Clinical trial NCT03372382
Conditions: Opioid Use Pain, Postoperative
Keywords: postpartum
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2017-12-13; Completion date: 2018-04-10
Enrollment: 170 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Postpartum patients delivered by cesarean section will be randomized to NSAIDS Vs NSAIDS plus opioid

Detailed description:
Women will be approached priors to discharge from the hospital, if they meet inclusion criteria and consent for the study, they will be randomized to one of two possible analgesic regimens. They will be followed at 1-2 weeks and 4-6 weeks after discharge to assess pain level.

Arms: arm 1: women that had a C-section will be discharged home with prescriptions for ibuprofen and acetaminophen arm 2: women that had a C-section will be discharged home with prescriptions for ibuprofen and acetaminophen/hydrocodone (Norco)
Interventions: intervention 1: Ibuprofen intervention 2: Acetaminophen intervention 3: Norco
Intervention descriptions: intervention 1: NSAID intervention 2: analgesic intervention 3: acetaminophen plus opioid

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
 
 
 
 
 
 
 
 
 
Ibuprofen and Acetaminophen versus Ibuprofen and Acetaminophen plus 
Hydrocodone for Analgesia after Cesarean Section: A Randomized Controlled, 
Comparative Effectiveness, Equivalence Trial 
 
The IVY trial 
 
NCT03372382 
 
Version Date: 05/02/2018 
 
 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
 
 
 
 
 
 
 
 
 
Ibuprofen and Acetaminophen versus Ibuprofen and Acetaminophen plus Hydrocodone 
for Analgesia after Cesarean Section: A Randomized Controlled, Comparative 
Effectiveness, Equivalence Trial 
 
The IVY trial 
 
 
 
 
 
 
 
 
Jenifer Dinis, MD 
Eleazar Soto, MD 
Claudia Pedroza, PhD 
Baha Sibai, MD 
 
 
 
 
 
Division of Maternal Fetal Medicine. 
 
Department of Obstetrics, Gynecology, and Reproductive Sciences. 
 
University of Texas McGovern Medical School. 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
Background 
 
Opioid use after cesarean section 
 
Currently there is an opioid abuse epidemic in the United States (1). Contrary to common 
belief, One of the most common sources of drugs for abuse are prescribed medications 
(2). According to the CDC, in 2015 there were 3,988,733 births, 32% of which were 
cesarean sections (3) thus, prescription of opioids for postpartum women may be one of 
the most common sources of leftover medications that have potential for abuse. 
 
The American College of Obstetricians and Gynecologist has issued guidelines for 
perinatal care (4) with a section on postpartum analgesia acknowledging that opioids can 
be necessary after a cesarean section, especially in the first 24 hours, but there is no 
standard recommendation regarding the type and amount of opioid to be prescribed. 
 
Although many studies have determined approximate opioid requirements in the first 
24-48 hrs after cesarean section (5), until recently there was a paucity of data regarding 
patterns of use once women are discharged from the hospital. Empirically, 30 to 40 
tablets of any opioid agent are prescribed upon discharge (6), Non Steroidal Anti- 
inflamatory Drugs (NSAIDS) are also prescribed as they can decrease concomitant 
opioid use and improve analgesia(7,8). A Cochrane review published in 2015 sought to 
determine the effectiveness, safety and cost-effectiveness of oral analgesia for post- 
caesarean pain relief.  This review included 8 trials that were not performed in the US, 
with a total of 962 women but no conclusions could be made regarding the safest and 
most effective form of oral analgesia due to poor quality of data (9) 
 
The limited evidence that exists regarding postpartum patterns of opioid use indicates 
that practitioners tend to prescribe more drugs than what the patients may need (10). 
Bartels et al (11) conducted a prospective cohort study including 30 patients undergoing 
cesarean section and 30 patients undergoing thoracic surgery. They sent an online 
survey to these patients during their postoperative period inquiring about the amount of 
medication consumed and storage and disposal methods for it. They found that 53% of 
patients had leftover opioids at 30 days postpartum. 
 
Osmundson et al (10) analyzed data from 179 women that were prescribed opioids after 
c-section. The study group   filled a survey regarding medication use during 
hospitalization and again 14 days after discharge; those still using opioids at the time of 
the second survey were contacted weekly until they reported discontinuation of opioid 
medication. The authors reported that women took opioids for a median of 8 days after 
discharge from the hospital and consumed a median of 75 morphine milligram 
equivalents, which equals 22 tablets of oxycodone 5mg or 15 tabs of hydrocodone 5mg. 
75% of women had leftover pills after their postpartum period. 
 
More recently, Bateman et(12) al enrolled 720 patients on a prospective study, patients 
that had undergone a c-section were contacted by phone 2 weeks after discharge to 
obtain information regarding use of opioid prescription. Their patients used a median of 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
20 opioid tablets and 83.5% of patients had leftover tablets. They reported that patient 
satisfaction did not correlate with amount of opioids prescribed and that the more 
opioids are prescribed, the more the patients use after leaving the hospital. 
 
To date, those are the only study that has published data regarding the amount of 
opioids used after discharge from the hospital.   Our research team is currently 
conducting a prospective study regarding patterns of opioid use postpartum as well as 
patient satisfaction, which could validate the findings mentioned above (POP study, 
HSC-MS-17-0293) 
 
Mechanism of Action of Opioids 
 
Papaver somniferum and P. album are the source of opium, which contains 10% 
morphine. Opioids bind to μ (mu), δ (delta) and κ (kappa) receptors located in the brain 
and spinal cord, responsible for transmission of pain signals. (13). All opioids are 
metabolized by the cytochrome P450 2D6 (CYP2D6) enzymes into more active 
metabolites and then glucuronized in the liver for excretion. The only exception to this is 
Hydromorphone, which   is   metabolized   in   the   liver   to   an   inactive   metabolite: 
hydromorphone-3-glucoronide. (13,14) 
 
CYP2D6 exhibits great polymorphism. There are three types of patients according to 
this enzyme’s activity (14): 
 
-Poor metabolizer (PM): patients with non functioning alleles for CYP2D6. 
 
-Intermediate metabolizer (IM): function is partial due to inheritances of only one 
functioning allele. 
 
-Extensive metabolizer (EM): considered normal functional status of the enzyme, 
resulting of inheritance of two functioning alleles for the enzyme gene. 
 
-Ultrarapid Metabolizer (UM): inheritance of extra functioning alleles, conferring 
increased enzyme action. 
 
PM and IM patients clear opioids via other compensatory CYCP450 enzymes. UM have 
increased accumulation of active metabolites, which can lead to opioid toxicity (15). 
People with North African or middle eastern ascendance have increased likelihood of 
being UM (15). 
 
Mechanism of Action of Ibuprofen 
 
Ibuprofen reversibly inhibits COX-1 and COX-2 and the production of thromboxane, 
prostaglandin, and prostacyclin. Arachidonic acid diversion to the leukotriene pathway 
when the cyclooxygenase-catalyzed prostaglandin pathway is blocked, might result in 
increase in leukotriene and bronchoconstriction. This form of allergy is more common 
among aspirin users than ibuprofen user (16). 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
Inhibition of prostaglandin synthesis results in anti-inflammatory and antipyretic effects. 
In neonates, ibuprofen can cause closure of a patent ductus arteriosus. (16) 
 
Mechanism of action of acetaminophen 
 
It  is  known  that  acetaminophen  has  both  peripheral  and  central anti-inflammatory 
properties, including COX inhibition, however the exact mechanism of analgesia has not 
been elucidated. It also has antipyretic effects (17,18). 
 
 
 
Rationale for this study 
 
Opioid use has quadrupled over the past decade with 259 million prescriptions in 2012 
alone in the United States, which consumes more prescription opioid pain relievers than 
any other nation (1,19).  This has led to concern that there is an opioid epidemic in the 
United States. Undoubtedly adequate analgesia is required after a cesarean section, 
but it is still unclear which the most appropriate analgesic treatment is after the patient 
has left the hospital after a cesarean section. 
 
According  to  the  CDC,  in  2015  there  were  3,988,733  births,  32%  of  which  were 
cesarean sections (3) thus, prescription of opioids for postpartum women may be one of 
the most common sources of leftover medications that have potential for abuse. Every 3 
minutes, a woman seeks care in an emergency department related to prescription 
opioid misuse(19). The rising prevalence of opioid use in pregnancy has led to a 
concomitant dramatic fivefold increase in neonatal abstinence syndrome over the past 
decade. Neonatal abstinence syndrome is a drug withdrawal syndrome that opioid- 
exposed neonates experience shortly after birth. 
 
In addition, the use of narcotics while breastfeeding may lead to adverse drug reaction 
on the breastfeed infant. Opioid analgesia during postpartum may affect infant alertness 
and suckling vigor. More importantly, the use of codeine or tramadol in breastfeeding 
women may result in fatal overdoses in extreme cases depending on the child drug 
metabolism.  Due  to those  concerns,  the  US  FDA  issued  a  warning  and 
contraindications for the use of codeine and tramadol in breastfeeding women in 2017. 
The statement suggests using opioids other than codeine or tramadol such as morphine 
or hydromorphone; which may not have the same effect of the neonate or infant but 
certainly can have serious effect on the mother in cases of overdose or misuse (19). 
 
The use of narcotics for pain control as outpatient therapy after a cesarean delivery 
appears to be standard practice in the United States. However, in many countries the 
use of narcotics is limited after cesarean delivery and often patients are treated as 
outpatient without narcotic medications (9). 
 
There have been no adequately powered studies to examine whether women that had a 
cesarean  section  truly  require  opioids  after  leaving  the  hospital.  Performing  a 
comparison  between  a  regimen  with  NSAIDS  (ibuprofen  and  acetaminophen)  and 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
another combining NSAIDS and an opioid medication (such as hydrocodone), would 
allow us to stablish prescription guidelines. The knowledge acquired by performing 
these study, could lead to decreased opioid prescriptions and thus aid in the fight 
against the national opioid epidemic. 
 
Hypothesis 
 
We hypothesize that there will not be a difference greater than 10mm on pain score 
measured with visual analogue pain scale at 1-2 weeks and at 4--6 weeks after 
discharge, among women who have had a cesarean section and are discharged with 
only a prescription for NSAIDS versus women who are discharged with prescriptions for 
both NSAIDS and opioids. We seek to determine if NSAIDS alone are equivalent to 
NSAIDS plus opioids for analgesia after a cesarean section 
 
Objectives 
 
Our primary aim is to determine whether NSAIDS alone can be prescribed after 
discharge from the postpartum ward without a significant change in pain scores and 
patient satisfaction in the postpartum period. 
 
RESEARCH DESIGN AND METHODS 
Study design 
This comparative effectiveness study will be conducted as a randomized, open label, 
controlled  equivalence  trial  of  NSAIDS  Vs  opioids  for  management  of  pain  after 
cesarean section. Previous studies have compared analgesics vs placebo, finding that 
analgesics are required after cesarean section for pain control (9), thus, a comparison 
against placebo would be unethical and has not been included in the trial design. 
 
Postpartum patients that have had a cesarean section and consent to participate in the 
study will be randomly allocated to receive either Ibuprofen and acetaminophen or, 
ibuprofen and acetaminophen plus hydrocodone prior to discharge from the hospital. 
Currently, opioids are recommended for inpatient analgesia after a cesarean section but 
there is no standard prescription recommended after discharge from the hospital. 
 
Inclusion criteria 
 
English or Spanish speaker women who had a cesarean section, between 18-50 years 
old, able to provide consent. 
 
Exclusion criteria 
 
- Inability or refusal to provide informed consent. 
 
- Reported current or prior opioid or benzodiazepine use disorder, including urine drug 
screen positive for a non prescribed opioid or benzodiazepine upon admission or during 
prenatal care. 
 
- Current treatment with methadone, buprenorphine or buprenorphine plus naloxone. 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
- Known alcoholism disorder. 
 
- Severe renal or hepatic impairment. 
 
-Severe peptic ulcer disease 
 
- Severe asthma (if patient has asthma but has previously tolerated NSAIDS, she will be 
allowed to participate) 
 
- Known CYP450/CY92D6 mutation conferring opioid ultra-rapid metabolizer status. 
 
- Allergy to any of the study drugs (anaphylaxis). 
 
-Incarcerated or institutionalized patients. 
 
- Inability to follow up as outpatient in our outpatient clinic. 
 
- wound dehiscence or infection diagnosed prior to discharge from the hospital 
 
- wound vac placed prior to discharge from the hospital. 
 
Recruitment 
 
Recruitment will occur on the labor and delivery and postpartum wards at Memorial 
Hermann Hospital-Texas Medical Center. Eligible women will be consented within the 
24 hours prior to discharge from the hospital. A member of our research team, either a 
physician or research assistant/nurse, will obtain written informed consent. 
 
Randomization 
 
Randomization  will  be  performed  based  on  a  computer-generated  list  that  will  be 
created by a non-clinical member of the research team.  Subjects will be randomized 
1:1 to NSAIDS only or NSAIDS and opioids using permuted blocks and stratified by 
repeat cesarean section (yes/no) and scheduled cesarean section (yes/no). REDCAP, a 
HIPPA compliant database, will be used for randomization and capture of study data. 
The randomization sequence will be uploaded in the system. After a patient has 
consented to be part of the study, pertinent information will be entered in REDCAP and 
the system will allocate the patient to a research group. 
 
Subjects included in the study will be followed until they stop using analgesics or until 4 
-6 weeks postpartum, whatever comes first. 
 
Methods 
 
Patients that have delivered by cesarean section will be approached within 24 hours 
prior to discharge from the hospital. Immediately after signing the consent form, the 
patient’s information will be input in REDCAP and she will be randomly allocated to 
either group 1 (prescription for Ibuprofen and acetaminophen after discharge) or group 
2 (prescription for ibuprofen, acetaminophen and hydrocodone upon discharge). 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
Pain level and satisfaction score will be recorded the day of discharge from the hospital 
along with a brief survey. This will be performed by a trained member of the research 
team (please see measurement instruments in upcoming sections). In our institution, 
patients routinely have up to two appointments after discharge from the hospital, one at 
1-2 weeks and another at 4-6 weeks. Pain level and satisfaction scores will be recorded 
during these visits as well, as part of another survey that will also be performed by train 
research team members. At the time of postpartum outpatient visits, patients will be 
asked to bring the bottles with their left over medication. The tablets will be counted and 
handed back to the patient. If a patient does not bring the bottle, she will be asked to tell 
us the number of pills that she has left over. 
 
If a patient cannot attend the postpartum appointment, she will be contacted via phone 
to obtain the information from the survey. An email with a link will be sent to record the 
information from pain scores. 
 
Medication regimen 
 
Patients will be randomized to either group 1 (prescription for Ibuprofen 600 mg po 
every 6 hours, 60 tablets total after discharge and acetaminophen 500 mg tabs, 1 tablet 
po every 4 hours, for a total maximum possible daily dose of 3000 mg, 60 tablets total) 
or group 2 (prescription for same ibuprofen regimen and hydrocodone-acetaminophen 
(Norco®) 5/325mg tab, one tab po q 4 hours or 2 tabs po q 6 hours, 15 tablets total). All 
patients will also be given a prescription for 30 tablets of ranitidine150mg tablets, to be 
taken every 12 hours in case for gastrointestinal upset symptoms. Any physician 
discharging the patient can write the prescriptions for the study medications. 
 
Please note that the patient’s obstetrician will decide which analgesic regimen to order 
during  hospitalization,  randomization  will  be  performed  prior  to  discharge  and  the 
patient will start these medications at home. The patients will be instructed to take the 
ibuprofen as scheduled regardless of pain level and only take other medications in case 
they require additional pain control. 
 
Patients will also be advised that if their pain is not well controlled with the prescribed 
regimen, they can call the obstetric physician on call for the hospital to obtain a rescue 
prescription for Norco®. 
 
 
 
Primary outcome 
 
Mean pain score, as measured by a visual analog scale and numerical pain scale. We 
will compare mean scores at discharge, 1-2 and 4-6 weeks postpartum, but our primary 
outcome will be the score at 1-2 weeks postpartum. 
 
The visual analog scale (VAS) is a widely validated tool, it consists of a 100 mm line, 
without markups. Patients are instructed to mark a point along the line that represents 
their pain level, the left hand end of the line represents no pain and the right hand end 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
of the line represents the worst pain possible. Mean measurements of pain with this tool 
have been widely described, as well as standard deviations and effect size. The sample 
size calculation for our study is based on VAS measurements. 
 
Despite the fact that VAS is widely used in research, it is not commonly used in clinical 
settings, thus, the numerical pain scale has been included, in which 0 means no pain 
and 10 means the worst pain. This will be an ordinal variable. This scale is commonly 
used by nurses while patients are in the hospital. 
 
A trained member of the research team will administer a survey and measure pain 
scores at discharge from the hospital and during the return appointments at 1-2 weeks 
and 4-6 weeks. Subjects will be asked to record their pain level using both instruments 
simultaneously. This will provide a good reference for research results application. 
 
As mentioned previously: if a patient cannot attend  the follow up appointments, we will 
attempt to contact her over the phone to administer a survey regarding satisfaction with 
pain medication regimen and we’ll also send an email containing the VAS pain scale so 
we can obtain this information. If the pain score is not obtained, the patient will be 
excluded from the analysis. 
 
Secondary outcomes 
 
Maternal: 
 
-Patient satisfaction score: Patients will be asked how satisfied are they with their 
inpatient analgesics prior to discharged, they will also be asked how satisfied were they 
with the assigned outpatient analgesic regimen during postpartum appointments at 1-2 
weeks and 4-6 weeks. Satisfaction will be measured in a 5 point scale, previously used 
in our prospective study. The patient will assign a number from the following scale: 
 
Table 1- Satisfaction scale 
 
1 
2 
3 
4 
5 
Very 
dissatisfied 
Somewhat 
dissatisfied 
Neutral 
Satisfied 
Very satisfied 
 
 
Other maternal outcomes include: 
 
-  Pain  scores  measured  by  visual  analogue  scale  at  4-6  weeks  and  pain  scores 
measured by numeric scale (0to 10) at 1-2 weeks and at 4-6 weeks 
 
- Number of days of opioid use after discharge from the hospital 
 
- Need for rescue opioid prescription (group 1 only) 
 
- Need for additional opioid refill (both groups) 
 
- Left over medication rate among study groups 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
-  Incidence  of  side  effects: Common  side  effects expected  for  Ibuprofen  use  are: 
nausea, gastroesophagic reflux, epigastric pain. Common side effects expected from 
hydrocodone use are: constipation, drowsiness, pruritus, nausea/emesis. 
 
- ER or hospital visit prior to appointment due to incisional pain 
 
Fetal: 
 
-Initiation and continuation of breastfeeding at hospital discharge and during postpartum 
period. 
 
The information for maternal and fetal outcomes would be obtained by trained research 
personnel by performing surveys prior to hospital discharge and during postpartum 
visits. Survey instruments will be attached in a separate document. 
 
Sample size 
 
Sample size calculations are based on VAS score at 1-2 weeks. In prior studies 
comparing NSAIDS vs opioids, the standard deviation (SD) of VAS scores has been 
described as 20 mm(20). In a recent study by Ankumah et al(21), the largest SD described 
for our patient population was 13.2 mm. In order to perform a conservative sample size 
calculation, an anticipated SD of 20mm will be used for our study. 
 
Previous studies using VAS have defined a significant effect size to be 10 mm(22). Thus 
we would consider NSAIDS alone to be equivalent to opioids if the difference in VAS 
score is no larger than 10 mm in either direction. We performed an equivalence sample 
size calculation using an SD of 20 mm, and a difference of 10 mm on the VAS score, 
80% power and two-sided alpha of 0.05. A total of 128 individuals would be needed to 
reject the non-equivalence hypothesis (64 on each study group). 
 
To account for a 30% attrition rate, a total of 184 subjects will need to be recruited, 92on 
each arm. 
 
Feasibility 
 
Approximately 300 births take place in Memorial Hermann Hospital-Texas Medical 
Center every month. At a cesarean section rate of 30%, that means that 90 women 
would potentially qualify for the study every month. Approximately 50% of these 
deliveries are performed by UTHealth physicians. Private physicians will be approached 
to inquire whether their patients can be included in this study, in order to perform a 
conservative calculation, we will assume that only 40 women every month will be 
candidates for the study. 
 
At a recruitment rate of 50%, 20 women could be enrolled every month and the study 
would be concluded after 8 months. 
 
Data analysis 


IRB NUMBER: HSC-MS-17-0777 
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Once a patient is randomized into the study, she will be followed and her information 
collected even if during the study she requires additional analgesics. 
 
Analysis will be performed on the basis of intent to treat. For the primary outcome, we 
will also perform a per-protocol analysis excluding those patients in NSAIDS only group 
that required rescue opioid prescriptions. Generalized linear models will be used to 
analyze all outcomes and will include treatment group and the two stratifying variables, 
repeat c-section and scheduled c-section, as covariates. For all outcomes we will 
evaluate the most appropriate distributional form (i.e., Normal, binomial, Poisson, etc) 
and/or variable transformation. A linear regression model will be used for the primary 
outcome of VAS score (with appropriate transformation if needed) to estimate the 
adjusted  mean  difference  and  2-sided  95%  CI.  Treatments  will  be  regarded  as 
equivalent if the upper bound of the 95% CI is below 10 mm and the lower bound is 
above -10 mm. 
 
For secondary binary outcomes we will use log binomial models (or robust log Poisson 
in case of non-convergence) to directly estimate relative risks and 95% CIs. For all other 
outcomes,  we  will  report  2-sided  95%  CIs  and  p-values.  A  secondary  regression 
analysis will be conducted for the primary outcome adjusting for parity and drug use. 
 
Bayesian analysis will be performed. 
 
 
 
Procedures to Maintain Confidentiality 
 
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. The database will be created using REDCAP. Subject information in this 
database will be de-identified, a linking log will be created in REDCAP as well. 
 
Potential benefits 
 
If we confirm that NSAIDS alone or with a reduced amount of opioids can be used to 
control  postoperative  pain  after  discharge  from  the  hospital,  this  could  potentially 
change   national   prescribing   guidelines   and   decrease   opioid   exposure   among 
postpartum women. This would indirectly contribute to decrease the amount of opioid 
pills available for potentially misuse across the nation. 
 
Known potential risks 
 
Maternal Side Effects of Opioids 
 
The following table summarizes commonly reported adverse effects of opioids, including 
hydrocodone (13,14, 25). 
 
Table 2: common side effects of opioid use 


IRB NUMBER: HSC-MS-17-0777 
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Acute Use 
Pruritus/Urticaria 
Nausea/vomiting 
Constipation 
Urinary retention 
Respiratory depression 
Sedation 
Delirium 
Myoclonus 
Seizures 
Chronic Use 
Tolerance, dependence and addiction 
Hyperalgesia 
Withdrawal symptoms 
Increased growth hormone secretion 
Hypogonadism 
 
 
 
Maternal side effects of Ibuprofen 
 
Ibuprofen has a short half-life of 2-4 hours and is the preferred analgesic during the 
postpartum period. Side effects include dyspepsia, heartburn, nausea, vomiting, 
anorexia, diarrhea, constipation, stomatitis, flatulence, bloating, epigastric pain, and 
abdominal pain. Peptic ulcer and GI bleeding have been reported (16,24). 
 
Symptoms of overdose include headache, loss of consciousness, tinnitus, CNS 
depression and seizures. May rarely cause metabolic acidosis, abnormal hepatic 
function,  hyperkalemia,  renal  failure,  dyspnea,  respiratory  depression,  coma,  acute 
renal failure, and apnea (primarily in very young pediatric patients) (24). 
 
 
 
Maternal side effects of acetaminophen 
 
Common side effects include nausea, rash and headache. Other side effects are 
hepatotoxicity, acute tubal necrosis, anema, thrombocytopenia and anaphylaxis(17) 
 
Lactation 
 
Hydrocodone: 
 
Opioids can cause neonatal central nervous system and respiratory depression (23). 
Effects are dependent on the amount of opioid transferred in breast milk. In a 2011 
report of hydrocodone concentrations in breast milk, Sauberan et(26) al found that 
breastfed neonates received 1.6% (range 0.2%–9%) of the maternal hydrocodone dose, 
this is a safe dose for neonates and it has not been associated with adverse neonatal 
effects. 
 
Theoretically any neonate born to mother that is an ultrarapid metabolizer (UM) could 
be at risk for opioid toxicity, but no cases of UM and hydrocodone used have been 
reported in the literature (29). 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
There are only two reports of adverse neonatal outcomes in mothers that used 
hydrocodone while breastfeeding, both associated with polymedication: In one report, 
the mother was taking acetaminophen, fluconazole and hydrocodone simultaneously 
and reported her neonate slept for most of the day, this symptom resolved after 
decreasing hydrocodone dose. In the second case the mother used methadone and a 
combination of hydrocodone with acetaminophen while breastfeeding, her neonate 
required emergency intubation and no other cause was found for the neonate’s 
respiratory depression (27). 
 
In conclusion, hydrocodone is considered safe during breastfeeding and is one of the 
drugs currently used for treatment of pain in the postpartum period. 
 
Ibuprofen: 
 
Early  studies  reported  that  ibuprofen  was  not  excreted  in  breast  milk(28)   however, 
studies using current technology report that ibuprofen is in fact excreted in breast milk, 
to a concentration that is <0.38% (0.04%-1.53%) of the weight-adjusted maternal 
daily dose, which equals 0.2% of the infant dose(29).  Ibuprofen is considered safe 
during breastfeeding. 
 
Acetaminophen: 
 
The concentration of acetaminophen in breast milk is < 0.1% than that of maternal 
serum. It is considered safe during breastfeeding (30) 


IRB NUMBER: HSC-MS-17-0777 
IRB APPROVAL DATE: 05/02/2018 
 
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Appendix A: pain scales 
 
Mark a point In the line below that represents your pain level 
No pain 
worst pain ever 
 
 
 
Using the pain scale below, which number would you assign to your current pain level? 
Please circle answer. 0= no pain, 10= worst pain ever. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10