Clinical Trial/Experimental Study Medicine ®

OPEN

Preoperative pregabalin prolongs duration

of spinal anesthesia and reduces early
postoperative pain
A double-blind, randomized clinical CONSORT study
∗
MiHye Park, MDa, Hyerim Lee, MDa, Younghoon Jeon, MD, PhDb,

Abstract
Background: The administration of oral pregabalin preoperatively has been reported to reduce acute postoperative pain.
However, no clinical study to date has yet fully investigated whether or not pregabalin premedication affects sensory and motor
blocks using spinal anesthesia and its effect upon early postoperative pain management. This prospective, randomized, and double-
blind clinical study was designed to evaluate the efficacy of a single dose of pregabalin in terms of spinal blockade duration and its
potential opioid-sparing effect during the first 24 hours subsequent to urogenital surgery.
Methods: Forty-four patients scheduled for urogenital surgery under spinal anesthesia were randomly allocated to 2 groups: group
C (no premedication; orally administered placebo 2 hours before surgery) and group P (orally administered 150 mg pregabalin 2
hours before surgery).
Results: The duration of sensory and motor blockade was significantly prolonged in group P patients when compared with that in
group C patients, and the pain scores at postoperative 6 and 24 hours were significantly lower in group P patients. Requests for
analgesics during the first postoperative 24 hours were lower among group P patients.
Conclusion: Premedication with a single dose of 150 mg pregabalin before surgery promoted the efficacy of intrathecal
bupivacaine and improved postoperative analgesia in patients undergoing urogenital surgery under spinal anesthesia.
Abbreviations: TUR-B = transurethral resection of the bladder, TUR-P = transurethral resection of the prostate, VAS = visual
analog scale.
Keywords: preemptive, pregabalin, sensory block, spinal anesthesia

1. Introduction mate, noradrenaline, substance P, and gastrin-releasing pep-

tide.[4] The administration of oral pregabalin preoperatively has
Various adjuvants have been used to prolong spinal anesthesia,
been reported to reduce acute postoperative pain[5–7] and to
with the additional advantages of delaying the onset of
prolong the duration of anesthesia produced by single-injection
postoperative pain and reducing postoperative analgesic
peripheral nerve blockade.[8] However, no clinical study to date
requirements.[1–3] Pregabalin is an r-aminobutyric acid analog
has yet fully investigated whether or not pregabalin premed-
that binds to the a2-d subunit of presynaptic voltage-gated
ication affects sensory and motor blocks using spinal anesthesia
calcium channels. It reduces the depolarization-induced calcium
and its effect upon early postoperative pain management.
influx at nerve terminals, with a consequent reduction in the
Preemptive analgesia is analgesic administration that precedes
release of several excitatory neurotransmitters, including gluta-
the painful stimulus, thus improving postoperative pain control.
It is an antinociceptive treatment that prevents the establishment
Editor: Helen Gharaei.
of altered processing of afferent input, which amplifies
The authors have no conflicts of interest to disclose.
a
postoperative pain.[9] This technique is utilized in acute
Department of Anesthesiology and Pain Medicine, Kyungpook National
postsurgical pain management to improve the efficacy of
University School of Medicine, b Department of Anesthesiology and Pain
Medicine, Kyungpook National University School of Dentistry, Daegu, Republic of analgesics and thereby reduce the requirement for opioids.[10]
Korea. In this prospective, randomized, double-blind, and placebo-
∗
Correspondence: Younghoon Jeon, Department of Anesthesiology and Pain controlled study, we hypothesized that single dose 150 mg
Medicine, Kyungpook National University Hospital, Kyungpook National University pregabalin premedication would prolong the sensory blockade of
School of Dentistry, 130 Dongduck-ro, Jung-gu, Daegu 41944, Republic of spinal bupivacaine anesthesia in urogenital surgery. A secondary
Korea (e-mail: [email protected])
objective of this study was to determine if premedication with
Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All pregabalin also reduces the need for medication to relieve
rights reserved.
This is an open access article distributed under the Creative Commons
postoperative pain.
Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial
and non-commercial, as long as it is passed along unchanged and in whole, with
credit to the author. 2. Methods
Medicine (2016) 95:36(e4828)
2.1. Patients and exclusion criteria
Received: 20 May 2016 / Received in final form: 3 August 2016 / Accepted: 18
August 2016 Patients between the ages of 19 and 70 years with American
http://dx.doi.org/10.1097/MD.0000000000004828 Society of Anesthesiologists grade I or II scheduled to undergo

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Park et al. Medicine (2016) 95:36 Medicine

Assessed for eligibility (n = 44)

Randomized (n = 44)

C group P group
(no premedication) (pregabalin premedication)

Lost to follow-up (n = 1)
Lost to follow-up (n = 0)
: conversed to general anesthesia

Analyzed (n = 22) Analyzed (n = 21)

Figure 1. Flow diagram of the study.

either transurethral resection of the bladder (TUR-B) or (group P) received capsules containing 150 mg of pregabalin in
transurethral resection of the prostate (TUR-P) under spinal the ward. Electrocardiography, blood pressure, and oxygen
anesthesia were included in this study. Patients were excluded if saturation were monitored upon arrival to the operating room
they were known to be allergic to any medicines, had a history of and subsequently every 5 minutes. A transverse line connecting
drug or alcohol abuse, were taking opioids or sedative the tops of the right and left iliac crests was defined as the level of
medications, and had a history of psychiatric conditions. Patients L 4 to L 5. First, 2% lidocaine for the purpose of local anesthesia
with a history of taking pregabalin or gabapentin were also was administered via infiltration at the L 3 to L 4 in the lateral
excluded. decubitus position. Then, all patients received spinal anesthesia
with 2.4 mL of 0.5% hyperbaric bupivacaine through the L 3 to L
4 interspace using a midline approach with a 25-G Quincke
2.2. Anesthesia and data collection needle. Before completion of intrathecal injection, intravenous
After receiving Kyungpook National University Institutional crystalloid was administrated at 6 mL/kg. After the injection,
Review Board approval (KNUH 2014-05-027), all patients were the patient was returned to the supine position and remained
provided with a written informed consent. This study was in that position for at least 20 minutes. All patients in this
registered at www.clinicaltrials.gov (NCT 02690506). Forty- study were positioned similarly during the entire surgical
four consecutive patients scheduled to undergo elective urogeni- procedure. When the patient experienced either a decrease in
tal surgery (TUR-B and TUR-P) under spinal anesthesia were systolic blood pressure >30% from baseline values or a mean
enrolled in this randomized, placebo-controlled, and double- arterial blood pressure <60 mm Hg, intravenous ephedrine
blind trial. Cases were divided into 2 randomized groups of 22 4 mg or phenylephrine 50 mcg was administered. When the
patients. Patients were randomized to a treatment group using a heart rate decreased to <45 bpm, intravenous atropine 0.5 mg
computer-generated randomization sequence (Fig. 1). Both the was administered. Intraoperative sedation was not provided.
patient and anesthesiologist were double-blinded to the treat- Sensory blockade was assessed using a pinprick test in at
ment, and all records were recorded by an anesthesiologist the midaxillary line on both sides of the chest. Pinprick tests
blinded to group allocation. Identical capsules of either were performed every 1 minute until maximum sensory
pregabalin or placebo were prepared by the hospital pharmacy, blockade was achieved in the relevant body segment and
and a doctor who was not involved in the perioperative subsequently every 5 minutes for the next 30 minutes. Thereafter,
evaluation administered the capsule according to the randomi- assessments were performed every 15 minutes until recovery of
zation sequence. sensation in the L2 segment. The time to T10 sensory block, peak
Two hours before surgery, the control patients (group C) sensory level, and time from the injection to the peak level were
received capsules containing placebo, and pregabalin patients recorded.

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Table 1 the Student t test, X2 test, or Mann–Whitney–Wilcoxon test as

Demographic characteristics and duration of surgery. appropriate. Continuous parameters such as age, weight, surgery
time, time of the first request for analgesics, and the duration of
Control group Pregabalin group
blockade were compared between 2 groups using the unpaired
(n = 22) (n = 21) P
Student t test. Categorical scales such as adverse effects and the
Age, y 50 ± 15 53 ± 15 0.616 number of postoperative analgesics were analyzed using Fisher
Female/male 9/13 5/16 test. Associations between the duration of the sensory blockade
Height, cm 164.4 ± 7.9 167.2 ± 6.6 0.307
and the time to the first analgesic request, as well as the time to the
Weight, kg 66.9 ± 9.4 70.1 ± 11.1 0.783
Operation duration, min 43.7 ± 27.9 41.6 ± 21.4 0.783
first analgesic request and the dosage of analgesics during the first
24 hours postoperative, were analyzed using Pearson correlation.
Data are mean ± standard deviation. A P value <0.05 was considered significant.

3. Results
Recovery time from the sensory blockade was defined as a 2-
dermatome regression of anesthesia from the maximum level. In Forty-three patients completed the study according to the
addition, immediately after sensory block assessment, the motor protocol and were included in the analysis. One patient received
block was evaluated using a modified Bromage scale as reported general anesthesia in addition to the initial spinal block because
in previous studies (grade 0: no paralysis; grade 1: unable to raise of prolonged surgery. When the 2 groups were compared in terms
an extended leg but able to move the knees and ankles; grade 2: of age, gender, height, weight, and operation duration, no
unable to flex knees, can flex ankle, grade 3: no movement).[11] significant differences were found (Table 1). All surgical
The time to reach Bromage 1 was recorded. Motor block procedures were completed without complications.
duration was defined as the time for return to Bromage 2. The mean duration of 2-dermatome regression from peak
Postoperative pain was controlled by rescue analgesics sensory block levels in group P (88.8 ± 13.1 minutes) was
administered by hospital personnel without patient-controlled significantly longer than in group C (67.1 ± 10.9 minutes) (P =
analgesia. Postoperative pain was assessed by the patient using 0.000). The time for regression to L2 sensory block levels was
the visual analog scale (VAS, 0 = no pain; 10 = worst possible significantly prolonged in group P as well. In addition, the
pain) at 6 and 24 hours after the operation. Patients with a VAS regression time from Bromage 1 to Bromage 2 was prolonged in
score of 4 or more received 25 mg pethidine intravenously. If, group P (198 ± 16.8 minutes) than group C (168.2 ± 31.6
after pethidine was injected twice, the patient complained of a minutes) (P = 0.000). The mean time of onset for T10 sensory
VAS score of 4 or more, then 50 mg tramadol was given blockade was similar between the 2 groups. The time to reach
intravenously. The times of the first request for postoperative Bromage score 1 motor block was not significantly different (P =
analgesia and the number of injections were recorded. 0.106), and the maximum level was similar in both groups
The presence of any of the following possible complications (Table 2).
during the first 24 hours postoperative was recorded by the The postoperative 6- and 24-hour VAS pain scores were
nurses in the relevant hospital ward: drowsiness (no eye opening decreased in group P. The time to the first request for
in response to a verbal command), dizziness, dry mouth, and postoperative supplemental analgesia was significantly pro-
nausea/vomiting. longed in group P (404.0 ± 123.2 minutes) when compared with
group C (204.8 ± 37.6 minutes) (P = 0.000). The total rescue
dosages of pethidine and tramadol were lower in group P (P =
2.3. Sample size 0.000) (Table 3) (Fig. 2).
The sample size for this study was calculated based on a pilot The time for 2-dermatome regression from peak sensory block
study. We determined that if the difference between the 2 groups levels was positively correlated with the time to the first request
was 15 minutes (±standard deviation of 17 minutes) to achieve a for postoperative analgesics (r = 0.365, P = 0.016). Further, the
sensory regression of 2 dermatomes with an a-error = 0.05 at time to first request for postoperative analgesics was significantly
80% power, at least 21 patients per group were needed. negatively correlated with the total rescue dosages of pethidine
(r = 0.729, P = 0.000) and tramadol (r = 0.670, P = 0.000).
The frequencies of bradycardia and hypotension during
2.4. Statistical analysis
intraoperative time did not differ between the groups. No
Data were analyzed using SPSS 20.0 (SPSS Inc., Chicago, IL). differences were observed in the postoperative adverse effects
Demographic data and clinical variables were compared using between the 2 groups during the first 24 hours following surgery
(Table 4).
Table 2
Onset time and duration of sensory and motor blocks. 4. Discussion
Control group Pregabalin group We investigated whether pregabalin premedication prolonged the
Variables, min (n = 22) (n = 21) P
duration of a sensory block as well as the time to the first request
Time to T10 sensory block 5.0 ± 1.0 4.9 ± 1.3 0.790 for postoperative analgesics. This study showed that oral
Time to Bromage 1 block 8.1 ± 1.4 7.3 ± 1.4 0.106 pregabalin administered 2 hours before spinal anesthesia pro-
Mean of maximal sensory level T7 T7 longs both sensory and motor blocks induced by spinal
Time of 2-segment regression 67.1 ± 10.9 88.8 ± 13.1 0.000 bupivacaine anesthesia. The time to the first request for
Time for regression to L2 130.0 ± 16.7 156.0 ± 14.5 0.000
postoperative analgesics was delayed, and lower rescue analgesic
Time for regression to Bromage 2 168.2 ± 31.6 198.1 ± 16.8 0.000
requirements were observed during the early postoperative 24
Data are mean ± standard deviation. hours. The length of the delay to the first request for

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Table 3 provides analgesia through a different mechanism than opioids

Pain score, cumulative analgesics consumption, and time to first and therefore makes a reasonable addition to a multimodal
postoperative analgesics request during the first 24 hours. analgesic treatment plan.[17] The use of gabapentin might be
limited by its negative side effects, such as dizziness, somnolence,
C group P group
(n = 22) (n = 21) P confusion, and ataxia.[16] Pregabalin has antihyperalgesic,
anticonvulsant, and anxiolytic properties similar to those of
Pain score at 6 h postoperative 4.2 ± 1.0 3.1 ± 1.2 0.002 gabapentin, but with fewer side effects as well as dose-
Pain score at 24 h postoperative 2.2 ± 0.7 1.6 ± 0.7 0.005
independent absorption.
First analgesics request, min 204.8 ± 37.6 404.0 ± 123.2 0.000
Total dose of pethidine, mg 50.0 ± 0.0 35.7 ± 16.9 0.000
Preemptive usage of pregabalin in infraclavicular nerve blocks
Total dose of tramadol, mg 54.6 ± 30.5 16.7 ± 28.9 0.000 has been reported to result in early initiation of the motor block
and prolongation of sensory block.[8] Unlike in our study in
Data are mean ± standard deviation. spinal anesthesia, the duration of the motor block was not
prolonged. In addition, 150 and 300 mg doses of pregabalin
premedication showed no differences as anxiolytic agents in
postoperative analgesics was significantly related to the total dose peripheral nerve blocks.[8] White et al[18] found that preoperative
of postoperative analgesics required. pregabalin administration (70–300 mg) increased perioperative
Meta-analyses have demonstrated that pregabalin leads to a sedation in a dose-related fashion. Single dose of preemptive
reduction in postoperative pain scores.[6,7] However, only a pregabalin administration was also shown to reduce postopera-
limited number of studies have been published to date about the tive pain in third molar dental surgery (75 mg) as well as double-
efficacy of pregabalin in regional anesthesia,[8,12] and the effect of jaw surgery (150 mg) under general anesthesia.[13,15] However,
administration of a single dose of preemptive pregabalin on the greater side effects were seen with 300 mg pregabalin in patients
effectiveness of spinal anesthesia has not been fully reported to for dental surgery under general anesthesia.[19] Thus, the basis of
date. previously published studies as well as our own pilot study, we
Bafna et al[12] compared the time to the first analgesic request determined that a dose of 150 mg pregabalin premedication was
for the groups of single dose 600 mg gabapentin and 150 mg most appropriate for this study. In addition, we observed no
pregabalin premedication in gynecological surgeries under spinal significant difference in the postoperative adverse effects between
anesthesia. Both medications prolonged the mean duration of the 2 groups during the first 24 hours following surgery.
effective analgesia of a spinal bupivacaine block, but pregabalin The mechanisms by which pregabalin premedication prolongs
showed significantly longer duration of effective analgesia. In the motor and sensory blocks using local anesthetics in spinal
pregabalin group, the analgesic effect was maintained for 535 anesthesia are not fully understood. There may be several reasons
minutes (±32.8), which was a longer duration than our result for the prolongation of spinal anesthesia. Gabapentinoids are an
(404 minutes [±123.2]). This might be because of the dose of r-aminobutyric acid analog that binds to a2-d subunit of
bupivacaine and the difference between the types of surgery. The presynaptic voltage-gated calcium channels, and this inhibition
efficacy of perioperative administration of gabapentinoids decreases postsynaptic excitability by reducing potassium-
(gabapentin and pregabalin) has been investigated in various evoked excitatory transmitter release. These medications provide
surgeries, and clinical studies have confirmed the potential of antiepileptic, anxiolytic, and analgesic features by modulating
gabapentinoids as an adjuvant for pain treatment, mostly in acute both GABAergic neurotransmission and calcium influx. Gaba-
and persistent postoperative pain.[5,13–16] Gabapentin is a useful pentinoid compounds produce a significant and clinically
adjunct for the management of postoperative pain since it important improvement in preoperative anxiety scores.[8,14,20]

postoperative analgesics Postoperative VAS pain scores

60 6
Group
Group
50 C 5 C
P P
40 4

30 3

20 2

10 1

0 0
6 24
pethidine tramadol Time after spinal anesthesia (hr)
Figure 2. Visual analog scale pain scores and analgesics consumption in the first 24 postoperative hours.

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lower limb surgery: a double-blind, randomized clinical CONSORT

Table 4
study. Medicine 2016;95:e2880.
Postoperative adverse effects during the first 24 hours. [3] Ota K, Namiki A, Iwasaki H, et al. Dose-related prolongation of
Variables C group (n = 22) P group (n = 21) P tetracaine spinal anesthesia by oral clonidine in humans. Anesth Analg
1994;79:1121–5.
Dizziness 2 (9) 3 (14) 0.600 [4] Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical
Drowsiness 0 (0) 0 (0) 1.000 practice. Epilepsia 2004;45(suppl 6):13–8.
Dry mouth 4 (18) 4 (19) 0.943 [5] Clarke H, Page GM, McCartney CJ, et al. Pregabalin reduces
Nausea/vomiting 3 (14) 2 (10) 0.678 postoperative opioid consumption and pain for 1 week after hospital
discharge, but does not affect function at 6 weeks or 3 months after total
Values are presented as a number (proportion, %). hip arthroplasty. Br J Anaesth 2015;115:903–11.
[6] Lam DM, Choi SW, Wong SS, et al. Efficacy of pregabalin in acute
postoperative pain under different surgical categories: a meta-analysis.
Medicine 2015;94:e1944.
Since patients may be anxious in the perioperative period, the [7] Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute
anxiolytic effects and euphorigenic effects of pregabalin may be and persistent postoperative pain: a systematic review and meta-analysis.
beneficial. Br J Anaesth 2015;114:10–31.
In this study, a single dose of 150 mg pregabalin 2 hours before [8] Cegin MB, Soyoral L, Yuzkat N, et al. Pregabalin administered as an
anxiolytic agent in ultrasound-guided infraclavicular block: a controlled,
spinal anesthesia showed sufficient efficacy during the first double-blind, dose-ranging trial. Eur Rev Med Pharmacol Sci 2016;20:
postoperative 24 hours. Pregabalin has an elimination half-time 568–74.
estimated to range from 5.5 to 6.7 hours, which is independent of [9] Kissin I. Preemptive analgesia. Anesthesiology 2000;93:1138–43.
the dose and frequency of administration.[21] On the other hand, [10] Bromley L. Pre-emptive analgesia and protective premedication. What is
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[11] Bromage PR, Burfoot MF, Crowell DE, et al. Quality of epidural
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300 mg pregablain oral administration, the cerebrospinal fluid [12] Bafna U, Rajarajeshwaran K, Khandelwal M, et al. A comparison of
pregabalin level is high enough to reduce central nervous system effect of preemptive use of oral gabapentin and pregabalin for acute post-
hypersensitivity. Evoked pain during movement is enhanced by operative pain after surgery under spinal anesthesia. J Anaesthesiol Clin
Pharmacol 2014;30:373–7.
central neuronal sensitization,[23] and the persistent pregabalin [13] Ahiskalioglu A, Ince I, Aksoy M, et al. Effects of a single-dose of pre-
effects observed in our study were likely the result of preoperative emptive pregabalin on postoperative pain and opioid consumption after
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There were limitations to the present study. First, since only 1 Surg 2016;74:53.e1–7.
[14] Shimony N, Amit U, Minz B, et al. Perioperative pregabalin for reducing
dosage of pregabalin was evaluated, we could not determine the
pain, analgesic consumption, and anxiety and enhancing sleep quality in
most effective dosage. Second, clinically meaningful improve- elective neurosurgical patients: a prospective, randomized, double-blind,
ments in recovery were not assessed. Adequate postoperative and controlled clinical study. J Neurosurg 2016;1–0. [Epub ahead of
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hospitalization, and increased patient satisfaction. Third, [15] Cheung CW, Choi WS, Leung YY, et al. A double-blind randomized
crossover study to evaluate the timing of pregabalin for third molar
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We investigated the effects of single dose preoperative
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