Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis.

BJA Advance Access published September 10, 2014 British Journal of Anaesthesia Page 1 of 22 doi:10.1093/bja/aeu293

Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis B. M. Mishriky, N. H. Waldron and A. S. Habib* Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710, USA * Corresponding author. E-mail: [email protected]

Editor’s key points

† They found a significant positive effect (in terms of improved pain scores, opioid-sparing and reduction in nausea, vomiting, and pruritus), but a slight increase in some side-effects.

Keywords: meta-analysis; postoperative pain; pregabalin

Pregabalin is a g-aminobutyric acid analogue that binds to a2d subunits of the voltage-gated calcium channels.1 It reduces the excitability of the dorsal horn neurones after tissue damage.2 The use of pregabalin for the management of postoperative pain is off-label, and therefore, there are no dosing guidelines for this indication. For other indications, the recommended starting dose is 150 mg day21 in two to three divided doses, increased within 1 week to 300 mg day21 with a maximum recommended dose of 600 mg day21.2 Studies investigating the perioperative use of pregabalin used doses ranging from 50 to 300 mg and daily doses ranging from 50 to 750 mg. The efficacy of perioperative administration of pregabalin was investigated in previous meta-analyses,3 – 5 with all showing better postoperative analgesia with pregabalin. Those meta-analyses grouped studies based on the total daily dose of pregabalin. Zhang and colleagues5 reported that pregabalin doses of ,300 and ≥300 mg day21 reduced 24 h opioid consumption but not pain scores after surgery. Engelman and Cateloy4 grouped the analysis over a wide time-frame (6 h –7 days after surgery) according to the daily dose of pregabalin (50– 150, 225 –300, and 600 –750 mg) and reported that the lowest effective dose for reducing postoperative analgesic consumption was 225 –300 mg with no

reduction in pain scores. Since doses were reported in those meta-analyses as total daily dose, it is not clear if the individual dose or frequency of administration of pregabalin affect outcome. For instance, it is not clear from those reviews if individual single doses lower than 225 –300 mg have analgesic efficacy or if twice daily dosing of a particular dose of pregabalin would be more effective than single preoperative administration of the same dose. Some studies have investigated the impact of pregabalin on preoperative anxiety, but this was not addressed in those previous meta-analyses. More than 30 studies investigating perioperative pregabalin administration on acute pain outcomes have been published after the publication of those reviews, which included 115 and 184 studies. In addition, while one previous meta-analysis3 assessed the impact of the perioperative administration of pregabalin on chronic pain, it included only three studies.6 – 8 Seven other studies9 – 15 addressing persistent pain after pregabalin administration have since been published. Therefore, we performed this systematic review to provide an updated meta-analysis of the impact of pregabalin administration on postoperative pain scores and opioid consumption and investigate whether those outcomes differ according to individual pregabalin dose, frequency of administration, type

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† The authors reviewed the evidence for the use of pregabalin for pain relief in the perioperative period.

Summary. We performed this systematic review to assess the analgesic efficacy of perioperative pregabalin. Subgroup analyses and meta-regression were performed to assess the impact of individual dose and frequency of pregabalin administration on analgesic efficacy. We included 55 studies. When all doses and administration regimens were combined, pregabalin was associated with a significant reduction in pain scores at rest and during movement and opioid consumption at 24 h compared with placebo {mean difference [95% confidence interval (CI)]¼20.38 (20.57, 20.20), 20.47 (20.76, 20.18), and 28.27 mg morphine equivalents (210.08, 26.47), respectively}. Patients receiving pregabalin had less postoperative nausea and vomiting and pruritus compared with placebo [relative risk (RR) (95% CI)¼0.62 (0.48, 0.80) and 0.49 (0.34, 0.70), respectively]. Sedation, dizziness, and visual disturbance were more common with pregabalin compared with placebo [RR (95% CI)¼1.46 (1.08, 1.98), 1.33 (1.07, 1.64), and 3.52 (2.05, 6.04), respectively]. All doses of pregabalin tested (≤75, 100–150, and 300 mg) resulted in opioid sparing at 24 h after surgery. There were no significant differences in acute pain outcomes with pregabalin 100–300 mg between single preoperative dosing regimens and those including additional doses repeated after surgery. Data were insufficient to reach conclusions regarding persistent pain, but limited data available from two studies suggested that pregabalin might be effective for the reduction of neuropathic pain. In conclusion, this review suggests that pregabalin improves postoperative analgesia compared with placebo at the expense of increased sedation and visual disturbances.

BJA of anaesthesia, or type of surgery. Secondary aims were to assess the impact of pregabalin administration on anxiety scores and persistent pain, and provide an updated metaanalysis of the side-effects of pregabalin administration.

Methods

(i) Patients: type of surgery, type of anaesthesia, and number of patients. (ii) Interventions: pregabalin dose and frequency of administration. (iii) Comparison: control group regimen. (iv) Outcomes: (a) acute pain outcomes: pain scores at rest and during movement, opioid consumption, and duration of post-anaesthesia care unit (PACU) and hospital stay, (b) preoperative anxiety scores, (c) adverse effects: nausea, vomiting, sedation, dizziness, confusion, headache, visual disturbance, pruritus, difficulty passing urine, dry mouth, fatigue, and request for rescue antiemetics, and (d) persistent pain: pain scores and incidence of persistent pain. Data presented in graphs were requested from the authors. If authors did not respond, data were extracted from the graph. Discrepancies between the two authors were resolved by discussion with the third author (A.S.H.). The primary outcomes of this meta-analysis were pain scores and opioid consumption at 2 and 24 h. Secondary outcomes were duration of PACU and hospital stay, incidence of persistent pain at 1, 3, 6, and 12 months, preoperative anxiety scores, and side-effects.

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Analyses performed for the research questions and synthesis of data Acute pain outcomes In studies involving different doses of pregabalin, we combined all pregabalin doses for the main analysis assessing the impact of pregabalin administration on postoperative pain scores and opioid consumption. Visual analogue scale (VAS) scores for pain reported as 0 – 100 was converted to the 0 – 10 scale for analysis (0, no pain; 10, worst possible pain). Opioids were converted to morphine equivalents (ME) for analysis using a conversion factor of 3:1 for oxycodone,18 0.15:1 for parenteral hydromorphone,18 10:1 for fentanyl,18 20:1 for codeine,18 10:1 for tramadol,5 and 1:1 for both ketobemidone19 and piritramide.20 If ketorolac was the only analgesic used, it was converted to ME using a conversion factor of 3:1.21 If results were not reported at the time points specified in this analysis, those recorded close to those time points were used instead. To evaluate different pregabalin dosing regimens, we performed subgroup analyses for pain scores and opioid consumption at 2 h after operation according to the individual dose of pregabalin administered before surgery (≤75, 100 – 150, and 300 mg). For pain scores and opioid consumption at 24 h, we performed a subgroup analysis according to the dose and frequency of administration of pregabalin comparing the three dose levels (≤75, 100– 150, and 300 mg) and single vs multiple dosing at each dose level. Single dosing refers to studies that administered a single preoperative dose of pregabalin, while multiple dosing refers to studies that used at least one postoperative dose of pregabalin in addition to the preoperative dose or administered more than one preoperative dose. We also performed sensitivity analyses according to the type of surgery and type of anaesthesia (general vs regional) for the primary outcomes of pain scores and opioid consumption at 2 and 24 h. To evaluate predictors that could impact our primary outcomes, we also performed a metaregression using pregabalin dose, type of surgery, and type of anaesthesia (general or regional) as predictors for the 2 h outcomes. The frequency of administration of pregabalin (single vs multiple dosing) was used as an additional predictor for 24 h outcomes.

Preoperative anxiety We pooled preoperative anxiety scores after administration of pregabalin compared with placebo. VAS scores for anxiety reported as 0–100 were converted to the 0–10 scale for analysis.

Side-effects of perioperative pregabalin administration We pooled adverse effects after administration of pregabalin compared with placebo. If an event rate was reported over multiple time intervals instead of the entire duration of the study, the highest recorded incidence over the duration of the study was used in the analysis. Sedation was defined as scores 3 – 6 on the Ramsay sedation scale (1, patient is anxious and agitated or restless; 2, patient is co-operative,


We followed the recommendations of the PRISMA statement.16 We searched MEDLINE (1966 – 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE (1947 – 2014), and CINAHL for randomized controlled trials (RCTs) that compared pregabalin with control in patients undergoing surgery. Databases were searched using the term ‘pregabalin’ combined with the MESH terms: ‘Pain, postoperative’, ‘Postoperative period’, ‘Pain, acute’, ‘Pain, chronic’, ‘Opioids’, and ‘Analgesics, opioid’. The search was performed without language restriction. The last literature search was done on March 31, 2014. We also searched the bibliographies of retrieved articles for additional studies. Reviews, abstracts, letters to the editor, and retrospective studies were not included. Articles were included if pregabalin was administered before operation and pain scores, opioid consumption, incidence of persistent pain, and/or time to first analgesia were reported. We excluded studies where pregabalin administration was initiated after operation, the endpoints of interest were not reported or if a placebo group was not included. The articles meeting the inclusion criteria were assessed separately by two authors (B.M.M. and N.H.W.) using the risk of bias table suggested by the Cochrane Collaboration.17 A data collection sheet was created and two authors (B.M.M. and N.H.W.) extracted data on:

Mishriky et al.

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Pregabalin and postoperative pain

Persistent pain We compared the incidence of persistent pain at 1, 3, 6, and 12 months after surgery after pregabalin vs placebo administration. We also compared pain scores at 1 and 3 months after surgery between pregabalin and placebo. Continuous data were summarized as mean difference (MD) with 95% confidence interval (CI). If the 95% CI included a value of 0, we considered that the difference between pregabalin and placebo was not statistically significant. Dichotomous data were summarized as relative risk (RR) with 95% CI. If the 95% CI included a value of 1, we considered the difference not statistically significant. If the pooled results were not statistically significant and the CIs included values that exceeded a 30% difference in the pregabalin group compared with the control group, we considered that no conclusion could be derived from the pooled results due to the wide CIs. Analyses were performed using the Review Manager (RevMan), Version 5.1, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011, and Comprehensive Meta-Analysis Software (version 3.0). A random effects model (which assumes that the effects being estimated in the different studies are not identical, but follow some distribution) was used.17 We assessed heterogeneity using the I 2-test. Heterogeneity was assumed to be present if the I 2 was .50%. Forest plots were used to graphically represent and evaluate treatment effects. Subgroup analysis was performed using the Q-test. We assessed for publication bias for the primary outcomes using the Egger’s test.22 We also performed a sensitivity analysis for the primary outcomes after removing papers with an unclear or high risk of bias. To exclude a small study effect, we compared the results of the random effects and fixed effect models for our primary outcomes. We assessed the proportion of the total variance explained by each of the covariates (R 2) included in the meta-regression (pregabalin dose, frequency of administration, type of anaesthesia, and type of surgery) for the primary outcomes. Meta-regression was performed using the method of moments.

Results Six hundred and ninety-five studies were assessed for inclusion in this review (Fig. 1). Fifty-five studies6 – 15 23 – 67 with 4155 patients (2270 received pregabalin and 1885 served as control) were included in the final analysis. Additional data from 16 studies13 – 15 24 – 27 36 37 40 – 42 46 48 50 57 were provided by the authors. Forty-nine studies investigated acute pain,7 – 11 13 – 15 23 – 29 31 – 57 59 61 – 64 66 68 and 10 chronic pain.6 – 15 The characteristics of the included studies are shown in Table 1. The risk of bias of the included studies is shown in Table 2.

Primary outcomes Pain scores Pain scores at 2 h Pain scores at rest at 2 h (Fig. 2) were investigated in 339 – 11 13 – 15 24 27 28 34 – 38 40 – 44 46 49 51 – 57 61 – 63 66 68 studies and during movement in 149 – 11 13 14 29 36 37 40 – 42 44 51 57 studies. Pooled results showed a statistically significant reduction in pain scores at rest [MD (95% CI)¼ 20.81 (21.07, 20.51, I 2 ¼88%)] and during movement [MD (95% CI)¼ 20.58 (20.94, 20.21, I 2 ¼82%)] in pregabalin-treated patients. There was no evidence of publication bias for pain scores at rest or movement (P¼0.07 and 0.71, respectively). For pain scores at rest, 9% of the total variance was explained by the dose of pregabalin used, 11% by the type of surgery, and 1% by the type of anaesthesia. For pain scores on movement, 16% of the total variance was explained by the dose of pregabalin, 10% by type of surgery, and none was explained by type of anaesthesia. In subgroup analysis, pain scores at rest were reduced with all doses of pregabalin (Fig. 2). Pain scores with movement were only reduced with the 300 mg dose. There were no significant differences between the three dose groups for pain at rest (P¼0.95) or with movement (P¼0.29). Sensitivity analysis according to type of surgery showed a reduction in pain scores at rest for all types of surgery except minor surgery and cardiac surgery (Table 3). Pain scores on movement were only reduced in open abdominal and head and neck surgeries. Pain scores at rest and on movement were reduced in studies using general anaesthesia but not regional anaesthesia. The meta-regression found type of surgery (P¼0.02), but not pregabalin dose (P¼0.74) or type of anaesthesia (0.16) to be a significant predictor of 2 h pain scores at rest. The type of anaesthesia was a significant predictor of pain scores on movement at 2 h (P¼0.046), but not type of surgery (P¼0.10) or pregabalin dose (0.81). Pain scores at 24 h

Pain scores at rest at 24 h (Fig. 3) were investigated in 40 studies7 9 – 11 13 – 15 23 26 – 28 31 32 34 – 38 40 – 57 59 62 64 66 and during movement in 18 studies.7 9 – 11 13 14 23 29 31 36 37 40 – 42 46 51 57 59 Pooled results showed a statistically significant reduction in pain scores at rest [MD (95% CI)¼20.38 (20.57, 20.20, I 2 ¼77%)] and during movement [MD (95% CI)¼20.47 (20.76, 20.18, I 2 ¼70%)] with the perioperative administration of pregabalin. There was no evidence of publication bias (P¼0.94 and 0.65 for pain scores

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oriented, and tranquil; 3, patient responds to commands only; 4, patient exhibits brisk response to light glabellar tap or loud auditory stimulus; 5, patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus; 6, patient exhibits no response), 2 – 5 on the five-point scale (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), and 2 – 4 on the four-point scale (1, awake; 2, mild sedation; 3, sleepy but rousable; and 4, very sleepy), while severe sedation was considered for scores 4 – 6, 4 – 5, and 3 – 4 on the Ramsay, five-point scale, and four-point scale, respectively. In studies investigating sedation on the four-point scale (none, mild, moderate, and severe), sedation was defined as any sedation (mild, moderate, or severe). If sedation was not reported, somnolence or drowsiness was used instead for the analysis.

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Mishriky et al.

Literature search Databases: MEDLINE, EMBASE, CENTRAL, and CINAHL Last date of search: 03/31/2014

695 studies were identified

82 studies assessed for inclusion 24 Excluded 6 Full text could not be obtained 6 No control group 4 Endpoints other than specified by our analysis 2 Pregabalin administered postoperatively 2 Study completed but not published 1 Cross over study 1 Retracted 1 Retrospective study 1 Non-surgical

58 studies met the inclusion criteria 3 Excluded 2 Inconsistent data 1 Not reporting standard deviations 55 studies included in the final analysis

Fig 1 PRISMA flow chart detailing retrieved, excluded, assessed, and included trials.

at rest and on movement, respectively). For pain scores at rest, 1% of the total variance was explained by the dose of pregabalin used, 32% by the type of surgery, 0.28% by the frequency of pregabalin administration, and none was explained by the type of anaesthesia. For pain scores on movement, type of surgery explained 26% of the total variance and type of anaesthesia 0.22%. The dose of pregabalin and frequency of administration did not explain any of the total variance. In subgroup analysis, pain scores at rest were reduced with pregabalin doses ≥100 mg, but not ≤75 mg (Fig. 3), with no significant differences between dose levels (P¼0.87). When accounting for dosing frequency (Table 4), pain scores at rest were not reduced by any of the doses of pregabalin compared with placebo when given in single doses, but were reduced with

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multiple dosing of pregabalin ≤75 mg (P¼0.03) and 100–150 mg (P¼0.0001). There were no significant differences between single and multiple dosing at the ≤75 mg (P¼0.17), 100 –150 mg (P¼0.86), or 300 mg (P¼0.27) dose levels. Pain scores at rest were only reduced in open abdominal and head and neck surgeries (Table 3). Sensitivity analysis according to type of anaesthesia showed a reduction in pain scores at rest with general but not regional anaesthesia. The meta-regression found type of surgery (P¼0.008), but not type of anaesthesia (P¼0.21), pregabalin dose (P¼0.67), or pregabalin frequency (P¼0.61) to be a significant predictor of 24 h pain scores at rest. Pain scores on movement were reduced only with doses of 300 mg compared with placebo, but there were no significant differences between the three dose levels of pregabalin (P¼0.42). When accounting for dosing frequency (Table 3),


614 Excluded 254 Reviews 181 Duplicates 52 Conference abstract 48 Case-reports 32 Editorial, letter, or correspondence 27 Not studying pregabalin 7 Surveys 8 Animal studies 4 Practice guidelines 1 News letter

Participant characteristics

Interventions

Comparison

Outcomes

Surgery type

Anaesthesia

Postoperative analgesia

Experimental groups (n)

PGB administration time

Control group (n)

Primary outcome

Study follow-up

Acin and colleagues12

Mesh hernia repair

GA

Non-steroidal anti-inflammatory drugs

PGB 75 mg (70)

Multiple dosing: 75 mg at night for 3 days before operation and 75 mg at night till POD 12

Placebo (70)

Persistent pain

12 months

Agarwal and colleagues23

Laparoscopic cholecystectomy

GA

PCA fentanyl

PGB 150 mg (27)

Single dosing: 1 h before surgery

Placebo (29)

Pain scores and opioid consumption

24 h

Alimian and colleagues52

Dacrocystorhinostomy

GA

PRN opioid

PGB 300 (40)


Placebo (40)

Pain scores

24 h

Balaban and colleagues24


GA

I.V. fentanyl 25 mg as needed

PGB 150 mg (30); PGB 300 mg (30)


Placebo (30)


24 h

Bekawi and colleagues53


GA

I.M. meperidine and diclofenac PRN

PGB 150 mg (30)

Multiple dosing: 2 h before surgery and then every 12 h for 2 days

Placebo (30); gabapentin 1200 mg* (30)


24 h

Bornemann-Cimenti and colleagues25

Transperitoneal nephrectomy

GA

PCA piritramide

PGB 300 mg (13)


Placebo (13)

Opioid consumption

48 h

Burke and Shorten7

Lumbar discectomy

GA

PACU: i.v. morphine; ward: regular oral codeine phosphate, paracetamol, and diclofenac+i.m. opioids (dihydrocodeine, tramadol, and morphine) for breakthrough pain

PGB 300 mg (18)

Multiple dosing: 300 mg 90 min before operation and 150 mg at 12 and 24 h after operation

Placebo (20)

Pain score up to 3 months after operation

3 months

Buvanendran and colleagues6

Total knee arthroplasty

GA

PCEA followed by oral opioids as needed to keep pain score ,4

PGB 300 mg (120)

Multiple dosing: 300 mg 1– 2 h before surgery, 150 mg twice daily for 10 days, 75 mg twice daily on days 11 and 12, and 50 mg twice daily on days 13 and 14

Placebo (120)

Neuropathic pain at 6 months

6 months

Continued

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Reference


Table 1 Characteristics of included studies. n, number of patients in the group; PGB, pregabalin; GA, general anaesthesia; POD, postoperative day; Dex, dexamethasone; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; VAS, verbal analogue scale; NSAID, non-steroidal anti-inflammatory drug; PACU, post-anaesthesia care unit; ICU, intensive care unit; CSE, combined spinal – epidural. *Group not included in the analysis

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Interventions

Comparison

Outcomes

Surgery type

Anaesthesia




Control group (n)

Primary outcome

Study follow-up


Total knee replacement

Spinal

Patient-controlled intrathecal analgesia

PGB 150 mg multi-dose (16); PGB 150 mg single dose (16)

1 h before surgery (single and multiple dosing groups)+150 mg at 12 and 24 h in multi-dose group

Placebo (16)

Level of spinal neurotransmitters

32 h

Cabrera Schulmeyer and colleagues27

Laparoscopic sleeve gastrectomy

GA

Infusion of ketoprofen 300 mg 24 h21 +i.v. morphine as rescue therapy

PGB 150 mg (39)


Placebo (40)

Opioid consumption

24 h

Chang and colleagues28


GA

I.V. ketorolac 30 mg as needed

PGB 300 mg (39)

Multiple dosing: 1 h before induction of anaesthesia and 12 h after the initial dose

Placebo (38)

Shoulder pain and abdominal pain

48 h

Clendenen and colleagues32

Arthroscopic rotator cuff repair

GA

Oral celecoxib, oxycodone, and paracetamol 325 mg every 4– 6 h as needed

PGB 150 mg (23)

Multiple dosing: 150 mg before sedation then every 12 h for a total of 4 doses

Placebo (24)

Opioid consumption

48 h

Chaparro and colleagues29

Liposuction+ augmentation mammoplasty/ abdominoplasty

GA

PACU: i.v. morphine; then: oral paracetamol and codeine or tramadol or hydrocodone+ibuprofen or diclofenac for rescue

PGB 75 mg (50)

Multiple dosing: 75 mg the night before surgery and 1 h before surgery, then every 12 h through POD 4

Placebo (49)

Pain score during movement

96 h

Choi and colleagues31

Lumbar spinal surgery

GA

Continuous infusion of i.v. fentanyl until 48 h+i.v. ketorolac 30 mg for VAS pain ≥5

PGB 150 mg+placebo (36); PGB 150 mg+Dex* (36)

Multiple dosing: 1 h before surgery and every 12 h after initial dose until POD 3

Placebo (36)

Pain scores and need for rescue analgesia

6 months

Demirhan and colleagues55

Rhinoplasty

GA

Tramadol PCA



Placebo (20)

Opioid consumption and pain scores

24 h

El Rahmawy and colleagues65

Elective general surgeries below the umbilicus (inguinal hernia, varicocele, varicose veins)

Spinal

I.M. diclofenac every 12 h

PGB 150 (43)


Placebo (43)

Incidence of post-dural puncture headache

24 h

Mishriky et al.

Reference


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Table 1 Continued

GA

PRN nalbuphine

PGB 300 mg (40)

Multiple dosing: 12 and 1 h before surgery

Placebo (40)

Postoperative pain scores

24 h

Fassoulaki and colleagues13

Abdominal hysterectomy or myomectomy

GA

First 2 days: PCA morphine, then oral codeine with paracetamol as needed

PGB 150 mg (39)

Multiple dosing: 8 hourly administration starting on the day before surgery and continued to POD 5

Placebo (41)

Opioid consumption

3 months

George and colleagues57

Abdominal hysterectomy

GA

PCA morphine, scheduled oral NSAID

PGB 75 mg (31); PGB 150 mg (28)

Multiple dosing: 2 h before surgery and 12 h after initial dose

Placebo (30)

Opioid consumption

24 h

Ghai and colleagues33


GA

I.M. diclofenac sodium; i.v. tramadol if pain not controlled

PGB 300 mg (30)

Single dosing: 1 –2 h before surgery


Opioid consumption

24 h

Ghoneim Hegazy58

Cystectomy with urinary diversion

GA

Morphine PCA and i.v. paracetamol

PGB 75 mg (30)

Multiple dosing: 75 mg every 12 h for 10 days before surgery

Placebo (30)

Opioid consumption

48 h

Gianesello and colleagues14

Major spinal surgery

GA

Continuous infusion of morphine+ketorolac until 48 h after surgery, VAS ≥3: i.v. morphine

PGB 300 mg (30)

Multiple dosing: 300 mg 1 h before surgery then 150 mg twice daily for 48 h

Placebo (30)

Opioid consumption

48 h

Gonano and colleagues34

Minor orthopaedic surgery

GA

PACU: i.v. piritramide; after PACU: oral mefenamic acid

PGB 300 mg (20)

Single dosing: at least 1 h before surgery

Placebo (20)

VAS anxiety immediately before anaesthesia induction

24 h

Ittichaikulthol and colleagues35


GA

PACU: i.v. morphine; ward: PCA morphine

PGB 300 mg (38)


Placebo (40)

Pain scores

24 h

Jain and colleagues59

Unilateral total knee arthroplasty

Epidural

Bupivacaine/morphine PCEA, oral diclofenac rescue

PGB 75 (20)

Multiple dosing: 75 mg twice daily starting preop and continued through POD2

Placebo (20)

PCEA morphine use

48 h

Jo and colleagues11


GA

PACU: i.v. fentanyl; after PACU: PCA fentanyl

Remifentanil –PGB 150 mg (20)


Remifentanil (20); placebo* (20)

PACU opioid consumption

48 h

Jokela and colleagues36

Day-case gynaecological laparoscopic surgery

GA

I.V. fentanyl (in PACU) or oral paracetamol and codeine (after PACU) as needed

PGB 75 mg (30); PGB 150 mg (26)


Placebo (28)


24 h


Laparoscopic hysterectomy

GA

I.V. oxycodone then PCA oxycodone until next morning, then oral ibuprofen and paracetamol/codeine for breakthrough pain

PGB 150 mg (27); PGB 300 mg (29)

Multiple dosing: 1 h before surgery and 12 h after the initial dose

Placebo (29)


5 days

Continued

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Shoulder arthroscopy



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Eskandar and Ebeid56

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Interventions

Comparison

Outcomes

Surgery type

Anaesthesia




Control group (n)

Primary outcome

Study follow-up

Joshi and Jagadeesh9

Off-pump coronary artery bypass grafting

GA

I.V. paracetamol every 6 h, breakthrough pain treated with tramadol first, then i.v. diclofenac

PGB 150 mg (20)

Multiple dosing: 150 mg before operation, then 75 mg every 12 h for 2 postoperative days

Placebo (20)

Pain scores

3 months

Khurana and colleagues60

Lumbar discectomy

GA

I.V. tramadol for breakthrough pain

PGB 75 mg (30)

Multiple dosing: 75 mg before operation, then 75 mg every 8 h for 7 postoperative days


Pain scores

3 months

Kim and colleagues15

Robot-assisted endoscopic thyroidectomy

GA

PACU: i.v. fentanyl; ward: i.m. tramadol

PGB 150 mg (47)


Placebo (47)

Pain scores

48 h


Mastectomy

GA

PACU: i.v. fentanyl; ward: i.m. tramadol

PGB 75 mg (42)


Placebo (42)

Pain scores on movement

48 h


Lumbar spinal fusion surgery

GA

PCA fentanyl+ketorolac

PGB 75 mg (28); PGB 150 mg (28)

Multiple dosing: 1 h before surgery and 12 h after surgery

Placebo (28)

Analgesic consumption, pain scores, and need for rescue analgesics

48 h

Kohli and colleagues39

Hysterectomy

Spinal

Not reported

PGB 150 mg (50); PGB 300 mg (50)


Placebo (50)

VAS anxiety scores

24 h

Koyuncu and colleagues54

Modified radical mastectomy

GA

PCA morphine

PGB 150 (30)

Multiple dosing: 150 mg preop and 75 mg 12 h postop

Placebo (30)


12 h

Kumar and colleagues61

Lumbar discectomy

GA

I.V. fentanyl, i.v. diclofenac, or both for breakthrough pain

PGB 150 (25); tramadol 100 (25)*

Single dosing: 1 h before operation

Placebo (25)

Pain scores

6h

Lee and colleagues62

Laparoscopic urologic surgery

GA

PCA with solution containing morphine, ketorolac, and 5-HT3 antagonist

PGB 300+high dose (0.3 mg kg21 min21) remifentanil (31)


High-dose remifentanil (0.3 mg kg21 min21) (29); low-dose remifentanil (0.05 mg kg21 min21)* (30)

Pain scores, PCA use, and hyperalgesia

24 h

Martinez and colleagues63

Total hip arthroplasty

GA

Morphine PCA

PGB 150 mg (35); PGB 150 mg+intraoperative ketamine (35)*; Intraoperative ketamine (34)*


Placebo (38)

Pain scores

48 h

Mishriky et al.

Reference


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Table 1 Continued

Tonsillectomy

GA

Paracetamol+i.v. morphine and oral ketobemidone upon patient request

Paracetamol+PGB 300 mg+placebo (45); paracetamol+PGB 300 mg+Dex* (43)


Paracetamol+placebo +placebo (43)

Pain during swallowing at 2 h

24 h

Mathiesen and colleagues42


GA

PACU: i.v. morphine; after PACU: regular paracetamol+PCA morphine

Paracetamol+PGB 300 mg+placebo (43); Paracetamol+PGB 300 mg+Dex* (42)


Paracetamol+placebo +placebo (43)

Opioid consumption

24 h


Hip arthroplasty

Spinal

Regular oral paracetamol+PCA morphine



Placebo+placebo (42)

Opioid consumption

24 h

Nutthachote and colleagues64

Laparoscopic gynaecologic surgery

GA

Scheduled oral NSAID, oral paracetamol, and i.v. meperidine for breakthrough pain

PGB 75 mg (27)

Multiple dosing: 2 h before surgery and every 12 h for total of three doses

Placebo (27)

Pain scores (shoulder)

48 h

Ozgencil and colleagues43

Lumbar laminectomy and discectomy

GA

PCA morphine

PGB 150 mg (30)

Multiple dosing: 2 h before surgery and every 12 h from initial dose for 2 days


Opioid consumption

24 h

Paech and colleagues68

Minor gynaecological surgery

GA

PACU: i.v. fentanyl then i.v. tramadol followed by oral diclofenac if target pain score not achieved. After discharge: paracetamol as needed

PGB 100 mg (45)


Placebo (45)

Pain scores

24 h

Peng and colleagues44


GA

PACU: i.v. fentanyl as needed; after PACU: paracetamol/ codeine orally upon request

PGB 50 mg (48); PGB 75 mg (48)

Multiple dosing: 1 h before surgery and every 12 h after initial dose for a total of 3 doses

Placebo (46)

Pain scores

7 days

Pesonen and colleagues8

Cardiac surgery

GA

ICU: i.v. oxycodone; ward: oral or i.m. oxycodone; after discharge: oral paracetamol

PGB 150 mg (32)

Multiple dosing: 150 mg 1 h before surgery then 75 mg every 12 h from POD 1 to POD 5

Placebo (32)

Opioid consumption

3 months

Sagit and colleagues66

Septoplasty

GA

I.M. diclofenac

PGB 75 mg (50); PGB 150 mg (46)


Placebo (47)

Pain scores

24 h

Sahu and colleagues45

Infra-umbilical surgeries

Spinal

Not reported

PGB 150 mg (35)

Multiple dosing: 12 and 1 h before surgery

Placebo (35)

Pain scores

24 h


Continued

BJA


Page 9 of 22


BJA


Interventions

Comparison

Outcomes

Reference

Surgery type

Anaesthesia




Control group (n)

Primary outcome

Study follow-up

Sarakatsianou and colleagues67


GA

PCA morphine

PGB 300 (20)

Multiple dosing: the night before surgery and immediately before operation

Placebo (20)

Pain scores

24 h

Spreng and colleagues46

Lumbar discectomy

GA

PCA morphine

PGB 150 mg (22)


Placebo (24)

Pain scores

24 h

Sundar and colleagues47

Off-pump coronary artery bypass grafting

GA

I.V. fentanyl

PGB 150 mg (30)


Placebo (30)

Haemodynamic response to intubation and opioid consumption

24 h

Wang and colleagues48

Bunionectomy

Regional

PCA hydromorphone then oral hydrocodone/ paracetamol

PGB 300 mg (32)

Multiple dosing: 300 mg 1 h before surgery then 150 mg every 8 h up to 40 h

Placebo (28); naproxen sodium* (29)

Opioid consumption and time to first PCA use

48 h

White and colleagues49

Elective ambulatory and short stay surgical procedures

GA

I.V. fentanyl

PGB 75 mg (27); PGB 150 mg (27); PGB 300 mg (27)

Single dosing: 60 –90 min before surgery

Placebo (27)

VAS anxiety

7 days

Yadeau and colleagues50

Foot or ankle surgery

Popliteal nerve block+CSE

PCA hydromorphone then oral oxycodone or hydrocodone or hydromorphone and paracetamol

PGB 100 mg (30)

Multiple dosing: 100 mg 1 h before surgery and 50 mg every 12 h for 3 days

Placebo (30)

Number of hours of moderate to severe pain

48 h

Yucel and colleagues51


GA

PCA morphine

PGB 150 mg (30); PGB 300 mg (30)

Multiple dosing: 4 h before surgery and at 12 h after operation

Placebo (30)

Opioid consumption

24 h

Mishriky et al.


Page 10 of 22

Table 1 Continued

BJA


Table 2 Risk of bias table. Low, low risk of bias; high, high risk of bias; unclear, unclear risk of bias Randomization sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective reporting

Acin and colleagues12

Unclear

High

High

High

Low

Low

Agarwal and colleagues23

Low

Low

Low

Low

Low

Low

Alimian and colleagues52

Unclear

Low

Low

Low

Low

Low

Balaban and colleagues24

Low

Low

Low

Low

Low

Low

Bekawi and colleagues53

Low

Low

Low

Low

Unclear

Low

Bornemann-Cimenti and colleagues25

Low

Low

Low

Low

Low

Low

Burke and Shorten7

Unclear

Low

Unclear

Unclear

Low

Low


Low

Low

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low

Cabrera Schulmeyer and colleagues27

Low

Unclear

Low

Low

Low

Low

Chang and colleagues28

Unclear

Low

Low

Low

Low

Low

Clendenen and colleagues32

Low

Low

Low

Unclear

Low

Low

Chaparro and colleagues29

Low

Low

Low

Low

Low

Low

Choi and colleagues31

Low

Low

Low

Low

Low

Low

Demirhan and colleagues55

Low

Low

Low

Low

Low

Low

El Rahmawy and colleagues65

Low

Low

Low

Low

Unclear

Low

Eskandar and Ebeid56

Low

Low

Low

Unclear

Low

Low

Fassoulaki and colleagues13

Low

Low

Low

Unclear

Low

Low

George and colleagues57

Low

Low

Low

Low

Low

Low

Ghai and colleagues33

Low

Low

Low

Low

Low

Low

Ghoneim and Hegazy58

Low

Low

Low

Low

Low

Low

Gianesello and colleagues14

Low

Low

Low

Low

Low

Low

Gonano and colleagues34

Low

Unclear

Low

Low

Low

Low

Ittichaikulthol and colleagues35

Unclear

Unclear

Low

Low

Low

Low

Jain and colleagues59

Low

Low

Low

Low

Low

Low

Jo and colleagues11

Low

Unclear

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low

Joshi and Jagadeesh9

Low

Low

Low

Low

Low

Low

Khurana and colleagues60

Low

Low

Low

Low

Unclear

Unclear


Unclear

Low

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low

Kohli and colleagues39

Low

Low

Unclear

Unclear

Low

Low

Koyuncu and colleagues54

Low

Low

Unclear

Unclear

Unclear

Unclear

Kumar and colleagues61

Low

Low

Low

Low

Low

Low

Lee and colleagues62

Unclear

Unclear

Unclear

Unclear

Low

Low

Martinez and colleagues63

Low

Low

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low


Low

Low

Low

Low

Low

Low

Nutthachote and colleagues64

Low

Low

Low

Low

Low

Low

Ozgencil and colleagues43

Low

Unclear

Low

Unclear

Low

Low

Paech and colleagues68

Low

Low

Low

Low

Low

Low

Peng and colleagues44

Low

Low

Low

Low

Low

Low

Continued

Page 11 of 22


Reference

BJA

Mishriky et al.

Table 2 Continued Randomization sequence generation

Allocation concealment

Pesonen and colleagues8

Low

Low

Low

Low

Low

Low

Sagit and colleagues66

Low

Unclear

Low

Low

Low

Low

Sahu and colleagues45

Low

Unclear

Unclear

Low

Low

Low

Sarakatsianou and colleagues67

Low

Low

Low

Low

Low

Low

Spreng and colleagues46

Low

Low

Low

Low

Low

Low

Sundar and colleagues47

Low

Unclear

Low

Low

Low

Low

Wang and colleagues48

Low

Low

Low

Low

Low

Low

White and colleagues49

Low

Low

Low

Low

Low

Low

Yadeau and colleagues50

Low

Low

Low

Low

Low

Low

Yucel and colleagues51

Low

Low

Low

Low

Low

Low

pain on movement was not reduced by anyof the doses of pregabalin compared with placebo when given in single doses, but were reduced by multiple doses at the ≤75 mg (P¼0.02) and 300 mg dose levels (P¼0.04). Multiple dosing was significantly more effective than single dosing at the ≤75 mg level (P¼0.02), but not at the 100– 150 mg (P¼0.39) or the 300 mg (P¼0.89) doses. Pain scores on movement were reduced in open abdominal, orthopaedic, and cardiac surgery (Table 3). Sensitivity analysis according to type of anaesthesia showed a reduction in pain scores with movement with general but not regional anaesthesia. None of the covariates was a significant predictor in the meta-regression model [type of surgery (P¼0.08), pregabalin dose (P¼0.14), pregabalin frequency (P¼0.27), and type of anaesthesia (P¼0.77)].

Opioid consumption Opioid consumption at 2 h Opioid consumption at 2 h (Fig. 4) was investigated in 23 studies.7 11 13 14 24 28 29 34 – 36 38 40 – 44 46 49 51 55 – 57 68 Pooled results showed a statistically significant reduction in opioid consumption [MD (95% CI)¼22.09 mg ME (22.87, 21.30, I 2 ¼94%)] with the administration of pregabalin. There was no evidence of publication bias (P¼0.83). Twenty per cent of the total variance was explained by the dose of pregabalin. Type of anaesthesia or surgery did not explain any of the total variance. In subgroup analysis, opioid consumption was reduced by the 100 –150 and 300 mg doses compared with placebo, but not the ≤75 mg dose (Fig. 4). This reduction was significantly different among the three groups (P¼0.005) with pairwise comparisons showing significantly lower opioid sparing in the ≤75 mg group compared with the 100 –150 mg (P¼0.001) and the 300 mg (P¼0.0007) groups, and no difference between the 100– 150 and 300 mg groups. Sensitivity analysis according to type of surgery showed a reduction in opioid consumption at 2 h in orthopaedic, open abdominal, and minor surgical procedures. Two hours opioid sparing was seen with general anaesthesia but not regional anaesthesia (Table 3). In the meta-regression model, pregabalin dose was

Page 12 of 22

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective reporting

a significant predictor of 2 h opioid consumption (P¼0.02), but not type of surgery (P¼0.34) or type of anaesthesia (0.34).

Opioid consumption at 24 h Opioid consumption at 24 h (Fig. 5) was investigated in 29 studies.8 11 13 14 23 25 27 – 29 33 35 – 38 40 – 44 46 – 48 50 51 54 – 58 Pooled results showed a statistically significant reduction in opioid consumption with the administration of pregabalin [MD (95% CI)¼ 28.27 mg ME (210.08, 26.47, I 2 ¼95%)]. There was no evidence of publication bias (P¼0.21). Fourteen per cent of the total variance was explained by the dose of pregabalin, 3% by the type of anaesthesia, whereas type of surgery and frequency of pregabalin administration did not explain any of the variance. In subgroup analysis, all doses of pregabalin reduced 24 h opioid consumption compared with placebo when given as a single preoperative dose or as multiple doses (Table 3). There were no statistically significant differences between administration of a single preoperative dose and administration of multiple doses for the ≤75 mg (P¼0.87), 100– 150 mg (P¼0.44), and the 300 mg (P¼0.66) dose levels. There were also no significant differences between the three dose levels of pregabalin when all studies were combined (P¼0.25, Fig. 5). Opioid consumption at 24 h was reduced in all types of surgery except minor surgical procedures and head and neck surgery. Pooled results of both general anaesthesia and regional anaesthesia studies showed a reduction in 24 h opioid consumption (Table 3). The type of anaesthesia was a significant predictor of 24 h opioid consumption (P¼0.0496) in the meta-regression model, but not type of surgery (P¼0.11), pregabalin dose (P¼0.92), or frequency of pregabalin administration (P¼0.26). Sensitivity analysis according to study risk of bias assessment Our sensitivity analysis showed no difference in primary outcomes when papers with unclear risk of bias7 11 – 13 15 27 28 32 34 35 39 43 45 – 47 52 – 54 56 60 62 65 66 in any of the risk of bias assessments were removed from the analysis.


Reference

BJA


Pregabalin Control Study or Subgroup Mean SD Total Mean SD Total Weight 1.1.1 Pregabalin 75 mg 4.1 2 31 2.2% George 5.4 2.2 30 30 2.81 1.37 Jokela BJA 2008 2.95 1.2 2.7% 28 Kim 2011 2.4% 42 6 2 5 2 42 Kim JC 2011 2 2.22 28 3 1.48 28 2.3% Peng 1.5 2.32 96 2 2.96 46 2.3% Sagit 4.46 2.19 50 5.72 2.19 47 2.4% White 4 3 27 4 3 27 1.6% Subtotal (95% Cl) 304 248 15.8% Heterogeneity: Tau2 = 0.17; Chi2 = 10.61, df = 6 (P = 0.10); I 2 = 43%

Mean Difference IV, Random, 95% Cl


–1.30 [–2.36, –0.24] 0.14 [–0.52, 0.80] –1.00 [–1.86, –0.14] –1.00 [–1.99, –0.01] –0.50 [–1.47, 0.47] –1.26 [–2.13, –0.39] 0.00 [–1.60, 1.60] –0.71 [–1.18, –0.23]

Test for overall effect: Z = 2.91 (P = 0.004)

–0.30 [–0.70, 0.10] –1.33 [–2.09, –0.57] –2.62 [–3.96, –1.28] –1.70 [–2.63, –0.77] –1.10 [–2.21, 0.01] –0.95 [–1.68, –0.22] –0.23 [–1.03, 0.57] 0.65 [–0.33, 1.63] –0.20 [–0.73, 0.33] –0.20 [–1.13, 0.73] 0.00 [–0.88, 0.88] –0.50 [–0.87, –0.13] –2.40 [–3.02, –1.78] –1.86 [–2.41, –1.31] 0.60 [–0.41, 1.61] –1.72 [–2.63, –0.81] –1.08 [–1.78, –0.38] 0.00 [–1.36, 1.36] –0.21 [–0.52, 0.10] –0.79 [–1.16, –0.42]


1.1.2 Pregabalin 100–150 mg 0.7 0.8 Balaban 30 30 1 0.8 3.0% 2.6% 30 3.73 1.7 30 2.4 1.28 Bekawi 1.8% 39 5.93 2.98 41 3.31 3.11 Cabrera Schulmeyer 2.3% 37 40 Fassoulaki 6.4 2.16 4.7 2.01 2.1% 30 28 George 5.4 2.2 4.3 2.1 2.6% 20 20 3.65 1.46 Jo 2.7 0.8 2.5% 28 26 2.81 1.37 Jokela BJA 2008 2.58 1.61 2.3% 29 27 2.53 1.71 Jokela Pain 2008 3.18 2.01 2.8% 20 Joshi 2.4 0.82 20 2.2 0.89 2.3% Kim 2010 5.7 2.1 47 47 5.5 2.5 2.4% Kim JC 2011 3 1.48 28 28 3 1.85 3.0% Koyuncu 2.5 0.74 30 30 2 0.74 2.7% 25 6.04 0.93 25 Kumar 3.64 1.28 2.8% 30 5.36 1.03 30 Ozgencil 3.5 1.13 2.2% 45 Paech 1 2.19 45 1.6 2.67 2.4% Sagit 47 46 5.72 2.19 4 2.3 2.6% Spreng 22 2.25 1.44 1.17 0.96 24 1.8% White 27 2 4 3 4 27 3.0% Yucel 30 6.23 0.56 6.02 0.66 30 Subtotal (95% Cl) 601 47.4% 587 Heterogeneity: Tau2 = 0.52; Chi2 = 105.20, df = 18 (P < 0.00001); I 2 = 83% Test for overall effect: Z = 4.16 (P < 0.0001) 1.1.3 Pregabalin 300 mg 2.7 1.4 5.4 1.6 2.7% 40 Alimian 40 0.3 0.7 3.0% 1 0.8 30 30 Balaban 2.5% 5.2 1.9 4.9 1.8 38 39 Chang 1 2.96 1 4.44 Demirhan 20 20 1.0% 5.8 1.32 4.65 1.53 40 40 2.7% Eskander 1.8 0.4 Gianesello 3.7 0.5 30 30 3.1% 2.7 1.1 Gonano 2.6 1.2 20 20 2.6% 3.8 1.9 lttichaikuthol 5.4 2.9 38 40 2.1% 2.38 1.8 Jokela Pain 2008 29 2.53 1.71 29 2.4% 5.48 0.89 Lee 31 5.76 0.91 29 2.9% 0.45 0.93 Mathiesen 2008 40 0.56 1.01 38 2.9% 3.83 2.2 Mathiesen 2009 39 4.03 2.04 40 2.3% 3.73 2.52 Mathiesen 2011 45 43 4.5 2.38 2.2% White 4 27 27 4 3 1.3% 4 4.37 0.49 Yucel 3.1% 30 6.23 0.56 30 36.8% 494 498 Subtotal (95% Cl) Heterogeneity: Tau2 = 0.74; Chi2 = 163.74, df = 14 (P < 0.00001); I 2 = 91%

–2.70 [–3.36, –2.04] –0.70 [–1.08, –0.32] 0.30 [–0.53, 1.13] 0.00 [–2.34, 2.34] –1.15 [–1.78, –0.52] –1.90 [–2.13, –1.67] 0.10 [–0.61, 0.81] –1.60 [–2.68, –0.52] –0.15 [–1.05, 0.75] –0.28 [–0.74, 0.18] –0.11 [–0.54, 0.32] –0.20 [–1.14, 0.74] –0.77 [–1.79, 0.25] 0.00 [–1.89, 1.89] –1.86 [–2.13, –1.59] –0.81 [–1.30, –0.32]

Test for overall effect: Z = 3.25 (P = 0.001) Total (95% Cl) 1389 1343 100.0% Heterogeneity: Tau2 = 0.65; Chi2 = 321.89, df = 40 (P < 0.00001); I 2 = 88% Test for overall effect: Z = 5.51 (P < 0.00001) Test for subgroup differences: Chi2 = 0.11, df = 2 (P = 0.95); I 2 = 0%

–0.79 [–1.07, –0.51] –4

–2

0

Favours pregabalin

2

4

Favours control

Fig 2 Forest plot for pain scores at rest at 2 h. SD, standard deviation; CI, confidence interval; IV, inverse variance.

Comparing random effects and fixed effect models for primary outcomes

Secondary outcomes

The fixed effect model yielded very comparable results with the random effects model for the primary outcomes of our review.

The duration of PACU stay was reported in four studies28 34 46 49 and duration of hospital stay or time to achieve hospital discharge criteria in five studies.6 8 14 32 49 There was no difference

Duration of PACU and hospital stay

Page 13 of 22

BJA

Page 14 of 22 Table 3 Sensitivity analysis according to type of surgery and type of anaesthesia. Data are MD (95% CI) (number of studies included in the analysis). ME, morphine equivalents; NA, not applicable; NE, not estimable Type of surgery or anaesthesia

Pain scores at rest at 2 h

Pain scores during movement at 2 h

Opioid consumption at 2 h (mg ME)

Pain scores at rest at 24 h

Pain scores during movement at 24 h

Orthopaedic surgery

21.13 (21.77, 20.48, I 2 ¼92%) (8)14 34 38 40 43 46

21.07 (22.73, 0.58, I 2 ¼95%) (2)14 40

21.99 (23.48, 20.49, I 2 ¼94%) (8)7 14 34 38 40 43 46 56

20.25 (20.52, 0.03, I 2 ¼53%) (14)7 14 26 31 32 34 38

20.65 (21.27, 20.02, 211.70 (215.41, 27.99, I 2 ¼69%) (6)7 14 40 46 59 31 I 2 ¼84%) (8)14 38 40 43 46 48 50 56

56 61

Open abdominal surgery

Opioid consumption at 24 h (mg ME)

40 43 46 48 50 56 59

21.05 (21.34, 20.76, I 2 ¼16%) (6)11 13 35 42 51 57

20.58 (20.85, 20.32, I 2 ¼0%) (5)11 13 42 51 57

23.13 (24.54, 21.72, I 2 ¼80%) (6)11 13 35 42 51 57

20.67 (21.12, 20.21, I 2 ¼73%) (7)11 13 35 42 51 45 57

20.31 (20.60, 20.02, I 2 ¼0%) (5)11 13 42 51 57

212.70 (217.41, 27.99, I 2 ¼94%) (9)11 13 33 35 42 51 25 57 58

Laparoscopic abdominal surgery

20.47 (20.90, 20.03, I 2 ¼70%) (8)24 27 28 36 37 44

20.00 (20.49, 0.49, I 2 ¼0%) (3)36 37 44

2

22.17 (24.98, 0.64, I ¼97%) (4)24 28 36 44

53 62

20.39 (20.84, 0.07, I 2 ¼83%) (9)23 27 28 37 44 36 53

20.05 (20.83, 0.73, I 2 ¼73%) (3)23 36 37

26.59 (211.65, 21.52, I 2 ¼90%) (6)23 27 28 36 37 44

62 64 2

2

Minor surgical procedures

0.38 (20.42, 1.18, I ¼0%) (2)49 68

NA

20.99 (21.78, 20.19, I ¼0%) (2)49 68

1.33 (0.42, 2.24, I 2 ¼NE) (1)49

NA

21.78 (26.98, 3.42, I 2 ¼83%) (2)29 36

Head and neck surgery

21.18 (22.23, 20.13, I 2 ¼83%) (5)15 41 52 55 66

21.71 (22.79, 20.63, I 2 ¼NE) (1)41

20.74 (22.11, 0.63, I 2 ¼83%) (2)41 55

20.94 (21.25, 20.64, I 2 ¼18%) (5)15 41 52 66 55

20.80 (21.80, 0.20, I 2 ¼NE) (1)41

22.29 (23.52, 21.06, I 2 ¼0%) (2)41 55

Cardiac surgery

20.20 (20.73, 0.33, I 2 ¼NE) (1)9

20.20 (20.52, 0.12, I 2 ¼NE) (1)9

NA

20.36 (21.22, 0.49, I 2 ¼91) (2)9 47

21.30 (21.88, 20.72, I 2 ¼NE) (1)9

23.87 (25.27, 22.47, I 2 ¼0%) (2)8 47

Breast and plastic surgery

20.60 (20.98, 20.21, I 2 ¼9%) (2)10 54

20.76 (23.21, 1.69, I 2 ¼94%) (2)10 29

0.00 (20.58, 0.58, I 2 ¼NE%) (1)10 29

20.49 (21.47, 0.49, I 2 ¼77%) (2)10 54

21.08 (22.94, 0.78, I 2 ¼89%) (2)10 29

0.48 (20.43, 1.40, I 2 ¼0%) (2)29 54

General anaesthesia

20.88 (21.17, 20.58, I 2 ¼86%) (32)9 – 11 13 – 15 24

20.69 (21.15, 20.23, I 2 ¼85%) (13)9 – 11 13 14

22.05 (22.89, 21.21, I 2 ¼94%) (22)7 11 13 14 24 28 29

20.40 (20.60, 20.20, I 2 ¼75%) (34)7 9 – 11 13 – 15 23

20.54 (20.90, 20.18, 28.04 (210.03, 26.05, I 2 ¼73%) (16)7 9 11 13 14 23 I 2 ¼95%) (26)8 11 13 14 23 25

27 28 34 – 38 41 – 44 46 49 51 – 57

29 36 37 41 42 44 51 57

34 – 36 38 41 – 44 46 49 51 55 – 57 68

27 28 31 32 34 – 38 41 – 44 46 47 49

29 31 36 – 38 41 42 46 51 57

61 – 63 66 68

20.11 (20.54, 0.32, I 2 ¼NE%) (1)40

20.21 (20.80, 0.38, I 2 ¼NE%) (1)40

2

20.70 (21.48, 0.08, I ¼NE) (1)40

20.71 (21.42, 0.00, I 2 ¼77%) (6)26 40 45 48 50 59

27 – 29 33 35 – 38 41 – 44 46 47 51 54 – 58

20.77 (21.89, 0.34, I 2 ¼74%) (2)40 59

219.24 (226.49, 211.98, I 2 ¼38%) (3)40 48 50

Mishriky et al.


Regional anaesthesia

51 – 57 62 64 66

BJA


Pregabalin Control Study or Subgroup Mean SD Total Mean SD Total Weight 2.1.1 Pregabalin 75 mg George 1.4 1.4 31 30 1.9 1.6 2.1% 2.4% jain 2.2 0.69 20 20 3.5 1.2 2.6% Jokela BJA 2008 1.29 1.01 30 0.81 0.98 28 2.2% Kim 2011 2 1.75 42 42 3 1.5 1.4% 3 2.22 28 28 3 2.22 Kim JC 2011 2.3% 3.17 1.21 27 2.84 1.21 27 Nutthachote 2.0% 3 2.59 96 46 4 2.22 Peng 2.5% 1.38 1.17 50 2.09 1.45 47 Sagit 1.6% 3 2 2 27 2 27 White Subtotal (95% Cl) 351 295 19.0% Heterogeneity: Tau2 = 0.46; Chi2 = 37.94, df = 8 (P < 0.00001); I 2 = 79%



–0.50 [–1.26, 0.26] –1.30 [–1.91, –0.69] 0.48 [–0.03, 0.99] –1.00 [–1.70, –0.30] 0.00 [–1.16, 1.16] 0.33 [–0.32, 0.98] –1.00 [–1.82, –0.18] –0.71 [–1.24, –0.18] 1.00 [–10.07, 2.07] –0.33 [–0.85, 0.18]

Test for overall effect: Z = 1.28 (P = 0.20)

2.1.3 Pregabalin 300 mg 2.5% 1.6 1.5 40 40 Alimian 0.6 0.8 1.4% 18 2.38 1.77 20 Burke 1.73 2.02 1.8 1.4 2.2% 39 38 Chang 2.1 1.8 0 2.96 20 20 Demirhan 0 0 2.8% 40 1.95 0.83 40 Eskander 2.1 0.79 0.5 0.5 2.9% 30 30 Gianesello 0.6 0.8 2.6 1.2 20 20 Gonano 2.6 1.2 2.1% 3.4 1.8 38 40 lttichaikuthol 2 1.3 2.2% 29 1.11 1.37 29 Jokela Pain 2008 0.86 1.06 2.3% 31 2.38 0.68 Lee 29 1.42 0.5 2.9% 40 1.29 1.29 38 Mathiesen 2008 1.28 1.12 2.5% 35 1.65 1.8 39 Mathiesen 2009 1.39 1.78 2.0% 45 4.67 2.83 43 Mathiesen 2011 3.71 2.56 1.5% 32 5.12 1.54 28 Wang 4.08 1.5 2.1% 2 3 27 27 White 4 2 1.2% 30 1.73 0.9 30 Yucel 1.47 0.5 2.8% Subtotal (95% Cl) 514 511 33.3% Heterogeneity: Tau2 = 0.28; Chi2 = 66.36, df = 14 (P < 0.00001); I 2 = 79% Test for overall effect: Z = 2.02 (P = 0.04) 1555 1497 100.0% Total (95% Cl) Heterogeneity: Tau2 = 0.29; Chi2 = 200.02, df = 46 (P < 0.00001); I 2 = 77% Test for overall effect: Z = 4.02 (P < 0.0001) Test for subgroup differences: Chi2 = 0.29, df = 2 (P = 0.87); I 2 = 0%

–1.50 [–2.71, –0.29] –0.53 [–0.85, –0.21] 0.12 [–1.29, 1.53] –1.33 [–2.29, –0.37] –1.00 [–2.08, 0.08] –0.80 [–2.26, 0.66] –0.60 [–1.44, 0.24] –0.80 [–1.52, -0.08] –0.10 [–0.53, 0.33] 0.56 [–0.05, 1.17] 0.36 [–0.38, 1.10] –0.80 [–1.17, –0.43] –0.60 [–1.07, –0.13] 0.00 [–0.99, 0.99] 0.00 [–0.63, 0.63] –0.40 [–0.90, 0.10] –1.76 [–2.22, –1.30] –1.96 [–2.90, –1.02] –0.26 [–1.11, 0.59] 0.07 [–0.28, 0.42] 1.00 [–0.07, 2.07] 0.40 [–0.91, 1.71] –0.16 [–0.55, 0.23] –0.44 [–0.71, –0.16]


2.1.2 Pregabalin 100–150 mg 29 1.4% 3.5 2.96 27 Agarwal 2 1.48 30 2.9% 30 1.13 0.63 0.6 0.62 Bekawi 16 1.1% 32 3.32 2.55 3.44 1.9 Buvanendran 2012 2.1 2.83 41 1.7% 0.77 1.33 39 Cabrera Schulmeyer 3 2.96 36 1.5% 2 1.48 36 Choi 3.9 2.7 24 1.1% 3.1 2.4 Clendenen 23 3.1 1.79 39 1.9% 2.5 1.92 Fassoulaki 36 1.9 1.6 30 1.1 1.2 2.1% George 28 1.7 0.7 1.6 0.7 20 2.7% Jo 20 1.37 1.26 28 2.4% Jokela BJA 2008 26 0.81 0.98 1.47 1.46 Jokela Pain 2008 29 2.1% 27 1.11 1.37 1 0.59 1.8 0.59 Joshi 20 2.8% 20 1.6 1.1 2.2 1.2 Kim 2010 2.6% 47 47 3 1.48 3 2.22 K1mJC 2011 28 1.7% 28 1 0.96 Koyuncu 1 1.48 30 2.3% 30 Ozgencil 1.5 0.77 1.1 1.18 30 2.6% 30 Sagit 0.33 0.66 46 2.09 1.45 2.7% 47 Sahu 1.97 1.75 35 3.93 2.24 1.8% 35 Spreng 2.36 1.53 22 2.62 1.39 1.9% 24 Sundar 2.07 0.74 2 0.64 30 2.8% 30 White 3 2 27 2 1.6% 27 2 YaDeau 3.4 2.4 3 1.9 21 1.2% 21 Yucel 1.57 0.6 30 1.73 0.9 30 2.8% Subtotal (95% Cl) 690 691 47.8% Heterogeneity: Tau2 = 0.29; Chi2 = 94.68, df = 22 (P < 0.00001); I 2 = 77% Test for overall effect: Z = 3.14 (P = 0.002)

–1.00 [–1.53, –0.47] –0.65 [–1.86, 0.56] 0.30 [–0.42, 1.02] Not estimable 0.15 [–0.21, 0.51] 0.10 [–0.24, 0.44] 0.00 [–0.74, 0.74] –1.40 [–2.09, –0.71] –0.25 [–0.88, 0.38] –0.96 [–1.26, –0.66] –0.01 [–0.55, 0.53] –0.26 [–1.08, 0.56] –0.96 [–2.09, 0.17] –1.04 [–1.81, –0.27] 2.00 [0.64, 3.36] –0.26 [–0.63, 0.11] –0.33 [–0.65, –0.01]

–0.38 [–0.57, –0.20] –2

–1

Favours pregabalin

0

1

2

Favours control

Fig 3 Forest plot for pain scores at rest at 24 h. SD, standard deviation; CI, confidence interval; IV, inverse variance.

Page 15 of 22

BJA

Page 16 of 22

7.79 (1.02, 59.37), I 2 ¼NE%, (2)28 67 2.03 (0.85, 4.87), I 2 ¼61%, (4)39 – 42 38 57

2.72 (1.05, 7.02), I 2 ¼0%, (5)11 23 26 27 39 0.50 (0.03, 7.41), I 2 ¼NE%, (2)38 57

2.50 (0.35, 17.97), I 2 ¼NE%, (3)26

3.36 (1.25, 9.07), I 2 ¼0%, (2)6 7 1.25 (0.55, 2.87), I 2 ¼66%, (4)32 43

50 57

1.41 (0.85, 2.34), I 2 ¼19%, (5)11 23 24 27 39 1.00 (0.83, 1.21), I 2 ¼22%, (3)44 57 60

1.73 (1.02, 2.94), I 2 ¼94%, (9)24 33 34 39 – 42 52 67

28.66 (212.18, 25.14), I 2 ¼90%, (6)14 28 37 48 51 56 27.51 (210.56, 24.45), I 2 ¼77%, (9)8 13 37 38 43 50 51 54 57 210.01 (215.58, 24.45), I 2 ¼75%, (6)11 23 27 36 46 47 25.28 (29.98, 20.57), I 2 ¼96%, (5)29 38 44 57 58

210.02 (214.91, 25.14), I 2 ¼97%, (7)25 33 35 40 – 42 55

20.27 (20.51, 20.02), I 2 ¼0%, (4)7 14 37 51 20.22 (20.82, 0.39), I 2 ¼14%, (3)40 – 42 20.67 (21.41, 0.07), I ¼82%, (6)9 13 31 37 51 57 20.23 (20.91, 0.45), I 2 ¼59%, (4)11 23 36 46 21.08 (21.89, 20.27), I 2 ¼72%, (4)10 29 57 59

56

0.23 (20.48, 0.94), I 2 ¼NE%, (1)36

24.75 (29.20, 20.30), I 2 ¼NE%, (1)36

NA

NA

Pain scores with movement, 0 –10 scale

Opioid consumption, mg morphine equivalents

Sedation

Severe sedation

2

55 62 54 57 49 66

20.13 (20.40, 0.15), I 2 ¼49% (7)7 14 28 37 48 51 20.45 (20.96, 0.05), I 2 ¼80% (9)34 35 40 – 42 49 52 20.47 (20.70, 20.23) I 2 ¼50% (15)9 13 15 26 31 32 37 38 43 45 50 51 53 20.40 (21.07, 0.27), I 2 ¼89% (8)11 23 27 36 46 47 20.61 (21.16, 20.05), I 2 ¼69% (6)10 38 44 57 59 64

Multiple dosing Single dose Multiple dosing Single dose Multiple dosing

0.19 (20.79, 1.18), I 2 ¼85%, (3)36 49 66

Single dose

Persistent pain Four studies9 10 13 15 reported VAS pain scores at 1 month with no difference in pooled results between the groups [MD (95% CI)¼0.04 (20.34, 0.26, I 2 ¼70%)]. VAS pain scores at 3 months at rest were investigated in three studies7 9 13 and during movement in two studies7 9 with no statistically significant differences between the groups. The incidence of persistent pain at 1, 3, 6, and 12 months were reported in four,8 11 – 13 six,6 8 11 13 – 15 two,6 12 and two12 14 studies, respectively. Two studies specified that the pain was neuropathic,6 12 while the other five studies8 10 11 13 14 reported the presence of persistent pain without specifying the type. Both studies specifying that the pain was neuropathic reported a significant reduction in the incidence of neuropathic pain with pregabalin at 3,6 6,6 12 and 1212 months. Pooled results showed a statistically significant reduction in the incidence of pain at 6 (4 vs 15%) and 12 months (9 vs 20%) with pregabalin administration [RR (95% CI)¼0.31 (0.10, 0.92, I 2 ¼15%) and 0.47 (0.23, 0.97, I 2 ¼0%), respectively], while at 1 and 3 months, no conclusion can be made due to the wide CIs of the pooled results [RR (95% CI)¼0.65 (0.27, 1.56, I 2 ¼81%) and 0.73 (0.40, 1.33, I 2 ¼41%), respectively]. Excluding studies with a higher baseline risk of persistent pain13 14 did not change the overall results. For the 3 month assessment, excluding the one study reporting neuropathic pain6 abolished the heterogeneity but did not change the overall pooled results [RR (95% CI)¼0.88 (0.60, 1.30, I 2 ¼0%)]. Excluding one study with a high risk of bias12 leaves only one study for the 6 and 12 month assessments. For the 6 month assessment, the study by Buvanendran and colleagues6 reported a statistically significant reduction in the incidence of neuropathic pain with pregabalin (P¼0.014), while at 12 months, the study by Gianesello and colleagues14 did not report a reduction in the incidence of pain in pregabalintreated patients.

Side-effects

Pain scores at rest, 0 –10 scale

Pregabalin 300 mg Pregabalin 100 – 150 mg Pregabalin ≤75 mg Outcome

between the groups in the duration of PACU stay [MD (95% CI)¼22.05 min (29.76, 5.66, I 2 ¼66%)]. On the other hand, pregabalin-treated patients had a shorter hospital stay or achieved hospital discharge criteria 13.75 h earlier than those receiving placebo (95% CI¼223.26, 24.24, I 2 ¼97%).

Side-effects are presented in Table 5. Sedation, severe sedation, and dizziness at 24 h, and visual disturbance up to 24 h were significantly more common in pregabalin-treated patients. At 0–2 h, no conclusion could be reached about those outcomes due to the wide CIs of the pooled results. On the other hand, the administration of pregabalin was associated with a lower incidence of postoperative nausea and vomiting (PONV) and pruritus at 24 h when compared with control. Sedation scores at 2 and 24 h were reported using a VAS scale in seven8 24 43 47 49 56 58 and seven8 23 43 47 48 51 56 studies, respectively, with pregabalin being associated with significantly more sedation at 2 h, but not at 24 h [MD (95% CI)¼0.62 (0.19, 1.05, I 2 ¼85%) and 20.06 (20.29, 0.18, I 2 ¼82%), respectively]. The risk of sedation and severe


Table 4 Impact of single and multiple dosing regimens of different doses of pregabalin on 24 h outcomes. Data are MD or RR (95% CI) (number of studies included in the analysis); NA, not applicable; NE, not estimable

Mishriky et al.

BJA


Pregabalin Control Study or Subgroup Mean SD Total Mean SD Total Weight 1.4.1 Pregabalin 75 mg 50 1.48 4.6% Chaparro 2 1.48 2 49 George 17.7 7.8 31 17.2 6.3 30 2.4% 30 18.6 Jokela BJA 2008 16.3 7.7 28 1.7% 10.7 Kim JC 2011 6.1 2.89 28 6.95 2.44 28 4.1% 46 Peng 1.95 1.41 96 3 0.81 4.6% White 8.4 7.1 27 9.3 7.6 27 2.2% Subtotal (95% Cl) 262 208 19.5% Heterogeneity: Tau2 = 0.24; Chi2 = 9.82, df = 5 (P = 0.08); I 2 = 49% Test for overall effect: Z = 1.83 (P = 0.07)

1.4.3 Pregabalin 300 mg Balaban 1.49 1.04 30 7.33 1.62 30 4.5% Burke 1.55 2.1 18 3.3 3.8 20 3.7% Chang 5.4 5.03 39 5.8 6.43 38 3.1% Demirhan 2 1.48 20 2 1.48 20 4.4% Eskander 10 1.03 40 14.4 1.01 40 4.6% Gianesello 2.3 1.5 30 3.5 1 30 4.6% 4 3 20 3.9% 2 20 Gonano 2 Ittichaikuthol 3.5 2.25 38 8 1 40 4.5% Mathiesen 2009 16.6 5.86 39 18.2 6.47 40 3.0% Mathiesen 2011 1.1 1.32 45 2.5 1.71 43 4.6% White 8.1 13.2 27 9.3 7.6 27 1.3% 11.37 2.17 30 4.4% 30 14.77 1.45 Yucel Subtotal (95% Cl) 376 378 46.6% Heterogeneity: Tau2 = 3.84; Chi2 = 219.59, df = 11 (P < 0.00001); I 2 = 95% Test for overall effect: Z = 4.00 (P < 0.0001) 954 915 100.0% Total (95% Cl) Heterogeneity: Tau2 = 3.40; Chi2 = 433.49, df = 28 (P < 0.00001); I 2 = 94% Test for overall effect: Z = 5.22 (P < 0 .00001) Test for subgroup differences: Chi2 = 10.44, df = 2 (P = 0.005); I 2 = 80.8%


0.00 [–0.58, 0.58] 0.50 [–3.05, 4.05] –2.30 [–7.13, 2.53] –0.85 [–2.25, 0.55] –1.05 [–1.42, –0.68] –0.90 [–4.82, 3.02] –0.62 [–1.28, 0.04]

–4.07 [–4.83, –3.31] –2.00 [–3.88, –0.12] –2.90 [–6.59, 0.79] –0.95 [–13.35, –4.67] –1.30 [–6.87, 4.27] 0.00 [–1.43, 1.43] –1.73 [–3.73, –1.27] –1.00 [–1.82, –0.18] –5.45 [–10.03, –0.87] –0.10 [–5.11, 4.91] –1.74 [–2.44, –1.04] –2.29 [–3.46, –1.13]

–5.84 [–6.53, –5.15] –1.75 [–3.68, –0.18] –0.40 [–2.98, –2.18] –0.00 [–0.92, –0.92] –4.40 [–4.85, –3.95] –1.20 [–1.85, –0.55] –2.00 [–3.58, –0.42] –4.50 [–5.28, –3.72] –0.60 [–4.32, 1.12] –1.40 [–2.04, –0.76] –1.20 [–6.95, 4.55] –3.40 [–4.33, –2.47] –2.47 [–3.68, –1.26]

–2.09 [–2.87, –1.30] –10 –5 0 5 10 Favours pregabalin Favours control

Fig 4 Forest plot for opioid consumption at 2 h. SD, standard deviation; CI, confidence interval; IV, inverse variance.

sedation according to pregabalin dosing regimens is presented in Table 3. There was a statistically significant increase in the risk of sedation with single and multiple dosing of pregabalin 300 mg and the risk of severe sedation with multiple doses of 300 mg. The CIs with other pregabalin regimens were wide, suggesting that the data are insufficient to draw conclusions with the lower two doses of pregabalin.

Preoperative anxiety scores Preoperative anxiety scores after pregabalin administration were investigated in 10 studies (general anaesthesia in nine7 13 34 36 37 43 46 49 61 and spinal anaesthesia in one).39 Seven 13 34 36 37 39 46 49 studies used VAS scale, one43 used a sevenpoint scale (1, relaxed; 2, apprehension; 3, mild anxiety; 4, moderate anxiety; 5, manifest anxiety; 6, severe anxiety; 7, very

severe anxiety), one used a five-point scale (0, calm and comfortable; 1, uneasy; 2, worried and anxious; 3, very upset and worried; 4, frightened/terrified),61 and one7 used hospital anxiety and depression scale. Pooled results from the seven studies13 34 36 37 39 46 49 that used the VAS scale had wide CIs, and therefore, no conclusion could be reached about this outcome [MD (95% CI )¼20.68 (21.58, 0.22, I 2 ¼82%)]. Significantly lower preoperative anxiety scores with pregabalin administration were reported in the three studies7 43 61 that used scales other than the VAS scale.

Discussion In this systematic review and meta-analysis, we found that the perioperative administration of pregabalin was associated

Page 17 of 22


1.4.2 Pregabalin 100–150 mg Balaban 3.26 1.37 30 7.33 1.62 30 4.5% 30 Fassoulaki 3 9 4.8 3.7% 37 7 14.3 7.9 George 28 17.2 6.3 30 2.3% 20 36.63 7.91 20 1.9% Jo 27.62 5.97 Jokela BJA 2008 26 18.6 10.7 28 1.4% 17.3 10.2 Kim JC 2011 6.95 2.98 28 6.95 2.44 28 4.1% Ozgencil 8.27 4.51 30 3.6% 10 3.28 30 45 10 1.25 4.5% Paech 9 2.5 45 Spreng 22 11.29 10.21 5.84 4.98 24 1.8% White 9.2 10.9 27 9.3 7.6 27 1.6% Yucel 13.03 1.3 30 14.77 1.45 30 4.5% Subtotal (95% Cl) 316 329 33.9% Heterogeneity: Tau2 = 2.31; Chi2 = 54.90, df = 10 (P < 0.00001); I 2 = 82% Test for overall effect: Z = 3.86 (P = 0.0001)


BJA

Mishriky et al.

Pregabalin Control Mean Difference IV, Random, 95% Cl Study or Subgroup Mean SD Total Mean SD Total Weight 41.3.1 Pregabalin 75 mg 4.1% 2.32 50 Chaparro 4.5 4 2.32 49 0.50 [–0.41,1.41] 1.4% George 53.1 22.7 31 54 26.2 30 –0.90 [–13.22, 11.42] 2.3% –37.00 [–44.86, –29.14] 30 58 Ghoneim 21 30 11 19 3.3% Jokela BJA 2008 25.65 7.31 30 30.4 9.73 28 –4.75 [–9.20, 0.30] 3.1% Kim JC 2011 103.82 11.71 28 100.41 7.2 28 3.41 [–1.68, 8.50] 4.1% Peng 5.7 2.95 96 6.75 3.2 46 –1.05 [–2.15, 0.05] Subtotal (95% CI) 265 211 18.3% –5.14 [–9.34, –0.94] Heterogeneity: Tau2 = 20.28; Chi2 = 94.24, df = 5 (P < 0.00001); I 2 = 95% Test for overall effect: Z = 2.40 (P = 0.02)


41.3.3 Pregabalin 300 mg 3.9% 37.03 2.3 13 53.48 2.9 13 Bornemann-Cimenti 2.8% 12.83 13.73 39 13.7 13.83 38 Chang 2.3% 5 11.85 20 11 13.33 20 Demirhan 3.8% 33.8 6.89 40 46.4 5.72 40 Eskander 4.1% 4.28 1.87 30 10.5 2.36 30 Ghai 2.9 0.79 30 9.5 0.9 30 4.1% Gianesello 7.11 5.57 38 21.18 7.12 40 3.8% Ittichaikuthol 7.71 3.17 29 10.95 5.84 29 3.9% Jokela Pain 2008 23.9 13.8 40 48.7 27.8 38 1.9% Mathiesen 2008 39.8 22.2 35 42.3 20.3 39 1.9% Mathiesen 2009 5.3 3.08 45 7.5 2.88 43 4.1% Mathiesen 2011 22.67 12.8 32 43.33 24.27 28 1.8% Wang 33.79 5.77 30 46.97 6.67 30 3.7% Yucel Subtotal (95% CI) 421 418 41.9% 2 2 2 Heterogeneity: Tau = 15.05; Chi = 233.44, df = 12 (P < 0.00001); I = 95% Test for overall effect: Z = 7.41 (P < 0.00001) Total (95% CI) 1116 1076 100.0% Heterogeneity: Tau2 = 20.43; Chi2 = 654.98, df = 33 (P < 0.00001); I 2 = 95% Test for overall effect: Z = 9.00 (P < 0.00001) Test for subgroup differences: Chi2 = 2.80, df = 2 (P = 0.25); I 2 = 28.6%

–16.45 [–18.46, –14.44] –0.87 [–7.03, 5.29] –6.00 [–13.82, 1.82] –12.60 [–15.38, –9.82] –6.22 [–7.30, –5.14] –6.60 [–7.03, –6.17] –14.07 [–16.90, –11.24] –3.24 [–5.66, –0.82] –24.80 [–34.62, –14.98] –2.50 [–12.23, 7.23] –2.20 [–3.45, –0.95] –20.66 [–30.68, –10.64] –13.18 [–16.34, –10.02] –9.26 [–11.72, –6.81]

–8.27 [–10.08, –6.47] –20 –10 0 10 20 Favours pregabalin Favours control

Fig 5 Forest plot for opioid consumption at 24 h. SD, standard deviation; CI, confidence interval; IV, inverse variance.

with a statistically significant reduction in pain scores at rest (MD of 0.81 at 2 h and 0.38 at 24 h), pain scores during movement (MD of 0.58 at 2 h, and 0.47 at 24 h), and opioid consumption (MD of 2.09 mg ME at 2 h, and 8.27 mg ME at 24 h) after surgery compared with placebo. The incidence of opioidrelated side-effects (PONV and pruritus) was significantly reduced with pregabalin administration by 38% and 51%, respectively, relative to placebo at 24 h after surgery. The administration of pregabalin was associated with a significantly higher incidence of sedation (46% increase), dizziness (33% increase), and visual disturbance (3.5 times more likely) relative to placebo. Of note, pregabalin-treated patients achieved hospital discharge criteria 14 h earlier than controls. Although we

Page 18 of 22

were not able to reach a definitive conclusion regarding preoperative anxiety due to the wide CIs of the non-statistically significant pooled results, six of the 10 studies investigating preoperative anxiety reported significantly lower anxiety with pregabalin. Similarly for persistent pain, we were not able to reach a conclusion regarding the incidence at 3 months, while at 6 and 12 months, there was limited information suggesting a possible benefit. The only two studies investigating neuropathic pain reported a benefit from pregabalin administration. The optimal dose or frequency of administration of pregabalin is unclear.69 In the included studies, the individual dose of pregabalin administered before surgery ranged from 50 to 300 mg. Our analyses suggested that the opioid-sparing


41.3.2 Pregabalin 100–150 mg 2.9% –20.23 [–26.16, –14.30] Agarwal 55.52 12.48 27 75.75 9.93 29 3.5% –11.56 [–15.40, –7.72] Cabrera Schulmeyer 11.51 7.93 39 23.07 9.57 41 2.7% –12.00 [–18.37, –5.63] Fassoulaki 21 12 36 33 16 39 1.4% George 44.3 20.9 28 54 26.2 –9.70 [–21.86, 2.46] 30 1.3% Jo 70.88 16.74 20 79.61 23.97 –8.73 [–21.54, 4.08] 20 3.2% Jokela BJA 2008 25.4 8.84 26 30.4 9.73 28 –5.00 [–9.95, –0.05] 3.7% Jokela Pain 2008 9.9 5.94 27 10.95 5.84 29 –1.05 [–4.14, 2.04] 2.9% –15.50 [–21.30, –9.70] Kim JC 2011 84.91 13.91 28 100.41 28 7.2 1.7% Koyuncu 34.5 16.1 30 36 24.3 –1.50 [–11.93, 8.93] 30 Ozgencil 3.2% –11.00 [–15.78, –6.22] 26.33 9.41 30 37.33 9.5 30 Pesonen 4.0% 9.6 2.49 29 13.54 31 –3.94 [–5.36, –2.52] 3.1 Spreng 1.5% –11.67 [–23.27, –0.07] 25.93 19.54 22 37.6 20.61 24 Sundar 2.0% 24.17 17.89 30 25.17 18.15 –1.00 [–10.12, 8.12] 30 1.9% –12.30 [–22.11, –2.49] 30.9 13.02 28 43.2 23.06 28 YaDeau 3.8% 40.8 3.42 30 46.97 6.67 30 –6.17 [–8.85, –3.49] Yucel Subtotal (95% CI) 430 –8.57 [–11.40, –5.74] 447 39.8% Heterogeneity: Tau2 = 19.88; Chi2 = 71.04, df = 14 (P < 0.00001); I 2 = 80% Test for overall effect: Z = 5.93 (P < 0.00001)

BJA


Table 5 Side-effects after pregabalin administration. Data are presented as RR (95% CI) (number of studies included in the analysis); PONV, postoperative nausea and vomiting; NA, not applicable; NE, not estimable 0 –2 h

0– 24 h

1.11 (0.88, 1.40, I 2 ¼91%) (8)11 27 34 35 40 – 42 57

1.46 (1.08, 1.98, I 2 ¼81%) (21)6 7 11 23 24 27 32 – 34 39 – 44 50 52 57 60 63 67

Severe sedation

1.52 (1.02, 2.26, I 2 ¼0%) (10)11 27 28 35 38 40 – 42 49 57

2.11 (1.14, 3.90, I 2 ¼40%) (12)11 23 26 – 28 38 – 42 57 67

Dizziness

1.44 (0.97, 2.14, I 2 ¼49%) (9)13 27 32 34 38 41 42 49 68

1.33 (1.07, 1.64, I 2 ¼53%) (31)6 7 13 27 32 – 41 43 44 46 47 51 – 53 55 56 60 62 – 68

Confusion

NA

3.44 (0.57, 20.77, I 2 ¼31%) (2)6 44

Sedation

Visual disturbance

3.55 (1.21, 10.40, I 2 ¼0%) (2)13 68

3.52 (2.05, 6.04, I 2 ¼0%) (16)6 7 13 34 36 – 38 43 52 55 56 62 64 65 67 68

Dry mouth

NA

0.84 (0.64, 1.12, I 2 ¼13%) (5)6 34 44 62 66

Headache

0.40 (0.08, 1.96, I 2 ¼NE) (2)38 68

0.91 (0.64, 1.29, I 2 ¼39%) (15)6 23 26 36 – 38 43 44 46 50 52 55 56 67 68

Lack of concentration

NA

1.04 (0.85, 1.26, I 2 ¼0%) (5)36 37 44 66 67

Difficulty passing urine

NA

0.89 (0.56, 1.43, I 2 ¼17%) (6)24 43 44 46 56 63

Fatigue

NA

0.72 (0.49, 1.05, I 2 ¼NE) (1)44

Opioid-related side-effects 0.62 (0.39, 1.01, I 2 ¼0%) (8)32 34 38 40 – 42 46 61

0.83 (0.71, 0.96, I 2 ¼1%) (20)6 8 24 26 32 38 – 44 46 50 52 55 56 60 63 68

0.33 (0.04, 2.99, I 2 ¼0%) (5)34 36 – 38 61

0.86 (0.69, 1.06, I 2 ¼5%) (22)6 8 24 26 36 – 44 46 47 50 52 55 56 60 63 68

PONV

0.76 (0.32, 1.84, I 2 ¼4%) (5)34 36 – 38 61

0.62 (0.48, 0.80, I 2 ¼46%) (20)7 23 27 31 33 35 – 38 46 51 – 53 55 60 62 – 66

Rescue antiemetic

NA

0.84 (0.72, 0.99, I 2 ¼7%) (11)8 23 27 40 – 42 50 55 59 67 68

Pruritus

NA

0.49 (0.34, 0.70, I 2 ¼13%) (13)6 24 26 36 37 43 44 46 50 51 56 63 67

Constipation

NA

0.88 (0.59, 1.31, I 2 ¼0) (2)44 66

effect of pregabalin seemed to be limited to doses 100 –150 and 300 mg but not ≤75 mg at 2 h after surgery, whereas at 24 h, no statistically significant differences were detected between the three dose levels. These doses are lower than the lowest effective daily dose of 225 mg suggested in an earlier meta-analysis.4 Pregabalin has an elimination half-life estimated to range from 5.5 to 6.7 h which is independent of the dose and frequency of administration.69 With nearly half the included trials studying single dosing while the other half using multiple dosing, we investigated whether the frequency of administration impacts the analgesic efficacy of pregabalin. While the opioid-sparing effect was statistically significant with both single and multiple dosing of pregabalin ≤75– 300 mg, the reduction in pain scores seemed to be limited in general to multiple dosing. The further reduction in pain scores with multiple dosing over single dosing however was modest and likely not clinically relevant. In fact, there were no statistically significant differences between single and multiple dosing with regard to opioid consumption and pain scores, except for pain scores on movement with the ≤75 mg dose. These results might suggest that for acute pain outcomes, there is no significant benefit of repeated dosing of pregabalin compared with a single preoperative dose. This agrees with the results of the only study that prospectively compared single dose of pregabalin 150 mg vs three perioperative doses and reported no difference in acute pain outcomes between the groups.26 In a previous meta-analysis, Clarke and colleagues3 investigated the incidence of persistent pain at 3–6 months after surgery and, pooling results from two studies, reported an odds ratio (95% CI) of 0.09 (0.02– 0.52) with pregabalin compared with control. More recently, Chaparro and colleagues70 investigated the incidence of persistent pain at 3 months

after surgery and found a reduction in this incidence with pregabalin after pooling the results of four studies [RR (95% CI)¼0.70 (0.51, 0.95)]. However, the authors stated that these positive results in favour of pregabalin were mainly due to one positive study, while the other three studies showed no benefit. This positive overall result is likely due to the use of the fixed effect model in that review. We however used a random effects model, which we deemed more appropriate, given the clinical heterogeneity of the studies, and including six studies, we found the data insufficient to reach a conclusion about pain at 3 months due to the wide CIs of the pooled results. While we found a statistically significant reduction in the incidence of persistent pain at 6 months [RR (95% CI)¼0.31 (0.10, 0.92) and 12 months [0.47 (0.23, 0.97)], each of these two analyses included only two studies, with one of them12 having a high risk of bias. Only two studies investigated neuropathic pain,6 12 with both studies reporting a benefit from pregabalin administration; however, one of those studies12 had a high risk of bias. The optimum pregabalin regimen needed for affecting chronic pain is not clear. Most of the studies studying the impact of pregabalin on chronic pain used multiple doses starting before operation and extending to several days after operation.6 – 8 10 12 – 15 Studies comparing the impact of single vs multiple dosing of pregabalin on the incidence of chronic post-surgical pain are lacking. Overall, pregabalin produced a clinically relevant opioid sparing of 25% at 24 h. The impact on pain scores was less pronounced with 19% and 16% reduction in the mean pain scores at rest and on movement at 24 h, and therefore might not be clinically relevant. Pregabalin-induced opioid sparing was however associated with a reduction in opioid-related side-effects such as PONV and pruritus. However, these benefits were at the expense of increased risk of sedation and dizziness. The available

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Nausea Vomiting

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– Heterogeneity: We combined different types of surgery, different pregabalin doses, different anaesthetic types, and different regimens (single and multiple dosing) in our main analysis, which created heterogeneity within that analysis. It has been suggested that this is expected and inevitable in a meta-analysis, and that any amount of heterogeneity is acceptable, provided that the predefined eligibility criteria for the meta-analysis are sound and the data are correct.72 In order to investigate the efficacy of different dosing regimens of pregabalin and the efficacy of pregabalin in different types of surgery and with different anaesthetic techniques, we performed a number of sensitivity and subgroup analyses and meta-regressions. However, results from these analyses should be regarded as observational in nature, may be biased and limited by the small number of studies included in some of the subgroups, and should therefore be interpreted with caution.17 While included trials might have allocated treatment randomly, their inclusion in this review is not random. Furthermore, while we used a random effects meta-analysis due to the clinical heterogeneity, this method weighs the studies more equally than a fixed effect meta-analysis. To exclude a small study effect on the results of our analysis, we compared the results of the fixed and random effects model on our primary outcomes and those yielded comparable results further strengthening the internal validity of our findings. – Risk of bias in individual studies: Limiting the review to RCTs limits the potential for bias. Our risk of bias assessment indicated that most included studies had a low risk of bias. Furthermore, our sensitivity analysis excluding the few studies with unclear or high risk of bias did not affect our conclusions. Another limitation was the inconsistency of reporting outcomes among the studies, and the lack of response from some authors with regard to data that we requested. However, the results of our review were consistent in the various sensitivity analyses. Some important clinically relevant outcomes such as the duration of PACU stay and of hospital stay were only rarely reported.

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Multiple areas for future research have been identified. Large studies with adequate power are needed to compare the efficacy and side-effect profile of different doses of pregabalin. Studies are also needed to assess the efficacy and side-effects of single vs multiple dosing of pregabalin. In addition, further investigation is needed to assess the ideal pregabalin regimen for the reduction in persistent pain in surgical patients. Those studies should focus on surgeries associated with a high risk of chronic post-surgical pain. Studies also need to specifically address neuropathic pain and make a distinction between different types of persistent pain. In conclusion, this systematic review and meta-analysis confirms previous meta-analyses suggesting that the perioperative administration of pregabalin is associated with a significant reduction in opioid consumption after surgery. In this review, we also found a significant reduction in pain scores with pregabalin administration. The impact on opioid consumption seemed to be more pronounced, while the reduction in pain scores was only modest. Other new findings from our review are the fact that the analgesic effect of pregabalin seemed to be associated with much lower doses than previously reported.4 Furthermore, our review suggested that overall there was no difference in acute pain outcomes between single and multiple dosing of pregabalin. Neuropathic pain might be reduced with pregabalin, but available data are sparse. Consistent with previous meta-analyses, sedation, dizziness, and visual disturbance occurred more commonly in pregabalin-treated patients.

Authors’ contributions B.M.M. was involved in conducting the study, extracting data, data analysis, and manuscript preparation. N.H.W. was involved in conducting the study, extracting data, data analysis, and manuscript preparation. A.S.H. was responsible for the concept and design of the study, conduct of study, extracting data, data analysis, and manuscript preparation.

Declaration of interest None declared.

Funding This article was supported solely by departmental funds.

References 1 Ha KY, Carragee E, Cheng I, Kwon SE, Kim YH. Pregabalin as a neuroprotector after spinal cord injury in rats: biochemical analysis and effect on glial cells. J Korean Med Sci 2011; 26: 404– 11 2 Dahl JB, Mathiesen O, Moiniche S. ‘Protective premedication’: an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anaesthesiol Scand 2004; 48: 1130– 6 3 Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg 2012; 115: 428–42


data allowed only limited assessment of the impact of sedation on patients’ recovery. For instance, only four studies reported on the duration of PACU stay, and this did not seem to be impacted by pregabalin. Furthermore, interestingly, the duration of hospital stay was reduced with pregabalin administration, but this was only reported in five of the included studies. Since type of surgery and type of anaesthesia can influence postoperative analgesic outcomes, we included both in addition to pregabalin dosing in the meta-regression models. In fact, both were significant predictors of some of the outcomes in our analysis. For instance, type of surgery was a significant predictor of pain scores at rest at 2 and 24 h. This agrees with previous studies showing that type of surgery is a significant predictor of postoperative analgesic outcomes.71 The type of anaesthesia also predicted 2 h pain scores on movement and 24 h opioid consumption, likely due to the analgesic effect of regional anaesthesia in the early postoperative period. There are several limitations to this review:

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Mishriky et al.

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Gabapentinoids: gabapentin and pregabalin for postoperative pain management.

Effects of pregabalin and gabapentin on postoperative pain and opioid consumption after laparoscopic cholecystectomy.

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Postoperative pain treatment after total hip arthroplasty: a systematic review.

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Impact of the Electronic Medical Record on Mortality, Length of Stay, and Cost in the Hospital and ICU: A Systematic Review and Metaanalysis.

Pharmacoeconomic outcomes for pregabalin: a systematic review in neuropathic pain, generalized anxiety disorder, and epilepsy from a Spanish perspective.

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Systematic review and metaanalysis on nonclassic cardiovascular biomarkers after hypertensive pregnancy disorders.

Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis.

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Effects of single-dose pregabalin on postoperative pain in dacryocystorhinostomy surgery.