Predictors of Postoperative Pain Following Oocyte Retrieval for Assisted Reproduction
Phase: PHASE4
Conditions: Oocyte Retrieval, Postoperative Pain
Sponsor: Brigham and Women's Hospital

PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Lawrence C. Tsen, MD  
 
PROTOCOL TITLE 
Predictors of Postoperative Pain Following Oocyte Retrieval for Assisted 
Reproduction 
 
FUNDING 
Departmental/Internal Funding 
 
VERSION DATE 
9/13/2010 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
The central objective of this study will be to evaluate the relationship 
between estrogen levels and the pain following oocyte retrieval in women 
undergoing in vitro fertilization. 
 
Our primary hypothesis is that higher estrogen levels will result in greater 
postoperative pain.   Thus, our primary outcome will be : 
  - The amount of discomfort following oocyte retrieval with a standardized 
anesthetic regimen, as measured by verbal analogue scoring and the 
amount of postoperative pain medications required.   
 
Secondary outcomes will be: 
 - The identification of other possible predictors of postoperative pain, 
including: 
- pre-procedure oocyte count,  
- actual oocyte count,  
- pre-oocyte retrieval verbal analogue score for pain, or 
- other co-morbid conditions (e.g. anxiety, depression, pelvic 
inflammatory disease, inflammatory bowel disease, endometriosis).   
 
 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Pain perception is modulated by hormones. The in-vitro fertilization process 
raises a unique opportunity to investigate the effect of estrogen, as it is the 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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predominant hormone manipulated, and through the course of the IVF cycle, 
undergoes dramatic changes from almost complete suppression to 
supraphysiologic levels. Previously, our group has demonstrated that 
estrogen levels, as a result of hormonal stimulation for oocyte retrieval, are 
correlated to an increased sensitivity to a cold thermal, but not pressure, 
noxious stimuli. Clinically, we would like to determine if the estrogen level is 
a principle factor in modulating, and more specifically predicting, 
postoperative pain following occyte retrieval. Such a study could promote a 
greater understanding of pain mechanisms, identify elements responsible for 
greater discomfort or pain, and potentially offer strategies for postoperative 
pain management following oocyte retrieval. 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
The study will enroll 100 subjects. There is only one study group. The 
patient’s estrogen levels, pain ratings and pain medication consumption will 
be recorded. 
Inclusion criteria will be American Society of Anesthesiologists (ASA) I to III 
health status (moderate systemic disease), age between 18 and 50 yrs, 
undergoing oocyte retrieval under intravenous general anesthesia. 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
Subject will undergo standard clinical protocols for the entire oocyte 
stimulation cycle and all assisted reproductive procedure decisions and 
algorithms will be decided entirely independent of this study.  Pre and post 
oocyte retrieval estrogen levels are part of the standard clinical care, and the 
data will be  abstracted from the existing laboratory record.  
 
The anesthetic and postoperative pain regimens will use the same agents 
(fentanyl and propofol for anesthesia; fentanyl, acetaminophen and Percocet 
for postoperative analgesia) and dose ranges used in clinical standard 
practice; however, the regimens will be standardized, so as to limit 
confounding variables. The study regimen for anesthesia will differ from the 
current, clinical standard by the mandated use of actual body weight (in 
current practice, actual, adjusted ideal, or ideal body weights are used), the 
use of fentanyl 1 mcg/kg IV (instead of 100 mcg for everyone), and the 
standardization of postoperative analgesia (noted below). The total amount 
of fentanyl, propofol, and postoperative drugs will be recorded.   
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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Postoperative analgesia will be standardized based on the subject’s self 
reported verbal analogue score (VAS) and the timing of the report. The 
agents and timing used below differ from the current clinical standard by 
assessing VAS and responding with a certain regimen.  Although the same 
agents are used in clinical practice and the response is similar and guided by 
VAS, the nurse and anesthesiologist of the day are at their own discretion as 
to what is given; there is no regimented algorithm.  As such, there is 
variability in the response.  The study doses noted below were derived from 
a concensus of nursing and anesthesia practitioners.    
 
PACU Arrival VAS 1-2 
VAS 3-4  
VAS 5-7 
8-10 
≤30 min 
Heating Pad 
Fentanyl 0.5 
mcg/kg 
Fentanyl 1 
mcg/kg 
Fentanyl 1 
mcg/kg + 
Tylenol 1 
gm  
                    Heating Pad 
Acetaminophen 
1 gm 
Percocet 1-2 
tab  
Percocet 1-2 
tab + 
Fentanyl 1 
mcg/kg 
 
The verbal analogue score (VAS) will be used to assess baseline and 
postretrieval discomfort.  Post-procedure assessments will occur in the 
postoperative anesthesia care unit (PACU) on arrival (time 0) and at 15, 30, 
60, and 120 minutes. The patients will be told that VAS corresponds to 0 (no 
pain) to 10 (worst pain imaginable).  Patients will be administered the 
analgesic agents in accordance to the table noted above.  No more than 
acetaminophen 1 gm and Percocet 2 tablets will be given during the entire 
study period. Following the provision of pain medications, a period of 15 min 
will be given before additional medications can be given.  The VAS scores 
and the total amount of analgesic agents provided will be recorded. 
 
Prior to discharge from PACU, the recovery room nurse will give the patient 
discharge instructions in accordance to IVF protocol.  Patients will be 
instructed to write the time, dose and type of analgesic drugs, and how 
much pain they are experiencing immediately prior to taking the medication, 
on a “postoperative pain medication record”. Patients will also be 
reminded that no more than 4 gm Acetaminophen (as labeled 
tablets, or contained in Percocet) should be taken within each 24 hr 
period.  In addition, they will be requested to bring this medication record 
with them at the time of their embryo transfer (almost always on post-
oocyte retrieval day 3) or their next IVF clinic visit. 
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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The anesthetic and postoperative pain regimens will use the same agents 
and dose ranges used in clinical standard practice; however, the regimens 
will be standardized, so as to limit confounding variables. No alternative or 
study-only drugs will be administered.  Please note the discussion 
immediately above, which indicates specifically how the clinical and study 
regimens differ.  
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
The risks in this study are minimized by the use of standard of care 
anesthetic and obstetric interventions.  
 
There is a potential for less or more postoperative discomfort than usual 
care, because instead of having the intraoperative fentanyl and the 
postoperative pain medications administered by each individual practitioner, 
a standardized approach based on the verbal analogue pain scores will be 
used.   
 
The risks associated with opioids include nausea and vomiting, sedation, and 
respiratory depression.  Given the limited duration of surgery and typically 
limited amounts of additional opioids administered in the postoperative 
period, it would be uncommon for these side effects to occur to any 
significant degree. Acetaminophen (e.g. Tylenol) can cause increased levels 
of liver enzymes, however, this is unlikely due to the limited doses (up to 
two tablets) provided.     
 
No additional inpatient hospital time is anticipated by participating in this 
study. 
 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
Safety of the subjects will be ensured by the inclusion of two early endpoints 
(drop criteria):   
1) Subject decision for withdrawal from participation at any time.   
2) Any operative or medical condition changes prior to or during the 
entire study period deemed unacceptable by the obstetrician, 
anesthesiologist, or physician investigator.   
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
The risks and discomforts to the mother should be minimal. No new 
drugs/devices/procedures are being studied or administered soley for 
research purposes. 
 
There is a potential for less or more discomfort than usual care, because 
instead of having the postoperative pain medications administered by each 
individual practitioner, a standardized approach based on the verbal 
analogue pain scores will be used. 
 
All data collected in the study will be considered confidential with procedures 
in place to limit access to subject charts and information from the study. 
 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
No benefits may be seen in the participants in this study. However, the 
identification of predictor factors for post-operative pain could generate an 
individualized approach and a better management of post-operative pain. 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
The study will only be conducted in women. Non-English speaking subjects 
will be approached with the use of translators.  
 
No other vulnerable populations will be specifically targeted, nor will any one 
group bear a disproportionate share of the burdens or the benefits of the 
research. 
 
Women undergoing oocyte retrieval as part of the Assisted Reproduction 
Cycle are included in the study, but the potential benefit of better 
understanding the estrogen association with post-operative pain and 
identifying predictors for post-operative pain extends to all women 
undergoing surgery. 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
NA 
 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          http://healthcare.partners.org/phsirb/nonengco.htm 
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
Prior to approaching a potential subject, the subject’s reproductive 
endocrinologist will be contacted. Subjects will be approached when 
they are admitted for a preoperative reproductive endocrinology and 
anesthetic assessment for their oocyte retrieval.  Typically, this 
preoperative assessment occurs approximately 7 days prior to their 
oocyte retrieval. The reproductive endocrinologist will ask the 
potential subject’s permission to be approached by a physician 
investigator. If the response is affirmative, a physician investigator 
will then approach the potential subject. 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
The study is not anticipated to cause any additional inconvenience to 
patients. 
 
There will be no costs to the subjects related to the conduct of this study, as 
there are no additional medications or tests that are not already the routine 
standard of care at Brigham and Women’s Hospital. 
 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          http://healthcare.partners.org/phsirb/recruit.htm

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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          Guidelines for Advertisements for Recruiting Subjects
          http://healthcare.partners.org/phsirb/advert.htm
 
          Remuneration for Research Subjects
          http://healthcare.partners.org/phsirb/remun.htm
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
Informed consent will be obtained from all subjects prior to enrollment after 
a thorough explanation and discussion of the study plan with the physician 
investigator.  Subjects will be approached at their preoperative reproductive 
endocrinology and anesthetic asessement, which typically occurs 
approximately 7 days prior to oocyte retrieval.   
 
Subjects will be given the opportunity to ask questions and discuss their 
decision to participate with the treating physicians.  Following satisfactory 
completion of the recruitment procedures, subjects will be consented by the 
principal investigator or physician co-investigator. 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
http://healthcare.partners.org/phsirb/newapp.htm#Newapp
 
For guidance, refer to the following Partners policy: 
          Informed Consent of Research Subjects
          http://healthcare.partners.org/phsirb/infcons.htm
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
The principal investigator will review all forms and data with every 5th 
subjects to ensure accuracy, adherence and completeness of the protocol. 
An independent data monitor will not be used, as all agents and dose ranges 
used in this study are part of standard practice. 
 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
All adverse events will be recorded on the Adverse Experience Form within 
the Case Report Forms (CRFs).  The study investigators will follow Food and 
Drug Administration (FDA) regulations requiring rapid reporting of any 
adverse event that is Serious, Unexpected, and Associated with the use of 
the study drug.  Adverse events and unanticipated problems involving 
risks to subjects or others will be reported to the HRC in accordance 
to HRC adverse event and unanticipated problem guidelines.   
 
The investigators will notify the principal investigator immediately of any 
serious adverse events.  All adverse events will be reported to the IRB as 
per the HRC guidelines. 
 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
The principal investigator will be responsible for validating and ensuring the 
integrity of the data, and will do so by examining the data sheets and the 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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primary documents (medical and anesthetic record) of the case.  Such a 
review will occur with every 5th completed subject.  Moreover, the PI will be 
in the first case of each of the co-investigators and will be available for 
consultation throughout the study.   Finally, an initial training session and 
regular investigator meetings will occur to review the study progress, and 
adherence to the IRB/HRC approved protocol and guidance (for study 
conduct and reporting of adverse events).  
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
          http://healthcare.partners.org/phsirb/datasafe.htm
 
          Adverse Event Reporting Guidelines
          http://healthcare.partners.org/phsirb/adverse_events.htm
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
All clinical and other data obtained during this study will be considered 
confidential.  Individually identifiable information will be stored in binders in  
the locked office of the primary investigator.  The names of study 
participants will be known only to the investigators.  The database 
established for this study will use the patient’s initials and last 4 digits of the 
MRN, and will be kept on a password protected computer which is secured to 
the desk within the locked office of the prinicipal investigator.   
 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
NA 
 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
NA 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
NA