Analgesic efficacy of preemptive pregabalin administration in arthroscopic shoulder surgery: a randomized controlled trial
Can J Anesth/J Can Anesth
Analgesic efficacy of preemptive pregabalin administration in arthroscopic shoulder surgery: a randomized controlled trial Efficacite? analge?sique de la pre?gabaline en administration pre? ventive lors d'une arthroscopie de l'e?paule: une e?tude randomise?e contr o?le?e
Sowoon Ahn 0 1 2
. Sung Hye Byun 0 1 2
. Kibum Park 0 1 2
. Jong Lin Ha 0 1 2
. Byeonghun Kwon 0 1 2
. Jong Chan Kim 0 1 2
0 K. Park, MD Department of Anesthesiology and Pain Medicine, Keimyung University School of Medicine , Daegu , South Korea
1 S. H. Byun, MD Department of Anesthesiology and Pain Medicine, School of Medicine, Catholic University of Daegu , Daegu , South Korea
2 S. Ahn, MD, PhD J. L. Ha, MD B. Kwon, MD J. C. Kim, MD , PhD (&) Department of Anesthesiology and Pain Medicine, CHA Bundang Medical Center, CHA University , 59 Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 463-712 , South Korea
Purpose The purpose of the current study was to evaluate the effects of pregabalin administration as an adjunct to fentanyl-based intravenous patient-controlled analgesia on opioid consumption and postoperative pain following arthroscopic shoulder surgery. Methods In this randomized controlled trial, 60 adult patients undergoing arthroscopic shoulder surgery were randomly assigned to receive either pregabalin 150 mg (Pregabalin group, n = 30) or placebo (Control group, n = 30) one hour before anesthetic induction. The primary outcome was the cumulative amount of fentanyl consumption during 48 hr postoperatively. Secondary outcomes were pain intensity, the number of rescue analgesics administered, and adverse effects related to the analgesic regimen, which were serially assessed during 48 hr postoperatively. Results The cumulative fentanyl consumption during 48 hr postoperatively was significantly lower in the Pregabalin group than in the Control group ([1,126.0 (283.6) lg vs 1,641.4 (320.3) lg, respectively; mean difference, 515.4 lg; 95% confidence interval [CI], 359.0 to 671.8; P = \ 0.001). Numeric rating scores for pain (0 to 10) were significantly lower in the Pregabalin group at six hours (mean difference, 2.9; 95% CI, 1.8 to 4.0), 24 hr (mean difference, 2.9; 95% CI, 1.9 to 3.8), and 48 hr (mean difference, 1.5; 95% CI, 0.6 to 2.3). The incidence of adverse effects related to the analgesic regimens, including nausea, sedation, and dizziness, were similar between the two groups. Conclusion A preoperative dose of pregabalin 150 mg administered before arthroscopic shoulder surgery resulted in significant analgesic efficacy for 48 hr in terms of opioid-sparing effect and improved pain intensity scores without influencing complications. This trial was registered at: http://cris.nih.go.kr, number CT0000578.
Author contributions Sowoon Ahn and Jong Chan Kim helped
design this study and analyze the data. Sowoon Ahn, Sung Hye Byun,
and Jong Chan Kim helped prepare the manuscript. Sung Hye Byun,
Kibum Park, Jong Lin Ha, and Byeonghun Kwon helped conduct the
study. Jong Lin Ha and Byeonghun Kwon helped collect the data. All
authors reviewed the manuscript.
Objectif L?objectif de cette e?tude e?tait d?e?valuer les
effets d?une administration de pre?gabaline comme
supple?ment a` une analge?sie contr?ole?e par le patient
intraveineuse a` base de fentanyl sur la consommation
d?opio??des et la douleur postope?ratoire apre`s une
arthroscopie de l?e?paule.
Me?thode Dans cette e?tude randomise?e contr?ole?e, 60
patients adultes subissant une arthroscopie de l?e?paule ont
e?te? randomise?s a` recevoir soit 150 mg de pre?gabaline
(groupe pre?gabaline, n = 30), ou un placebo (groupe
te?moin, n = 30) une heure avant l?induction de
l?anesthe?sie. Le crite`re d?e?valuation principal e?tait la
quantite? cumule?e de fentanyl consomme?e durant les
premie`res 48 h postope?ratoires. Les crite`res secondaires
comprenaient l?intensite? de la douleur, le nombre
d?analge?siques de sauvetage administre?s et les effets
secondaires lie?s au re?gime analge?sique, lesquels ont e?te?
e?value?s en se?rie pendant 48 h apre`s l?intervention.
Re?sultats La consommation cumule?e de fentanyl pendant
48 h postope?ratoires e?tait significativement plus basse dans
le groupe pre?gabaline que dans le groupe te?moin ([1126,0
(283,6) lg vs 1641,4 (320,3) lg, respectivement; diffe?rence
moyenne, 515,4 lg; intervalle de confiance [IC] 95 %,
359,0 a` 671,8; P = \ 0,001). Les scores d?e?valuation
nume?rique de la douleur (0 a` 10) e?taient significativement
plus bas dans le groupe pre?gabaline a` six heures
(diffe?rence moyenne, 2,9; IC 95 %, 1,8 a` 4,0), 24 h
(diffe?rence moyenne, 2,9; IC 95 %, 1,9 a` 3,8), et 48 h
(diffe?rence moyenne, 1,5; IC 95 %, 0,6 a` 2,3). L?incidence
d?effets secondaires ne?fastes lie?s aux re?gimes
analge?siques, y compris la nause?e, la se?dation et les
e?tourdissements, e?taient semblables dans les deux groupes.
Conclusion Une dose pre?ope?ratoire de 150 mg de
pre?gabaline administre?e avant une arthroscopie de
l?e?paule a entra??ne? une efficacite? analge?sique
significative durant 48 h en termes de re?duction en
besoin d?opio??des et a ame?liore? les scores d?intensite? de
la douleur sans influencer les complications. Cette e?tude a
e?te? enregistre?e au: http://cris.nih.go.kr, nume?ro
Apart from patient perceptions of discomfort, postoperative
pain after arthroscopic shoulder surgery is also known to
complicate the postoperative course by hindering patient
early mobilization and rehabilitation.1 Accordingly, there
have been many studies on various methods to control
postoperative pain after arthroscopic shoulder surgery,
including subacromial/intra-articular infiltration of local
anesthetic,2,3 suprascapular and/or axillary nerve block,4
and interscalene block.5,6 Notwithstanding their analgesic
efficacy, however, these methods present procedural
difficulties and are accompanied by complications
inherent in their invasive nature.7
Among the noninvasive methods to control
postoperative pain, intravenous opioid-based
patientcontrolled analgesia (IV-PCA) has been widely accepted
as effective and safe. Yet IV-PCA is also accompanied by a
high incidence of opioid-related adverse effects, including
respiratory depression, pruritus, constipation, and nausea.
The use of a multimodal analgesic regimen that
incorporates non-opioids in conjunction with IV-PCA has
been advocated as a standard practice to reduce opioid
consumption without compromising the analgesic
In the same context, pregabalin, a ligand of the a2-d
subunit of presynaptic voltage-gated calcium channels
widely used for neuropathic pain, has shown promising
results as an adjunct to a multimodal approach for the
control of postoperative pain without any apparent side
effects.10-13 Considering the need for analgesic regimens
that are specific to a particular surgical procedure, evidence
is lacking regarding pregabalin?s efficacy on acute
postoperative pain and its ability to provide an
opioidsparing effect following arthroscopic shoulder surgery.
In this prospective randomized controlled trial, we
tested our hypothesis that pregabalin would decrease
opioid consumption for postoperative pain control while
providing sufficient analgesia in adult patients undergoing
shoulder arthroscopic surgery during 48 hr postoperatively.
This study protocol was approved by the Ethical
Committee of Kyungpook National University Hospital, a
tertiary referral medical centre, in October 2012. Sixty
adult patients (aged 20-65 yr) scheduled for arthroscopic
shoulder surgery (Bankart or rotator cuff repair) during
October 2012 to March 2013 provided their informed
consent and were enrolled in the study. One day prior to the
scheduled surgery, a staff member who was not involved in
this study randomly assigned the patients to either the
Control group (n = 30) or the Pregabalin group (n = 30)
according to a computerized randomization table (without
being blocked or stratified by procedure). The Control
group received placebo capsules one hour before induction
of anesthesia, and the Pregabalin group received pregabalin
150 mg at the same point in time. The hospital pharmacy
prepared all medications in identical capsules, and an
independent nurse who was not involved in this study
administered the capsules orally with sips of water. Sealed
envelopes were used to conceal group allocation from staff
members involved in clinical care and from study
participants collecting data. To ensure blinding,
randomization results were not disclosed until data
analysis. Exclusion criteria included patients with an
American Society of Anesthesiologists physical status III
or higher, those with a history of cardiovascular or
respiratory disease, dizziness or frequent headaches,
alcohol or substance abuse, daily intake of analgesics or
intake of any analgesics within 48 hr preoperatively,
impaired kidney or liver function, or an inability to use an
IV-PCA device. The Figure displays the flow
chart showing the patients? enrolment for randomization.
Figure Flow chart of patient participation
Sedative premedication was withheld from all patients
and standardized anesthetic and analgesic management was
provided to all patients. Anesthesia was induced with
propofol 2 mg kg-1and remifentanil 0.5-1 lg kg-1, and
tracheal intubation was facilitated with rocuronium 0.6
mg kg-1. Anesthesia was maintained with a continuous
infusion of remifentanil 0.05-0.2 lg kg-1 min-1 and
sevoflurane 1.5-2.5 vol% to maintain a bispectral index
score of 40-60. At the beginning of surgery, palonosetron
0.75 mg was administered intravenously. After surgery, the
patients were turned to the supine position, sevoflurane was
discontinued, and remifentanil was continued at an infusion
rate of 0.02-0.05 lg kg-1 min-1. Neuromuscular blockade
was reversed with glycopyrrolate and pyridostigmine, and
remifentanil was discontinued following tracheal
extubation. After satisfactory recovery, the patients were
taken to the postanesthesia care unit (PACU). The duration
of anesthesia and surgery and the type of surgery were
After completion of the surgical procedure, IV-PCA was
initiated using the AutoMed 3200 (ACE Medical, Korea).
The IV-PCA regimen consisted of fentanyl 20 lg kg-1 in
0.9% saline (total volume of 100 mL), and it was
programmed to deliver a basal rate of 1 mL hr-1 and 1
mL each time the patient pressed the activation button,
with a 15 min lockout. If patients complained of pain C 5
on the numeric rating scale (NRS), they were allowed to
receive intravenous ketorolac 30 mg as a rescue drug
according to their comfort and following the standard
The primary variable for determining efficacy was the
opioid-sparing effect in terms of the total amount of
cumulative fentanyl consumption during 48 hr
postoperatively. Secondary variables for determining
efficacy were pain intensity, the number of rescue
analgesic drugs administered, and the incidence of
nausea. Fentanyl consumption, pain intensity, rescue
analgesic requirement, and nausea were further assessed
upon arrival at the PACU and at six, 24, and 48 hr
postoperatively. Adverse effects related to the multimodal
analgesic regimen, including sedation, dizziness, headache,
and visual disturbances, were also assessed for 48 hr
postoperatively. Pain intensity was measured on a NRS for
pain that ranged from 0 = no pain to 10 = worst pain
imaginable. Sedation was assessed using a numeric score
of 1-5 (1 = completely awake; 2 = awake but drowsy; 3 =
asleep but responsive to verbal commands; 4 = asleep but
responsive to tactile stimulus; 5 = asleep and not
responsive to any stimulus). Patients with scores of 4 and
5 were regarded as sedated and the number of these
patients was recorded. Sedated patients were closely
observed with pulse oximetry and managed appropriately
as necessary. An investigator blinded to group allocation
evaluated all of these variables at the end of each time
SPSS version 18 (SPSS Inc.; Chicago, IL, USA) was used
for statistical analyses, and data were expressed as number
of patients, mean [standard deviation (SD)]. Sample size
was calculated based on the primary endpoint, i.e.,
comparison of the volume of infused IV-PCA between
the groups. Based on an institutional preliminary study, the
anticipated mean (SD) infused volume of IV-PCA for 48 hr
was 60 (18) mL after surgery, and we considered a 30%
reduction (18 mL) to be clinically significant.14 We
determined that 26 patients would be required in each
group to show this difference with a error of 5% and power
of 90% using the independent Student?s t test. Allowing for
a 10% dropout rate during the study period, 30 patients
were enrolled in each group. We used the Chi square
statistic or Fisher?s exact test for categorical variables and
the independent Student?s t test or Mann-Whitney U test
for continuous variables as appropriate. All reported P
values are two sided. Values measured repeatedly were
compared by repeated measures analysis of variance using
the Bonferroni correction for post hoc analysis.
Arthroscopic surgery was performed successfully in all
patients, and none of the patients developed any
complications related to perioperative anesthesia or
surgery. Thus, data from all 60 patients could be
collected and analyzed. The patients? characteristics and
operative data, including the type and duration of surgery,
were similar between the groups (Table 1).
The mean (SD) amount of cumulative fentanyl
consumption for 48 hr postoperatively was significantly
less in the Pregabalin group than in the Control group
[1,126.0 (283.6) lg vs 1,641.4 (320.3) lg, respectively;
mean difference, 515.4 lg; 95% confidence interval [CI],
359.0 to 671.8; P = \0.001] (Table 2). The preoperative
pain scores of all patients were \ 3 and were similar
between the groups (data not shown). Pain intensity scores
expressed on the NRS at six, 24, and 48 hr after surgery
were all significantly lower in the Pregabalin group than in
the Control group. Also, the frequency of additional pain
rescue drug (ketorolac) administered during 24-48 hr was
significantly less in the Pregabalin group than in the
Control group (Table 3).
The occurrence of complications related to the
multimodal analgesic regimen, including sedation,
headache, dizziness, and blurred vision, were similar
between the groups during the study period. Also, the
incidence of postoperative nausea was similar between the
groups, and none of the patients experienced postoperative
vomiting (Table 4).
In this randomized controlled study, we evaluated the
efficacy of administering a single preemptive dose of
pregabalin 150 mg before arthroscopic shoulder surgery as
Control (n = 30)
Pregabalin (n = 30)
Table 1 Patients? characteristics
Values are number (proportion) or mean (standard deviation)
an adjunct to an opioid-based IV-PCA. This resulted in a
significant beneficial effect in terms of a reduction in
opioid consumption, pain intensity, and requirement for
pain rescue medication. In addition, these beneficial effects
of pregabalin were not accompanied by any increase in side
Opioid-based IV-PCA is being widely used as it is able
to provide analgesia for a chosen duration of time after
surgeries that accompany significant pain. Nevertheless,
Table 2 Fentanyl consumption
many studies have shown that this method is associated
with several adverse effects, including sedation, respiratory
depression, constipation, urinary retention, as well as
nausea and vomiting. To reduce these opioid-related
adverse effects, a multimodal approach to the
management of acute postoperative pain has been
advocated for many years.15 Accordingly, the efficacy of
several drugs as adjuvants has been studied, including
NSAIDs, ketamine, local anesthetics, and opioids.16-19
Recently, gabapentinoids have attracted attention in the
surgical setting as an adjuvant to a multimodal
postoperative pain management strategy. Gabapentinoids
bind at the a2-d subunit of presynaptic voltage-gated
calcium channels and exert analgesic effects by reducing
the release of several excitatory neurotransmitters such as
calcitonin gene-related peptide, glutamate, noradrenaline,
and substance P.20 Also, gabapentinoids administered
before surgical trauma have been shown to interact with
other analgesics additively or synergistically to decrease
inflammatory hyperalgesia.21 These properties of
gabapentinoids may be useful in decreasing opioid
consumption when the agents are administered as an
adjunct to a multimodal approach to postoperative pain
Control (n = 30)
Pregabalin (n = 30)
Mean difference (95% CI)
Values are mean (standard deviation). CI = confidence interval; PACU = postanesthetic care unit. A Bonferroni correction was applied to adjust
for multiple comparisons. P values of \ 0.0125 should be considered statistically significant
Control (n = 30)
Pregabalin (n = 30)
Mean difference (95% CI)
Table 3 Pain scores and incidence of pain rescue
Values are mean [standard deviation (SD)] or number (proportion). Pain scores = numeric rating scale for pain ranging from 0 = no pain to 10 =
worst imaginable pain; CI = confidence interval; PACU = postanesthetic care unit. A Bonferroni correction was applied to adjust for multiple
comparisons. P values of \ 0.0125 should be considered statistically significant
Control (n = 30)
Pregabalin (n = 30)
Values are number (proportion)
management.22,23 Among the gabapentinoids, pregabalin
shows reliable pharmacokinetic profiles across its
therapeutic dose range with low intersubject variability.24
These theoretical advantages have led to clinical studies
validating the analgesic efficacy of oral pregabalin for
postoperative pain in various surgical settings.25,26
In the current trial, a single preoperative dose of
pregabalin 150 mg was beneficial in controlling pain
intensity with an opioid-sparing effect for a period of 48 hr
after arthroscopic shoulder surgery. Contradictory results
found in previous studies evaluating the effect of
pregabalin on acute postoperative pain might be related
to different doses and the type of surgery. In the case of
single preoperative administration, pregabalin 150 mg was
reported as being beneficial in decreasing postoperative
pain and opioid consumption after laparoscopic
cholecystectomy,22 while administration of pregabalin
100 mg did not result in a beneficial effect after minor
gynecologic surgery.27 On the other hand, administration
of pregabalin 300 mg before and after laparoscopic
hysterectomy resulted in increased pregabalin-related side
effects, although the agent?s analgesic efficacy was
present.13 Therefore, we administered a 150 mg dose of
pregabalin to patients in this study and observed significant
analgesic efficacy without the cost of untoward side effects.
Most of the studies showing negative results involved
minimally invasive surgery, including laparoscopic
surgery, minor gynecological surgery, and surgery
performed using regional anesthesia, types of procedures
that are associated with relatively less postoperative
pain.25-27 A recent meta-analysis recommended further
studies to evaluate the analgesic effect of pregabalin in
more painful surgeries, pointing to the importance of a
surgery-specific analgesic regimen.28 In addition, it was
suggested that pregabalin?s analgesic efficacy was evident
only in patients who received general anesthesia and opioid
analgesia.26 These findings are consistent with the results
of the current trial, as arthroscopic shoulder surgery
(Bankart or rotator cuff repair) is generally considered to
be associated with severe postoperative pain.1
An additional strength of this study is our strategy to
evaluate the analgesic efficacy of pregabalin for 48 hr after
surgery and our finding that the drug?s beneficial influence
extended beyond its elimination half-life. Many studies
examining the effect of a single dose of pregabalin
evaluated its analgesic effect for only 24 hr
postoperatively, as it has an elimination half-life of
4.66.8 hr. Although acute postoperative pain is commonly
recognized as nociceptive pain, surgical trauma has been
established to induce hyperalgesia, which can lead to
abiding postoperative pain.25 Preventive analgesia is a type
of treatment that begins before surgical stimuli in order to
prevent the central sensitization of the dorsal horn caused
by incisional injury. Pregabalin is well known to reduce
central sensitization and hyperalgesia after tissue injury by
inhibiting calcium influx in voltage-gated calcium
channels.29 The beneficial effect of preemptive analgesia
with gabapentinoids has been reported in many other
studies.30-32 In the current trial, fentanyl consumption, pain
intensity, and rescue analgesic requirement during 24-48 hr
postoperatively were all significantly lower in the
Pregabalin group than the Control group. Thus, the
extended beneficial influence of pregabalin observed in
the current trial may be attributed to the abovementioned
mechanism, although it is beyond the scope of this study to
draw such a conclusion due to lack of mechanistic analysis
and adequate statistical power for analysis of interim time
There are certain limitations to this study. First, caution
should be exercised when generalizing the results of our
study as it was carried out in a single institution in Korean
patients only. Second, although our results point to clear
analgesic efficacy of preemptive pregabalin administration,
pain intensity scores upon PACU arrival were considerably
high in both groups, requiring rescue analgesic
administration in most of the patients. This observation
may be attributed to the possible occurrence of acute
hyperalgesia from the discontinuation of remifentanil after
surgery.33 Although patients were allowed to press fentanyl
bolus delivery and receive ketorolac rescue, our
multimodal analgesic regimen requires further
modification to improve pain control during the
immediate postoperative period.
In conclusion, single administration of pregabalin 150
mg before arthroscopic shoulder surgery resulted in
significant analgesic efficacy in terms of opioid-sparing
effects and improved pain intensity scores without
influencing side effects for 48 hr postoperatively.
Acknowledgements The authors thank Jae-Kwang Shim MD PhD
(Yonsei University College of Medicine, Seoul, South Korea) for his
valuable comments on the manuscript.
Conflicts of interest None declared.
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