A Randomized, Controlled Trial of IV Acetaminophen Versus IV Morphine to Manage Pain in Pregnancy: Can Opioid Use be Reduced in Pregnant Women?
Phase: NA
Conditions: Pain Management in Pregnant Women
Sponsor: The University of Texas Health Science Center, Houston

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A randomized, controlled trial of IV acetaminophen versus IV morphine to manage pain in 
pregnancy: Can opioid use be reduced in pregnant women? 
 
NCT02267772 
 
Version Date: 01/10/2014 

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IRB NUMBER: HSC-MS-13-0763 
IRB APPROVAL DATE: 01/10/2014 
 
 
A randomized, controlled trial of IV acetaminophen versus IV morphine to manage 
pain in pregnancy: Can opioid use be reduced in pregnant women? 
Jerrie S. Refuerzo, M.D. 
Marissa Tsao, M.D. 
Jaideep Mehta, M.D. 
Sean Blackwell, M.D. 
 
 
Pain during pregnancy 
Pain control is considered an important measure of quality in healthcare. Women 
encounter pain at various times during their pregnancy.[1] The pain may range from 
mild discomfort associated with the physiologic changes of pregnancy to moderate pain 
from labor contractions, and ultimately to severe pain associated with surgery from 
cesarean section. Myometrial pain associated with uterine contractions are typically a 
visceral pain associated with nociceptor stimuli.[2] Although the intensity of pain 
changes with pre-labor contractions and at various stages of labor, pregnant women 
have reported that their highest intensity of pain occurs in the first stage of labor at less 
than 5 cm dilation. In addition, maternal medical conditions such sickle cell crises and 
pyelonephritis or even a simple headache may cause pain that is not relieved by simple 
oral analgesics. In these scenarios, various opioids are often administered parenterally 
for systemic analgesia. 
 
Parenteral opiods in pregnancy 
In pregnancy, parenteral opioid administration, particularly in labor, results in minimal 
reduction in maternal pain scores and are associated with adverse side effects.[1] 
These effects from opioid can range from nausea, vomiting and pruritus but also be 
associated with dangerous events such as maternal respiratory depression and 
aspiration.[3- 4] All opioids cross the placenta and reside in the neonatal system for up 
to three to six days.[5] Opioids are associated with alterations in the fetal heart rate 
pattern including variability, accelerations and decelerations. [6-7] Moreover, in high 
doses opioids are associated with increased risk of depressed neonates requiring 
resuscitation at delivery.[1] Due to both maternal and fetal effects, it is preferred to 
refrain from opioid agents if alternative options are available. 
 
Intravenous acetaminophen 
Acetaminophen is a common medication used to treat pain. When administered 
intravenously, it has been shown to be an effective in controlling pain and reducing the 
need for narcotics in postoperative patients. [8-13] Until recently, intravenous 
acetaminophen was only available in its prodrug form, paracetamol, which is 
metabolized to acetaminophen post-injection. It has been in use for over 25 years and 
has been shown to be very effective in pain control [14] Intravenous (IV) acetaminophen 
is currently approved by the FDA for use to treat fever, mild to moderate pain, and 
moderate to severe pain when used with adjunctive opioid analgesics. Pain relief is 
reached within 15 minutes of IV acetaminophen [15]. High plasma concentrations 

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appear to help drive IV acetaminophen across the blood brain barrier to work in the 
central nervous system by likely inhibition of central prostaglandin synthesis. While the 
area under the curve for both oral and intravenous acetaminophen is similar, clinical 
and anecdotal evidence appears to weigh heavily towards a greater analgesic effect for 
intravenous administration [15]. Most importantly, IV acetaminophen is associated with 
a reduction in opiod consumption in surgical patients. [16-17] 
 
IV Acetaminophen in pregnancy 
In pregnancy, IV acetaminophen has also been shown to be effective in controlling pain. 
Prior randomized controlled trials have been conducted, but none within the United 
States. [14, 18-21,] These smaller trials ranged in size from 45 to 80 women in each 
trial. When IV acetaminophen was compared to placebo in women with cesarean 
section, visual analog scores (VAS) of pain were significantly reduced in the following 24 
hours. [14, 20] Women in the placebo group required a higher frequency of rescue 
courses of medication and reported lower patient satisfactions scores. When IV 
acetaminophen was compared to IV meperidine in women following cesarean section, 
there were similar VAS scores, but reduced frequency of rescue analgesia and total 
analgesia consumed.[19] In comparing women receiving IV acetaminophen versus IV 
pethidine (meperidine) in the first stage of labor, IV acetaminophen significantly 
reduced pain scores. However, maternal side effects were reported in 64% of women 
who received pethidine. [22] 
 
Rationale for this clinical trial 
The goal of analgesia in pregnancy is to reduce pain while minimizing both maternal and 
fetal adverse effects. Current opioids used in pregnancy provide minimal pain relief and 
are associated with adverse effects. IV acetaminophen has been shown to significantly 
improve pain control following cesarean section and in the first stage of labor. 
Moreover, IV acetaminophen reduces the need and consumption of opioids following 
surgery. If IV acetaminophen can be as effective in controlling pain associated with 
maternal medical conditions and uterine contractions with labor, then the use of 
parenteral opiods in pregnant women and its exposure to the fetus could be reduced. 
This could provide new opportunities in the medical management of pain in pregnancy. 
Thus we propose a comparative effectiveness trial of IV acetaminophen compared to IV 
morphine. 
 
Hypothesis: 
We hypothesize that IV acetaminophen is as effective as IV morphine in reducing pain in 
pregnant women. In doing so, IV acetaminophen can reduce the amount of narcotics 
needed in women with pain. 
 
Objectives: 
To determine if IV acetaminophen can: 
1. Decrease pain in pregnant women 
2. Reduce the amount of opioid use in pregnant women who encounter pain 

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3. Reduce maternal and fetal adverse effects compared to opioids 
 
Study Design: 
For this comparative effective trial, we propose a randomized, controlled trial of IV 
acetaminophen vs. IV morphine in pregnant women. Prior studies have confirmed that 
IV acetaminophen is effective in controlling pain compared to placebo.[14,20] Thus, 
administering just a placebo for pain control is not justified at this time. 
 
We will include 3 different groups of pregnant populations who encounter pain for 
different reasons. 
Group 1: Pregnant women with uterine contractions, but not in labor 
Group 2: Pregnant women with uterine contractions in the first stage of labor 
Group 3: Pregnant women with a medical condition associated with pain. 
 
Inclusion criteria: 
Group 1. We will include pregnant women greater than 34 weeks of pregnancy who 
present with uterine contractions, but are not in labor and who are warranting 
treatment with intravenous medication for pain control as part of their routine 
treatment. This will be defined as the presence of uterine contractions documented on 
the tocodynanometer. However, the cervix remains less than 2 cm dilated and has not 
changed after 1 hour after re-examining her cervix.[23] 
 
Group 2. We will include pregnant women greater than 37 weeks of pregnancy who 
present with uterine contractions and are in the first stage of labor and who are 
warranting treatment with intravenous medication for pain control as part of their 
routine treatment. This will be defined as the presence of uterine contractions 
documented on the tocodynanometer and cervical dilation greater than 2 cm, but less 
than 4 cm. [23] 
 
Group 3. We will include pregnant women greater than 16 weeks of pregnancy who 
present with pain due to a maternal medical condition including sickle cell crisis, 
pyelonephritis, pancreatitis, cholecystitis, nephrolithiasis or headache and who are 
warranting treatment with intravenous medication for pain control as part of their 
routine treatment. 
 
Exclusion criteria: 
We will exclude women less than 18 years of age, less than 16 weeks gestation, with 
weight less than 50 kg, and contraindications to acetaminophen including reported 
elevated liver function tests, hepatic injury, hepatic disorder, active liver disease, 
alcoholism, chronic malnutrition, known coagulapathy, hemorrhage, creatinine > 1.0, or 
known allergy or hypersensitivity to acetaminophen. We will also exclude women who 
have received any opioids within the last 24 hours. 
 
Recruitment: 

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All participants will be admitted for hospital care either for observation, to the 
antepartum unit or to labor and delivery. Eligible women will be identified after it is 
deemed necessary by the caring physician to provide medical treatment for pain control 
according to each of the 3 groups. Those who meet study criteria will be approached 
about the study in the admission area/OB triage at the time of admission. Written, 
informed consent will be obtained by a member of our research team, either a physician 
or research assistant. 
 
Randomization: 
Randomization will be performed based on a computer generated list that will be 
created by a non-clinical member of the research team. Randomization will be stratified 
by site and by group/patient type. A permuted block randomization with a random 
fashion will be used to prevent imbalances between groups. The medication based on 
the computer generated list will be typed out on a piece of paper with the medication 
regimen written according to the below regimens. This piece of paper will be placed in 
an opaque envelope and numbered according to the computer generated list. The 
opaque envelopes will be kept on the obstetrical unit and be managed by the research 
nurses and team. 
 
Methods: 
Women will receive the first dose of either IV acetaminophen or IV morphine after it is 
determined necessary that the patient will require medications for pain by the caring 
physician according to clinical management. Data will also be collected regarding 
maternal demographics, pregnancy characteristics, medications administered, visual 
analog scales, and maternal/fetal adverse effects. 
 
Medication regimen: 
Women randomized to IV acetaminophen will receive 1000 mg IV, repeated every 6 
hours as needed up to a maximum of 24 hours [total 4 doses]. 
 
Women randomized to IV morphine will receive morphine 2 mg IV, repeat every 4 hours 
as needed up to a maximum of 24 hours [total 6 doses]. 
 
The regimens above were chosen based on the regimens used in prior studies. 
Morphine was chosen as the comparative opioid since prior studies have demonstrated 
that morphine provides better pain control, has more patient satisfaction and less 
adverse effects. [3,5] 
 
Rescue regimen: 
If it is determined that either the IV acetaminophen or IV morphine is not adequate in 
controlling the patient’s pain, then a rescue course of opioids [higher dose morphine, 
meperidine or hydromorphone] may be administered to capture the pain according to 
the managing physicians. Analgesics that contain acetaminophen will not be 
administered as a rescue regimen to prevent the potential for acetaminophen toxicity. 

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If a rescue regimen is required, IV acetaminophen will resume for all 4 doses with its 
continued intent to treat pain. 
 
Primary Outcome: 
The primary outcome variable will be the summed difference in pain intensity in those 
women in Group 2 in the first stage of labor. Pain intensity will be based on a 100 mm 
visual analog scale. The subject will be asked to mark with a pen on the scale to rate 
their pain. If they are unable to mark the scale with a pen, this will be noted. 
 
The pain intensity via the VAS will determined at 6 time points: 
[1] prior to administration of the medication 
[2] 15 minutes after administration 
[3] 1 hours after administration 
[4] 2 hours after administration 
[5] 6  hours after administration. This will be obtained within 30 minutes after the 
second dose is given. 
[6] 24 hours after administration if the patient is still hospitalized. This will be obtained 
within 30 minutes after 24 hour dose is given. 
 
The summed difference in pain intensity will be defined as the difference in pain scale 
from each point 2-6 minus point 1. 
 
Secondary outcomes: 
Secondary outcomes will include the following: 
1. Pain relief based on a 5 point verbal scale at 15 minutes, 1, 2, 6 and 24 hours 
2. The time to first rescue medication 
3. The quantity of rescue medication over 24 hours or hospital stay 
4. Total amount of either acetaminophen, morphine or other analgesics over 24 
hours 
5. Patient’s global satisfaction at 24 hours. This will be patient reported. 
6. Reports of maternal adverse effects such as nausea, vomiting, pruritus, 
headache, pyrexia, insomnia, sedation 
7. Effects on fetal heart rate tracing including acceleration, decelerations, change in 
baseline and variability. This will occur about 30 minutes after the medication is 
given with a range of ± 30 minutes. 
 
No human specimens will be obtained for this study. 
 
Sample size: 
The sample size calculation is based on the mean difference in the VAS at 2 hours in 
women who received IV acetaminophen (mean=75.7) compared to IV pethidine 
(mean=72.7) in women with pain during the first stage of labor. There are no trials of IV 
acetaminophen versus IV morphine. Based on the above means, an alpha of 0.05 and a 
power of 0.80, a sample size of 44 women in each arm would be needed for a total of 88 

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women. To account for a 20% attrition rate from withdrawal, etc., 110 women for each 
pregnancy population will be enrolled with 55 in each medication group. Thus, for the 3 
pregnancy populations [pre-labor contractions, first stage of labor and maternal medical 
conditions], we will enroll a total of 330 women. 
 
 
Data analysis 
Analysis will be performed on the basis of intent to treat. Chi-square tests will be used 
to compare categorical data between the two treatment groups. Student’s t-test will be 
used to compare numerical data. Logistic regression analysis will include patient group 
as a stratifying variable. 
 
Procedures to Maintain Confidentiality 
All information and data will be kept on paper research charts that will be stored in a 
locked file cabinet within a locked research office of our research team/research 
coordinator. In addition, an electronic database of information and data will be stored 
on the computer of our research coordinator that is password protected, and in a locked 
office of the research coordinator. We will record subject information only by study 
code number. 
 
Potential Benefits and Risks 
In general, women will be a part of a study that may potentially affect how we manage 
pain control in pregnancy. As a specific benefit, half of the patients will be given IV 
acetaminophen, a drug associated with reduced opioid requirements and opioid-related 
side effects in non-pregnant women and post-surgical patients. 
 
Acetaminophen is a classified as a Category C medication. There are no studies focusing 
on congenital malformations from IV acetaminophen in pregnancy. However, 
epidemiologic data on oral acetaminophen use in pregnancy show no increased risk of 
major congenital anomalies. A large population-based prospective cohort study of 26, 
424 women with exposure to oral acetaminophen during the first trimester indicated no 
increased risk for congenital malformations.[24]  Another population based, case 
control study from the National Birth Defects Prevention Study showed that 11,610 
children with prenatal exposure to oral acetaminophen during the first trimester had no 
increased risk of birth defects compared to 4500 children in the control group. [24] 
Since the administration of IV acetaminophen will occur greater than 16 weeks, the risks 
are predicted to be very low. 
 
There are no studies focusing on IV acetaminophen and breastfeeding. Acetaminophen 
is secreted in human breast milk after oral administration. Based on 15 nursing 
mothers, the infant daily dose of acetaminophen is approximately 1-2 % of the maternal 
dose, which is considered minimal. [24] 

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Hepatic toxicity and renal toxicity are rare adverse effects of acetaminophen. Thus, 
subjects with known liver or kidney conditions will be ineligible for and excluded from 
this study. [24] 
 
 
 
 
 
References 
1. Obstetric analgesia and anesthesia. ACOG Practice Bulletin No. 36. American 
College of Obstetricians and Gynecologists. Obstet Gynecol 2002;100:177-191. 
2. Lowe NK. The nature of labor pain. American Journal of Obstetrics and 
Gynecology 2002;186:S16–S24. 
3. Ullman R, Smith LA, Burns E, Mori R, Dowswell T. Parenteral opioids for maternal 
pain management in labour. Cochrane Database of Systematic Reviews 2010, 
Issue 9. 
4. Jones L, Othman M, Dowswell T, Alfirec Z, Gates S, Newburn M, Jordan S, 
Lavendar T, Nielson JP. Pain management for women in labour: an overview of 
systematic reviews. Cochrane Database of Systematic Reviews 2012, Issue 3. 
5. Bricker L, Lavender T. Parenteral opioids for labor pain relief: a systematic 
review. American Journal of Obstetrics and Gynecology 2002;186(5 Suppl 
Nature):S94–109. 
6. Sekhavat L, Behdad S. The effects of meperidine analgesia during labor on fetal 
heart rate. International Journal of Biomedical Science 2009;5(1):59–62. 
7. Solt I, Ganadry S, Weiner Z. The effect of meperidine and promethazine on fetal 
heart rate indices during the active phase of labor. Israel Medical Association 
Journal 2002;4(3): 178–80. 
8. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. 
Efficacy and safety of single and repeated administration of 1 gram intravenous 
acetaminophen injection (paracetamol) for pain management after major 
orthopedic surgery. Anesthesiology 2005;102:822-31. 
9. Arici S, Gurbet A, Türker G, Yavaşcaoğlu B, Sahin S. Preemptive analgesic effects 
of intravenous paracetamol in total abdominal hysterectomy. Agri. 2009 
Apr;21(2):54-61. 
10. Candiotti KA, Bergese SD, Viscusi ER, Singla SK, Royal MA, Singla NKCandiotti Pain 
Med. Safety of multiple-dose intravenous acetaminophen in adult inpatients. 
2010 Dec;11(12):1841-8. 
11. Jokela R, Ahonen J, Seitsonen E, Marjakangas P, Korttila K. The influence of 
ondansetron on the analgesic effect of acetaminophen after laparoscopic 
hysterectomy. Clin Pharmacol Ther. 2010 Jun;87(6):672-8. 
12. Marty J, Benhamou D, Chassard D, Emperaire N, Roche A, Mayaud A, Haro D, 
Baron X, Hiesse-Provost O. Effects of single-dose injectable paracetamol versus 
propacetamol in pain management after minor gynecological surgery: a multi- 

8 
IRB NUMBER: HSC-MS-13-0763 
IRB APPROVAL DATE: 01/10/2014 
 
 
center, randomized double-blind, active-controlled, two-parallel-group study. 
Curr Ther Res 2005;66(4)294-306. 
13. Wininger SJ, Miller H, Minkowitz HS, Royal MA, Ang RY, Breitmeyer JB, Singla NK. 
A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study 
of two intravenousacetaminophen dosing regimens for the treatment of pain 
after abdominal laparoscopic surgery. Clin Ther. 2010 Dec;32(14):2348-69. 
14. Omar AA, Khaled AA. Intravenous paracetamol (Perfalgan) for analgesia after 
cesarean section: a double-blind randomized controlled study. Rawal Med J 
2011; 36: 269-73. 
15. Moller PL, Sindet-Pedersen S, Petersen CT, Juhl GI, Dillenschneider A, Skoglund 
LA. Onset of acetaminophen analgesia: comparison of oral and intravenous 
routes after 
third molar surgery. Br J Anaesth. 2005 May;94(5):642-8. 
16. Ceelie I, de Wildt SN, van Dijk S, van den Berg MM, van den Bosch GE, 
Duivenvoorden HJ, de Leeuw TG, Mathot R, Knibble C, Tibboel D. Effect of 
intravenous paracetamol on postoperative morphine requirements in neonates 
and infants undergoing major non cardiac surgery. JAMA 2013; 309 (2): 149-154. 
17. Mound E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and 
selective and non-selective anti-inflammatory drugs for the reduction in 
morphine-related side-effects after major surgery: a systematic review. British J 
Aneasth 2011; 106(3): 292-7. 
18. Alhashemi JA, et al. Intravenous acetaminophen vs oral ibuprofen in combination 
with morphine PCIA after Cesarean delivery. Can J Anesth 2006; 53(12):1200-06. 
19. Inal M, et al. IV paracetamol infusion is better than IV meperidine infusion for 
postoperative analgesia after Caesarean section. The Internet Journal of 
Anesthesiology 2007; 15(1). 
20. Kiliçaslan A, Tuncer S, Yüceaktaş A, Uyar M, Reisli R. The effects of intravenous 
paracetamol on postoperative analgesia and tramadol consumption in cesarean 
operations. Agri. 2010 Jan;22(1):7-12. 
21. Prasanna A, Sharma K. Pre-incision analgesia prevents immediate incidential pain 
after LSCS-randomized blinded study. J Anesth Clin Pharmacol 2010;23(3): 375- 
378. 
22. Elbohoty AE, Ebd-Elrazek H, Abd-El-Gawad M, Salama F, El-Shorbagy M, Ebd-El- 
Maeboud KH. Intravenous infusion of paracetamol versus intravenous pethidine 
as an intrapartum analgesic in the first stage of labor. Int J Gynecol Obstet 
2012;118(1):7-10. 
23. Dystocia and augmentation of labor. ACOG Practice Bulletin No. 49. American 
College of Obstetricians and Gynecologists. Obstet Gynecol 2003;102:1445-54. 
24. OfirmevTM (acetaminophen) injection prescribing information. Cadence 
Pharmaceuticals, Inc. 

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