Research Paper

Perioperative use of pregabalin for acute pain—a systematic review and meta-analysis Naveen Eipea, John Penninga, Fatemeh Yazdib, Ranjeeta Mallickb, Lucy Turnerb, Nadera Ahmadzaib, Mohammed Toseef Ansarib,*

Abstract Evidence supporting postoperative pain management using pregabalin as an adjunct intervention across various surgical pain models is lacking. The objective of this systematic review was to evaluate “model-specific” comparative effectiveness and harms of pregabalin following a previously published systematic review protocol. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through August 2013. Data were screened and single extraction with independent verification and dual risk of bias assessment was performed. Quality of evidence (QoE) was rated using the GRADE approach. Primary outcomes were pain relief at rest and on movement and reduction in postoperative analgesic consumption. A total of 1423 records were screened, and 43 studies were included. Perioperative pregabalin resulted in: 16% (95% confidence interval [CI], 9%-21%) reduction in analgesic consumption (moderate QoE, 24 trials) and a small reduction in the magnitude of pain in surgeries associated with pronociceptive pain. Per 1000 patients, 10 more will experience blurred vision (95% CI, 5-20 more; moderate QoE, 17 trials) and 41 more sedation (95% CI, 13-77 more, 17 trials). To prevent 1 case of perioperative nausea and vomiting, the number needed to treat is 11 (95% CI: 7-28, 25 trials). Inadequate evidence addressed outcomes of enhanced recovery and serious harms. Pregabalin analgesic effectiveness is largely restricted to surgical procedures associated with pronociceptive mechanisms. The clinical significance of observed pregabalin benefits must be weighed against the uncertainties about serious harms and enhanced recovery to inform the careful selection of surgical patients. Recommendations for future research are proposed. Keywords: Pregabalin, Acute Pain, Postoperative, Surgical Models, Systematic Review, Meta-analysis

1. Introduction Pregabalin was first introduced in 2004 as an antiepileptic and more potent successor to gabapentin.25 Pregabalin has followed gabapentin on an almost identical path of clinical utilization. Currently, the Food and Drug Administration and Health Canada approve the use of pregabalin for seizures and chronic pain (postherpetic neuralgia, fibromyalgia, and diabetic peripheral neuropathy).25 In the European Union, pregabalin is also approved for use in generalized anxiety disorders.59 Pregabalin binds to the alpha2delta subunit of the voltage-gated calcium channel in the central nervous system (CNS), and this decreases the release of a variety of neurotransmitters. Although its approved use continues as an antiepileptic and in chronic pain, the identification of its antipronociceptive properties led to its use in Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a

Department of Anesthesiology, The Ottawa Hospital, Ottawa, ON, Canada, Knowledge Synthesis Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada

b

*Corresponding author. Address: Clinical Epidemiology Program, Ottawa Hospital Research Institute, Box 201B, General Campus, Ottawa, ON K1H 8L6, Canada. Tel: 613 761 5555 extn 13809; fax: 613 761 5032. Email address: [email protected] (M.T. Ansari). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.painjournalonline.com). PAIN 156 (2015) 1284–1300 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/j.pain.0000000000000173

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perioperative pain management. Clinical trials with pregabalin in perioperative pain followed the anecdotal and observational evidence that suggested its usefulness in treating acute neuropathic symptoms and indicated an apparent opioid-sparing effect.16 Existing systematic review evidence has established the effectiveness of perioperative pregabalin; however, the investigation of effect modification by specific surgical patient populations is conspicuous by its absence.20,46,63 Our clinical experience with this drug has been extensive, and we have previously published a clinical algorithm that guides appropriate patient and surgical procedure selection to maximize the benefit and minimize harms of perioperative pregabalin in acute pain management.18 Driven by clinical acumen, the algorithm, however, remains hypothesis driven. Furthermore, since the last meta-analysis,20 a large number of randomized controlled trial (RCTs) on the perioperative use of pregabalin for acute pain have been published. With the emergence of new evidence, and our clinical hypothesis that the balance of benefit vs harm of pregabalin use might favor only a subset of patients undergoing certain surgical procedures, a surgical model-specific systematic review of the literature is warranted.

2. Methods We prospectively registered our systematic review with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42012002078). We then published an a priori peer-reviewed detailed protocol to which our research conduct has been adherent.19 PAIN®

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Our eligibility criteria included RCT reports if they compared perioperative oral pregabalin use with placebo or another active comparator drug in adults undergoing elective surgical procedures. Primary outcomes were pain relief at rest and on movement and reduction in postoperative opioid and other analgesic consumption. Other outcomes included postoperative nausea and vomiting, anxiolysis, early feeding and ambulation, and length of hospital stay, sleep restoration, chronic pain, and adverse events including serious events and mortality. 2.1. Data sources and searches We searched MEDLINE (1946-August 2013), EMBASE (1947August 2013), and the Cochrane Central Register of Controlled Trials (up to Issue 8 of 12, August 2013) for relevant studies. Details of the strategies used to search these databases are provided (Appendix 1, available online as Supplemental Digital Content at http://links.lww.com/PAIN/A70). No restrictions were placed on year or language. Finally, we reviewed reference lists of previously published systematic reviews on this topic. 2.2. Study selection Two reviewers (N.E. and J.P.) independently screened records for eligibility (excluded studies are reported in Appendix 2, available online as Supplemental Digital Content at http://links.lww.com/PAIN/A71). Disagreements were resolved by consensus. One reviewer extracted relevant data (F.Y. or N.A.) and sought data clarification by contacting authors (for 13 studies). Data were verified by a second reviewer (F.Y. or N.A.). 2.3. Data extraction and quality assessment Two reviewers (F.Y. and N.A.) independently used the Cochrane risk of bias and Jadad tools to evaluate the internal validity of the design and conduct of the included studies.3,17 The overall outcome-specific risk of bias judgments was categorised as low, moderate, and high using the Cochrane tool and were scored out of 5 with the Jadad tool. We planned to investigate the risk of publication bias when there were at least 10 studies of unequal sizes without important concerns about their methodological and clinical diversity, but these a priori criteria were not met for any quantitative synthesis. We used guidance of the GRADE working group to grade our confidence on results for preidentified important outcomes of mortality, serious adverse events, respiratory depression or arrest, visual disturbances, pain relief or scores, analgesic consumption, sleep restoration, and enhanced recovery (early feeding and ambulation and the length of hospital stay).3 We noted poor concordance between Cochrane and Jadad risk of bias judgments for pain outcome (kappa: 20.29, 95% confidence interval [CI], 20.44 to 20.13); 70% of moderate risk of bias studies had Jadad scores 4 to 5. As such, we used the currently more widely adopted Cochrane tool to inform outcome-specific risk of bias for the body of evidence while grading the quality of evidence (QoE).

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a post hoc decision to pool data using ratio of means. For ease of interpretation, we also used the ratio of means when outcomes were not reported on the same scale.23,24 Ratio of means can be interpreted as percentage change in the mean value of the intervention group compared with that of the control group. Where medians and interquartile ranges were reported, standard approaches to include these data were applied.29 When estimates of variance were not reported, no imputations were made and the data were omitted from analyses. Both analgesic consumption and pain outcomes were categorized by total daily pregabalin dosage (#150 mg, .150-300 mg, .300 mg) and by timing of outcome assessment (0-24 hours, 24-48 hours, 48 hours or greater) for analysis. For adverse events, the maximum dosage and greatest time point reported by study events were included. Opioid analgesics used as rescue or for analgesic consumption were recorded as morphine equivalents, and other opioids used were converted using standard conversion charts (hydromorphone 0.2 mg 5 oxycodone, 0.5 mg 5 piritramide, 0.75 mg 5 morphine 1 mg). For pain-related outcomes, an investigation of effect modification was done for model 1—surgical models associated with pronociceptive (acute hyperalgesia) mechanisms (eg, spine, joint arthroplasty and amputations), model 2—surgical models not associated with pronociceptive mechanisms (eg, abdominal laparoscopic surgery, gynecological procedures, etc), and model 3—surgical models with unknown association with pronociceptive mechanisms (eg, cardiac surgery, dental extractions, etc). When model-specific findings were judged not to be inconsistent, we pooled data across the models with a view towards adding to the precision of effect estimates. Also, when sparse evidence existed for the various pain models, we pooled data across the various models to add metaanalytic power unless precluded by substantial heterogeneity. Evidence syntheses for other outcomes (including unintended side effects) were conducted irrespective of the surgical pain model.

2.4. Data synthesis and analysis We used RevMan 5.1 software (The Cochrane Collaboration, available online at www.cochrane.org) to meta-analyze outcome data using random-effects model in keeping with the Cochrane methods guidance.15,17 For dichotomous data, risk ratios and associated 95% CIs are reported. For continuous data reported in the same unit, the mean difference and 95% CIs are reported. Because intervention dosages varied across studies, we made

Figure 1. Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) flow chart.

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Table 1

Characteristics of RCTs included in this systematic review. Author (year)

Country of Sample conduct size

Surgery type

% Male Pregabalin dose (per day) participants

Burke (2010)6 Kim (2011)36

Ireland South Korea

N 5 38 N 5 84

Spine: lumbar discectomy Spine: posterior lumbar spinal fusion

28.9 All male

Spreng (2011)56 Hegarty (2011)28

Norway Ireland

N 5 46 N 5 32

Spine: lumbar discectomy Spine: lumbar discectomy

47.8 46.9

Gianesello (2012)28

Italy

N 5 60

Ozgencil (2011)48

Turkey

Buvanendran (2010)7 Freedman (2008)22

United States United States Korea Germany

N 5 84 Breast: mastectomy N 5 149 Oral: third molar removal

100 55.6

Bornemann-Cimenti (2012)5 Peng (2010)52

Germany

N 5 26

57.7

Agarwal (2008)2

India

Chang (2009)11

South Korea

Balaban (2012)3

Turkey

General/abdominal: transperitoneal nephrectomy N 5 142 General/abdominal: laparoscopic cholecystectomy N 5 56 General/abdominal: laparoscopic cholecystectomy N 5 77 General/abdominal: laparoscopic cholecystectomy N 5 90 General/abdominal: laparoscopic cholecystectomy

Ghai (2011)26

India

N 5 60

100

Kohli (2011)39

India

General/abdominal: hysterectomy N 5 150 General/abdominal: hysterectomy

Przesmycki (2011)54

the Netherlands

N 5 80

General/abdominal: hysterectomy

100

Mathiesen (2009)44

Denmark

N 5 86

100

Ittichaikulthol et al.31 Thailand

N 5 78

Mathiesen (2008)42

Denmark

N 5 84

General/abdominal: hysterectomy with or without (salpingooophorectomy) General/abdominal: female patients scheduled for hysterectomy Joint: hip replacement

Pesonen (2011)53

Finland

N 5 60

Mathiesen (2011)43

Denmark

N 5 99

Kim (2011)38

Korea

N 5 94

Cabrera Schulmeyer (2010)9

Chile

N 5 80

Paech (2007)49

Australia

N 5 86

Jokela (2008)-I low dose PG34

Finland

N 5 84

Kim (2011)38 Hill (2001)30

Canada

Spine: decompressive lumbar 61.7 laminectomy with spinal fusion for degenerative spinal stenosis N 5 60 Spine: decompressive lumbar 55.6 laminectomy and discectomy N 5 240 Joint: total knee arthroplasty 27.1 N 5 80

Model 1

Model 2

Model 3

Risk of bias (pain)†

.300 mg/d (high dose) Two groups: #150 mg/d (low dose); .150-300 mg/d (intermediate dose) #150 mg/d (low dose) .150-300 mg/d (intermediate dose) .300 mg/d (high dose)

ü ü

Moderate Low

ü ü

Moderate Moderate

ü

Low

.150-300 mg/d (intermediate dose) .300 mg/d (high dose)

ü

Low

ü

Moderate

#150 mg/d (low dose)

ü ü

58.8

#150 mg/d (low dose) Two groups: #150 mg/d (low dose); .150-300 mg/d (intermediate dose) .150-300 mg/d (intermediate dose) #150 mg/d (low dose)

31.7

Breast: bilateral mammaplasty 100

Cardiac: coronary artery bypass grafting General/abdominal: tonsillectomy General/abdominal: thyroidectomy General/abdominal: laparoscopic sleeve gastrectomy General/abdominal: gynecological surgery (minor) General/abdominal: gynecological laparoscopic

Surgical models*

Moderate

ü

Low Moderate

ü

Low

ü

Moderate

#150 mg/d (low dose)

ü

Moderate

NR

.300 mg (high dose)

ü

Low

65.0

Two groups: #150 mg/d (low dose); .150-300 mg/d (intermediate dose) .150-300 mg/d (intermediate dose) Two groups: #150 mg/d (low dose); .150-300 mg/d (intermediate dose) Two groups: #150 mg/d (low dose); .150-300 mg/d (intermediate dose) .150-300 mg/d (intermediate dose)

ü

Moderate

ü

Low

ü

Moderate

ü

Moderate

ü

Low

100

.150-300 mg/d (intermediate dose)

ü

Moderate

59.0

NR

.150-300 mg/d (intermediate dose) .150-300 mg/d (intermediate dose) .150-300 mg/d (intermediate dose) .150-300 mg/d (intermediate dose) #150 mg/d (low dose)

100 100

100

47.1 34.1 94.7

ü

Moderate ü

Moderate

ü

Low

ü

Low

ü

Moderate

#150 mg/d (low dose)

ü

Low

#150 mg/d (low dose)

ü

Low (continued on next page)

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Table 1 (continued) Author (year)

Country of Sample conduct size

Surgery type

% Male Pregabalin dose (per day) participants

Jokela (2008)-II high dose PG33

Finland

N 5 56

General/abdominal: laparoscopic hysterectomy

100

Clendenen (2010)15

United States United States United States Korea

N 5 47

Joint: shoulder arthroscopic rotator cuff repair Joint: ankle surgery

23.4

Yadeau (2012)60 Wang (2010)58 Lee (2013)41

Sarakatsianou Greece (2013)55 Jain (2012)32 India Nimmaanrat (2012)47 Thailand Fassoulaki (2012)21

Greece

Chaparro (2012)12

Canada

Choi (2013)13 Pakravan (2012)50

Korea Iran

Buvanendran (2012)8 United States Kumar (2013)40 United States Carmichael (2013)10 Canada Joshi (2013)35 India

N 5 56 N 5 59

Other: soft tissue: metatarsal bunionectomy N 5 60 General/abdominal: laparoendoscopic urological surgery N 5 40 General/abdominal: laparoscopic cholecystectomy N 5 40 Joint: total knee arthroplasty N 5 56 Other: soft tissue: arthroscopic ligament reconstruction N 5 80 General/abdominal: hysterectomy or myomectomy N 5 99 Other: soft tissue: cosmetic surgery (abdominal, hips, and thighs, also mamoplasty or abdominoplasty) N 5 72 Spine: lumbar spine surgery N 5 100 Optic: photorefractive keratectomy

41.7

Surgical models* Model 1

Two groups: .150-300 mg/d (intermediate dose); .300 mg/d (high dose) .150-300 mg/d (intermediate dose) #150 mg/d (low dose)

Model 2

Model 3

ü

Risk of bias (pain)† Moderate

ü

Moderate

ü

Moderate

ü

Moderate

51.1

.150-300 mg/d (intermediate dose) .300 mg/d (high dose)

ü

Moderate

34.0

#150 mg/d (low dose)

ü

Moderate

65.0 11.0

#150 mg/d (low dose) .300 mg/d (high dose)

100

83.3

ü

ü

Moderate Moderate

#150 mg/d (low dose)

ü

Moderate

100

.150-300 mg/d (intermediate dose)

ü

Moderate

48.6 57.3

ü

ü

Moderate Low

N 5 48

Joint: total knee replacement

70.8

#150 mg/d (low dose) Twos groups: #150 mg/d (low dose); .150-300 mg/d (intermediate dose) #150 mg/d (low dose)

N 5 50

Spine: lumbar laminectomy

66.7

#150 mg/d (low dose)

ü

N 5 31 N 5 40

Joint: total hip arthroplasty Cardiac: off-pump coronary artery bypass surgery

NR 7.5

#150 mg/d (low dose) .300 mg/d (high dose)

ü

ü

ü

Moderate Moderate

Moderate Moderate

* Surgical models: model 1: surgeries associated with pronociceptive pain; model 2: surgeries not associated with pronociceptive pain; model 3: surgeries with unclear association with pronociceptive pain. † Cochrane risk of bias assessment (low, moderate, high). RR, risk ratio.

Where applicable, additional exploration of heterogeneity or subgroup effect was considered for methodological and clinical covariates preidentified in the protocol.

3. Results 3.1. Overall characteristics We screened 1437 unique records and finally included 43 RCTs studying 3378 adult patients managed with multimodal analgesia (Fig. 1). Only parallel arm RCTs were included. Studies were conducted in Europe (17 studies in Denmark, Finland, Germany, Greece, Ireland, Italy, the Netherlands, and Norway), Asia (14 studies in Korea, South Korea, India, Iran, and Thailand), North America (10 studies in Canada, the Unites States), Australia (1 study), and South America (1 study in Chile). Twelve studies were conducted exclusively in females, and one was conducted only in male participants undergoing posterior lumbar spinal fusion. Various surgical procedures were employed across studies including 7 joint,6,7,9,14,32,42,60 22 abdominal or general surgery,1,2,4,8,10,11,21,26,31,33,34,37,39,41,43,44,47,49,52,54,55,58 8 spine,5,12,27,28,36,40,48,56 2 cardiac,35,53 2 mamoplasty or mastectomy,22,38 1 eye,50 and 1 oral.30 The need for a priori classification of surgical models was conceptualized from the published algorithm18 and outlined in the review protocol.19 However, the paucity of evidence addressing

chronic postsurgical pain (CPSP) model compelled us to rearrange our model categorisation in terms of presence (model 1) or absence (model 2) of pronociceptive pain or uncertain association (model 3) with it. Thirteen studies (30%) were judged to involve surgeries associated with pronociceptive pain mechanisms (model 1),5–7,9,12,27,28,32,36,40,42,48,56 22 (51%) as those not associated with pronociceptive mechanisms of pain (model 2),1,2,4,8,10,22,26,31,33–35,37–39,41,43,44,49,50,52,54,55 and 8 (19%) were judged as involving surgeries with an unclear association (model 3). 11,14,21,30,47,53,58,60 Few studies used active comparators (N 5 3), so we restricted syntheses of evidence synthesis to those studies that included comparisons with placebo or no treatment. A general description of the patients and interventions included can be found in Table 1.

3.1.1. Risk of bias assessment For pain as an outcome, 13 (30%) of the studies were rated as low risk of bias. The remaining 30 studies were rated as having a moderate to large risk of bias because of unclear reporting of methods used for randomization (6 studies) and allocation concealment (21 studies), or blinding of medication (13 studies) for participants or outcome assessors. None of the studies were rated as having a high risk of bias.

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Table 2

Reviewers’ confidence in effect estimates—GRADE quality of evidence. No. of studies

Design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

Quality assessment No. of studies

No of patients

Pregabalin

Effect

Placebo

Relative (95% CI)

G1, pain on movement with pregabalin 150-300 mg/d (model 1) (measured with: 11-point scale [0-10]; better indicated by lower values) 5 141 142 — G2, pain at rest with pregabalin 150-300 mg/d (model 2) (measured with: 11-point scale [0-10]; better indicated by lower values) 7 228 222 — G3, pain at rest with pregabalin 150-300 mg/d (model 1) (measured with: 11-point scale [0-10]; better indicated by lower values) 5 135 138 Ratio of means 0.84 (0.79, 0.91)

None None None

None

·

G1, pain on movement with pregabalin 150-300 mg/d (model 1) (measured with: 11-point scale [0-10]; better indicated by lower values) 5 Randomised trials Serious* No serious inconsistency No serious indirectness No serious imprecision G2, pain at rest with pregabalin 150-300 mg/d (model 2) (measured with: 11-point scale [0-10]; better indicated by lower values) 7 Randomised trials Serious* No serious inconsistency No serious indirectness No serious imprecision G3, pain at rest with pregabalin 150-300 mg/d (model 1) (measured with: 11-point scale [0-10]; better indicated by lower values) 5 Randomised trials No serious risk of No serious inconsistency No serious indirectness No serious imprecision bias G4, pain at rest with pregabalin 150-300 mg/d (model 2) (measured with: 11-point scale [0-10]; better indicated by lower values) 8 Randomised trials Serious* Serious† No serious indirectness No serious imprecision G5, analgesic consumption: minutes to rescue analgesia with pregabalin ,150-300 mg/d (model 2) (better indicated by higher values) 5 Randomised trials Serious‡ Serious† No serious indirectness Very serious§ G6, analgesic consumption with pregabalin 150-300 mg/d: total dose (mixed models) (better indicated by lower values) 24 Randomised trials Serious* No serious inconsistency No serious indirectness No serious imprecision G7, analgesic consumption: patients requiring additional analgesia at 24 hours with pregabalin 300 mg/d (model 2) 2 Randomised trials No serious risk of No serious inconsistency No serious indirectness Very serious§ bias G8, sleep restoration (reported as sleep disturbance, mixed models) (follow-up 1 d; measured with: 11-point scale [Buvanendran] and NR [Nimmaanrat]; better indicated by lower values) 2 Randomised trials Very serious{ Very serious# No serious indirectness Serious** G9, length of hospital stay: pregabalin 300-600 mg/d (mixed models) (better indicated by lower values) 4 Randomised trials Serious‖ Serious†† No serious indirectness No serious imprecision G10, chronic postoperative pain on movement: pregabalin 150-300 mg/d (model 1) (follow-up 3-6 months; better indicated by lower values) 2 Randomised trials Serious‡‡ No serious inconsistency No serious indirectness Serious** G11, chronic postoperative pain at rest: pregabalin 150-300 mg/d (model 1) (follow-up 3-6 months; better indicated by lower values) 2 Randomised trials Serious‡‡ No serious inconsistency No serious indirectness Serious** G12, visual disturbances: pregabalin (various doses, longest follow-up, mixed models) 17 Randomised trials Serious* No serious inconsistency No serious indirectness No serious imprecision

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Quality assessment

None None None

None None None None None Quality

Absolute MD 0.94 lower (1.23 to 0.65 lower)

Moderate

MD 0.31 lower (0.77 lower to 0.15 higher)

Moderate

MD 1.09 lower (1.8 to 0.37 lower)

High (continued on next page) PAIN®

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Placebo

Relative (95% CI)

G4, pain at rest with pregabalin 150-300 mg/d (model 2) (measured with: 11-point scale [0-10]; better indicated by lower values) 8 263 263 —

MD 0.45 lower (1.03 lower to 0.13 higher)

Low

MD 21.64 higher (15.96 lower to 59.23 higher)

Very low

Moderate

352 fewer per 1000 (from 464 fewer to 51 more) G8, sleep restoration (reported as sleep disturbance, mixed models) (follow-up 1 d; measured with: 11-point scale [Buvanendran] and NR [Nimmaanrat]; better indicated by lower values) 2 133 139 — Not pooled. Conflicting findings of no difference to significant mean difference of MD 21.7 (2.56 lower to 0.84 lower) G9, length of hospital stay: pregabalin 300-600 mg/d (mixed models) (better indicated by lower values) 4 202 205 — MD 0.76 lower (2.22 lower to 0.69 higher) G10, chronic postopretaive pain on movement: pregabalin 150-300 mg/d (model 1) (follow-up 3-6 months; better indicated by lower values) 2 54 56 — MD 0.66 lower (1.52 lower to 0.19 higher) G11, chronic postopretaive pain at rest: pregabalin 150-300 mg/d (model 1) (follow-up 3-6 months; better indicated by lower values) 2 54 56 — MD 0.42 lower (1.49 lower to 0.64 higher) G12, visual disturbances: pregabalin (various doses, longest follow-up, mixed models) 17 57/587 (9.7%) 0.5%§§ RR 3.08 (1.91 to 4.96) 10 more per 1000 (from 5 more to 20 more)

Number 7

G6, analgesic consumption with pregabalin 150-300 mg/d: total dose (mixed models) (better indicated by lower values) 730 728 Raito of means Percent of mean dose 0.84 (0.79, 0.91) consumed 16 lower (21 to 9 lower) G7, analgesic consumption: patients requiring additional analgesia at 24 hours with pregabalin 300 mg/d (model 2) 2 18/92 (19.6%) 51%‖ RR 0.31 (0.09 to 1.1)

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G5, analgesic consumption: minutes to rescue analgesia with pregabalin ,150-300 mg/d (model 2) (better indicated by higher values) 5 164 166 —

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No of patients

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Table 2 (continued) Quality assessment

Low

Very low

Low

Low

Low

Moderate

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* Several studies at unclear risk of bias across various domains. † Nonoverlapping estimates suggesting contrasting conclusions. ‡ Some concerns about attrition and/or detection bias. § Wide confidence interval (CI) and very low information size. ‖ Median control event rate across studies. { High risk of bias for selective outcome reporting. # Inconsistent results favoring pregabalin (Buvanendran) or no significant difference (Nimmaanrat). ** Overall inadequate sample size. Fragile results. †† One of 4 study shows significant reduction in hospital stay of approximately 2 hours. ‡‡ Several domains were judged as unclear risk of bias. §§ Median control event rate across studies was actually zero. This value is the lowest imputation we could use to generate a measure of absolute risk difference.

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Figure 2. Pregabalin 150-300mg/day vs. placebo: pain on movement (pronociceptive pain –– model 1; no pronociceptive pain –– model 2).

Ten studies (23.2%) were funded by industry, and 19 (44.2%) received no funding or were supported by nonindustry organizations. Information on financial support was not reported in 14 studies (32.6%), and the authors of one of these studies declared no conflict of interest. 3.2. Primary perioperative efficacy outcomes 3.2.1. Pain relief Pain improvement was measured either on a visual analog scale or a numerical rating scale at rest or movement. Where required, scores were standardised on an 11-point rating scale of 0 to 10. Data were pooled when there was no substantial heterogeneity or heterogeneity could not be explained by risk of bias or obvious clinical factors (eg, dose, surgical pain model, duration of follow-up). 3.2.1.1. Pain at movement Few studies categorised as involving either surgical pain model 1 or 2 contributed data to pregabalin dose, follow-up time, and surgical model–specific meta-analyses of main import. Pooled estimates indicated either significant improvement with pregabalin (24 and 48 hours, 150 mg/d, pain model 1) or very wide (inconclusive) CIs (all other pain model 1 and model 2 analyses for pregabalin doses varying from 150-600 mg/d) because of inadequate power in the body of evidence. Also, no significant effect modification by dose was observed; as such, we metaanalysed (mostly 24- to 48-hour follow-up) evidence for pregabalin 150 to 300 mg/d restricting analyses to specific surgical pain models. Moderate QoE from 5 trials significantly favoured pregabalin in patients with pronociception with a (pooled) mean reduction in score of 0.94 (95% CI, 1.23-0.65);

for model 2 (no association with pronociceptive pain), moderate QoE from 7 trials did not demonstrate pregabalin’s analgesic advantage (G1 and G2 in Table 2; Fig. 2). 3.2.1.2. Pain at rest Our primary attempt to pool very homogenous body of evidence in terms of pregabalin dose, follow-up duration, and surgical pain model type again limited meaningful conclusions because of insufficient data. Also, no significant effect modification by dose was observed; as such, we meta-analysed (mostly 24-48 hours of follow-up) evidence for pregabalin 150 to 300 mg/d restricting analyses by surgical pain models. High QoE from 5 trials significantly favoured pregabalin in patients with pronociception with a (pooled) mean reduction in score of 1.09 (95% CI, 1.800.37); for model 2 (no association with pronociceptive pain), low QoE from 8 trials demonstrated no pregabalin advantage (G3 and G4 in Table 2; Fig. 3). 3.2.2. Analgesic consumption Very low QoE from 5 trials showed inconclusive evidence (wide CIs) for the comparative efficacy of pregabalin in surgeries not associated with pronociception for the outcome of time (in minutes) to rescue analgesia (G5 in Table 2; Fig. 4). We found that study risk of bias did not explain the observed between-study heterogeneity. The evidence we examined was underpowered to detect any effect modification by dose of pregabalin. No evidence specifically addressed surgical pain model 1 (ie, pronociception). For total (other) analgesic consumption, our primary pregabalin dose, follow-up time (ie, 24 and 48 hours), and surgical pain model–specific meta-analyses either showed statistically significant results favouring pregabalin (some of the model 1

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Figure 3. Pregabalin 150-300mg/day vs. placebo: pain at rest (pronociceptive pain – model 1; no pronociceptive pain –– model 2).

meta-analyses) or lacked adequate power with wide, nonsignificant CIs incorporating possibilities for significant improvement with pregabalin, no difference between intervention and control, or even a potential increase in analgesic consumption. The evidence was also underpowered to detect any dose-related effect modification; as such, we meta-analysed (mostly 24-48 hours of follow-up) evidence for analgesic consumption restricting to the commonly administered pregabalin doses of 150 to 300 mg/d for the surgical pain models of interest. Statistically significant reductions in analgesic consumption were noted for model 1 (8 trials) and model 2 (13 trials), but because of the much smaller total sample size (N , 200; 3 trials), the evidence failed to show important differences across model 3 (various surgeries with unclear association with pronociception) studies. Because no significant differences were noted between model-specific estimates of effects, we additionally pooled data across surgical pain models for pregabalin doses of 150 to 300 mg/d and graded our

confidence in the overall pooled estimate of effect. Moderate QoE from 24 trials showed that pregabalin use could significantly reduce mean analgesic consumption by as much as 21% to as little as 9% (pooled ratio of means: 0.84, 95% CI, 0.79-0.91) across various surgical pain models (G6 in Table 2; Fig. 5). Low QoE from 2 small trials that analysed analgesic consumption based on the number of patients requiring additional analgesia yielded inconclusive evidence (pooled risk ratio 0.31, 95% CI, 0.09-1.10) (G7 in Table 2). 3.2.3. Secondary perioperative and long-term outcomes 3.2.3.1. Postoperative nausea or vomiting In the early postoperative period (#3 days), pregabalin use resulted in significant improvement in the symptoms of nausea or vomiting (pooled RR 0.77; 95% CI, 0.65-0.91; 25 individually underpowered studies at mostly low to moderate risk of bias, N 5 1621). In terms

Figure 4. Pregabalin, 150-300mg/day vs. placebo: time (minutes) to rescue analgesia in surgeries not associated with pronociceptive pain.

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Figure 5. Pregabalin 150-300mg/day vs. placebo: mean dosage of other analgesics consumed as ratio of means (pronociceptive pain –– model 1; no pronociceptive pain –– model 2; unclear association with pronociception – model 3).

of absolute risk difference, given the 95% CI, for every 1000 treated patients, from 36 fewer to 140 fewer patients will experience postoperative nausea or vomiting (number need to treat 5 11, 95% CI, 7-28). The evidence did not suggest a significant dose-specific effect but was largely inadequate to rule out a dose–response relationship (Fig. 6). Because of sparse evidence, we were unable to draw meaningful conclusions regarding the individual outcomes of nausea and vomiting.

3.2.4. Anxiolysis Inconsistent evidence from 2 small RCTs (N , 100) of low or moderate risk of bias addressed anxiolysis over a follow-up duration of 1 or 5 days.21,48 Estimates of effect indicated either a significant 6% improvement in anxiety or no clinically and statistically significant difference.

3.2.5. Sleep restoration Two studies of high risk of bias, because of serious concerns about selective outcome reporting, provided conflicting evidence regarding sleep restoration. Although Nimmaanrat et al. qualitatively reported no difference in sleep disturbance over a 24-hour period,47 In a trial, Buvanendran et al. demonstrated a statistically significant reduction in sleep disturbance ratings on an 11-point scale (mean difference: 21.7; 95% CI, 22.56 to 20.84) over the first 24 hours. This significant benefit, however, was not observed during subsequent nights.6 The quality of this conflicting evidence was graded as very low (G8 in Table 2). 3.2.6. Length of hospital stay The evidence was inadequate for pain model and dose-specific analyses. As such, we pooled data from all 4 studies irrespective of pain model. Low QoE from 4 trials showed clinically

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Figure 6. Pregabalin vs. placebo (,150-.300mg/day): patients with nausea or vomiting.

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Figure 7. Pregabalin vs. placebo: length of hospital stay in hours.

unimportant differences in hospital stay implying no important difference for this outcome (G9 in Table 2; Fig. 7). 3.2.7. Chronic postoperative pain Two trials (N 5 110) judged at moderate risk of bias reported longer-term data for pronociception (at rest or on movement).5,12

Pregabalin 150 to 300 mg/d was administered perioperatively (1-4 days). Additional analgesia as needed was allowed. The evidence for chronic postoperative pain was of low quality and did not demonstrate any significant differences for this outcome over a 3 to 6 month observation period irrespective of whether the pain was at rest or with movement (G10 and G11 in Table 2).

Figure 8. Pregabalin vs. placebo: patients with somnolence.

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3.2.8. Perioperative harm outcomes 3.2.8.1. Somnolence Somnolence was reported in 8 RCTs of low to moderate risk of bias for this outcome.2,5,8,11,26,28,41,48 One trial with a single patient experiencing this outcome was excluded because the longest observation period for this outcome was well short of 24 hours (6 hours after single dose of intervention or placebo).2 Because of small sample sizes, most studies yielded imprecise estimates of effects with overlapping CIs. As such, we pooled data across all pregabalin doses. A pooled estimate significantly favored the control (RR: 1.72, 95% CI, 1.08-2.72) (Fig. 8).

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When this outcome was measured in terms of sedation score, pooled results from 8 trials (N 5 470) did not corroborate the findings above. No significant differences were noted for the meta-analytic estimate of ratio of mean sedation scores (Fig. 10). 3.2.10. Visual disturbances Meta-analysis of 17 trials (N 5 1190) yielded moderate QoE of an increase in the reversible outcome of blurred vision with pregabalin dose (RR: 3.08, 95% CI, 1.91-4.96). The absolute risk difference, however, is likely to be low (G12 in Table 2; Fig. 11). Dose effect modification was not significant across these studies.

3.2.9. Sedation Meta-analysis of 17 trials of low to moderate risk of bias (N 5 1232) demonstrated significantly increased moderate to severe sedation in the pregabalin group receiving 150 to 300 mg of the drug per day (RR: 1.51, 95% CI, 1.16-1.96). Per 1000 treated patients, the absolute risk difference (95% confidence) was 13 more patients with moderate–severe sedation to as high as 77 more patients. Estimates of doses specific effects were not statistically significant (Fig. 9).

3.2.11. Withdrawal due to adverse events Across all 11 data contributing studies of generally low to moderate risk of bias, 40 of 977 patients withdrew due to adverse events. Irrespective of the dose and surgical pain model type, no significant differences were noted between pregabalin (150-600 mg/d, mean dose 300 mg/d) and placebo—absolute risk difference per 1000 patients of 6 fewer to 23 (95% CI bounds) more withdrawals due to adverse events (Fig. 12).

Figure 9. Pregabalin 150–300mg/day vs. placebo: patients with moderate to severe sedation.

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Figure 10. Pregabalin ,150–300mg/day vs. placebo: sedation score.

3.2.12. Other adverse events Sparse evidence precluded meaningful conclusions regarding the outcomes of mortality, serious adverse events respiratory depression, total adverse events, withdrawal due to lack of pregabalin efficacy, early ambulation, early feeding, confusion, and cognitive dysfunction.

4. Discussion Our systematic review not only updates extant systematic review evidence (addition of 28 new randomized controlled clinical trials amounting to a total of 43 studies and more than 3600 patients) but also adds additional insight into the previously established effectiveness of pregabalin in the management of acute postoperative pain. To our knowledge, this is the first systematic review that empirically establishes that improved pain control with pregabalin is small in magnitude (approximately 10%) and is primarily restricted to surgical procedures associated with pronociceptive mechanisms. Although analgesic consumption decreased with pregabalin use across the various pain models irrespective of their association with pronociceptive pain, a significant improvement in pain was not observed in models not associated with pronociceptive pain. These contrasting findings merit further exploration but could be explained by physician-prescribing practices influenced by pregabalin coprescription. We acknowledge that the proposed surgical models are based on our clinical acumen; as such, evidence syntheses should be interpreted for the models as we have categorised. These surgical models were defined in our a priori systematic review protocol.19 However, the paucity of data, particularly for CPSP, limited model categories to model 1 (ie, pronociception), nonmodel 1 (ie, model 2), or unclear (model 3), thereby impacting the discriminatory power of our investigation of pregabalin effect modification by various surgical models. In the past decade, the scope of perioperative pain management has broadened from solely treating the pain to more comprehensive and global goals of enhanced recovery (early

ambulation, early feeding, and shortened length of stay) with fewer side effects and the potential for long-term benefits (prevention of CPSP, etc). This widespread adoption and implementation of perioperative multimodal analgesia is intended not only to improve analgesia but also to reduce opioid requirements and their immediate side effects and the longterm consequences. It is with these goals that the role of “adjuvant drugs” such as pregabalin are being used in the perioperative period to improve the management of acute pain. More recently, the role of perioperative pain management has been evaluated in more long-term outcomes—for the prevention of CPSP.13 These investigators suggest that pregabalin administered for acute pain may have a more promising and effective role in the prevention of CPSP syndromes. This increased use of pregabalin as a component of multimodal analgesia is evident from the increased conduct and reporting of clinical trials in acute pain. But, this systematic review and metaanalysis confirms that pregabalin should be administered only to some patients undergoing certain procedures to optimize the clinical efficacy of this drug. We believe a better understanding of this perioperative role of pregabalin should influence both current clinical practice and future clinical trials. Others have begun to explore a surgical model-specific review of pregabalin efficacy and have limited their analysis to single surgical procedures (hysterectomy,61 spinal cord injury,45 and spine surgery62). We find this trend encouraging, but we would recommend comparing outcomes between models as we have proposed. The clinical algorithm we had previously published was based on our experience with this drug and was supported by both animal models of acute hyperalgesia and clinical trials on human subjects with chronic neuropathic pain. The algorithm provided a more nuanced approach to prescribing pregabalin in acute postoperative settings encouraging pregabalin particularly for pronociceptive surgical pain. The aforementioned findings lend evidence-based credence to our algorithm. Investigators have explained the inconsistencies observed in the analgesic efficacy of perioperative pregabalin with evidence from basic science

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Figure 11. Pregabalin ,150–300mg/day vs. placebo: blurred vision.

literature.63 They and others have proposed that pregabalin may reduce hyperexcitability of dorsal horn neurones induced by tissue damage (rather than reduce the afferent input from the site of tissue injury itself) and therefore be effective in surgical models in which acute neuropathic pain exists. 20 Despite this understanding, none of the previous systematic reviews explored the effect of pregabalin on surgical models that were associated or not associated with pronociception. This has now been done in our systematic review. Furthermore, the GRADE approach we have used in grading the QoE enhances our confidence that the estimates of effects that we obtained will help inform future clinical practice guidelines for postoperative analgesia. There is currently no information on economic outcomes associated with pregabalin for acute pain. Without cost analysis, the overall impact of the risk-benefit findings of perioperative pregabalin use will remain incomplete.51 Future clinical research also will have to include cost–benefit analyses to better guide perioperative pregabalin policy makers. Pregabalin has significant effects on the CNS and is approved as an antiepileptic and for generalized anxiety disorder.25 In the perioperative period, these CNS depressant effects may present as adverse effects.57 This systematic review found that, although

the absolute risk differences were low, pregabalin use was significantly associated with reversible blurred vision, sedation, and somnolence. Limitations in quantity and validity of evidence addressing the effectiveness of pregabalin in terms of length of hospital stay and other outcomes of enhanced recovery, chronic postoperative pain, and serious adverse events precluded our drawing any confident conclusions. Along with the clinical relevance of the small magnitude of incremental analgesic effect restricted to pronociceptive pain observed for pregabalin, these represent important gaps in evidence that needs to be considered in patient-centered decision making and selection of surgical patients. Findings from our review compel the following future research recommendations for pregabalin use for postoperative pain control. Future research should: 1. Focus on restricting studies to surgeries associated with pronociceptive mechanisms 2. Evaluate the clinical significance of incremental dose effects 3. Include well-powered, well-designed, and pragmatic studies investigating major and serious adverse events and outcomes of enhanced recovery

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Figure 12. Pregabalin vs. placebo: withdrawals due to adverse events (observation period ,72hours).

4. Investigate the cost-effectiveness of adjuvant pregabalin added onto multimodal analgesia 5. Take on the initiative of developing standardized core outcome set for research purposes in this field.

Article history: Received 21 November 2014 Received in revised form 20 March 2015 Accepted 23 March 2015 Available online 31 March 2015

5. Conclusions With moderate confidence, we have demonstrated that pregabalin analgesic effectiveness is largely restricted to surgical procedures associated with pronociceptive mechanisms. Given the small magnitude of reduction in pain perception and analgesic consumption, the significance of pregabalin effectiveness should be considered in decision making along with the balance of benefits and uncertainties about serious harms for careful selection of surgical patients. Instead of replicating earlier study designs, future trials should be large pragmatic investigations of clinically important pain control, enhanced recovery, and unintended serious adverse events of add-on pregabalin vs the alternative of stepping up opioid analgesia in pronociceptive surgical pain. Furthermore, this research field is in dire need of development of standardised core outcome set for research purposes.

Conflict of interest statement The authors have no conflicts of interest to declare. This project was supported by funds from the Department of Anesthesiology (TOH) and Ottawa Hospital Research Institute (OHRI).

Acknowledgements The authors acknowledge the contributions of Alexandra Davis (Librarian, TOH) for the search strategies and literature search, Raymond Daniel (OHRI) for the bibliography, and Chantelle Garrity (OHRI) for the administrative support.

Appendix A. Supplemental Digital Content Supplemental Digital Content associated with this article can be found online at http://links.lww.com/PAIN/A70 and http://links. lww.com/PAIN/A71.

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