Assessing Efficacy of Intravenous Acetaminophen for Perioperative Pain Control for Oocyte Retrieval: a Randomized, Double Blind, Placebo-controlled Trial
Phase: PHASE4
Conditions: Infertility, Female, Pain, Postoperative
Sponsor: Massachusetts General Hospital

 
 
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DETAILED PROTOCOL 
 
Assessing efficacy of IV acetaminophen for perioperative pain control for oocyte retrieval: a 
randomized, double blind, placebo-controlled trial 
 
Principal Investigator: John C. Petrozza, MD 
Version Date: July 10, 2019 
 
I. BACKGROUND AND SIGNIFICANCE 
 
a. Historical background 
 
Due to the current opioid crisis, non-opioid options for effective multimodal postoperative 
anesthesia have been explored in many recent studies. Intravenous acetaminophen has rapid 
onset and potent analgesic properties, but due to its high cost and relatively limited clinical data 
concerning its efficacy compared with other agents, physicians are hesitant to use intravenous 
acetaminophen in the perioperative period. Importantly, for minor outpatient procedures such as 
oocyte retrievals, use of IV acetaminophen offers the opportunity to greatly reduce perioperative 
narcotic intake in women of reproductive age. 
 
b. Previous pre-/clinical studies supporting the proposed research 
 
Postoperative pain 
The majority of postoperative patients experience moderate to severe postsurgical pain, which 
can lead to complications such as impaired wound healing.1,2 Although we rely heavily on 
opioids to alleviate much of postoperative pain, this analgesia is not without adverse effects. 
Opioids are associated with drowsiness, postoperative nausea and vomiting, ileus, respiratory 
depression, and bladder dysfunction, all of which can hamper post-operative recovery and 
discharge.3 Thus, as we attempt across surgical specialties to reduce the use of opiates for 
outpatient procedures, IV acetaminophen is an important consideration for multimodal 
anesthesia for oocyte retrievals.4 
 
Safety of IV acetaminophen 
Although IV acetaminophen is more expensive than PO acetaminophen and less likely to be fully 
reimbursed by insurance companies, there is evidence that favors the intravenous formulation 
over the oral agent. The bioavailability of IV acetaminophen in cerebrospinal fluid compared 
with oral acetaminophen after the administration of 1 gram over 6 hours is 24.9 versus 14.2 
μg•hr/mL.5 IV acetaminophen produces more consistent plasma concentrations of 
acetaminophen over time than PO administration, leading to a longer duration of therapeutic 
drug plasma level.1 The intravenous route also peaks much faster (15 minutes vs. 45 minutes).1 
Though the risk for overdose always exists, there is evidence that IV acetaminophen may be 
safer than the same dose of PO acetaminophen: IV administration creates a lower accumulation 
of acetaminophen’s toxic metabolite (n-acetyl-p-benzoquinoneimine) than oral administration 
and produces a peak acetaminophen concentration in the liver estimated to be 50% less than the 
same oral dose.6  
 

 
 
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IV acetaminophen for postsurgical analgesia 
A recent review of 14 randomized controlled trials examining the efficacy of IV acetaminophen 
for postoperative pain in a wide variety of surgeries found that patients receiving IV 
acetaminophen had improved analgesia in 12 of the studies examined.7 Sinatra et al. showed that 
IV acetaminophen use (one gram every six hours) was associated with a decrease in morphine 
consumption by 46% (p=0.0003) on postoperative day one after total hip replacement or total 
knee replacement and increased time until rescue morphine (hip replacement, 3.9 hours and knee 
replacement, 2.1 hours) compared with placebo (0.8 hours).8 Other studies in hysterectomy and 
laminectomy patients suggest that patients receiving IV acetaminophen may have a reduction in 
postoperative nausea and vomiting, although this has yet to be formally evaluated.7 Furthermore, 
both preemptive (before surgical incision) and preventive (after surgical incision) use of IV 
acetaminophen appears to produce a decrease in pain scores 6 hours after surgery compared with 
placebo (p<0.001).9 Therefore, the available evidence suggests that the addition of IV 
acetaminophen can bolster effective analgesia in patients while decreasing the amount of opioids 
required.2,3,9,10 
 
c. Rationale behind the proposed research, and potential benefits to patients 
and/or society. 
 
The use of IV acetaminophen is approved by the Food and Drug Administration for the 
management of mild to moderate pain, the management of moderate to severe pain with opioid 
analgesic adjuncts, and fever reduction in adults and children over the age of 2.11 As discussed 
above, recent studies have shown several benefits of using IV acetaminophen perioperatively, 
including a reduction in opiate consumption, improved analgesia, and reduced postoperative 
nausea and vomiting.3,10 While the cost effectiveness of using IV acetaminophen has not been 
extensively evaluated in surgical patients, a randomized controlled trial of bariatric surgery 
patients suggests that IV acetaminophen significantly decreases mean direct hospital costs and 
emergency department visits within 30 days of surgery.12 However, more research is needed to 
better assess the efficacy of IV acetaminophen compared to PO acetaminophen in treating 
postoperative pain and to further evaluate the potential reduction in opioid use. 
 
In our field, recent attention has focused on prescribing practices after oocyte retrievals as many 
opiate addictions begin with prescription medications.13,14 However, there are no studies to our 
knowledge assessing multimodal options for optimal pain control in the perioperative period, 
which may also impact the perceived need for pain medication prescriptions. Additionally, since 
cost is one of the limiting factors for giving patients IV acetaminophen, studies like this one that 
compare IV acetaminophen to oral acetaminophen and assess the impact on time to PACU 
discharge in both inpatient and outpatient settings are warranted. Our primary goal is to assess 
the efficacy of pre-operative IV versus PO Acetaminophen compared to placebo (standard of 
care) for pain control after oocyte retrieval, with the hypothesis that IV acetaminophen will 
reduce pain scores, reduce overall narcotic burden, shorten time to discharge from PACU, 
increase time to rescue medication, and decrease opiate-associated side effects. 
 
Investigating the use of non-opiate alternatives for perioperative anesthesia is a crucial aspect of 
reducing the overall use of opiates in outpatient procedures. IV acetaminophen has the potential 

 
 
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to be a versatile and worthwhile addition to achieving adequate postoperative analgesia in 
patients undergoing a wide variety of surgical procedures and in numerous hospital settings. 
 
II. SPECIFIC AIMS 
 
a. Specify objective and hypotheses to be tested in the project 
 
Objective: 
- To compare the efficacy of pre-operative IV acetaminophen versus PO acetaminophen, versus 
placebo (standard of care) for adjunctive pain control in the setting of oocyte retrieval in an in 
vitro fertilization clinic setting. 
 
Hypothesis: 
- Our hypothesis is that patients receiving IV acetaminophen pre-operatively will have improved 
postoperative pain scores, lower overall opiate consumption, and shortened time to discharge 
from PACU than those receiving PO acetaminophen or placebo. 
 
III. RESEARCH DESIGN AND METHODS 
 
This randomized, double blind, placebo-controlled study will be conducted over approximately 
12 months at the MGH Fertility Center. Our goal recruitment is 174 patients to achieve statistical 
power for our primary outcomes. 
a. Inclusion/exclusion criteria. 
 
Inclusion Criteria: 
[ ] Patient is 18 years or over, undergoing oocyte retrieval. 
[ ] Patient is English-speaking. 
 
Exclusion criteria: 
[ ] Allergy to acetaminophen or opiates. 
[ ] Any history of liver disease, history of alcohol depending, or renal impairment as reported in 
the electronic health record. 
[ ] Any history chronic opiate use or chronic pain disorder as reported in the electronic health 
record. 
[ ] Weight less than 50kg as reported in the medical record. 
 
b. Source of subjects and recruitment methods. 
 
Adult patients from the reproductive endocrinology practice at MGH undergoing oocyte 
retrieval. Patients will be recruited at the time of their IVF cycle. 
 
IV. SUBJECT ENROLLMENT 
 
a. Methods of enrollment, including procedures for patient registration and/ 
or randomization 
 

 
 
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All patients will be offered the chance to enroll in the study by a licensed MD at the time of their 
baseline ultrasound (IVF cycle start). The licensed physician will introduce the study and provide 
an information packet containing the study recruitment letter and informed consent at that time. 
The patient will have the opportunity to opt out of the study at any time. Study staff will confirm 
patients’ study eligibility by telephone during the cycle and indicate their participation on their 
IVF cycle monitoring schedule if they are eligible. Consent will occur in person during the IVF 
cycle by a licensed MD (see below). 
 
When the enrolled patient’s egg retrieval is scheduled (two days in advance of procedure), study 
staff will order the research medications in EPIC and will notify the IVF team and research 
pharmacy via secure email of the study patient’s procedure date/time to coordinate medication 
pick up. 
 
A computer-generated blocked randomization schema with alternating block sizes 
(http://www.randomization.com) will be generated by the research pharmacy. The fellow will 
enter a randomization number into the study patient’s EPIC medication order, and the pharmacist 
will associate this number to the patient’s assigned study group. The research pharmacist will 
prepare the appropriate medications, and the IVF care team will be blinded to the medications.  
 
b. Procedures for obtaining informed consent 
A licensed MD will consent the patient during one of their morning ultrasound appointments 
prior to the egg retrieval. It should be noted at the time of consent that participation in the study 
will in no way impact their infertility treatment or cycle management, that they will receive 
standard of care anesthesia, and that all perioperative pain will be treated. Consented patients 
must agree to avoid taking pain medications (including acetaminophen or NSAIDs) during the 
24hrs prior to their procedure, which will be confirmed prior to data collection on the day of 
procedure, as this would necessitate exclusion from study. 
 
c. Study interventions and data collection 
The study staff will transport the blinded medications from the research pharmacy to the IVF 
suite on the day of the procedure. Anesthesia will log medications in EPIC per research 
pharmacy protocols. 
 
Group 1: In the pre-op suite, these patients will receive 1000mg IV acetaminophen and PO 
placebo, followed by standard protocol anesthesia and pain control as needed. 
 
Group 2: In the pre-op suite, these patients will receive 1000mg PO acetaminophen and IV 
placebo, followed by standard protocol anesthesia and pain control as needed. 
 
Group 3: 
In the pre-op suite, these patients will receive PO and IV placebo, followed by standard protocol 
anesthesia and pain control as needed. 
 
In all groups, pain control will be provided by anesthesia peri-operatively as needed. Pain 
medication such as opiates may be given post-operatively as needed for pain measured by VAS 
score. In order to be consistent in assessment of immediate post-operative pain, narcotic use, and 

 
 
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discharge timing per our primary outcomes, NSAIDs will be avoided in the recovery room for all 
study patients, regardless of embryo transfer timing, as they are routinely contraindicated in our 
practice for any patient undergoing a fresh embryo transfer. However, patients not undergoing 
fresh transfer may take NSAIDs at home post-operatively as needed per standard of care. 
 
The PACU nurses will assess and document VAS numeric pain scores as they do routinely in 
EPIC as well as on the study data collection sheet for the study patients. Data collection sheets 
will be secured in a lock box until input into Redcap by study staff. Study staff will review the 
data collection and study protocols with the PACU nurses prior to the start of patient enrollment. 
 
After same-day discharge from the PACU, patients will receive a call from a trained member of 
the study staff on POD2 to assess their recovery and pain medication use. The POD2 phone visit 
data collection form will be completed at this time. Ability to use NSAIDs in the non-transfer 
subgroup will be taken into account at the time of the statistical analysis. 
 
The anesthesia and IVF providers will retain the discretion to exclude patients on the day of the 
procedure from the study if they took extra analgesics in the 24 hours prior to the procedure or 
experience any non-study related complications of anesthesia and/or surgery. 
d. Current standard of care 
Current standard of care for patients undergoing oocyte retrieval involves monitored MAC 
anesthesia with opiates for pain control. 
e. Risks 
Risks to the patients will be minimized because they will be undergoing anesthesia that is the 
current standard of care, and pain will be treated, as the patient requires. The patients’ IVF cycle 
management and oocyte retrieval approach will not be altered in any way by participation in the 
study. 
An adverse reaction to acetaminophen could occur. Hepatotoxicity is possible but unlikely in the 
setting of one dose of IV acetaminophen. 
f. Equitable selection of patients  
All patients presenting for oocyte retrieval≥ 18 years old who speak English and do not possess 
any other exclusion criteria may be eligible for inclusion. Our exclusion criteria are relatively 
few and do not impair our ability to make conclusions that may benefit these patients. 
People who do not speak English will be excluded from this study due to the low volume of 
these patients in our clinic population and the inconsistent ability to arrange for appropriate 
interpreters during all study-associated interactions in the cycle. 
 
V. BIOSTATISTICAL ANALYSIS 
 
a. Specific data variables being collected for the study (e.g., data collection sheets). 
 

 
 
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Clinical data regarding pain levels, pain medication use, and time to discharge will be collected 
on a PACU data collection sheet and POD2 phone visit data collection sheet. The EPIC record 
will be used to record clinical and IVF cycle history, perioperative care, embryology findings, 
and pregnancy outcomes. 
 
b. Study endpoints. 
 
The primary study endpoints will include post-operative pain levels in PACU and after discharge 
through POD2, post-operative pain medication requirements and timing in PACU and through 
POD2, and time to discharge from PACU. Secondary endpoints include procedure length, post-
operative nausea, embryology outcomes, and pregnancy outcomes. 
 
c. Statistical methods.  
The difference in pain scores will be assessed by using Fisher’s Exact and chi-square tests as 
appropriate. A multivariable regression model will be performed to control for potentially 
confounding variables, such as maternal age, BMI, medical comorbidities, procedure duration, 
and oocytes retrieved. 
 
d. Power analysis (e.g., how sample size determined, evaluable subjects, etc.)  
 
We plan to enroll 58 patients in each of the three treatment groups (n = 174). Allowing for 
attrition of 5 patients per group (approximately 10%), we assume that we will be able to evaluate 
outcome data for 159 patients. Based on OR times from 13 patients, we estimate a mean 
recovery time of 88 minutes, with a standard deviation (SD) of 19 minutes.  Using this SD, we 
anticipate 80% power to detect a difference in mean recovery time between either of the two 
treatment groups and the standard of care of 8 minutes or greater in absolute value, or 
approximately 10%, based on two-sample t-tests at the 0.025 two-tailed significance level, where 
this significance level reflects adjustment for the two comparisons with the control group.  
 
From these 13 patients, we also estimated the SD of the VAS post-operative pain rating to be 
approximately 2.8. Using this SD, we anticipate 80% power to detect a difference in mean post-
operative pain between either of the two treatment groups and the standard of care of 1.7 or 
greater in absolute value, based on two-sample t-tests as above. Alternatively, assuming that the 
population mean pain scores for the three groups are 1, 1.5 and 2.5, respectively, then we will 
have 80% power to detect that the three group means are different, based on a one-way ANOVA 
at the 0.05 two-tailed significance level. 
 
VI. RISKS AND DISCOMFORTS (STRATIFY BY COMMON AND UNCOMMON) 
 
Drug side effects and toxicities 
Potential side effects of acetaminophen include nausea, headache, loss of appetite, rash, and 
itching. However, acetaminophen is generally very well tolerated. All other medications 
proposed for this study are currently standard of care for perioperative analgesia. 
 
Serious: 
Acetaminophen: anaphylaxis, hepatotoxicity 

 
 
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Risk to privacy: 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to data that are necessary to investigate the efficacy of the study treatment protocol. The 
treatment plans and medications will be blinded by the MGH Research Pharmacy, and the 
randomization key will be maintained securely per pharmacy protocols. Study members whose 
responsibilities require access to personal data agree to keep the identity of the study subjects 
confidential. The subject’s information will be kept confidential according to HIPAA guidelines. 
Psychosocial (non-medical) risks 
Because the treatment plan involves standard care for egg retrievals with immediate management 
of pain with medications as needed, we estimate no psychosocial risks. 
 
VII. POTENTIAL BENEFITS 
 
a. Potential benefits to participating individuals. 
- Improved analgesia postoperatively 
- Decreased overall consumption of opiates postoperatively which may reduce opiate related 
complications such as postoperative nausea and vomiting 
- Decreased time to discharge from the PACU 
 
b. Potential benefits to society (e.g., increased understanding of disease process, etc.) 
Investigating the use of non-opiate alternatives for perioperative anesthesia is a crucial aspect of 
reducing the overall use of opiates in the outpatient setting and preventing new opiate addiction. 
IV acetaminophen has the potential to be a versatile and worthwhile addition to achieving 
adequate postoperative analgesia in patients undergoing a wide variety of outpatient surgical 
procedures. This research will help establish whether PO and IV acetaminophen are cost-
effective adjuncts for multimodal analgesia during oocyte retrievals. 
 
VIII. MONITORING AND QUALITY ASSURANCE 
 
a. Independent monitoring of source data 
Data will be collected by study staff from the Department of Reproductive Endocrinology and 
Infertility. Eligible patients will be logged in a secure data form on a Partner’s password-
protected computer accessible only to study staff. Data collection sheets will be stored securely 
in a lock box on Yawkey 10 during study recruitment and then entered into RedCap, a secure 
online database program, with de-identified patient ID numbers assigned. Only the PI and 
research team will have access to the online and hard copy database, and identifying information 
will not be released. After the first subject has been enrolled, the data collection binder will be 
reviewed monthly by a member of the study staff and the PI at a research meeting in a de-
identified manner. The PI will be responsible for determining whether the research should be 
altered or stopped. 
 
b. Safety monitoring (e.g. Data Safety Monitoring Board, etc.) 
The PI will evaluate all acute safety data. If 3 subjects experience a grade 2 or greater Adverse 
Event (AE) that is possibly related to study procedures, the study will be paused to fully evaluate 

 
 
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the safety of continuing enrollment. The PI will be responsible for reviewing the data and 
determining whether the research should be altered, paused, or stopped. Any adverse events and/ 
or decision to stop enrollment will be reported to the IRB. 
 
c. Outcomes monitoring 
The research assistant and IVF fellows will collect and monitor the data collection forms and 
Redcap database monthly for accuracy and completeness. The PI will also conduct periodic 
review of the case report forms and source documentation. The study staff will meet after 50% 
desired enrollment to review data on enrolled subjects, CRFs, and source documentation. 
 
d. Adverse event reporting guidelines. 
Throughout the duration of the study, the PI will perform ongoing evaluation of subject safety 
data in order to identify AEs and trends as soon as possible. Any unanticipated problems, 
involving risks to subjects or others including AEs, will be reported to the IRB in accordance 
with PHRC unanticipated problems reporting guidelines. 
 
IX. References 
 
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Bortoletto P, Prabhu M, Garry EM, Huybrechts KF, Anchan RM, Bateman BT. Opioid 
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