Clinical trial NCT04369950
Conditions: Physiological Effect of Drugs Morphine Analgesics Analgesics, Opioid Central Nervous System Depressants Narcotics
Keywords: cesarean delivery c-section chloroprocaine lidocaine morphine post-operative pain post-cesarean analgesia
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2020-05-11; Completion date: 2021-07-11
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to show that the effect of 3% 2-chloroprocaine prior to epidural morphine administration will be not inferior to the effect of epidural 2% lidocaine with 1:200,000 epinephrine on total opioid use for 24h

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: 2% lidocaine with 1:200,000 epinephrine and epidural morphine intervention 2: 3% 2-chloroprocaine and epidural morphine
Intervention descriptions: intervention 1: Epidurals will be dosed with 2% lidocaine with 1:200,000 epinephrine to T4 level in 5ml increments, epidural morphine 3mg will be given after delivery of neonate. T4 level maintained throughout cesarean delivery with additional epidural doses of 2% lidocaine with 1:200,000 epinephrine for both groups. Post-operative orders of scheduled acetaminophen and ibuprofen, and oxycodone as needed will be written. intervention 2: Epidurals will be dosed with 3% 2-chloroprocaine to T4 level in 5ml increments, epidural morphine 3mg will be given after delivery of neonate. T4 level maintained throughout cesarean delivery with additional epidural doses of 2% lidocaine with 1:200,000 epinephrine for both groups. This is the critical component to bridge the latency period between the offset of 3% 2-chloroprocaine and the peak action of epidural morphine.Post-operative orders of scheduled acetaminophen and ibuprofen, and oxycodone as needed will be written.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-19-
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Page 1 of 7IRB APPROVAL DATE: 05/04/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-cesarean analgesia with epidural morphine following epidural 2-
chloroprocaine 
 
NCT04369950 
 
Version Date: 05/04/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB NUMBER: HSC-MS-19-
0951 
Page 2 of 7IRB APPROVAL DATE: 05/04/2020 
Protocol Template Version Jan 2018  
Adapted from NIH protocol template and ICH Guidelines 
Protocol Title: 
Post-cesarean analgesia with epidural morphine following epidural 
2chloroprocaine  
Principal Investigator: 
Linden O. Lee  
Co-Investigators: 
Ana-Lisa Ramirez-Chapman, Maya Suresh  
Study Coordinator: 
N/A 
Population: 
80 pregnant female subjects (40 subjects in two groups), age 18-50, 
scheduled for cesarean delivery of live singleton birth at MHH-TMC or LBJ 
Hospital, with a functional labor epidural in place 
Number of Sites: 
MHH-TMC and LBJ Hospital 
Study Duration: 
March 2020-March 2021 
Subject Duration: 
24 hours 
 
General Information 
An investigation into whether or not 3% 2-chloroprocaine administered via epidural for cesarean 
delivery antagonizes epidural morphine resulting in diminished post-operative analgesia.  
Background Information 
Patients with labor epidurals in place who require cesarean delivery are typically dosed with either 2% 
lidocaine with 1:200,000 epinephrine or 3% 2-chloroprocaine to achieve surgical anesthesia. The utility 
of 3% 2-chloroprocaine lies in that it has a more rapid onset of action compared to 2% lidocaine with 
1:200,000 epinephrine, making it a valuable medication in emergent cesarean deliveries when trying to 
avoid general anesthesia. However its duration of action is shorter (30-45 minutes) compared to that of 
epidural 2% lidocaine with 1:200,000 epinephrine (60-120 minutes). Neuraxial morphine is frequently 
administered during cesarean deliveries and provides post-operative analgesia for approximately 24 
hours.  
Studies have suggested that administration of epidural 3% 2-chloroprocaine prior to epidural morphine 
results in decreased effectiveness of epidural morphine.1,2 Karambelkar et al. compared patients given 
epidural 3% 2-chloroprocaine to those given epidural 2% lidocaine with 1:200,000 epinephrine prior to 
epidural morphine. As epidural 3% 2-chloroprocaine has a duration of action of 30-45 minutes and the 
onset time of epidural morphine is at least 1 hour, Karambelkar et al. re-dosed those receiving epidural  
                                                          
1 Karambelkar DJ, Ramanathan S. 2-Chloroprocaine antagonism of epidural morphine analgesia. Acta Anaesthesiol 
Scand 1997;41:774-8. 
2 Toledo P, et al. The Interaction Between Epidural 2-Chloroprocaine and Morphine: A Randomized Controlled Trial 
of the Effect of Drug Administration Timing on the Efficacy of Morphine Analgesia. Anesth Analg 
2009;109(1):16873. 


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3% 2-chloroprocaine with additional doses of 3% 2-chloroprocaine when patients became 
uncomfortable. The results of this study were that patients who received epidural 3% 2-chloroprocaine 
had faster regression of their sensory block, increased IV PCA morphine use at 4 and 24 hours, and 
increased pain scores at 1 and 2 hours compared to those given epidural 2% lidocaine with 1:200,000 
epinephrine. Toledo et al. investigated patients undergoing post-partum tubal ligations comparing those 
receiving epidural 3% 2-chloroprocaine to those given epidural 2% lidocaine with 1:200,000 epinephrine 
prior to epidural morphine. If patients became uncomfortable, no additional epidural medications were 
administered, with the authors opting for IV midazolam or surgical infiltration with lidocaine. The results 
demonstrated that patients who received epidural 3% 2-chloroprocaine had higher pain scores on 
admission to PACU, 33% compared to 0% in the epidural 2% lidocaine with 1:200,000 epinephrine group 
requested analgesia within 90 minutes of epidural morphine administration, however 48 hour opioid 
consumption was similar between the groups.   
The belief that administration of epidural 3% 2-chloroprocaine prior to epidural morphine results in 
decreased effectiveness of epidural morphine is controversial and may be an effect of 3% 2- 
chloroprocaine wearing off prior to the peak action of epidural morphine rather than true antagonism.3 
Our hypothesis from anecdotal observation is that this phenomenon is secondary to 3% 2chloroprocaine 
wearing off prior to the peak action of epidural morphine rather than true antagonism. We believe that 
the results seen from Karambelkar and Toledo were secondary to the latency period between epidural 
3% 2-chloroprocaine wearing off and the peak onset of epidural morphine. By redosing those that 
initially received epidural 3% 2-chloroprocaine with epidural 2% lidocaine with 1:200,000 epinephrine, 
the latency period could be bridged and higher pain scores immediately after cesarean delivery may be 
avoided. This is an important question to answer as obstetric anesthesiologists attempt to avoid general 
anesthesia whenever safely possible and alleviating or confirming concerns about diminished post-
cesarean analgesia with 3% 2-chloroprocaine will help guide future practice.  
Objectives 
Primary objective is to show that the effect of 3% 2-chloroprocaine on total opioid use for 24h after 
epidural morphine administration will be not inferior to the effect of epidural 2% lidocaine with 
1:200,000 epinephrine. Secondary objectives will be to evaluate the following endpoints between two 
arms: time until first opioid request, pain (11 point scale; 0-10), nausea and pruritis (3 point scale; none, 
mild, moderate-severe) – every 4h for the first 12h, and every 12h for 24h. 
The study’s purpose is to determine if the previously observed diminished analgesia with epidural 
chloroprocaine and epidural morphine is secondary to antagonism or a latency period. If we are able to 
demonstrate that epidural chloroprocaine followed by epidural lidocaine top-ups and epidural morphine 
provides equivalent analgesia to epidural lidocaine followed by epidural morphine, it would support our 
hypothesis of a latency period. These results would help guide future anesthetic practices and reduce 
concerns that some anesthesiologists have in using chloroprocaine for cesarean deliveries.   
                                                          
3 Hess PE, et al. Chloroprocaine may not affect epidural morphine for postcesarean delivery analgesia. J Clin Anesth 
2006;18(1):29-33. 


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Study Design 
This study will be a prospective comparison between epidural 2% lidocaine with 1:200,000 epinephrine 
and 3% 2-chloroprocaine on the analgesic effect of epidural morphine. We intend the duration of the 
study to be 12 months and include a total of 80 subjects (40 subjects in each group)  
Patients with labor epidurals in place scheduled for cesarean delivery due to arrest of dilation or arrest 
of descent will be recruited. The patients will be randomized via a computer-generated random number 
sequence to one of two groups (lidocaine, chloroprocaine) with 40 subjects in each group. Epidurals will 
be dosed with 3% 2-chloroprocaine or 2% lidocaine with 1:200,000 epinephrine to T4 level in 5ml 
increments, epidural morphine 3mg will be given after delivery of neonate. The patient will be blinded 
to which medication she receives however the physician administering the medication will not be 
blinded. T4 level maintained throughout cesarean delivery with additional epidural doses of 2% 
lidocaine with 1:200,000 epinephrine for both groups. This is the critical component to bridge the 
latency period between the offset of 3% 2-chloroprocaine and the peak action of epidural morphine.  
Post-operative orders of scheduled acetaminophen and ibuprofen, and oxycodone as needed will be 
written.  
3% 2-chloroprocaine without epinephrine will be used which has a concentration of 30mg/ml. A 
maximum of 20ml (600mg) will be used, which is below the recommended maximum recommended 
dose of 800mg. 2% lidocaine with epinephrine will be used which has a concentration of 20mg/ml. A 
maximum of 20ml (400mg) will be used, which is below the recommended maximum recommended 
dose of 500mg. 
Primary endpointswill be total opioid use for 24h after epidural morphine administration. Secondary 
endpoints will be time until first opioid request, pain (11 point scale; 0-10), nausea and pruritis (3 point 
scale; none, mild, moderate-severe), total opioids used at each timepoint – every 4h for the first 12h, 
and every 12h for 24h. 
The patients who receive epidural 2% lidocaine with 1:200,000 epinephrine and epidural morphine are 
receiving routine therapy for urgent cesarean delivery in patients with labor epidurals in place.  The 
patients who receive 3% 2-choloroprocaine and epidural morphine are receiving routine therapy for stat 
cesarean delivery in patients with labor epidurals in place. Both will have scheduled acetaminophen and 
ibuprofen, and PRN PO oxycodone available for breakthrough pain.   
The adverse event rates of chloroprocaine and lidocaine are quite low; allergic reactions to local 
anesthetics are very rare, hypotension as a result of sympathectomy secondary to neuraxial anesthesia 
is an expected side effect and is regularly treated with fluids and vasopressors. Local anesthetic systemic 
toxicity is the most serious complication however the risk is minimized by frequent aspiration of the 
epidural catheter, small incremental doses of local anesthetics, and ensuring the sensory level is rising 
appropriately with each intervention.  
There are frequent minor side effects with neuraxial morphine that include nausea, vomiting, and 
pruritis – which are side effects of all opioids. Respiratory depression with neuraxial morphine is 
described but is extremely rare.   


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Study Population 
All patients with labor epidurals in place scheduled for cesarean delivery due to arrest of dilation or 
arrest of descent will be recruited. Patients may refuse to participate in this study or withdraw at any 
time. Inclusion criteria includes pregnant females, between age 18-50 years, with live singleton 
pregnancy. Exclusion criteria includes BMI >40, obstructive sleep apnea, drug abuse, chronic pain, 
chronic opioid use, nonfunctioning epidural. 
Study Procedures 
Patient will have pre-existing labor epidurals in place prior to recruitment. Following the consent and 
randomization process, the epidural will be dosed with either 3% 2-chloroprocaine or 2% lidocaine with 
1:200,000 epinephrine in 5ml increments until a T4 sensory level to pinprick is achieved. Epidural 
morphine 3mg will be given after delivery of neonate and a T4 level maintained throughout cesarean 
delivery with additional epidural re-dosing with 2% lidocaine with 1:200,000 epinephrine in 5ml 
increments for both groups. The number of additional epidural lidocaine top-ups, total dose, and timing 
of top-ups will be documented for each patient and compared between groups. Post-operative orders of 
scheduled acetaminophen 650mg PO q4h and ibuprofen 600mg PO q6h, and oxycodone 5mg PO q4h 
PRN as needed will be written.  
Patients will be followed during the duration of their hospital stay with data being collected every 4h for 
the first 12h, and every 12h for 24h. We will record time until first opioid request, pain (11 point scale; 
0-10), nausea and pruritis (3 point scale; none, mild, moderate-severe), total opioids used at each 
timepoint, and total opioids used for 24h. Each patient will participate for 24h. Data will be collected 
and recorded, with paper records secured in a locked filing cabinet. 
Study Benefit 
The study’s purpose is to determine if the previously observed diminished analgesia with epidural 
chloroprocaine and epidural morphine is secondary to antagonism or a latency period. If we are able to 
demonstrate that epidural chloroprocaine followed by epidural lidocaine top-ups and epidural morphine 
provides equivalent analgesia to epidural lidocaine followed by epidural morphine, it would support our 
hypothesis of a latency period. These results would help guide future anesthetic practices and reduce 
concerns that some anesthesiologists have in using chloroprocaine for cesarean deliveries. This could 
increase the usage of chloroprocaine which could reduce the number of women that require general 
anesthesia for emergent cesarean delivery. The possible benefit to patients is the less frequent use of 
general anesthesia for emergent cesarean delivery which is associated with an increased incidence of 
failed intubation.    
Data and Safety Monitoring 
The potential adverse event that could occur is that patients dosed with 3% 2-chloroprocaine may 
experience antagonism with epidural morphine. They may then experience increased post-operative 
pain and may require more supplemental pain medications. However this therapy is the standard of 
care for patients undergoing stat cesarean delivery with labor epidurals in place. If patients have 
breakthrough pain over the post-operative pain medications ordered, they will be evaluated on a 
caseto-case basis with the option of increasing the dose or switching to a different modality (PCA). The 
rest of the risks are those standard for neuraxial anesthesia and for cesarean delivery.  


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Local anesthetic systemic toxicity is the most serious complication however the risk is minimized by 
frequent aspiration of the epidural catheter, small incremental doses of local anesthetics, and ensuring 
the sensory level is rising appropriately with each intervention. These and other adverse events will be 
noted and reported in the manuscript; if these events are occurring at an increased rate than what is 
normally expected then the study will be halted and study design re-evaluated by the research team. 
The research team will review the results monthly to ensure patients are receiving safe care and will 
notify the Data and Safety Monitoring Board if adverse events are occurring at a higher than expected 
rate. The Data and Safety Monitoring Board will hold meetings twice per year. 
Specific adverse drug reactions that will be measured are local anesthetic systemic toxicity (expected 
incidence 0.03%4), epidural failure requiring conversion to general anesthesia (expected incidence 
0.35%5), intravascular injection (expected incidence 0.02%6), intrathecal injection (expected incidence 
0.035%6), and high/total spinal (expected incidence 0.024%6). If these adverse events are occur, the 
research team will halt the study and evaluate these events. As all of these events occur at a rate of less 
than 1% (total study population is 80 subjects, if any event occurs more than twice the study will 
terminated. 
Statistics 
We plan to enroll 60 patients at MHH-TMC and 20 patients at LBJ Hospital. We intend to include all 
randomized subjects. Patients will be randomized at 1:1 ratio to two arms using the block randomization 
method with block size 4.  
In a prior study of similar arms 1, mean 24-hour morphine consumptions in lidocaine and 
2chloroprocaine arms were 4.07mg (SD=6.34) and 27.72mg (SD=18) respectively. We assume that our 
proposed 2-chloroprocaine arm will yield the same mean 24-hour opioid consumption as the lidocaine 
arm. We conservatively estimate the standard deviation to be 15mg. Let µc and µl denote the mean 
24hour opioid consumption for the 2-chloroprocaine and lidocaine arm, respectively. We use 90% 
twosided t confidence interval (CI) for µc-µl to evaluate non-inferiority. The arm of 2-chloroprocaine arm 
will be considered as no worse than the lidocaine arm if the upper limit of CI is less than 10mg. The 
target enrollment of 40 per arm provides the power of 90.8% for proving non-inferiority of the 
2chloroprocaine arm given the non-inferiority margin 10mg. If we permit 10% of dropout on enrolled 
patients, 36 eligible patients per arm provide the power of 87.4% for this non-inferiority assessment. 
We will conduct Kolmogorov–Smirnov test to examine distributions of continuous variables. If normality 
is satisfactory, we will report mean and standard deviation of the continuous variable in two arms. 
Twosample t test will be used to compare means. For 24-hour opioid consumption, we will construct a 
90% t CI for the difference in mean between two arms (µc-µl). The upper limit of CI will be assessed 
against the non-inferiority margin 10mg. If data follow skewed distribution, we will summarize data as 
                                                          
4 Barrington MJ, Kluger R. Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following 
peripheral nerve blockade. Reg Anesth Pain Med 2013; 38:289. 
5 Katircioglu K, Hasegeli L, Ibrahimhakkioglu HF, Ulusoy B, Damar H. A retrospective review of 34,109 epidural 
anesthetics for obstetric and gynecologic procedures at a single private hospital in Turkey. Anesth Analg 
2008;107:1742–5 
6 Jenkins JG. Some immediate serious complications of obstetric epidural analgesia and anaesthesia: a prospective 
study of 145,550 epidurals. Int J Obstet Anesth 2005;14(1):37-42. 


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median and interquartile range, and use Wilcoxon rank sum test to compare medians. In case that 24-
hour opioid consumption is skewedly distributed, we will construct a 90% CI based on Wilcoxon rank 
sum test. 
For side effects, we will report number of incidences as well as incidence rates in two arms. Score test 
will be used to compare the incidence rates. If a side effect appears only in one arm, Fisher’s exact test 
will be used to evaluate its association with intervention.  
Ethics 
We do not plan on obtaining approval from another IRB. Once it has been determined that a patient will 
require cesarean delivery, an investigator will obtain consent and describe the research project. If 
necessary, live or electronic translation services will be employed. 
Data handling and record keeping 
Data will be obtained from electronic medical records as well as from questioning during patient 
interactions. These paper records will be secured in a locked filing cabinet. These data will then be 
deidentified and transferred to a password protected spreadsheet document.  
Quality control and assurance 
The steps that will be taken to assure that the data collected are accurate, consistent, complete, and 
reliable will be periodic reviews of patients’ electronic medical records to ensure that our data collected 
is consistent with what has been documented by nursing staff. We do not plan to have ongoing third 
party monitoring.  
Publication Plan 
We plan to publish our research results in an obstetric anesthesiology journal. We do not plan to return 
any results to the research subjects unless they specifically request them.