Effectiveness of Clonidine, Dexmedetomidine, and Fentanyl Adjuncts for Labor Epidural Analgesia: A Randomized Controlled Quadruple Blinded Non-Inferiority Trial (CLASSIER Trial)
Phase: PHASE2
Conditions: Pregnancy Related
Sponsor: Grace Lim, MD, MS

 
 
 
 
 
 
 
 
STUDY TITLE: Effectiveness of Clonidine, Dexmedetomidine, and Fentanyl Adjuncts for Labor Epidural 
Analgesia: A randomized controlled trial (CLASSIER) 
IRB: STUDY22030095 
NCT05487196 
Study Protocol: 10 MAY 2022 
 
 

* Title of study: 
Effectiveness of Clonidine, Dexmedetomidine, and Fentanyl Adjuncts for Labor Epidural Analgesia: A 
Randomized Controlled Trial 
* Short title: 
CLASSIER Trial 
* Brief description: 
The purpose of this trial is to compare the effectiveness of labor analgesia with clonidine, 
dexmedetomidine, or fentanyl (usual care) adjuncts. 
Study Aims 
Research Key Question: 
Does the addition of dexmedetomidine to a ropivacaine solution used for epidural labor analgesia initiation, 
improve epidural labor analgesia when compared with a solution combining clonidine with ropivacaine, or a 
solution combining fentanyl with ropivacaine? 
Hypotheses: 
We hypothesize that the addition of dexmedetomidine to a ropivacaine solution used for epidural perfusion 
in labor analgesia improves epidural labor analgesia as evaluated by Visual Analogue Scores at various 
time points after epidural initiation compared with a solution combining clonidine with ropivacaine and 
fentanyl with ropivacaine. 
1. Background: 
In the current practice, the standardized epidural solution that is used in the labor analgesia 
protocol combines a local anesthetic with an opioid. The addition of opioids as adjuvants to local 
anesthetics has many advantages as they increase the quality of the epidural block. They also act by 
reducing the local anesthetic total dose which results in lower incidence of motor block and assisted vaginal 
delivery.  

 
The addition of opioids to the local anesthetic solution used for epidural perfusion has become a standard 
of practice in North America. Although the literature advocates for this practice, a small proportion of 
patients may benefit from a different approach.  
Patients with chronic pain and chronic opioid consumption are at risk of developing opioid 
tolerance defined as the use of the oral morphine equivalent of greater than or equal to 60 mg a day for 7 
days or longer. 5 Another population that could possibly benefit from this approach are parturient that are 
diagnosed with an opioid use disorder. These patients often develop opioid tolerance requiring higher 
dosage to address acute pain. Experts’ consensus advocates for a multimodal approach in this population.  
Moreover, some patients are consuming medication to treat opioid use disorders such as buprenorphine 
and methadone. These medications have an impact on the pharmacokinetics of opioids and alter their 
effect on the human body.  
Tailoring the approach to labor pain management in the population of parturient that are at risk for 
complex pain management is the cornerstone to an individualized approach, leading to optimal care. This 
approach may be achieved by substituting the opioid in the epidural solution with another adjuvant. For 
example, clonidine is an alpha-2-adrenergic agonist that has been extensively studied in the context of 
neuraxial anesthesia and analgesia 
Addition of clonidine to the epidural solution for postoperative analgesia has been studied widely in 
orthopedic and general surgery procedures. It offers a dose-sparing action of local anesthetics while 
increasing the duration of sensory blockade. It is also widely used for post-operative pain management 
after various pediatric surgical procedures and has shown a reassuring safety profile in this population.  
A systematic review and meta-analysis evaluated the effects of neuraxial clonidine added to local 
anesthetics in women admitted for caesarean section under neuraxial anesthesia. Their conclusions show 
that intrathecal clonidine reduced 24 h morphine consumption and prolonged time to first analgesic request. 

Neuraxial clonidine increased the incidence of intraoperative hypotension defined as a 20% reduction from 
the pre-anesthetic baseline systolic blood pressure. This augmentation of the intraoperative hypotension 
episodes did not translate into an augmentation of treatment with vasopressors such as ephedrine, which 
leads us to think that this hypotension was not clinically significant. Moreover, the usage of neuraxial 
clonidine did not negatively impact neonatal umbilical artery pH or Apgar scores. 
Clonidine added to ropivacaine for labor epidural analgesia has shown to provide a longer duration 
of analgesia and a reduction of the total ropivacaine dose over the first 4 hours.  It has been extensively 
studied for the initiation and maintenance of epidural analgesia in laboring women. The literature regarding 
the addition of clonidine to the local anesthetic solution perfused in epidural for labor shows an increased 
the quality of analgesia while reducing the need for rescue supplementation.  
It has also shown to prolong the duration of analgesia offered by a bupivacaine bolus after the initiation of 
epidural analgesia. Moreover, the addition of clonidine shortened the onset of analgesia and showed a 
decrease in the local anesthetic consumption in laboring patients.  
Dexmedetomidine is an alpha-2-agonist that has a greater affinity for the alpha-receptor. It is about 
8 times more selective towards this receptor. It is currently used in obstetric anesthesia for multimodal labor 
analgesia, post cesarean delivery analgesia and postoperative shivering. Some studies have also found a 
benefit in the quality of analgesia offered by dexmedetomidine when compared to opioids as adjuvants to 
epidural.  
A meta-analysis of randomized controlled trials reviewed the effects of epidural dexmedetomidine 
as an adjuvant to local anesthetics for labor analgesia. Nine studies were included in the qualitative 
synthesis presented in this meta-analysis. The group arrived to the conclusion that “epidural 
dexmedetomidine has the potential to oﬀer a better analgesic eﬀect than placebo, similar labor pain control 
to opioids, and has no deﬁnite adverse eﬀects on the parturient or fetus, but more high-quality studies are 
needed to conﬁrm these conclusions.” 

 
The usage of dexmedetomidine as an adjuvant to epidural during labor has been a subject of great 
interest in the last few years. Zhao and al. performed a RCT with 80 laboring patients that received an 
epidural with low concentration of epidural ropivacaine (0.125%) alone or combined with dexmedetomidine 
(0.5 mg/kg) as bolus. This anesthetic regimen that included dexmedetomidine reduced the pain scores at 
most time intervals evaluated after epidural initiation. It is also reassuring to see that other outcome such as 
the duration of the ﬁrst and second stage of labor, the rate of instrumental delivery and cesarean section, 
Apgar scores, umbilical artery pH, maternal motor blockade scores, intensity of maternal sedation, and the 
incidence of maternal complications did not show signiﬁcant diﬀerence between the two studied groups.  
Selim and al. carried out a study where they evaluated the impact of dexmedetomidine as an adjunct to 
bupivacaine compared to a standard fentanyl – bupivacaine solution. They aimed to explore uterine artery 
pulsatility index and umbilical artery pulsatility index during uterine contractions and relaxations. They were 
able to show that the bupivacaine – dexmedetomidine group had a shorter onset of analgesia and an 
increased duration of analgesia. Their analysis of the uterine artery pulsatility index and umbilical artery 
pulsatility index showed that dexmedetomidine did not induce any deleterious effects of uteroplacental 
circulation or neonatal outcomes.  
Zhang and al. did show that the combination of dexmedetomidine with ropivacaine for labor 
analgesia offered similar sensory block when compared to a control group that received a ropivacaine only 
solution. Moreover, the duration of the first and second stage of labor, the mode of delivery and the Apgar 
scores and umbilical arterial pH after birth were similar between both groups. Finally, side effects such as 
hypotension, bradycardia and pruritus were also similar between both cohorts.  
Dexmedetomidine has been used as an adjuvant to epidural in various surgical interventions. It has 
also been compared to clonidine to evaluate the benefits of this novel molecule compared to clonidine 
which has been on the market for a few decades. Dexmedetomidine is a better neuraxial adjuvant 

compared to clonidine since it provides early onset of sensory analgesia superior intraoperative analgesia, 
a prolonged postoperative analgesia while offering stability of the cardiorespiratory parameters. 
The intrathecal administration of dexmedetomidine in a cohort of patients admitted for lower limb 
surgery is associated with prolonged sensory and motor block, hemodynamic stability, and a reduction in 
the consumption of rescue analgesics in 24h period as compared to clonidine, fentanyl, or bupivacaine 
alone. When comparing dexmedetomidine to clonidine as adjuvants to local anesthetics in labor analgesia, 
it seems that both molecules offer an excellent quality of analgesia and a great safety profile. However, 
dexmedetomidine has shown a faster onset of analgesia a prolonged analgesia and a decrease in the time 
to achieve maximal analgesia.  
2. Significance/Rationale: (Why is the question worth pursuing? Will it reduce complications or costs, 
improve outcome, change practice?) 
This study is significant because it can potentially alternative non-opioid adjunctive agents for 
epidural labor analgesia. The opioid crisis in the United States has translated to an increasing number of 
pregnant women requiring care for labor and delivery. These trends have resulted in new questions about 
alternative epidural analgesia adjuncts besides lipophilic opioids (e.g., fentanyl and sufentanil) because: 1) 
many people with OUD desire to avoid opioids in all formulations and routes of administration; and 2) 
epidural fentanyl or sufentanil administration for labor can potentially interfere with the accuracy of urine 
drug screening in the postpartum period. 
Regarding the scope of the problem: A retrospective study evaluated the incidence of maternal 
opiate usage using a database that compiled information from 7.4 million discharges in 44 states. It shows 
that the maternal consumption of opioids has increased nearly fivefold in a 9-year observation period 
(2000-2009)57 while others report prevalence of opioid use disorder during pregnancy Increasing by 127% 
from 1998 to 2011. 58 It is estimated that 4.5% of pregnant women aged 15–44 years are using illicit or 
prescription opioid medications, which emphasizes the importance of this issue.  

 
Tailoring the approach to labor pain management in the population of parturient that are at risk for 
complex pain management is the cornerstone to an individualized approach, leading to optimal care. This 
approach may potentially be achieved by substituting the opioid in the epidural solution with another 
adjuvant such as clonidine or dexmedetomidine, two alpha2-adrenergic agonists. 
Some existing literature suggests that dexmedetomidine and clonidine are adjuncts to local 
anesthetics that offer a faster onset and a better quality of analgesia for patients requiring labor analgesia. 
Further studies are required to precise the dosage and regimens in a population of laboring patients. 
Study Design 
Total number of subjects to be enrolled at this site: 
400 (200 Mothers and their infants (200)) 
Describe and explain the study design: 
• This study is designed as a randomized, parallel arm, controlled trial in 3 groups allocated in a 
1:1:1 ratio 
Describe the primary and secondary study endpoints: 
Primary outcomes 
Pain as defined by Numeric Rating Score (NRS) (0-10 where 0 is no pain and 10 Is the worst Imaginable) 
at 30 minutes after initiation of epidural analgesia 
Secondary outcomes 
0-10 pain scores, obstetric outcomes related to delivery details; hemodynamic outcomes; patient reported 
scales of symptoms and ratings including nausea, vomiting, shivering, pruritus, satisfaction; fetal and 
newborn outcomes. 
Duration of an individual subject's active participation: 

Approximately 24 hours (duration of labor). Study participation ends 10 minutes after delivery ( for the 
newborn Apgar) 
Inclusion criteria 
1. >/ = 18 years 
2. ASA Physical Status 2 or 3 
3. Term pregnancy [> 37 gestational weeks] 
4. Planning epidural labor analgesia 
5. Singleton pregnancy 
6. Vertex presentation 
7. Planned vaginal delivery 
Exclusion criteria 
1. Pre-eclampsia with or without severe features 
2. New initiation of antihypertensive agent within 24 hours prior to enrollment 
3. Uncontrolled systemic comorbidities [i.e., diabetes, hepatic, renal or cardiac] 
4. Known or suspected fetal abnomalies 
5. Allergy to study agents 
6. Contra-indication to neuraxial anesthesia 
7. Inability to communicate or to participate in study procedures 
8. Current beta blocker therapy