Accepted Manuscript

The effect of pregabalin on acute postoperative pain in patients undergoing total knee
arthroplasty: a meta-analysis

Jian Dong, Wenmin Li, Yuling Wang

PII: S1743-9191(16)30839-1
DOI: 10.1016/j.ijsu.2016.08.521
Reference: IJSU 3039

To appear in: International Journal of Surgery

Received Date: 19 April 2016

Revised Date: 21 August 2016
Accepted Date: 24 August 2016

Please cite this article as: Dong J, Li W, Wang Y, The effect of pregabalin on acute postoperative pain
in patients undergoing total knee arthroplasty: a meta-analysis, International Journal of Surgery (2016),
doi: 10.1016/j.ijsu.2016.08.521.

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 ACCEPTED MANUSCRIPT

The effect of pregabalin on acute postoperative pain in patients

undergoing total knee arthroplasty: a meta-analysis

Jian Dong1 Wenmin Li2 Yuling Wang3

1 Department of Orthopedics, Linyi Peoples Hospital,Linyi,276003P.R. China; 2 Department of

Pharmacy, Linyi Cancer Hospital, Linyi, 276001, P.R. China; 3 Department of Rheumatology and

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Immunology, Linyi Peoples Hospital, Linyi, 276003, P.R. China

Corresponding to: Yuling Wang, From the department of Rheumatology and Immunology, Linyi

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Peoples Hospital, Linyi, 276003, P.R. China, E-mail: maodeyinglong@163.com

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 ACCEPTED MANUSCRIPT

The effect of pregabalin on acute postoperative pain in patients

undergoing total knee arthroplasty: a meta-analysis

Abstract

Objective: The purpose of this systematic review and meta-analysis of randomised controlled trials

(RCTs) was to evaluate the effect of pain control of pregabalin versus placebo after a total knee

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arthroplasty (TKA).

Methods: The electronic databases: Medline, Embase, PubMed, CENTRAL (Cochrane Controlled

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Trials Register), Web of Science and Google were searched from inception to February 2016. This

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systematic review and meta-analysis were performed according to the PRISMA statement criteria. The

primary endpoint was the visual analogue scale (VAS) after a TKA with rest or mobilization at 24

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hours and 48 hours, which represents the effect of pain control after TKA. The cumulative morphine

consumption is also assessed to the morphine-sparing effect. The complications of nausea, vomiting,
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dizziness and sedation were also compiled to assess the safety of pregabalin. Software Stata 12.0 was

used for the meta-analysis. After testing for publication bias and heterogeneity across studies, data were
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aggregated for random-effects modelling when necessary.

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Results: Six clinical trials with 769 patients were used for the meta-analysis. The meta-analysis

indicated that pregabalin can decrease the VAS with rest at 24 hours (MD= -8.14; 95% CI -12.57 to
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-3.71; P<0.001) and 48 hours (MD=-7.34; 95% CI -11.65 to -3.02; P<0.001). Pregabalin can decrease

the VAS with mobilization at 24 hours (MD=-6.56; 95% CI -10.45 to -2.66; P=0.001) and 48 hours
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(MD=-9.62; 95% CI -12.80 to -6.44; P<0.001). The results indicated that perioperative pregabalin can

decrease the cumulative morphine consumption at 24 hours (SMD=-0.97; 95% CI -1.17 to -0.78;
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P<0.001) and 48 hours (MD=-2.23; 95% CI -2.48 to -1.97; P<0.001). Moreover, pregabalin can
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decrease the occurrence of nausea and vomiting but increase the occurrence of dizziness and sedation.

Conclusion: Based on the current meta-analysis, pregabalin has an analgesic and opioid-sparing effect

in acute postoperative pain management without increasing the rate of nausea, vomiting.

Key Words: Pregabalin, Total knee arthroplasty, Pain management, Randomised controlled trials,

Meta-analysis

1 Introduction

Total knee arthroplasty (TKA) is now one of the most common orthopaedic surgeries and its main

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indication is for patients with osteoarthritis (OA) or rheumatic arthritis (RA) of the knee; however,

TKA has always been associated with a moderate to severe pain after operation[1]. Pang et al.[2]

reported that the pain occurrence in TKA is more painful than other orthopaedic surgeries, including

total hip arthroplasty. An effective pain control after TKA is important since adequate pain control after

TKA allows patients to achieve accelerated recovery and decrease the economic cost[3]. In recent

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decades, multiple anaesthesia including morphine has been used to control pain after TKA in order to

reduce the side effects of morphine-related complications such as nausea, vomiting and constipation[4].

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Methods include regional anaesthesia[5], peri-articular infiltration anaesthesia[6], intra-articular

infiltration anaesthesia[7] and anaesthesia with non-steroid drugs such as pregabalin[8].

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Perioperative multiple anaesthesia including oral pregabalin may reduce the pain and reduce the

morphine-related complications after TKA since the pregabalin can bind to the 2 subunit of the

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voltage-gated calcium channel to reduce the calcium influx into the terminal of presynaptic and thus
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can relieve the sensitisation of peripheral nociceptive nerve terminals and central neurons[9]. However,

the effect of pregabalin in reducing the visual analogue scale (VAS) and cumulative morphine
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consumption after TKA is controversial[10-12]. Base on the current studies, a definite conclusion

cannot be drawn, so a meta-analysis was necessary to analyse the effectiveness and safety of pregabalin
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in TKA.
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2. Materials and methods

2.1 Search Strategy

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The electronic databases Medline, Embase, PubMed, CENTRAL (Cochrane Controlled Trials

Register), Web of Science and Google were searched from inception to February 2016. The search
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strategies were performed based on medical subject headings and the appropriate corresponding terms

including pregabalin, total knee arthroplasty, total knee replacement, TKA and TKR. In addition, the
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reference lists of all of the full-text literature were reviewed to identify any initially omitted studies and

no restriction was made on the language of the publication. Two reviewers (Jian Dong, Wenmin Li)

independently searched and screened the literature. Any disagreements were resolved by the third

reviewer (Yuling Wang) and an examination of the full text to seek the final answer. Since this is a

meta-analysis, no ethics committee or institutional review board were required to approve the study.

2.2. Inclusion Criteria and Study Selection

Inclusion criteria are as follows: (1) to have taken part in RCTs; (2) to have undergone a primary
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TKA; (3) to have received interventions, including pregabalin with a control (placebo or nothing); and

(4) to have reported outcomes, including postoperative VAS pain with rest or mobilization at 24 hours

and 48 hours, cumulative morphine consumption for 24 hours and 48 hours, the incidence of nausea,

vomiting, dizziness and sedation. At least one of the outcomes mentioned above had to be included and

no language restriction was imposed. Studies on cadaver or artificial models were not take into

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consideration. Non-RCTs, letters, comments, editorials, practice guidelines and other studies with

insufficient data were also excluded for this meta-analysis.

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2.3. Data Abstraction and Quality Assessment

All the researched literature was imported into the software of Endnote and the duplicates were

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excluded by the software, then two authors independently read the titles and abstracts of the literature

to exclude the irrelevant papers. Most of the articles were excluded based on the topic of the article

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provided in the respective title or abstract, and disagreements about whether or not an article should be
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included were resolved by discussion or by a senior reviewer. The general characteristic data were

extracted and recorded in an Excel spread sheet: (1) the authors name, the number of patients in the
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pregabalin and control group , mean age of the pregabalin and control group, the ratio of male patients

to female patients, the anaesthesia method, the dose and time of administration of the pregabalin; and
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(2) the intraoperative and postoperative analgesia; and (3) the VAS with rest or mobilization at 24 hours
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and 48 hours for pain, the rates of nausea, vomiting, dizziness, sedation and and the morphine

cumulative consumption for 24 hours and 48 hours. Postoperative pain intensity was measured by a
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100-point VAS. When the numerical rating scale (NRS) was reported, it was converted to a VAS. The

10-point VAS was converted to a 100-point VAS[13]. Data in other forms (i.e., median, interquartile
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range, and mean 95% CI) were converted to mean SD according to the Cochrane Handbook[14]. If

the data were not reported numerically, we extracted this data using the GetData Graph Digitizer
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software from the published figures.

Risk of bias assessment of the included studies was performed in light of the Cochrane Handbook

Systematic Reviews of Interventions (version 5.1.0)[14], and software Review Manager, version 5.3

(The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2014) and was used to draw

the bias of summary and bias of each study. The content included seven items, sequence generation,

allocation sequence concealment, blinding of the participants and personnel, blinding of the outcome

assessment, incomplete outcome data, selective outcome reporting and other biases. The terms low
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risk, high risk, or unclear risk were used to assess the risk of bias of the included studies, using

Review Manager, version 5.3(The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen,

2014).

2.4. Statistical Analysis

Continuous outcomes (VAS with rest or mobilization for pain at 24 h and 48 h) were expressed as

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the mean difference (MD) with the respective 95% CIs. An Inverse-Variance Fixed-effects model was

performed to calculated MD according to the Cochrane Handbook for Systematic Reviews of

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Interventions. The cumulative anaesthesia consumption at 24 hours and 48 hours were expressed as the

standard mean difference (SMD) since the studies adopted different rescue drugs. Discontinuous

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outcomes (the rate of nausea, vomiting, dizziness and sedation) were expressed as the relative risk (RR)

with 95% CIs. Statistical significance was set at P<0.05 to summarise findings across the trials. The

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meta-analysis were calculated by the software of Stata, version 12.0 (Stata Corp., College Station, TX).
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Different pregabalin doses and dosing times in a single study were handled as subgroups within the

study. Statistical heterogeneity was tested using the chi-squared test and I2 statistic. A chi-squared test
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I2>50% was considered suggestive of statistical heterogeneity. When there was no statistical evidence

of heterogeneity, a fixed effect model was adopted; otherwise, a random effect model was chosen. In
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addition, we calculated numbers needed to harm (NNH) to examine the risk vs. benefit of pregabalin
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therapy for some endpoints[15]. Publication bias was evaluated by Beggs test and was none if the P

value obtained from Beggs test is greater than 0.5[16]. Moreover, funnel plot in Beggs test is
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symmetry provides evidence that there is no publication bias. Sensitivity analysis was conducted by

omitting one study at a time to evaluate the influence of a single study on the overall estimate. P-value
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<0.05 was considered to indicate statistically significant publication bias.

3 Results
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3.1 Search Results and Quality Assessment

In the initial search, we identified 312 potentially relevant studies, of which 30 duplicates were

removed by Endnote Software (Figure.1). According to the inclusion criteria, 276 studies were

excluded after reading the titles and abstracts. Finally, we included six clinical trials with 769 patients

in the meta-analysis[8,11,12,17-19]. One study[19] adopted three different doses of pregabalin for

reducing pain after TKA, and one study[18] performed the study with two different doses of pregabalin,

and these studies were divided into two trials and three trials respectively. Thus, a total of nine articles
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were included in our meta-analysis. The number of the patients ranged from 20 to 120 in the included

studies. The dose of pregabalin ranged from 50 mg to 300 mg and the time of administration of

pregabalin is different in the included studies. In four studies[10,11,17,19] administration of

postoperative anaesthesia was via patient-controlled anaesthesia (PCA), in one study administration

was by epidural infusion[8] and in one other study[18] peripheral nerve block was adopted. The general

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characteristic and the dose and time of pregabalin can be seen in Table 1 and Table 2. Details of the

quality assessment are shown in Figure. 2 and Figure. 3.

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3.2 Result of Meta-analysis

3.2.1 VAS with Rest

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Only three studies showed the VAS at 24 hours postoperatively with rest. The meta-analysis

indicated that pregabalin can decrease the VAS with rest at 24 hours (MD=-8.14; 95% CI -12.57 to

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-3.71; P<0.001, Figure. 4) and the VAS with rest at 48 hours (MD=-7.34; 95% CI -11.65 to -3.02;
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P<0.001, Figure. 4). Beggs test provided evidence of no publication bias regarding the effect of

pregabalin on the VAS with rest at 24 hours (P=0.091, Figure. 5. A) and at 48 hours (P=0.074, Figure. 5.
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B).

In the present meta-analysis, sensitivity analyses were also performed by sequential removal of
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each eligible study to assess their influence on the pooled estimate. We found that the omission study of
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Jain et al[17] clearly influenced the pooled VAS with rest at 24 h (Figure. 6. A) and 48 h (Figure. 6. B).

The estimate value in Jains study go beyond the upper confidence limit and influence the final result.
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3.2.2 VAS with Mobilization

A total of three component studies (313 patients) provided VAS at 24 hours with mobilization
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postoperatively. Pregabalin can decrease the VAS with mobilization at 24 hours (MD=-6.56; 95% CI

-10.45 to -2.66; P=0.001, Figure. 7) and the VAS at 48 hours (MD=-9.62; 95% CI -12.80 to -6.44;
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P<0.001, Figure. 7). As a result, a sensitivity analysis was conducted for VAS with mobilization at 24 h

(Figure. 8. A) and VAS with mobilization at 48 h (Figure. 8. B), and after each study was sequentially

excluded from the pooled analysis, the conclusion was not affected by the exclusion of any specific

study.

3.2.3 Cumulative morphine consumption at 24 hours and 48 hours

A total of five studies and four articles addressed the cumulative morphine consumption at 24

hours and 48 hours respectively after pregabalin and control. The results indicated that perioperative
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pregabalin can decrease the cumulative morphine consumption at 24 hours (SMD=-0.97; 95% CI -1.17

to -0.78; P<0.001, Figure. 9) and 48 hours (SMD=-2.23; 95% CI -2.48 to -1.97; P<0.001, Figure. 9).

3.2.4 Complications

Eight studies paid close attention to postoperative nausea. The meta-analysis indicated that

pregabalin can decrease the occurrence of nausea (RR, 0.73; 95% CI 0.610.88, P=0.001, Figure. 10),

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the NNH is 9.09, and vomiting (RR, 0.55; 95%CI 0.380.78, P=0.001, Figure. 10) with NNH value is

10.25. Five studies investigated the occurrence of dizziness in both methods and found pregabalin can

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increase the occurrence of dizziness (RR, 1.49; 95%CI 1.082.05, P=0.014, Figure. 11) and sedation

(RR, 1.84; 95%CI 1.422.39,P<0.001, Figure. 11). The NNH value for dizziness and sedation is 14.11

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and 4.38 respectively.

3.2.5 Subgroup analysis according to dosing regimen

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According to whether a single dose (prior to surgery) or multiple doses (starting from the night
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before surgery or days prior to surgery) were administrated. Results are shown in Table 3, the pooled

results indicated that multiple dose of pregabalin show superior than single dose pregabalin in VAS
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with rest at 48 h or mobilization at 24 h and 48 h and cumulative morphine consumption at 24 h and 48

h. And, multiple dose of pregabalin are associated with more pain scores than single dose pregabalin
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(-13.00 for single dose vs -2.58 for multiple dose).

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4. Discussion

To our knowledge, this is the first meta-analysis of RCTs comparing the efficacy and safety of
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pregabalin with placebo in the management of pain after a TKA. The present meta-analysis was

conducted on the basis of 6 randomised studies that found better pain control with rest or with
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mobilization at 24 hours and 48 hours postoperatively, with pregabalin compared to controls. In

addition, perioperative pregabalin can decrease the occurrence of nausea and vomiting. All the included
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trials were published from the year of 2010. The mean age of the two groups ranged from 60 to 69. The

dose of pregabalin ranged from 100 mg/d to 300 mg/d preoperatively and time to administration ranged

from 30 min to 2 hour. There are two studies administrated no dose of pregabalin after surgery[10,11].

Another oral dose of pregabalin ranged from 100 mg/d to 300 mg/d. One study continued treatment

(bid dosing) for 6 weeks post-TKA[18] and another two study last oral pregabalin for 16 days[8,19].

The quality of all the included studies is high; all the studies reported randomised sequence generation

using either the computer-generated randomisation table or random number table. The selection bias,
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performance bias, incomplete outcome data, attrition bias, reporting bias and other bias are low bias.

Only two studies do not report the blinding of the outcome data, this will generate a detection bias to

the final results. One report comes from a multiple centre RCT and the others come from one centre

RCT.

Although epidural analgesia combined with femoral nerve block and other anaesthesia methods

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have been administered to control pain after TKA, pain after TKA is still an unsolved problem that

troubles the surgeons and patients. Pain after TKA can not only prolong the length of hospital stay but

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also may lead to decreased functional improvements[20]. In recent decades, the perioperative pain

management has aimed solely at treating the pain to enhance recovery (early ambulation and decrease

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in the length of hospital stay) and to reduce the morphine-related complications[21]. Thus, multimodal

pain control strategy is preferred since there is a different mechanism for different analgesics. The

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preoperative administration pregabalin, NSAIDs and COX-2 inhibitors have been identified to provide
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an analgesic effect by reducing the occurrence of peripheral sensitisation. Current meta-analysis

indicated that pregabalin can decrease the VAS at 24 hours and 48 hours with rest or mobilization.
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Although our meta-analysis did reveal a significant difference in VAS score at 24 h and 48 h with rest

or mobilization between pregabalin versus placebo, significant heterogeneity were observed in these
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results. The weight of each studies is nearest. Sensitivity analysis was conducted and finally the
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omission of Jain study clearly influenced the pooled estimates[17]. Pregabalin can bind to the 2

subunit of the voltage-gated calcium channel in the central nervous system, thus, the variety of
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neurotransmitters can be decreased[22]. So, pregabalin has been identified to have a pharmacologic and

therapeutic effect on neuropathic pain associated with cancer, painful diabetic peripheral neuropathy
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and spinal cord injury[23-25]. This increased use of pregabalin as a component of multimodal

analgesia is evident from the published clinical trials in acute pain. But, this systematic review and
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meta-analysis confirms that pregabalin should be administered to patients undergoing TKA to optimize

the clinical efficacy of this drug. Subgroup analysis was performed according to the dose regimen,

results indicated that multiple dose of pregabalin show superior than single dose pregabalin in VAS

with rest at 48 h or mobilization at 24 h and 48 h and cumulative morphine consumption at 24 h and 48

h. For the results of VAS with rest at 24 h and 48 h, only one study performed the multiple dose of

pregabalin[17]. Thus, high quality dose-dependent RCT are needed to identify the optimal dose for

decreasing pain scores after TKA.

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In regard to the cumulative morphine consumption via PCA, preoperative pregabalin can decrease

the cumulative morphine consumption at 24 hours and 48 hours. This result agrees with those of other

studies examining the administration of pregabalin[8,12,17]. To data, spinal anaesthesia with morphine

is considered to be the most effective alternative for pain control after TKA, however, there is only a

limited choice (of treatments) available to reduce the morphine-related complications such as nausea

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and vomiting. Zhang et al[26] conducted a meta-analysis and drawn the conclusion that pregabalin can

decrease the diabetic peripheral neuropathy related pain.

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Nausea and vomiting, which are the most common morphine-related complications, can be

decreased when combined with the preoperative administration of pregabalin. Then NNH value was

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calculated to further analysis the adverse effects of pregabalin. NNH value of nausea is 9.09

(interpretation: after every 9.09 TKAs with treatment with pregabalin , one with nausea) and vomiting

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is 10.25(interpretation: after every 10.25 TKAs with treatment with pregabalin , one with vomiting)
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respectively. Whats more, pregabalin can increase the occurrence of dizziness and sedation. This result

contradicts with the results that adjunct with pregabalin can decrease of the cumulative morphine
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consumption after TKA. Based on current results, an NNH of 4.38 was appeared in the occurrence of

sedation when administration with pregabalin. The common adverse effects of pregabalin were
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dose-dependent dizziness and peripheral oedema[27]. Currently, there is no relevant information on

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economic outcomes with pregabalin for the reduction pain for TKA. With no cost analysis, the overall

impact of the risk-benefit outcome of preoperative administration of pregabalin is still incomplete.

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Further studies including the cost analysis to the treatment can help the policy makers to make a

reasonable policy.
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There were several limitations in this meta-analysis: (1) only 6 RCTs were included, and the

sample sizes were small, which might have affected the precision of the effect size estimations; (2) the
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duration of follow-up in some studies was unclear, studies including a multi-dimensional assessment

tool and follow-up at least to day 7 or best day 30 should be added; (3) the publication bias that existed

in the meta-analysis also influenced the results; (4) the dose and time of pregabalin differs in the

included studies, this will affect the accuracy of the result; (5) the pregabalin was combined with other

different anaesthetics, this will cause a bias to the final results; (6) even though the Beggs test provides

evidence of funnel plot symmetry indicating that there is no publication bias, we cannot completely

exclude publication bias because the number of the studies included was limited.
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Conclusion

In conclusion, though the number of studies and sample in each paper is limited, this is the first

meta-analysis that compared pregabalin with placebo in the management of pain after TKA. Based on

the current meta-analysis, pregabalin has an analgesic and opioid-sparing effect in acute postoperative

pain management without an increase in the rate of nausea and vomiting. However, the preoperative

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administration of pregabalin may increase the occurrence of dizziness and sedation. Since the sample

and number of the included studies is limited, a multiple centre randomised controlled trial is still

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needed to identify the effect and the optimal dose of pregabalin in order to reduce the pain after TKA.

Ethical approval

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No

Funding

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There was no funding for the systematic review and meta-analysis.
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Authors' contributions

J-D and W-M L conceived of the design of the study. Y-L W performed and collected the data and
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contributed to the design of the study. J-D finished the manuscript. All authors read and approved the

final manuscript.
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Conflicts of interest
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The authors declare that they have no competing interests.

Acknowledgments
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None.

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pharmacologic therapies for neuropathic pain associated with spinal cord injury. J Pain Res. 6

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[26] S. S. ZHANG, Z. Wu, L. C. ZHANG, et al. Efficacy and safety of pregabalin for treating

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Scandinavica. 59 (2) (2015) 147-159.
[27] E. BenMenachem. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia.
45 (s6) (2004) 13-18.

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Figure.1 The flow diagram of the included studies.
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Figure.2 The risk of bias graph.

Figure.3 The risk of bias summary.

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Figure.4 Forest plots comparing VAS at 24 h and 48 h with rest. An Inverse-Variance Fixed-effects

model was used. Mean difference with 95% CIs.

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Figure.5 (A) Beggs test for VAS with rest at 24 h. (B) Beggs test for VAS with rest at 48 h. WMD,
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weighted mean difference.

Figure.6 The sensitivity analysis of the VAS at 24 h (A) and 48 h with rest(B).
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Figure.7 Forest plots comparing VAS at 24 h and 48 h with mobilization. An Inverse-Variance

Fixed-effects model was used. Mean difference with 95% CIs.

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Figure.8 The sensitivity analysis of the VAS with rest at 24 h(A) and 48 h with mobilization(B).
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Figure.9 Forest plots comparing cumulative morphine consumption at 24 h and 48 h. An

Inverse-Variance Fixed-effects model was used. Standard Mean difference with 95% CIs.

Figure.10 The forest plot comparing the nausea and vomiting between the two groups.

Figure.11 The forest plot comparing the dizziness and sedation between the two groups.

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Number of Dose of gabapentin Time to administrated

Clinical trial Mean age(G/C,yr) Male/Female Anesthesia
patients(G/C) preoperatively preoperatively

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combined spinal epidural block in
Jain 2012 20/20 60/58 14/26 75 mg twice a day 2 h before surgery
the lumbar region

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combined spinal-epidural
Buvanendran 2010 120/120 64/63.3 65/175 no dose administrated no
anesthetic

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femoral nerve block followed by a
30 min before transfer to
YaDeau 2015 90/30 68/66,65/66,67/66 53/67 combined spinal and 100 mg/200 mg/300mg
the operating room
epidural

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one dose (150 mg or 300

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Singla 2015 194/98 63.0/63.3,63.7:63.3 107/185 NS mg) at 12 h and one dose 2 hour before surgery
(150 mg or 300 mg)

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1 hour before starting
Niruthisard 2013 25/27 69/67 NS spinal anesthesia 150 mg
anesthesia

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Lee 2015 21/20 63.38/67.60 NS general anesthesia 150mg 1 hour prior to operation
Table 1 The general characteristic, dose and time to administrated pregabalin of the included studies. NS: not stated, P: pregabalin, C: control.

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Clinical trial Time to use the pregablin postoperatively
150 mg at 6:00 AM and 6:00 PM on the first
Jain 2012
and second postoperative days
300 mg 1-2h before surgery, and 150mg
twice daily on the first 10 postoperative
Buvanendran 2010
days, 75 mg twice daily on day 11 and 12
and 50 mg twice daily on 13 and day 14
received one capsule (50, 100, 150 mg)
twice a day until POD14 (total daily dose of
YaDeau 2015
100, 200, or 300mg pregabalin), then one
capsule at bedtime on POD15 and POD16
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12 hours and 2 hours before surgery and
Singla 2015 continued treatment (bid dosing) for 6
weeks post-TKA
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Intraoperative analgesai
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mixture of 2.5 ml Bup 0.5% and
fentanyl 25 g spinally
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1.5 ml of 0.75% hyperbaric Bup
with 25 g of fentanyl
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An ultrasound-guided FNB was
performed followed by a combined
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spinal and epidural Bup
Sedation with midazolam
or propofol (25-75 g/kg/h)
infusion
Postoperative analgesics
Postoperative analgesia was provided
with an PCEA solution containing Bup
0.0625% and morphine 0.05 mg/ml
an epidural infusion of fentanyl (5 g/mL)
and Bup(1 mg/mL)
PCEA Bup 0.06% plus
hydromorphone10 g/ml; 10 min
lock-out
PNB and then switched to oral analgesia
5 mg hydrocodone bitartrate; or
oxycodone/acetaminophen and/or
intravenous opioid PCA depending on
the sites standard care
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All patients received PCA

All patients received spinal
morphine starting in the recovery room
anesthesia with 0.5 % hyperbaric

Niruthisard 2013
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no dose administrated till 48 hours postoperatively with a
Bup 3-3.2 mL plus preservative-free
PCA-dose of 1 mg and lockout of 6
morphine 0.2 mg

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minutes without basal infusion
a periarticular injection containing

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20 ml of 0.5% Bup, 5 ml of
morphine sulfate, 0.3 ml of fentanyl-based, IV PCA was initiated.
Lee 2015 no dose administrated epinephrine, and 1 ml of Pain control in the PACU was initially a

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methylprednisolone acetate were 20-g loading dose

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mixed with sterile normal solution
to a combined volume of 50 ml
Table 2 The dose and time to administration pregabalin, intraoperative and postoperative anesthesia of the included studies, PACU, post-anesthetic care unit, PCA,

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patient-controlled analgesia, Bup, bupivacaine, FNB, femoral nerve block, PCEA, patient controlled epidural anesthesia, PNB, peripheral nerve block, AM,
afternoon, PM, post meridiem, POD, postoperative days.

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Overall effects Heterogeneity
Outcome Studies 2
Effect estimate 95%CI P value I (%) P value
VAS with rest at 24 h
Single dose 2 -13.00 -19.07, -6.93 0.436 66.6 0.016
Multiple dose 1 -2.58 -9.07, 3.91 <0.001 0 -
VAS with rest at 48 h
Single dose 2 -1.53 -7.67, 4.61 0.625 55.4 0.134
Multiple dose 1 -13.00 -19.07, -6.93 <0.001 0 -

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Cumulative morphine
consumption at 24 hours
Single dose 2 -0.36 -0.77, 0.06 0.091 74.8 0.046

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Multiple dose 3 -1.14 -1.38, -0.93 <0.001 0 0.430
Cumulative morphine

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consumption at 48 hours
Single dose 1 -0.84 -1.48, -0.20 0.010 0
Multiple dose 3 -2.48 -2.76, -2.21 <0.001 81.9 0.004
Table 3 Subgroup analysis the different dose of pregabalin after TKA.

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Highlights
We carried on a meta-analysis to identify the efficacy and safety of pain control of pregabalin versus
placebo after a TKA.
Six RCTs were included finally.
Pregabalin has an analgesic and opioid-sparing effect in acute postoperative pain management
without increase the rate of nausea, vomiting.

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If you are submitting an RCT, please state the trial registry number ISRCTN

NCT01333956

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NCT00551135
NTC01344213

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Author contribution

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Please specify the contribution of each author to the paper, e.g. study design, data
collections, data analysis, writing. Others, who have contributed in other ways should
be listed as contributors.
Jian Dong : data collections, data analysis and writing.

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Wenmin Li and JianDong: data collections and data analysis.
Yuling Wang: data analysis and writing.
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Yuling Wang: study design, data collections
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Guarantor
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and/or the conduct of the study, had access to the data, and controlled the decision to
publish.
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Yuling Wang