International Journal of Obstetric Anesthesia (2018) xxx, xxx–xxx

0959-289X/$ - see front matter ! 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.ijoa.2018.01.001

ORIGINAL ARTICLE
www.obstetanesthesia.com

Use of epidural clonidine for the management of analgesia in

the opioid addicted parturient on buprenorphine maintenance
therapy: an observational study
M.R. Hoyt,a U. Shah,b J. Cooley,c M. Templed
a
Anesthesiology Institute, Hillcrest Hospital, Cleveland Clinic Health System, 6870 Mayfield Road, Cleveland,
OH 44124, United States
b
Department of Anesthesiology, Robert Wood Johnson University Hospital, 125 Paterson Street – CAB 3100,
New Brunswick, NJ 08901, United States
c
Department of Anesthesiology, University of Tennessee College of Medicine, Chandler Building, Suite 600,
877 Jefferson Avenue, Memphis, TN 38103, United States
d
Department of Pharmacy, Hillcrest Hospital, Cleveland Clinic Health System, 6780 Mayfield Road, Cleveland,
OH 44124, United States

ABSTRACT
Objectives: Management of labor analgesia and post-cesarean delivery pain is challenging in the patient taking buprenorphine as
opioid addiction maintenance therapy. We observed whether substituting clonidine for fentanyl in an epidural solution would pro-
vide adequate analgesia for labor and after cesarean delivery.
Methods: We substituted our standard 2 mg/mL fentanyl in 0.0625% bupivacaine epidural solution with 2 mg/mL clonidine in
0.0625% bupivacaine, or 1.2 mg/mL clonidine in 0.1% bupivacaine, for labor and post-cesarean analgesia in parturients on
buprenorphine therapy. All cesarean deliveries were performed with a combined spinal-epidural technique and the catheters main-
tained for immediate postoperative analgesia using an epidural infusion. Catheters were discontinued the next day and patients
were then managed with other analgesics based on obstetric preference. We recorded pain scores during labor and in the immediate
post-surgical period; and supplemental medications given after epidural catheter removal.
Results: Fourteen patients were included in the study, of whom seven presented in spontaneous labor and seven had elective cesar-
ean delivery. All laboring patients achieved good analgesia, and five of seven avoided supplemental opioid use in the postpartum
phase. Of the postsurgical patients, six of seven had pain scores less than 5/10 at epidural catheter removal and three of seven
avoided supplemental opioids postoperatively.
Conclusions: The combination of clonidine and bupivacaine appears effective in parturients on buprenorphine therapy for opioid
addiction maintenance. As study numbers were small and several factors were not examined, further confirmatory research is
needed, including to determine the ideal dose of epidural clonidine in this setting.
! 2018 Elsevier Ltd. All rights reserved.

Keywords: Buprenorphine; Clonidine; Analgesia; Labor; Epidural; Post-cesarean; Opioid addiction

Introduction treatment of opioid dependence with a mu-opioid recep-

Illicit drug use is at its highest point this decade, with
about 4.5% of pregnant women aged 15–44 years using
illicit or prescription opioid medications.1,2 Opioid
dependence during pregnancy is associated with both
obstetric and neonatal complications. Pharmacological
Accepted January 2018
Corresponding author at: M.R. Hoyt, Anesthesiology Institute,
Hillcrest Hospital, Cleveland Clinic Health System, 6870 Mayfield
Road, Cleveland, OH 44124, United States.
E-mail address: hoytm@ccf.org
tor agonist improves both maternal and fetal outcomes
in opioid-addicted mothers.3 Both methadone and
buprenorphine are approved medications for opioid
addiction maintenance therapy but have different mech-
anisms of action. Buprenorphine is a partial m-receptor
agonist with a very high receptor affinity, making it dif-
ficult to displace from the binding site. As such, pain
management with traditional opioids for labor and after
cesarean delivery is challenging for women on this ther-
apy. Pain scores are consistently higher and opioid
requirements can increase as much as 70% following a

Please cite this article in press as: Hoyt MR et al. Use of epidural clonidine for the management of analgesia in the opioid addicted parturient
on buprenorphine maintenance therapy: an observational study. Int J Obstet Anesth (2018), https://doi.org/10.1016/j.ijoa.2018.01.001
2 Use of epidural clonidine for the management of analgesia

cesarean delivery.4 Consequently, to achieve pain con-
trol patients require either greatly elevated doses of
other opioids, such as fentanyl, or a multimodal
approach using analgesics with other sites of action.
Clonidine is an a2-adrenergic agonist that provides
analgesia when given as a neuraxial injection. Used as
an adjuvant in lieu of opioids in a labor epidural solu-
tion, it can provide a local anesthetic dose-sparing effect
and does not appear to have significant side effects.5
This suggests clonidine may be a reasonable substitute
analgesic for neuraxial opioids in opioid addicted
parturients.
Increasing numbers of women on buprenorphine
therapy are presenting to our labor unit. From past
experience, we noted that our traditional labor and
post-cesarean pain management regimens were inade-
quate for these women. We hypothesized that the substi-
tution of clonidine for fentanyl in our epidural solution
would improve pain scores. We report our observational
experience using this substitution for pain management
in this population.
Case series
Our observational series consisted of 14 patients main-
tained on buprenorphine therapy for opioid addiction.
Institutional Review Board approved this study as
exempt research. As our standard bupivacaine/
fentanyl/epinephrine infusion solution did not provide
adequate analgesia in these patients, we exchanged
clonidine for fentanyl and the epinephrine was removed.
During initial consultation, the benefits of analgesia
with clonidine (without additional opioid) were dis-
cussed as well as the potential side effects (hypotension,
bradycardia, sedation). Seven patients presented in
active labor and seven presented for elective cesarean
delivery. Demographic and antenatal buprenorphine
dosing data are summarized in Table 1. All patients
were maintained on their daily buprenorphine dose
throughout their peripartum stay.
Patient data were separated by delivery mode. No
patient converted from labor to a cesarean delivery in
this series. The Pain Numeric Rating Scale was used
to assess pain, as is standard in our institution.
Spontaneously laboring patients requesting labor
analgesia had their epidural initiated with 10 mL of
our standard epidural bolus solution (0.125% bupiva-
caine, 5 mg/mL fentanyl and 1.2 mg/mL epinephrine)
which is stored on our labor unit and available for
immediate use. Meanwhile the Pharmacy Department
prepared and transported the bupivacaine/clonidine
epidural solution for use as a continuous solution. The
infusion solution of 1.2 mg/mL clonidine and 0.1% bupi-
vacaine was started at 10 mL/h with a patient-controlled
bolus option of 5 mL every 15 minutes.
Table 2 shows the infusions used and pain scores
attained in the pre- and immediate post-epidural place-
ment periods in the labor group. All patients received
the prepared clonidine solution except patient 4. She
was given a combined spinal-epidural (CSE) with 10
mg intrathecal fentanyl and 1.2 mg bupivacaine before
being placed on a 0.0625% bupivacaine with 2 mg/mL
clonidine mixture that her anesthesiologist had cus-
tomized. Initial analgesia was inadequate and she was
rescued with 100 mg of epidural clonidine before achiev-
ing her score of 0/10 after 10 minutes.
Data were not collected on the number of times
a patient used her bolus option and labor nurses incon-
sistently recorded pain scores during labor. However,
no patient requested a provider-supplied bolus to

Table 1 Patient data and buprenorphine dose antenatally

Delivery mode Age Gravida Para Gestational age Buprenorphine dose Buprenorphine
(y) (n) (n) (wk/days) (mg/day) dosing frequency
Vaginal delivery
1 24 2 1 37/4 24 BID
2 30 2 1 37/6 24 TID
3 25 3 2 37/5 16 BID
4 24 2 1 36/4 16 BID
5 27 3 2 41/1 16 TID
6 25 1 0 36/4 8 BID
7 27 2 1 39/3 2 QD
Cesarean delivery
8 20 1 0 34/3 16 BID
9 30 2 1 39 8 BID
10 26 5 4 37 8 QD
11 25 4 3 39/6 24 BID
12 26 6 2 38/6 8 BID
13 24 3 2 35/1 8 BID
14 25 1 0 39/3 2 BID
BID: twice daily; TID: three times daily; QD: daily.

Please cite this article in press as: Hoyt MR et al. Use of epidural clonidine for the management of analgesia in the opioid addicted parturient
on buprenorphine maintenance therapy: an observational study. Int J Obstet Anesth (2018), https://doi.org/10.1016/j.ijoa.2018.01.001
M.R. Hoyt et al. 3

Table 2 Epidural dosing and pain scores for women having a vaginal delivery
Patient number Bupivacaine Clonidine Pain score Pain score immediately
(%) (mg/mL) pre-epidural post-epidural
1 0.1 1.2 6/10 0/10
2 0.1 1.2 9/10 0/10
3 0.1 1.2 10/10 4/10
4 0.0625 2 9/10 0/10#
5 0.1 1.2 9/10 0/10
6 0.1 1.2 3/10 1/10
7 0.1 1.2 10/10 0/10
#
Combined spinal-epidural analgesia performed with fentanyl. Patient also dosed with 100 mg epidural clonidine before this score was reached.

Table 3 Post-cesarean delivery pain scores with epidural infusion

Patient number Bupivacaine Clonidine Hours on epidural infusion* Pain score pre-surgery Pain score at
(%) (mg/mL) epidural removal
8 0.1 1.2 24 0/10 2/10
9 0.1 1.2 21 0/10 3/10
10 0.1 1.2 27 0/10 4/10
11 0.1 1.2 25 0/10 2/10
12 0.0625 2 25 0/10 1/10
13 0.1 1.2 26 0/10 5/10
14 0.1 1.2 14 0/10 0/10
*
Infusion rate of 10 mL/h without bolus function.

supplement her infusion, nor were we asked to evaluate
any patient for inadequate analgesia. The clonidine/
bupivacaine solution provided excellent labor analgesia
for those delivering vaginally, with only one patient
reporting a pain score of 4/10 immediately after epidural
placement (patient 3). Despite her initial score, she did
not request a supplemental bolus.
The only side effect seen in the laboring group was
hypotension. Three of six laboring patients on the 1.2
mg/mL clonidine dose and the patient on the 2 mg/mL
concentration experienced hypotension. The systolic
blood pressure dropped below acceptable ranges in all
four patients within 30 to 60 minutes of initiating the
epidural infusion. All recovered with phenylephrine
and ephedrine boluses except patient 5 who developed
fetal decelerations due to significant hypotension. The
decelerations resolved with fluid and continued vaso-
pressor therapy and her epidural infusion rate was
decreased from 10 to 6 mL/h following this episode.
Fetal heart rates were continuously monitored in all
laboring patients and no other adverse effects were
noted in the fetuses. There were no incidences of seda-
tion, maternal bradycardia, or fetal bradycardia other
than that reported above.
Table 3 reports on those patients who had a cesarean
delivery. As none were in labor at the time of presenta-
tion, all had baseline pain scores of 0/10. All patients
were managed with a CSE technique. The spinal compo-
nent was 12 mg bupivacaine with or without 100 mg of
epinephrine as per provider preference. Maintenance of
anesthesia, if necessary, was achieved with 2% lidocaine
to which sodium bicarbonate was added (1 mEq to 10
mL of 2% lidocaine) and given through the epidural
catheter. Opioids were not administered by any method.
Upon arrival in the recovery area, the 0.1% bupivacaine
with 1.2 mg/mL clonidine epidural infusion was initiated
at 10 mL/h for all patients with one exception. Patient 12
was maintained on a 2 mg/mL clonidine with 0.0625%
bupivacaine solution, as her anesthesiologist had her
solution customized. The infusions were intended to
run for 24 hours before being discontinued and the
catheters removed. This target was chosen to maximize
pain relief in the immediate post-surgical period and
minimize delay in ambulation. One patient requested
an earlier removal, which was accommodated. No
patient requested an additional epidural bolus while on
the infusion or received any form of intravenous or oral
analgesia for breakthrough pain. The only side effect
noted was hypotension in the patient on the 2 mg/mL
clonidine with bupivacaine solution. This occurred once,
within 60 minutes of initiating the epidural infusion, and
recovered with fluid and phenylephrine boluses.
Of the seven patients who arrived in spontaneous
labor and completed a vaginal delivery, the substitution
provided satisfactory labor analgesia where 4/10 was the
highest score reported. Of the seven who underwent a
scheduled cesarean delivery, all had excellent anesthesia
from the spinal dose given as part of a CSE technique.
Patients were started on the epidural clonidine/bupiva-
caine infusion upon arrival in recovery and maintained

Please cite this article in press as: Hoyt MR et al. Use of epidural clonidine for the management of analgesia in the opioid addicted parturient
on buprenorphine maintenance therapy: an observational study. Int J Obstet Anesth (2018), https://doi.org/10.1016/j.ijoa.2018.01.001
4 Use of epidural clonidine for the management of analgesia

for up to 27 hours. All had good to excellent analgesia
during the infusion with no-one requesting supplemental
analgesics. One patient, whose highest pain score was
5/10, neither requested nor received other analgesics
despite her reported score.
Once epidural infusions were stopped, the labor ser-
vice managed post-delivery pain requirements with con-
sultative support from the Pharmacy Department and
our service. Analgesic needs varied by delivery mode.
Traditional medications for post-delivery pain were
intravenous ketorolac, oral acetaminophen, ibuprofen,
oxycodone, tramadol, and acetaminophen-oxycodone.
We suggested intravenous acetaminophen as a non-
traditional option for the post-surgical patients.
Pain scores were not assessed on a timed schedule but
rather as the postpartum nurse recorded them. There-
fore, median pain scores were determined for each
patient over the full course of their hospitalization.
Tables 4 and 5 show the variance in medications given
and postpartum analgesic effectiveness. Table 4
describes those patients who avoided opioid supplemen-
tation, and Table 5 is comprised of those who used sup-
plementation. Not surprisingly, those with a vaginal
delivery were most likely to avoid supplemental opioids
for analgesia. However, so did three of the seven surgi-
cal patients. We also observed that providing medica-
tions on a scheduled basis, rather than on an as-
needed regimen, provided more effective relief.
Discussion
Fourteen patients on opioid maintenance therapy with
buprenorphine received an epidural infusion for pain
control, with clonidine substituted for fentanyl. The lit-
erature is sparse regarding pain management for the
obstetric population on buprenorphine for opioid addic-
tion maintenance therapy. Successful labor analgesia, as
well as post-cesarean pain management, in patients on
this therapy has been described previously.6,7 Reports
have also described adequate pain control in the obstet-
ric population with the addition of markedly high doses
of opioids, supplemented with acetaminophen and
ibuprofen.6 The literature is non-existent on the use of
neuraxial clonidine for pain management in the opioid
addicted population, but epidural clonidine reduces
postoperative analgesic requirements and prolongs the
analgesic duration of epidural bupivacaine in opioid-
naı̈ve, obstetric and non-obstetric patients.5,8,9 We used
1.2 mg/mL clonidine combined with 0.1% bupivacaine,
as this solution was in the formulary and had proven
adequate for analgesia in the pediatric population at this
institution.
Labor analgesia was well controlled in our parturi-
ents, with pain scores at 0/10 to 1/10 within 30 minutes
after epidural initiation in six of seven patients. Despite
early concerns, we observed that the lower clonidine
dose provided good to excellent analgesia during labor.
Adverse side effects of clonidine include maternal or
fetal bradycardia, maternal sedation and hypoten-
sion.5,9,10 The only side effect we observed was hypoten-
sion that occurred in both patients at the 2 mg/mL dose
and in 25% of those on the 1.2 mg/mL dose. None of our
patients experienced maternal bradycardia, appeared
sedated or had a fetus which developed bradycardia
directly caused by the clonidine.
Although methadone and buprenorphine are both
approved for managing opioid addiction, buprenor-
phine is considered superior in pregnant patients due
to its lower risk of neonatal abstinence syndrome.11
Neonates exposed to buprenorphine have less severe
symptoms and shorter hospital stays compared with
methadone.12,13 Some research suggests that the bio-
physical profile scores of fetuses exposed to buprenor-
phine are better and non-stress tests more reactive at
32 weeks, compared to their methadone-exposed fetal
counterparts.13,14 However, bias and other confounding
elements may have distorted these findings, making
additional studies necessary.15
Buprenorphine is a partial m-agonist with j- and d-
receptor antagonist activity.16 Buprenorphine has low
intrinsic activity, meaning its analgesic effect is not
strong and side effects such as sedation, respiratory
depression and euphoria are less likely, all of which
contributes to the drug’s safety profile.16 It also has a

Table 4 Post-delivery medications and total dosages for patients refusing opioids
Patient number Delivery mode Oral acetaminophen Intravenous acetaminophen Ibuprofen Ketorolac
(mg) (mg) (mg) (mg)
1 Vaginal 650 0 4200 30
4 Vaginal 0 0 3000 90
5 Vaginal 3900 0 5400 0
6 Vaginal 6250 0 4200 0
7 Vaginal 0 0 3600 0
11 Cesarean 7800 0 5600 240
12 Cesarean 3900 1000 2400 0
13 Cesarean 10 300 1950 6000 150

Please cite this article in press as: Hoyt MR et al. Use of epidural clonidine for the management of analgesia in the opioid addicted parturient
on buprenorphine maintenance therapy: an observational study. Int J Obstet Anesth (2018), https://doi.org/10.1016/j.ijoa.2018.01.001
M.R. Hoyt et al. 5

variable half-life of 24–60 hours. This slow dissociation

Tramadol

1050

1100
(mg)
allows patients a more normal lifestyle as daily dosing

0
0
0

0
is not always necessary. Finally, it has the greatest affin-
ity for the m-receptor of any opioid, so that once
attached, it is very difficult to dislodge.17 In summary,
it is a very long acting analgesic that functions well for
opioid addiction management.
Oxycodone

Whether or not a patient actively taking buprenor-

(mg)

20

90
phine for addiction therapy should be given large
0
0

0
0 amounts of opioid to control acute pain raises an inter-
esting question.18 For the motivated patient on
buprenorphine therapy wishing to avoid other opioids,
a multimodal approach employing non-opioid therapies
may accommodate this request.
acetaminophen
Oxycodone/

The limitations of this study are many, the primary

120/7800

25/1625
5/325
(mg)

one being that it is observational. Our intent was to sim-

0

ply observe whether the substitution of clonidine for

fentanyl in our epidural infusion would better serve
the buprenorphine population, as it was clear from past
experiences that our routine management was insuffi-
cient. We did not compare different doses of clonidine,
even though two patients received a higher dose, nor
Ketorolac

did we compare our observed population with matched

(mg)

300

120
Post-delivery medications and total dosages for patients receiving supplemental opioids

20

90

30
0

controls. Additionally, we did not compare epidural

solutions with clonidine to those with local anesthetic
alone, but used the dose-sparing effect of clonidine to
avoid high doses of local anesthetic that might impact
labor outcome. Measurement of variables such as timed
Ibuprofen

pain scores; and scheduled versus as-needed medication

3000
4200
4200

1800
2100
(mg)

600

regimens, were not studied. Opportunities abound for

future studies utilizing clonidine as an adjuvant for pain
management in opioid addicted parturients on mainte-
nance buprenorphine therapy.
1000
2000
1000
3000

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Please cite this article in press as: Hoyt MR et al. Use of epidural clonidine for the management of analgesia in the opioid addicted parturient
on buprenorphine maintenance therapy: an observational study. Int J Obstet Anesth (2018), https://doi.org/10.1016/j.ijoa.2018.01.001