Clinical trial NCT01846221
Conditions: Labor Pain
Keywords: Analgesia Epidural Pregnancy Labor Clonidine Fentanyl Bupivacaine Childbirth
Sponsor: Columbia University
Start date: 2014-07-15; Completion date: 2017-01-20
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Epidural analgesia has proven to be an effective method for severe pain relief associated with labor and delivery. During labor, a low dose continuous infusion of local anesthetic and narcotic will be administered through an epidural catheter. As labor progresses and the baby's head makes it way through the pelvis, breakthrough pain may emerge and often needs further treatment. The investigators provide pain relief by administering analgesics through the epidural catheter. The patients will be randomly assigned to receive one of two medication mixtures believed to be successful in treating this type of pain associated with advanced labor. After this initial treatment, if pain relief is not attained, the patient may receive the other medication as well. The medications used in this study have been used at this institution for some time and have been found to be safe for mother and baby. The opioid (fentanyl) dose is small and only a small fraction will be transmitted to the baby. The other medication (clonidine) better known as a blood pressure medication has also been used for pain relief. Studies and clinical experience have shown that clonidine when given epidurally in the doses used in this study has minimal, if any effect, on the blood pressure of the mother or of the baby. The investigators will record medical and obstetric history and labor progress relevant to the patient. The patient will be asked questions regarding labor pain and side effects before and after the analgesic is administered. The primary objective is to determine which treatment regimen is more successful in abolishing breakthrough pain in advanced labor.

Detailed description:
Epidural analgesia is a popular choice among patients for relief of severe pain associated with labor and delivery. Currently, at the investigators' institution the investigators use a continuous infusion of low dose local anesthetic and narcotic (12 ml/hr of 0.0625% bupivacaine with 2 micrograms/ml fentanyl) after the initial spinal or epidural dose to maintain patient comfort until delivery. This dose of the infusion is chosen because it often provides adequate comfort without interfering with the mobility of the patient and her ability to effectively push during delivery. However, this low-dose epidural infusion strategy often results in recurrence of pain after an initial pain-free period. This recurring pain is known as breakthrough pain and is alleviated by administering small boluses of analgesics via the epidural catheter.

The pain occurring in labor is initially of visceral origin and is mediated by pain fibers originating from the low thoracic and upper lumbar segments of the spinal cord. As labor progresses to the late first phase (also known as transitional stage), pain sensations originating from the distension of the pelvic floor, vagina and perineum adds a somatic component to labor pain. This type of breakthrough pain, mediated by nerve fibers originating from the sacral nerves at dermatomes S2-S4, is often difficult to treat. Patients may experience inadequate analgesia even after boluses of analgesics are administered. Inadequate analgesia is deleterious due to subjective discomfort with its associated neurohumoral and physiological changes, and can be an initiator of the urge to bear down (push). Pushing before complete dilation of the cervix may lead to swelling, cervical injury and premature exhaustion of the mother. Adequate pain control will allow the cervix to fully dilate and motivate the mother to push effectively at the appropriate time. Although requests from patients to alleviate late stage breakthrough pain are common, there are no established data in the literature regarding the most effective strategy for pain management in this stage of labor.

This study is designed to compare the efficacy of two treatments for controlling late first stage breakthrough pain during labor: clonidine-bupivacaine versus fentanyl-bupivacaine. Both strategies are used at Columbia University Medical Center (CUMC) in this clinical situation, and there is no clear evidence whether one is superior.

Arms: arm 1: Participants randomized to this arm of the study receive 100 micrograms clonidine with the bupivacaine in their epidural when requesting pain relief in advanced labor arm 2: Participants randomized to this arm of study will receive 100 mcg fentanyl with the bupivacaine in their epidural when requesting pain relief in advanced labor
Interventions: intervention 1: Clonidine intervention 2: Fentanyl
Intervention descriptions: intervention 1: Subjects randomized to clonidine will receive a mixture of 100 micrograms clonidine and 12.5 mg bupivacaine 10 ml of volume. intervention 2: Subjects randomized to fentanyl will receive 100 mcg fentanyl and 12.5 mg bupivacaine in 10 ml of volume.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Comparison of fentanyl- bupivacaine and clonidine- bupivacaine for breakthrough pain in 
advanced labor in patients with continuous epidural analgesia  
 
Columbia University Medical Center  
Attached to Protocol: IRB-AAAL4101  
Principal Investigator: Allison Lee, MD  
Participation Duration: 1 day  
Anticipated Number of Subjects: 250 
 
PROTOCOL 
 
Study Purpose and Rationale: 
Epidural analgesia is a popular choice among patients for relief of severe pain associated with 
labor and delivery. Currently, at our institution we use a continuous infusion of low dose local 
anesthetic and narcotic (12 ml/hr of 0.0625% bupivacaine with 2 micrograms/ml fentanyl) after 
the initial spinal or epidural dose to maintain patient comfort until delivery. This dose of the 
infusion is chosen because it often provides adequate comfort without interfering with the 
mobility of the patient and her ability to effectively push during delivery. However, this low-
dose epidural infusion strategy often results in recurrence of pain after an initial pain-free period. 
This recurring pain is known as breakthrough pain and is alleviated by administering small 
boluses of analgesics via the epidural catheter.  
 
The pain occurring in labor is initially of visceral origin and is mediated by pain fibers 
originating from the low thoracic and upper lumbar segments of the spinal cord. As labor 
progresses to the late first phase (also known as transitional stage), pain sensations originating 
from the distension of the pelvic floor, vagina and perineum adds a somatic component to labor 
pain. This type of breakthrough pain, mediated by nerve fibers originating from the sacral nerves 
at dermatomes S2-S4, is often difficult to treat. Patients may experience inadequate analgesia 
even after boluses of analgesics are administered. Inadequate analgesia is deleterious due to 
subjective discomfort with its associated neurohumoral and physiological changes, and can be an 
initiator of the urge to bear down (push). Pushing before complete dilation of the cervix may lead 
to swelling, cervical injury and premature exhaustion of the mother. Adequate pain control will 
allow the cervix to fully dilate and motivate the mother to push effectively at the appropriate 
time. Although requests from patients to alleviate late stage breakthrough pain are common, 
there are no established data in the literature regarding the most effective strategy for pain 
management in this stage of labor.  
 
This study is designed to compare the efficacy of two treatments for controlling late first stage 
breakthrough pain during labor: clonidine-bupivacaine versus fentanyl-bupivacaine. Both 
strategies are used at Columbia University Medical Center (CUMC) in this clinical situation, and 
there is no clear evidence whether one is superior. 
 
Study Design and Procedures: 
After obtaining consent, the patients will be randomized into two groups using a random 
allocation table. At the onset of late stage breakthrough pain with a Visual Analogue Scale 
(VAS) greater than or equal to 5/10, subjects will randomly receive either a mixture of 100 mcg 


of clonidine and 12.5 mg of bupivacaine for a total volume of 10 ml ("CLON" group) and the 
other group will receive 100 mcg of fentanyl and 12.5 mg of bupivacaine for a total volume of 
10 ml ("FENT" group). Group assignment will be performed by opening a previously prepared 
numbered opaque envelope containing the assignment "CLO" or "FENT". 
 
The patient will be evaluated every 5 minutes for 15 minutes. If the patient reports a decrease in 
the VAS pain score by 4 points or more, the treatment will be declared a success. If the patient 
does not report a decrease in VAS score by 4 or more, the treatment will be declared a failure. If 
the treatment fails within 25 minutes from the end of injection of the initial study drug, the 
patient will receive the alternative of the initial treatment, which is 100 mcg of fentanyl or 100 
mcg of clonidine (i.e., whichever drug was NOT given in the study mixture) with bupivacaine 
12.5mg, diluted to a total of 10ml with sterile saline, via the epidural catheter (the observer will 
remain blinded to the identity of the medication). If this intervention fails to alleviate the pain, 
the caretakers will administer 5ml of 2% lidocaine via the epidural catheter. If the pain score still 
has not fallen by 4 or more points from baseline, 15 min after the dose of lidocaine the epidural 
catheter will be considered to be non-functioning. 
 
All drug handling/distribution/administration will be conducted in accordance with the policies 
of the Research Pharmacy and Columbia University Medical Center. 
 
Demographic and labor data (patient age, height, and weight, parity, hours in labor, cervical 
dilation and fetal station), details of labor analgesia preceding administration of the study drug 
(duration, type and amount of epidural or spinal analgesics, or other forms of analgesia), 
maternal and fetal heart rate and maternal blood pressure prior to and following administration of 
the study drug will be collected along with other clinical variables. 
 
The study terminates upon delivery of the baby. Maternal and fetal hemodynamic data (maternal 
BP and pulse, fetal heart rate) and other clinical data will be obtained for 2 hours after the study 
dose, or until delivery, whichever is earlier. Neonatal Apgar scores as well as the mode of 
delivery will be collected. 
 
Patients will be recruited by a study investigator after the establishment of labor epidural 
analgesia. The participants will be patients of the study team physicians. Informed consent with 
written documentation will be obtained from the research participant. 
 
STATISITCAL PROCEDURES 
 
The primary outcome is "success" or "failure" of the treatment as defined above. A clinically 
significant difference between the two treatments would be a 0.3 (30%) difference in 
probabilities for adequate analgesia. Assuming that the inferior treatment is successful in half of 
all patients, we aim to determine if the superior treatment is successful in 80%. For a power of 
80% and an alpha of 0.05, this requires 45 subjects per group, so we plan on studying 100 
overall.  
 
To obtain 100 subjects who require a dose for breakthrough pain in the late first stage or second 
stage of labor, we may need to recruit and consent more than 250 subjects, since women will be 


recruited after they are comfortable with their epidural analgesia, and it will not be known if they 
will eventually need a supplemental dose. Continuous data (VAS, total use of analgesics, 
maternal and fetal heart rate, maternal blood pressure) will be analyzed using ANOVA (with 
repeated measurements as appropriate) and categorical data (use of ephedrine, supplemental 
oxygen, fluid boluses and positional changes associated with administration of analgesics, 
instrumental delivery, cesarean section) will be analyzed using Chi-Squared analysis with Yates' 
continuity correction or Fisher's exact test as appropriate.