent such as the use of an FDA approved drug or device.  
b. 
International Research Risk Procedures 
N/A 
c. 
Procedures to Minimize Risk 
The subjects will be followed with study instruments that indicate pain, opioid use, 
anxiety, function. The patient will specifically be asked about depression and anxiety. 
Any patient who indicates severe depression or anxiety will be immediately contacted by 
Dr. Flood, the study drug stopped and referred to the emergency room if indicated. The 
subjects will have the ability to immediately contact Dr. Flood should any emergency 
occur. 
 
Identifiable data will be kept on encrypted systems and will only be accessible by study 
personnel.  
d. 
Study Conclusion 
The patient will use the study drug as long for 12-weeks or until the indicate complete 
recovery is indicated and the study terminated. Patients with significant side effects (most 
commonly sedation) will be advised to reduce dose and stop if required. If any patient's 
pain is uncontrolled, they will have the option to contact Dr. Flood and be seen by in pain 
clinic.  
e. 
Data Safety Monitoring Plan (DSMC) 
The Protocol Director will be the only monitoring entity for this study. 
8. 
BENEFITS 
Patients at high risk for prolonged pain, opioid use and poor functional recovery will be treated 
with study drug that may be helpful. Even those assigned to placebo will have the benefit of 
contact information for a pain specialist who can advise them in general pain management and 
follow up in clinic if needed. 
9. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health. 

SAP_001.pdf: 
Prevention of Persistent Pain and Opioid Use in Mothers – POMS 
NCT03472521 
September 8, 2021 
Pamela Flood, Principal Investigator 
Stanford University 
Stanford, California 94305 
 
Statistical Analysis Plan 
 
All analyses used an intention to treat approach. All tests used a 2-sided p=0.05 (type I error). Data are 
presented as median [interquartile range, IQR] or number (percentage). Survival analysis was conducted 
using the Kaplan-Meier method to estimate the time to opioid cessation in gabapentin and placebo group. 
A log rank test was used to compare the time to opioid cessation in the two groups. Similar survival 
analyses were completed for time to pain relief and self-reported recovery. The data from NIH PROMIS 
questionnaires (depression, anxiety, fatigue, and physical function) were compared between the two 
groups using repeated measures mixed-effects model with unstructured covariance. Pairwise deletion was 
used for missing data. Analyses were performed with STATA version 14.0 (StataCorp, College Station, 
TX).