Clinical trial NCT02605187
Conditions: Postoperative Pain
Keywords: cesarean postoperative pain patient choice
Sponsor: Stanford University
Start date: 2015-11-01; Completion date: 2017-05-22
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The ability to predict pain and then apply modified treatment protocols has been limited. Current practice is for physicians to select standard post-operative pain treatment protocols without patient consultation. This study hopes to determine if patient's involvement in analgesic drug/dosage selection can optimize pain relief while minimizing related side effects. This could result in a more patient-centered care model and individualized perioperative analgesic treatment protocols based on patient's preferences, needs and expectations.

Detailed description:
This randomized, controlled study will include a simple, preoperative questionnaire to obtain baseline demographic and obstetric data; and complete questions (that have previously been shown to be predictive of postoperative pain) from which we will determine their expected and target postoperative pain scores. These questionnaires should take less than 3-4 minutes to complete.

The subject will then be randomized into "choice" and "no choice" groups. The randomization for choice vs. no choice will be at a 1:3 ratio i.e. 1 woman will get no choice and 3 will get a choice for their analgesic protocol. All women will receive the same medications for intraoperative anesthetic management -- only the postoperative pain medications will be altered.

The no choice group will receive the current standard analgesic protocol: medium dose intrathecal morphine, and around the clock acetaminophen po q6h and ibuprofen po q6h.

The group with the choice will be offered 3 different protocols:

1\. low dose intrathecal morphine, and around the clock acetaminophen po q6h and ibuprofen po q6h. 2 medium dose intrathecal morphine, and around the clock acetaminophen po q6h and ibuprofen po q6h. 3. high dose intrathecal morphine, and around the clock acetaminophen po q6h and ibuprofen po q6h, as well as gabapentin po one time within 1 hr of delivery.

Women randomized to the "choice" group will select a protocol after being given a standard script explaining advantages and disadvantages of each protocol.

Drugs and doses utilized in the study are safe for postpartum women and within dose range routinely used at our and other institutions.

All breakthrough pain will be managed the same for all patients, and adequate analgesia will be available to treat post-operative pain.

Primary breakthrough rescue analgesic will be our standard oral opioid oxycodone managed using our current treatment algorithm. If pain 1-4 out of 10, 1 tablet (5 mg) will be offered, if pain \>4 out of 10, 2 tablets (10 mg) will be offered PRN. Pain not responding to oral opioids will be offered IV morphine boluses or PCA as per standard treatment protocols. Additional analgesic options (e.g. TAP blocks) will also be available as per standard care.

Following standard Cesarean delivery, postoperative data will be collected (directly from patients and from the electronic medical record) by study investigators blinded to group assignment.

Outcome measures:

1. Pain scores at rest and on to sitting (VPS 0-10) collected at 3, 6, 12, 24, 36, 48 hours post-cesarean
2. Overall daily pain score and its deviation from target and expected pain score will be determined at 0-24 and \>24-48 hours study periods.
3. Opioid use (oral and IV morphine) in the 0-24 and \>24-48 hour study periods.
4. Time to first analgesic for breakthrough pain (minutes from spinal)
5. Side effect: Pruritus score (0-100), nausea score (0-100) and number of episodes of vomiting for the 0-24 and \>24-48 hour post- operative periods
6. Any treatment of pruritus and/or nausea/vomiting
7. Satisfaction with postoperative analgesia score (0-100)
8. Discharge time (hours/minutes from surgery end)

Telephone follow-up for pain score, opioid use, and functional recovery will be performed at 1 week, 1 month, 3 months and 6 months post-Cesarean. The telephonic questions will last 3-4 minutes

Arms: arm 1: No choice given medium dose intrathecal morphine acetaminophen po q6h ibuprofen po q6h arm 2: Choice given low dose intrathecal morphine acetaminophen po q6h ibuprofen po q6h arm 3: Choice given medium dose intrathecal morphine acetaminophen po q6h ibuprofen po q6h arm 4: Choice given high dose intrathecal morphine acetaminophen po q6h ibuprofen po q6h gabapentin po one time dose
Interventions: intervention 1: No choice given intervention 2: Choice given intervention 3: Ibuprofen intervention 4: Acetaminophen intervention 5: Gabapentin intervention 6: Morphine (low) intervention 7: Morphine (med) intervention 8: Morphine (high)
Intervention descriptions: intervention 1: Patients are randomized to getting a choice or not getting a choice. If they do not get a choice, they receive standard dose. intervention 2: Patients are randomized to getting a choice or not getting a choice. If they do get a choice, they will receive the protocol they select. intervention 3: Ibuprofen 600mg po q6h intervention 4: Acetaminophen 650mg po q6h intervention 5: Gabapentin 600mg po one time within 1 hour of delivery intervention 6: Intrathecal morphine dose 50mcg intervention 7: Intrathecal morphine dose 150mcg intervention 8: Intrathecal morphine 300mcg

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Patient-Driven Analgesic Protocol Selection for 
Post-Cesarean Pain Management 
NCT02605187 
October 26, 2015 
Brendan Carvalho, Principal Investigator 
Stanford University 
Stanford, California 94305 
 
 
 


Title 
Patient-Driven Analgesic Protocol Selection for Post-Cesarean Pain Management 
 
PI and other key investigators 
Dr. Carvalho is an anesthesiologist, with an emphasis in obstetrical anesthesia and research. 
 
 is an anesthesiologist, with an emphasis in obstetrical anesthesia and statistical analysis. 
 is an experienced clinical research coordinator. 
 is an 
experienced clinical research manager. The OB anesthesia fellows will help conduct the study. 
 
Objectives/Purpose 
Our ability to predict pain and then apply modified treatment protocols has been limited.  
Current practice is for physicians to select standard post-operative pain treatment protocols 
without patient consultation. This study hopes to determine if patient's involvement in 
analgesic drug/dosage protocol selection can optimize pain relief and minimize related side 
effects. Specifically, we will learn whether patient choice of analgesic protocols influences post-
operative pain, analgesic use, side effects and maternal satisfaction in the first 48 hours 
following Cesarean delivery. This could result in a more patient-centered care model and 
individualized perioperative analgesic treatment protocols based on patient's preferences, 
needs and expectations. 
 
Background Information 
Acute pain after surgery is a major and largely unrecognized problem. Studies highlight the 
need for improving the management and prevention of postsurgical pain with aggressive early 
therapy, since the intensity of acute postoperative pain correlates with the risk of developing a 
chronic pain state, (Kehlet et al. 2006). Severe acute pain is associated with persistent pain and 
post-partum depression after cesarean (Eisenach et al. 2008; Lavand'homme 2006). We have 
recently demonstrated that post-cesarean pain can be improved and opioid use reduced when 
patients are able to select their intrathecal morphine dose. (SOAP Best Paper Finalist 2015).  
This study explores this concept further to see if patient choice in the postoperative pain 
protocol will improve the post-cesarean pain experience, as well as improve side effects and 
maternal satisfaction. 
 
Preliminary unpublished data 
Carvalho B, Mirza F, Flood P. Women Randomized to Choice of Intrathecal Morphine Dose 
Before Surgery Anticipates Post-Cesarean Delivery Pain and Opioid Requirement Independent of 
Dose Received (abstract presented at SOAP and submitted for publication consideration) 
We are also relying on previously published work on the role of patient choice in the 
management of post-operative analgesia. 
 
Study design 
Qualified subjects will be identified and contacted by the obstetric anesthesia team prior to 
their clinical evaluation for anesthesia for their cesarean delivery. The subjects will be women 
scheduled to have elective cesarean deliveries for uncomplicated, singleton pregnancies. 
Potential subjects will be informed of the study, and if they choose to participate, all questions 


will be answered and an informed consent form will be signed prior to any study related 
activities. We will record number of patients approached, number of people refusing to 
participate in the study, and number of patients withdrawing from the study. 
 
This randomized, controlled study will include a simple, preoperative questionnaire to obtain 
baseline demographic and obstetric data; and complete questions (that have previously been 
shown to be predictive of postoperative pain) from which we will determine their expected and 
target postoperative pain scores. These questionnaires should take less than 3-4 minutes to 
complete.  
 
The subject will then be randomized into "choice" and "no choice" groups. The randomization 
for choice vs. no choice will be at a 1:3 ratio i.e. 1 woman will get no choice and 3 will get a 
choice for their analgesic protocol. Breakdown will occur based on patient preference for the 
study protocols. 
 
Treatment of Subjects 
The no choice group will receive the current standard analgesic protocol: 150 mcg intrathecal 
morphine, and around the clock acetaminophen 625 mg po q6h and ibuprofen 600 mg po q6h. 
The group with the choice will be offered 3 different protocols: 
1. 50 mcg intrathecal morphine, and around the clock acetaminophen 625 mg po q6h and 
ibuprofen 600 mg po q6h. 
2 150 mcg intrathecal morphine, and around the clock acetaminophen 625 mg po q6h and 
ibuprofen 600 mg po q6h. 
3. 300 mcg intrathecal morphine, and around the clock acetaminophen 625 mg po q6h and 
ibuprofen 600 mg po q6h, as well as gabapentin 600 mg po one time within 1 hr of delivery. 
 
Women will decide on which protocol after being given a standard script explaining advantages 
and disadvantages of each protocol. Pain will be managed adequately no matter what group 
patients are assigned to or whatever protocol they choose. 
Drugs and doses utilized in the study are safe for postpartum women and within dose range 
routinely used at our and other institutions. 
 
All breakthrough pain will be managed the same for all patients, and adequate analgesia will be 
available to treat post-operative pain. Primary breakthrough rescue analgesic will be our 
standard oral opioid oxycodone managed using our current treatment algorithm. If pain 1-4 out 
of 10, 1 tablet (5 mg) will be offered, if pain >4 out of 10, 2 tablets (10 mg) will be offered PRN. 
Pain not responding to oral opioids will be offered IV morphine boluses or PCA as per standard 
treatment protocols. Additional analgesic options (e.g. TAP blocks) will also be available as per 
standard care. Following standard Cesarean delivery, postoperative data will be collected 
(directly from patients and from the electronic medical record) by study investigators blinded to 
group assignment. 
 
Assessment of Efficacy 
Outcome measures: 


1) Pain scores at rest and on to sitting (VPS 0-10) collected at 3, 6, 12, 24, 36, 48 hours 
post-cesarean 
2) Overall daily pain score and its deviation from target and expected pain score will be 
determined at 0-24 and >24-48 hours study periods. 
3) Opioid use (oral and IV morphine) in the 0-24 and >24-48 hour study periods. 
4) Time to first analgesic for breakthrough pain (minutes from spinal) 
5) Side effect: Pruritus score (0-100), nausea score (0-100) and number of episodes of 
vomiting for the 0-24 and >24-48hr postoperative periods 
6) Any treatment of pruritus and/or nausea/vomiting 
7) Satisfaction with postoperative analgesia score (0-100) 
8) Discharge time (hours/minutes from surgery end) 
 
Discontinuation of the Study 
Telephone follow-up for pain score, opioid use, and functional recovery will be performed at 1 
week, 1 month, 3 months and 6 months post-Cesarean. Participants for which deception was 
used will be debriefed at their 6 month follow-up phone call. After the final 6 month post-
Cesarean phone call, the study will be discontinued. 
 
Selection and Exclusion of Subjects 
Inclusion criteria:  
 Women age 18-50 with singleton, gestation fetuses >37 weeks, not in active labor and 
scheduled for their 1st, 2nd, or 3rd elective CS. 
 All scheduled Cesarean deliveries under spinal or CSE (with no additional epidural doses 
administered) anesthesia. 
Exclusion criteria:  
 History of chronic pain, anxiety or depression 
 Women unable to understand the concept of Verbal Numerical Pain Scale at the time of 
informed consent 
 Chronic consumption of opiates, antidepressants, or anticonvulsants 
 Intake of opioids, acetaminophen, or NSAIDs 48hrs prior to the psychophysical test 
 Preeclampsia (with any severe features) or diabetes (not controlled with diet and 
needing drugs) 
 Preterm delivery (<37 weeks gestation) 
 Patient refusal 
 
Assessment of Safety and Adverse Events and Reporting 
Patient care will follow standard of clinical care. Any adverse events will be reported to the PI 
and necessary adjustments to the protocol will be immediately instituted. 
 
Statistics, including power calculations justifying the number of subject and details of data 
analysis plan 
A priori power analysis predicts that we will require 160 study subjects (40/group) to detect a 
clinically meaningful 33% reduction in mg-morphine equivalents of opioid analgesic 


consumption (Power 0.8, alpha=0.05, variance=20 mg). The expected effect size and variance 
was based on previous data collected at our institution and estimates from the literature.6,8  
Potential associations between patient choice and demographic variables will be evaluated 
using Student’s t test for normally-distributed variables and Mann-Whitney test for non-
parametric comparisons. Associations among discrete variables will be investigated using Chi 
square and Fisher’s exact test where appropriate. Time series analysis of pain and opioid rescue 
will be performed with mixed-effects models to allow separation of fixed effects (e.g., patient 
choice, morphine dose) from random effects. Final parameter estimates will be considered 
significant at P < 0.05 with a 2-sided alpha after adjustment for multiple comparisons. 
 
Significance  
Showing that patient choice can influence postoperative pain can dramatically change our 
practice within the specialty. In addition we have previously found that simple questions about 
patients’ pain and opioid needs may help predict pain after cesarean delivery. We wish to 
explore this concept further applying these simple questions to validate its efficacy. A reliable 
bedside tool such as a simple questionnaire that predicts severe post-operative pain will allow 
us to alter intra- and postoperative analgesic regimens accordingly to improve analgesia. 
 
Quality Control and Assurance 
All investigators will be fully trained and familiar with our protocol. Consent for the study will 
only be obtained by these providers. Assignment to groups will be done by a separate provider 
who will not do outcome assessments in order to ensure appropriate blinding.  
 
Ethics 
Informed Consent: 
Adequate informed consent, including a discussion of the risks, benefits, and alternatives of 
participation in the study will be thoroughly discussed with each potential subject. Investigators 
will ensure that patients are aware of their ability to be unenrolled at any time for any reason. 
 
Beneficence/Nonmaleficence: 
The above procedures provide minimal risk to the subjects because the questionnaires should 
not cause any psychological harm (and would absolutely not cause physical harm). The 
intrathecal morphine doses and all the drugs in the protocols have previously and are currently 
used safely as standard of care. All these drugs, doses, and protocols are utilized in our or other 
peer institutions and are considered safe for post-Cesarean pain management. 
 
Data handling and Recordkeeping 
Information including, age, general health and gestational age and information regarding 
previous experiences with pain. Results of participants questionnaires, demographic 
information (e.g. age and race), and the dates of enrollment in the study will be obtained. 
Only study research personnel will have access to all the data during the study and study 
analysis.  
 


All data will be kept on Stanford encrypted and password protected computers. 
Coded data in the database will be used for statistical analysis (statistician to be identified) to 
see if there is a way to use our data to predict the incidence of acute severe pain and long-term 
chronic pain after surgery. Electronic Data will be stored on a password protected and secure 
computer that will be kept in a locked office. Hard data (paper records/collection forms) will be 
stored in a locked file cabinet in a locked office.  
 
All persons involved in this study will receive appropriate training and abide by confidentiality 
guidelines to protect the subject's privacy. Data will only be labeled with codes assigned to each 
patient. Only the research team will have access to data. The PD will maintain the key to the 
code on a Stanford encrypted and password-protected computer. 
 
References to current literature 
Carvalho B, Mirza F, Flood P. Women Randomized to Choice of Intrathecal Morphine Dose 
Before Surgery Anticipates Post-Cesarean Delivery Pain and Opioid Requirement Independent 
of Dose Received. SOAP Best Paper Finalist 2015. Publication status: submitted.  
Eisenach JC, Pan P, Smiley RM, Lavand'homme P, Landau R, Houle TT. Resolution of Pain after 
Childbirth. Anesthesiology. 2013;118(1):143-151. 
Eisenach, James C., et al. "Severity of acute pain after childbirth, but not type of delivery, 
predicts persistent pain and postpartum depression." Pain 140.1 (2008): 87-94. 
Kehlet, Henrik, Troels S. Jensen, and Clifford J. Woolf. "Persistent postsurgical pain: risk factors 
and prevention." The Lancet 367.9522 (2006): 1618-1625. 
Lavand'homme, Patricia. "Perioperative pain." Current Opinion in Anesthesiology 19.5 (2006): 
556-561.