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Review Article

A systematic review and meta-analysis of ketamine for

the prevention of persistent post-surgical pain

E. D. McNicol1, R. Schumann2 and S. Haroutounian3

1Department of Anesthesiology and Pharmacy, Tufts Medical Center, Boston, MA, USA, 2Department of Anesthesiology, Tufts MedicalCenter, Boston, MA, USA and 3Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA

While post-operative pain routinely resolves, persistent post-surgical pain (PPSP) is common in certain surgeries; it causesdisability, lowers quality of life and has economic consequences.The objectives of this systematic review and meta-analysis wereto evaluate the effectiveness of ketamine in reducing the preva-lence and severity of PPSP and to assess safety associated withits use.

We searched the Cochrane Central Register of ControlledTrials, MEDLINE and EMBASE through December 2012 for arti-cles in any language. We included randomized, controlled trialsin adults in which ketamine was administered perioperativelyvia any route.

Seventeen studies, the majority of which administeredketamine intravenously, met all inclusion criteria. The overallrisk of developing PPSP was not significantly reduced at anytime point in the ketamine group vs. placebo, nor did compari-sons of pain severity scores reach statistical significance. Sensi-tivity analysis of exclusively intravenous ketamine studies

included in this meta-analysis demonstrated statistically signifi-cant reductions in risk of developing PPSP at 3 and 6 months(P = 0.01 and P = 0.04, respectively). Adverse event rates weresimilar between ketamine and placebo groups.

The study data from our review are heterogeneous and dem-onstrate efficacy of intravenously administered ketamine only incomparison with placebo. Highly variable timing and dosing of ketamine in these studies suggest that no unifying effectiveregimen has emerged. Future research should focus on clinicallyrelevant outcomes, should stratify patients with pre-existingpain and possible central sensitization and should enroll suffi-ciently large numbers to account for loss to follow-up in long-term studies.

Accepted for publication 30 June 2014

© 2014 The Acta Anaesthesiologica Scandinavica Foundation.Published by John Wiley & Sons Ltd

Post-operative pain routinely resolves afterhealing of the surgical site; however, in some

patients, pain persists long after surgery. Persistentpost-surgical pain (PPSP, also referred to as‘chronic post-surgical pain’) is common, causes dis-ability, lowers quality of life and has economic con-sequences.1 Reviews of its prevalence report that22–67% of persons who underwent thoracotomy,30–81% of persons who had a limb amputated,

11–51% of women who had breast surgery, 3–56%of persons who had a cholecystectomy and 0–37%of persons who had an inguinal hernia repairdeveloped PPSP.1–4 Variations in estimates are inpart due to differences in the definitions of PPSP. Acommon definition is that PPSP develops after asurgical procedure, is not from a pre-existing con-dition, is of at least 2 months duration, and thatother causes of pain have been excluded.5 Whilethis definition is comprehensive and was devel-

oped with the aim of accurately identifying PPSP,its applications in research are challenging, withsome studies reporting its use, but not applying allcriteria.6 Risk factors for developing PPSP includepatient (demographic, psychosocial and genetic)and periprocedural or perioperative factors (dura-tion and type of surgery, extent of intraoperativenerve damage, and intensity and duration of post-operative pain).1,7

Specific perioperative analgesic interventionsmay reduce the incidence of PPSP, but it is unclearwhich regimen is of most benefit. Evidence from theuse of regional anesthesia and preemptive ormultimodal analgesia has presented mixed results.1

While the development of PPSP is multifactorial,one of the major suggested mechanisms for the tran-sition from acute to persistent post-operative pain iscentral sensitization.8 During surgery, repeatedpainful stimulation of primary afferent neurons

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Acta Anaesthesiol Scand 2014; 58: 1199–1213Printed in Singapore. All rights reserved

© 2014 The Acta Anaesthesiologica Scandinavica Foundation.

Published by John Wiley & Sons Ltd

ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/aas.12377

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results in the release of excitatory neurotransmitters,including glutamate, which binds to the N-methyl-D-aspartate (NMDA) receptor on the post-synapticmembrane in the dorsal horn. This event alterscalcium influx into the second-order neuron, ulti-mately producing progressively increaseddepolarization of the post-synaptic membrane.9

Perioperative opioid administration may also con-tribute to hyperalgesia via similar mechanisms.10

The increased excitability and synaptic efficacy of neurons in central nociceptive pathways secondaryto peripheral tissue damage and repeatednociceptive input is known as central sensitization;it reduces mechanical thresholds, exaggerates theresponse to noxious stimuli and facilitates a spreadof sensitivity to normal tissue.8 Patients may report both hyperalgesia (increased sensitivity to painfulstimuli) and allodynia (pain in response to normallynonpainful stimuli).9,11

Glutamatergic excitation occurs acutely and suba-cutely following peripheral injury to primary affer-ent neurons in animal models, and NMDA receptor blockade has been shown to attenuate spinalNMDA-mediated sensitization of dorsal hornneurons.12–16 Although the role of NMDA receptorsin long-term central sensitization is unknown, theconcept of perioperative NMDA receptor blockadeto attenuate or prevent central sensitization and sub-sequent development of PPSP has generatedincreasing clinician interest.

Ketamine, a noncompetitive NMDA receptor

antagonist, may have a role in reducing the inci-dence of PPSP, when administered perioperatively.17

Ketamine is a general anesthetic when used in highdoses. Even low (‘subanesthetic’) doses appear toreduce both pain and analgesic consumption inacute post-operative pain.18–20 Limited evidence alsodescribes its effectiveness in both chronic noncancerand cancer pain populations.21,22 Ketamine may beadministered intranasally, orally or subcutaneously,particularly when used for chronic pain, but is typi-cally administered intravenously and occasionallyepidurally in the perioperative setting. Patients may

receive a bolus and/or continuous infusion, pre-,intra- and/or post-operatively. It may also beadministered in combination with an opioid as acomponent of patient-controlled analgesia (intrave-nous or epidural) or with opioids and nonopioids inthe context of a multimodal analgesic regimen.Analgesic doses employed clinically vary widely, but intravenous bolus doses in the range of 0.2–0.75 mg/kg and infusions of 2–7 mcg/kg/min have been recommended.18,22,23 Common adverse reac-

tions include cardiovascular (hypertension, tachy-cardia) and central nervous system (vivid dreams,visual hallucinations, emergence delirium) events,which are thought to be less common or severe atsubanesthetic doses and with coadministration of a benzodiazepine.24 Ketamine is a chiral molecule andis typically administered as a racemic 50 : 50mixture of the two enantiomers S-ketamine andR-ketamine. Both enantiomers bind to NMDAreceptors, but S-ketamine is a more potent antago-nist and a more powerful analgesic.25

The objectives of this systematic review and meta-analysis are to evaluate the effectiveness of ketamineadministered perioperatively (pre-, intra- and post-operatively) in reducing the prevalence and severityof PPSP in adult patients and to assess both short-and long-term adverse events associated with itsuse in this setting.

MethodsInclusion and exclusion criteriaWe included randomized, placebo- or active-controlled trials (RCTs), described as double- blinded, in adults (aged 18 years and older)undergoing any type of surgical procedure involv-ing incision and associated with PPSP. Recognizingthat persistent pain maybe more easily preventedthan reversed, we nonetheless included studieswhere patients may have had pre-existing pain, aswe judged that stipulating patients who did nothave pain pre-operatively would severely limit thenumber of eligible studies.

We included studies administering any dose of ketamine by any route. Both single and multipledose studies and studies employing continuousinfusions were assessed. Studies where ketaminewas administered in addition to a traditional anal-gesic (opioid and/or nonopioid) regimen in onestudy group and compared with a group receivingthe same basic regimen (but without ketamine) werealso included.

For published studies, peer-reviewed journalpublication was required; abstracts were notincluded unless they were less than 3 years old. Weexcluded studies with fewer than 10 participants toovercome random play of chance on estimation of treatment effect.26 We excluded studies of experi-mental pain, case reports and clinical observations.

Outcome measures

Primary outcome: prevalence of PPSP. Our knowl-edge of the literature suggested that very few

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studies were rigorous enough to identify incidenceand that assessment of prevalence varied betweenstudies, particularly in regard to follow-up periods.We extracted incidence/prevalence of PPSP basedon its definition within each study. Where data werepresented in several formats, we chose the mostliberal definition of PPSP in an effort to employ themost uniform possible outcomes reported acrossotherwise heterogeneous studies. For example,where a study reported ‘number of patients withpain intensity > 3’, ‘number of patients with painworse than before surgery’ and ‘number of patientswith any pain’ at a relevant time point, we chose thelast definition as we expected this would be themost commonly reported. We meta-analyzed preva-lence at 3 months, 6 months and 1 year or later.

Secondary outcomes

1. Intensity or severity of PPSP as measured by

either visual analog or verbal rating scales,respectively

2. Number of participants experiencing any seriousadverse event

3. Number of participants experiencing specificadverse events

4. Severity of adverse events5. Withdrawals due to adverse events

We extracted adverse event data from the acuteperioperative period and from subsequent long-term follow-up to the end point of each study.

Search methods for identification of studiesWe searched the following databases throughDecember 2012: The Cochrane Register of Con-trolled Trials (CENTRAL), MEDLINE (via Ovid)and EMBASE (via Ovid). We combined search termsfor ketamine, PPSP and randomized, controlledstudies, without applying language restriction. Thesearch strategy for MEDLINE was as follows:

1. exp Ketamine/2. (persist* or chronic).mp. or exp Postoperative

Complications/

3. 1 and 24. randomized controlled trial.pt.5. controlled clinical trial.pt.6. randomized.ab.7. placebo.ab.8. drug therapy.fs.9. randomly.ab.

10. trial.ab.11. groups.ab.12. or/4–11

13. [animals not (humans and animals)].sh.14. 12 not 1315. 14 and 3

This strategy was adapted for each database.Additional studies were sought from the referencelists of retrieved articles and reviews. No attemptwas made to assess reporting bias; however, we

searched the clinical trial registry http://www.clinicaltrials.gov in an attempt to minimizepublication bias.

Data collection and analysisData extraction was divided among the reviewauthors, with each extraction being independentlyduplicated, using a standard form. Data suitable forpooling were entered into RevMan 5 software27 anddouble-checked by another author. Extracted dataincluded information about the type of surgery andnumber of participants treated, drug and dosing

regimen, study design (placebo or active control),study duration and follow-up, outcome measuresand results, withdrawals and adverse events.

Assessment of risk of bias in included studiesTwo review authors independently assessed the riskof bias of all included studies. The review authorsmade critical assessments for each of the followingdomains: sequence generation (randomization),allocation concealment, blinding, incompleteoutcome data and selective outcome reporting.Review author judgment for each domain wasentered into a risk of bias table, as either ‘low risk’,‘high risk’ or ‘unclear risk’ (indicating either lack of information or uncertainty over the potential for bias).

Measures of treatment effectDiscrete events such as the proportion of partici-pants experiencing PPSP, or the proportion of par-ticipants reporting adverse events, were used toperform meta-analyses of risk ratio (RR) with 95%confidence intervals (CIs).28 When a statistically sig-

nificant RR occurred between interventions, we alsocalculated the numbers needed to treat to benefit(NNTs) or harm (NNHs), which were derived fromthe absolute risk reduction (also known as risk dif-ference). Meta-analyses were also undertaken whencomparable data were available from continuousoutcomes, such as severity of PPSP, using weightedmean differences. We used a fixed effect model formeta-analysis of both dichotomous and continuousoutcomes. We performed sensitivity analysis to

Ketamine for prevention of PPSP

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assess the robustness of our results by alternatelyundertaking meta-analysis using a random effectsmodel.

We performed a per-protocol rather than anintention-to-treat (ITT) analysis. In interventiontrials for the treatment of existing conditions, par-ticipants lost to follow-up in an ITT approach areassumed to be nonresponders (i.e., still suffer fromthe condition). In this study, we assess the preven-tion of a potential event (PPSP) in patients receivinga brief perioperative intervention with ketamine.ITT analysis is not relevant in this case, as patientslost to follow-up cannot be assumed to experienceor not to experience the event. Therefore, per-protocol analysis was used, and discrepancies between number of participants enrolled andnumber of participants in whom outcomes werereported are noted in Table 1.

Assessment of heterogeneityWe visually assessed heterogeneity by studyingforest plots and quantified statistical heterogeneityusing the I2 statistic. An I2 value of greater than 50%is considered to indicate substantial heterogeneity.29

Where possible, we performed the following pre-determined subgroup analyses in an attempt toexplain heterogeneity: type of surgery, dosageregimen, route of administration, definition of PPSPand follow-up periods.

Results

Results of the searchOur literature search yielded 918 records(CENTRAL, 281; MEDLINE, 580; EMBASE 57). Oursearch of http://www.clinicaltrials.gov producedfive studies (NCT 01017393, NCT00313378,NCT00726258, NCT01017393, NCT00354029), all of which were also published articles and wereincluded in our literature search records.30–34 Forty-three articles were selected for full-text review(Fig. 1). Seventeen studies met all inclusioncriteria.30–46

All included studies were published since 2000,with the majority being less than 5 years old, reflect-ing the relative novelty of using ketamine in thisarena. All were placebo controlled. One study42 alsoincluded an active control group in which partici-pants received gabapentin. In total, 1015 participantswere randomized to receive ketamine and 785 toreceive placebo, although a small percentage of par-ticipants withdrew from their respective studies before receiving their assigned intervention. The

dose of ketamine administered varied both withinand between studies. Some studies administeredonly a single bolus dose of ketamine, whereas themajority administered a bolus plus a subsequentcontinuous infusion. Boluses were typically admin-istered immediately before surgery, with infusionsstarted directly afterward and continued for up to72 h post-surgically. The majority of studies admin-istered ketamine intravenously (Suppa et al.43

administered an intramuscular bolus in addition toan intravenous infusion). Two studies employed theepidural route; both administered ketamine addedto patient-controlled epidural analgesia.33,46 De Kocket al.36 included separate arms receiving either epi-dural or intravenous ketamine. Lastly, four studiesthat administered S-ketamine, either intrave-nously34,40,43 or epidurally,33 reported variously to be between two to four times as potent as the racemicmixture.47 Table 1 details the types of surgery per-

formed and duration of follow-up.

Risk of bias in included studiesAll but three30,31,45 included studies described satis-factory methods of randomization; however, onlynine studies adequately described methods of allo-cation concealment. Only 8 of the 17 studies usedadequate methods to ensure blinding. In the othernine studies, the risk of bias was unclear becauseattempts at blinding participants, at blinding asses-sors or both were not adequately described. Twostudies were assessed as being at high risk of attri-

tion bias (incomplete reporting of outcome data).43,45

In both studies, there were a large number of par-ticipants in both arms lost to follow-up, with nodescription of the reasons for withdrawal. In themajority of studies, due to their long-term nature,there were considerable losses to follow-up, butthese were generally balanced between arms alongwith similar reasons for withdrawal. For assessmentof selective reporting, most studies reported on allof the outcomes described in their Methods sectionsand most of these we considered clinically relevantfor this analysis. However, Sen et al.42 reported inci-

dence of PPSP as being significantly lower in thegabapentin group but did not include supportingdata, Suppa et al.43 evaluated residual pain at 6months but did not report it and one study did notreport adverse events.46 We were able to confirmthat all outcomes were reported in the five studiesalso published on the trial registry http://www.clinicaltrials.gov. Other potential sources of bias included the considerable variability in howeach study defined PPSP, although we attempted to


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Table 1

Summary of included studies, ketamine vs. placebo.

Stu dy Sur ge ry, ti me poi nt s w henPPSP assessed, number ofparticipants (enrolled/at eachtime point for selectedketamine regimen)

Ketamine regimen(s) Definition of PPSP used inanalysis

Secondary outcomesmeasured at 3 months or later

Results of secondaryoutcomes

Bilgen et al.35 C-Section under generalanesthesia

6 months and 1 year.K: 35/35/35

P: 35/35/35

B: 0.25, 0.5* or 1 mg/kg IVbefore induction ofanesthesia

Any pain Pain intensity (VRS): numberof patients with mild,moderate, severe or no painat all.

No participants had painseverity > mild at 6 monthsor 1 year.

Crousier et al.30 Radical mastectomy withaxillary lymph nodedissection

3 monthsK: 13/12P: 18/18

B: 0.5 mg/kg IV before incisionINF: 0.25 mg/kg/h infusion until

end of surgery

NPSI and BPI used, butunclear how PPSP wasdefined

NPSI total score (0–100), %with hyperalgesia at woundsite, surface area of site ofhyperalgesia, nature of pain.

NPSI score very low in bothgroups (4.9 vs. 4.45).

NS between groups for anysecondary outcome.

De Kock et al.36 Surgical resection of rectaladenocarcinoma

6 months and 1 year.K: 20/19/19P: 20/18/17

B: 30 min before skin incision,INF: until end of surgery.

IV arms: B 0.25 mg/kg, INF0.125 mg/kg/h; or 0.5 mg/kgand 0.25 mg/kg/h*

Epidural arms: B: 0.25 mg/kg,INF 0.125 mg/kg/h; or0.5 mg/kg and 0.25 mg/kg/h.

‘Do you feel any pain at thescar area?’

Analgesic use in thosereporting pain, pain at anyother place, unpleasantmanifestations experiencedsince operation.

Acetaminophen ± codeinesufficient in all participantsexperiencing residual pain.

NS between groups for allother secondary outcomes.

Duale et al.31 Elective thoracotomy4 monthsK: 42/34P: 44/35

B: 1 mg/kg IV at inductionINF: 1 mg/kg/h IV during

surgery, then 1 mg/kg over24 h

NPSI > 0 NPSI total score, SF-36. Median NPSI score = 0 in bothgroups.

SF-36 scores did not differbetween groups.

Dullenkopf et al.37 General and orthopedic(unspecified)

3 monthsK: 41/29P: 33/25

B: 0.15 or 0.5 mg/kg* IV Participant rating of painmanagement as ‘excellent’,‘acceptable’ or ‘poor’.

For analysis, anyone reporting‘acceptable’ or ‘poor’assigned to prevalence ofPPSP group.

Pain intensity (VAS 0–10)during rest and movement,patient satisfaction.

No difference between groups,but orthopedic placebosubgroup had worst pain(P = 0.041).

Hayes et al.38 Above and below kneeamputations

6 monthsK: 22/15P: 23/17

B: 0.5 mg/kg pre-inductionINF: 0.15 mg/kg/h × 72 h

post-operatively

Patient-reported phantom orstump pain during previous24 h (used stump pain foranalysis)

Incidence of stump andphantom limb ‘troublesomepain’ (NRS ≥ 6), severity ofstump and phantom limbpain (NRS highest, lowest orusual), duration of stumpand phantom limb pain.

NS between groups for allsecondary outcomes.

Note: The development ofsignificant phantom limbpain after day 3 was treatedwith amitriptyline and/orsodium valproate.

Joseph et al.32 Thoracotomy with partialpneumonectomy

3 monthsK: 24/18P: 27/19

B: 0.5 mg/kg epidural atanesthesia induction

INF: 3 mcg/kg/min epiduralintraop,1.5 mcg/kg/min × 48 hpost-operatively

Limitation of daily activities Pain intensity (NRS 0–10) atrest and with movement,analgesic consumption,limitation of normal activityinduced by pain, limitation ofthe abduction of the surgeryside arm, any complication.


Katz et al.39 Radical prostatectomy6 monthsK: 56/36P: 50/38

B: 0.2 mg/kg IV either 10 minbefore or 70 min* afterincision

INF: 2.5 mcg/kg/min IV fortotal of 80 min

Any pain at site of surgery MPQ, pain interference in dailylife, methods of pain reliefsought, medication use.

NS in number of participantstaking medication (none inany group).


Mendola et al.40 Thoracotomy with partial or fullpneumonectomy

3 and 6 monthsK: 33/31/29P: 33/30/28

S (+) ketamine INF:0.1 mg/kg/h IV viaelastomeric pump,pre-incision × 60 h

NPSI > 1 Worst pain intensity (NRS0–10), pain localization, totalamount of analgesics takenup to 6th post-operationmonth. PPSP consideredmild for NRS 0–3, moderateand severe if hamperingdaily life.


Remerand et al.41 Total hip replacement3 and 6 monthsK: 79/75/72P: 75/72/70

B: 0.5 mg/kg IV pre-incisionINF: 2 mcg/kg/min IV × 24 h

Unclear Pain intensity (NRS 0–100) atrest, with walking, in otherlocations, analgesic use,distance and difficultywalking.

At 6 months, 10 P group vs. 3K group NRS at rest > 3(P = 0.04).


Ryu et al.33 Thoracotomy3 monthsK: 103/65P: 106/68

S (+) ketamine PCEA (+ 0.12%levobupivacaine and2 mcg/ml fentanyl).

B: 1.2 mg as soon as patientarrived at operating room

INF: 1.2 mg/h, additionalboluses of 1 mg, lockout20 min, until 3rdpost-operative day

Any pain around the incisionsite

Pain severity (VAS 0–100) atrest and with movement,allodynia, numbness.


Sen et al.42 Elective abdominalhysterectomy

3 and 6 monthsK: 20/20/20P: 20/20/20

B: 0.3 mg/kg IV 1 h beforesurgery

INF: 0.05 mg/kg/h IV until endof surgery

‘Incidence of incisional pain’ –no further details.

Not reported in Results

Pain intensity (VRS 0–10),impact of pain on dailyactivities.

Pain intensity low in bothgroups and NS different.

Data not presented for impacton daily activities, butreported to be similar.

Spreng et al.34 HemorrhoidectomyK: 43/39P: 39/38

S (+) ketamineB: 0.35 mg/kg IV immediately

before incisionINF: 5 mcg/kg/min until 2 min

post-surgery

Any pain (NRS > 0) at rest Pain intensity at rest, sittingand with defecation.

NS between groups.


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homogenize data as much as possible, as describedabove. Also, the majority of studies were poweredto show a difference in acute outcomes rather thanfor those measured at 3 months and later.

Primary outcomeSixteen studies presented data that contributed tothe meta-analysis of prevalence of PPSP (Sen et al.42

did not report prevalence). In studies where morethan one ketamine regimen was administered, wechose the dose closest to those used in other studies.We were able to perform sub-analysis at three sepa-rate time points: 3 months (for one study, we useddata from 4 months31), 6 months and at 1 year orlater.

At 3 months, the overall RR of developing PPSP

when both intravenous and epidural routes wereassessed was 0.84 in the ketamine group vs. placebo;that is, a 16% relative reduction in the probability of developing PPSP, but this was not statistically sig-nificant (P = 0.06, 95% CI: 0.70–1.01) (Fig. 2). Nosingle study demonstrated a statistically significantdifference in PPSP risk between ketamine andplacebo. Overall, 109 of 384 (28%) participantsreceiving ketamine reported PPSP at 3 months vs.137 of 387 receiving placebo (35%).

At 6 months and at 1 year or later, the overall RRwas again not statistically significant when bothintravenous and epidural routes were assessed. Theoverall number of participants reporting declined at

each time point, with 260 participants from ketaminearms reporting at 6 months and 71 reporting at 1year or later. For the 6-month and 1-year or lateranalyses only one study demonstrated a statisticallysignificant reduction in risk of developing PPSP (at 6months).41 In this study of patients undergoing hipreplacement, 6 of 72 participants in the ketaminegroup vs. 15 of 70 participants in the placebo groupreported PPSP (P = 0.04).

One study compared ketamine with an activecomparator, gabapentin.42 The authors reported thatthe prevalence of incisional pain was reduced in the

gabapentin group at 3 and 6 months compared with both the ketamine and placebo groups, but did notpresent supporting data.

Secondary outcomesMean intensity of PPSP was reported in five studiesat 3 months and four studies at 6 months, usingeither a visual analog or verbal rating scale (zeroindicating no pain, 10 indicating worst imaginablepain). At 3 months, the reduction in pain intensity in

Table 1 Continued

Stu dy Sur ger y, t ime poi nt s w henPPSP assessed, number ofparticipants (enrolled/at eachtime point for selectedketamine regimen)

Ketamine regimen(s) Definition of PPSP used inanalysis

Secondary outcomesmeasured at 3 months or later

Results of secondaryoutcomes

Suppa et al.43 Elective repeat C-section3 yearsK: 28/13P: 28/13

S (+) ketamineB: 0.5 mg/kg IM 10 min

post-partumINF: 2 mcg/kg/min IV × 12 h

post-operatively

Any residual pain at the scararea

Analgesic drugs used forwound pain, wounddysesthesia, pain in othersites, analgesic drugs forpain in other sites.

All dichotomous, NS betweengroups.

Suzuki et al.44 Thoracotomy, primarily for lung

cancer3 and 6 monthsK: 25/22/22P: 25/22/22

INF: 0.05 mg/kg/h IV after

intubation × 72 hpost-operatively

Baseline (usual) NRS score

of ≥ 1

Pain intensity (NRS 0–10) at

baseline and worst,unpleasant sensations onthe surgical wound, pt feltinconvenienced by thewound, number of pts whoreceived pain medication.

Baseline pain intensity lower in

K group at 3 months(P = 0.02). Number of ptswho received painmedication lower at 3months (P = 0.03).

All other secondary outcomesNS between groups.

Sveticic et al.45 Major elective orthopedicsurgery

3 and 6 monthsK: 176/49/17P: 176/42/19

PCA: 1.5 mg (+ 1.5 mgmorphine) IV Q8 min prn upto 10× in 1 h, until ptsrequired an average of < 1PCA bolus/h during the last12 h

Pain at the same locationworse than before surgery

Pain intensity (VAS 0–10). Pain intensity NS betweengroups at 3 or 6 months.

Wilson et al.46 Above and below kneeamputation

3, 6 and 12 monthsK: 24/15/15/14P: 29/19/16/15

B: 0.5 mg/kg (+ 0.5%bupivacaine) epidural beforestarting surgery.

INF: 3.3 mg/kg/l (+bupivacaine 0.125%)epidural at 15 ml/hintraoperatively, 10–20 ml/hpost-operatively × 48–72 h

Any pain in the stump Pain intensity (VAS 0–10) ofphantom and stump pain,MPQ, NPSI, QST, Hospitalanxiety and depressionscale, analgesic use.

Anxiety (P < 0.001) anddepression (P = 0.003)reduced in K group vs.pre-operatively from 3months until end of study,but not in P group vs.pre-operatively.

All other secondary outcomes

NS between groups.

*Regimen used in meta-analysis.K, Ketamine; P, placebo; B, bolus; INF, infusion; IV, intravenous; BPI, brief pain inventory; MPQ, McGill Pain Questionnaire; NPSI, neuropathic pain symptom inventory; NS, not statisticallysignificant; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; QST, quantitative sensory testing; VAS, visual analog scale; VRS, verbal rating scale. PPSP,persistent post-surgical pain; NRS, numeric rating scale; IM, intramuscular.


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patients receiving ketamine (n = 154) vs. placebo(n = 147) was neither statistically nor clinically sig-nificant, applying interpretive standards for thelatter described elsewhere.48 Results were similar at6 months. There were insufficient data for meta-analysis beyond 6 months.

No individual studies demonstrated a reduction

in pain intensity at 3 months, and only one39

dem-onstrated a reduction in intensity in those receivingketamine at 6 months. In this study, those receivingketamine had a mean visual analog scale pain inten-sity of 2.8 ± 1.1 vs. those receiving placebo 3.4 ± 1.1(P = 0.02), although the number of participants waslow in each study arm (n = 36 and n = 38 in theketamine and placebo groups, respectively).

In the single active comparator study,42 partici-pants in the gabapentin group reported lower pain

scores at 3 and 6 months vs. ketamine and placebo,although mean verbal rating scale scores were lowin all groups. The authors stated that those receivinggabapentin suffered less impact of pain on theirdaily activities at 3 months, but did not present sup-porting data.

Adverse events were almost exclusively moni-tored during the acute administration phase, eitherfor the duration of the ketamine infusion or shortlythereafter. Adverse events were only mentioned atlong-term follow-up (3 months and onward) in rela-tion to participants withdrawing from thestudy.31,32,36,38,40,44,46 No long-term adverse eventswere attributed to the interventions by the investi-gators, and they appeared to be evenly balanced between ketamine and placebo groups. Mostly,long-term adverse events included death or recur-rence of presenting disease, at rates typical in suchpopulations. For adverse events monitored in the

acute phase (typically up to 72 h post-operatively)and commonly associated with ketamine, there wasno statistical difference between ketamine andplacebo for hallucinations and nightmares/vividdreams, but there was an increase in visual distur- bances (e.g., nystagmus, diplopia), with an RR of 3.13 (95% CI: 1.65–5.94), translating to a NNH of around 9 (95% CI: 6–17). Similarly, there were nodifferences between ketamine and placebo for seda-tion, nausea and vomiting, which are adverse effectsthat might be expected to be less frequent in theketamine arms because of reduced opioid consump-

tion attributed to ketamine administration. Thesingle study comparing ketamine with gabapentinreported no difference in the incidence of commonside effects. There were insufficient data to comparestudy withdrawal rates because of adverse events orseverity of adverse events. Lastly, there was no dif-ference in the rate of serious adverse events, all of which were attributed to underlying disease and notto the interventions.

Subgroup analysis investigation of heterogeneity

Dose of ketamine. We were unable to perform sub-

group analysis based on dose of ketamine as theregimens varied widely, particularly in the dose andduration of continuous infusions.

Follow-up period and surgical procedure. Results foreach time point (3 months, 6 months and 1 year orlater) and type of surgical procedure are presentedas subgroups within our analyses of the primaryoutcome; however, participant numbers for indi-vidual procedures are small, and only arthroplasty

918 records

identified

through database

searching

5 additional

records identified

through

clinicaltrials.gov

568 records after duplicates

removed

568 records

screened

525 records

excluded

43 full-text

articles

assessed foreligibility

17 studies

included in

quantitative

synthesis

(meta-

analysis)

17 studies

included in

qualitative

analysis

26 full-text articles excluded:

No pain outcome at ≥ 3

months: n = 20 (many studies

had additional reasons for

exclusion)

Ketamine part of multimodal

strategy not employed incontrol arm: n = 1

All arms received same dose of

ketamine: n = 1

Abstract > 3 years old: n = 1

< 10 participants in each group:n = 1

Retrospective study: n = 1

Single blind: n = 1

Fig. 1. Study flow diagram.


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Χ2

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Fig. 2. Forest plot of comparison: Incidence of persistent post-surgical pain: ketamine vs. placebo; outcome: Incidence at 3 months, allstudies. M-H, Mantel-Haenszel; CI, confidence interval.


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at 6 months shows a statistically significant reduc-tion in PPSP in those participants receivingketamine, with an RR of 0.43 (95% CI: 0.19–0.99).

Route of administration. While subgroup analysis byroute of administration was possible for the primaryoutcome, only three studies used the epiduralroute,33,36,46 therefore sub-analyses are presented forintravenous data only (including the study by Suppaet al.,43 which administered an intramuscular bolus before the intravenous infusion). Unlike the meta-analysis of combined routes, analysis of exclusivelyintravenous studies at 3 months demonstrated a sta-tistically significant RR of 0.75 (P = 0.01, 95% CI:0.60–0.93); that is, a 25% reduction in risk of devel-oping PPSP. This translates to an NNT of 12; that is,on average, 12 patients would need to be treatedwith ketamine for one less patient to develop PPSPthan would be the case if they received placebo

(Fig. 3). Similarly, at 6 months, removal of epiduraldata resulted in meta-analysis demonstrating astatistically significant RR of 0.70 (P = 0.04,95% CI: 0.50–0.98); that is, a 30% reduction in risk of developing PPSP (NNT of 14, Fig. 4). At 12 monthsor later, overall risk reduction remainednonstatistically significant for the intravenous datasub-analysis.

Definition of PPSP. We scrutinized the prevalenceof PPSP in the placebo group of each study. If eachstudy was measuring the same outcome in similar

populations and employing similar methodologies,PPSP rates should also be similar among studies of similar surgeries. In our analysis, where a study pre-sented data that would allow more than one defini-tion of PPSP prevalence (e.g., number of patientswith pain intensity > 1 on 0–10 numeric ratingscale), we chose the one which most closely alignedwith other studies in an attempt to homogenizeoverall data (Table 1). Consequently, prevalence of PPSP in placebo groups in the included studies wasgenerally consistent (and within ranges reported forvarious surgeries in the literature), but with some

outliers. For example, placebo rates of PPSP in theincluded thoracotomy studies were 69%, 63%, 43%and 64% at 3 months, and 39% and 50% at 6 months.Removing studies with outlying rates did not sig-nificantly affect our analysis.

Sensitivity analysisWe re-analyzed our results using random effectsmodels. All meta-analyses that had previously notdemonstrated a statistically significant difference

remained so. In addition, our sub-analyses of studies that only employed the intravenous or intra-muscular route were no longer statistically signifi-cant; that is, at 3 and 6 months, although best pointestimates were similar. For secondary outcomes,changing model of analysis had no effect on statis-tical significance of any of the analyses (i.e., theyremained nonsignificant), with the exception of vision disorders, which, when analyzed using arandom effects model no longer demonstrated sta-tistical significance.

Discussion

Summary of main resultsThe results for our primary outcome demonstratethat perioperative ketamine reduces the risk of developing PPSP at 3 and 6 months, but only afterremoval of epidural studies from our meta-

analyses. This result is consistent with a priorstudy. De Kock et al.36 compared epidural andintravenous routes and, perhaps surprisingly, givenexperimental work demonstrating the importanceof spinal NMDA receptors in nociceptive inputamplification, showed that intravenous, but notepidural, administration was successful in reduc-ing analgesic requirements at 6 months aftersurgery. Several reasons may be considered for thisapparently contradictory finding. The involvementof spinal NMDA receptors demonstrated in animalstudies of peripheral nerve injury may be less

important clinically in post-operative pain thanpreviously thought.24 If spinal NMDA receptors donot serve as the primary target of ketamine, thelower plasma concentrations achieved with epi-dural administration when compared with intrave-nous administration49 likely translates to a lowersystemic efficacy. On the other hand, ketaminegiven epidurally might be rapidly absorbed intothe bloodstream via epidural veins, and the epi-dural ketamine dose might be lower than the IVdoses employed, accounting for these results.Additionally, superior analgesia and opioid-

sparing effects associated with ketamine adminis-tration during the acute post-operative phase may be mediated primarily by attenuation of opioid-induced hyperalgesia, which has a substantialsupraspinal component.

Best point estimates at 6 months and at 1 year orlater show a trend toward greater risk reductions inketamine groups than at 3 months, suggesting thatlack of statistical significance may be due to thesmall sample size at these later time points.


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A 25% relative risk reduction in PPSP prevalenceat 3 months in the intravenous meta-analysis issmall, as reflected in the NNT of 12. Indeed, whensensitivity analysis was performed using a randomeffects model, the result was no longer statistically

significant, reflecting the slim margin of statisticalsignificance in our original analysis. However, evenminor reductions in the incidence of PPSP may havea considerable public health impact. A 1996 estimateof cost savings based on preventing the transition

I2

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I2

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Fig. 3. Forest plot of comparison: Incidence of persistent post-surgical pain: ketamine vs. placebo; outcome: incidence at 3 months,intravenous studies only. M-H, Mantel-Haenszel; CI, confidence interval.


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I2

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Fig. 4. Forest plot of comparison: Incidence of persistent post-surgical pain: ketamine vs. placebo; outcome: incidence at 6 months,intravenous studies only. M-H, Mantel-Haenszel; CI, confidence interval.


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from acute to PPSP in a 30-year-old patient, sug-gested that $1 million may be saved during thepatient’s lifetime.50

At 3 months, both the Chi2 and I2 statistics implythat the data are homogeneous, apparently justify-ing the use of a fixed effect model; however, thevariability in types of surgery, definitions of PPSPand dosing of ketamine suggest that heterogeneitydoes exist. The overall NNT of 12 may not be indica-tive of reductions in risk for specific surgeries wherethe prevalence of PPSP differs. In surgeries with alower PPSP prevalence, reductions in risk of devel-oping PPSP are likely to be of a lesser margin; that is,more patients would need to receive ketamine inorder to achieve a statistically significant reductionin the incidence of PPSP, resulting in a higher NNT.

The dosage regimens employed between studieswere heterogeneous and prevented a subgroupanalysis. However, in studies that assigned more

than one ketamine regimen, higher doses of ketamine do not appear to consistently improve thepersistent pain outcomes.35–37,39 Therefore, wecannot draw any conclusions regarding the optimaldose or timing (pre-emptive vs. preventative) of ketamine in reducing PPSP. It has been suggestedthat the inflammatory response may peak around48 h post-surgery and therefore, ketamine should beadministered for at least this duration post-operatively;33 but those studies32,34,38,40,44,46 that didadminister ketamine for 48 h or longer did not dem-onstrate increased efficacy vs. those that did not.

Similarly, the variability between studies inanesthetic and analgesic regimens employed inaddition to ketamine precluded us from performingsensitivity analyses based on general vs. regionalanesthesia or multimodal vs. conventional post-operative analgesia.

Reductions in pain intensity in participantsreceiving ketamine were neither statistically norclinically significant at either 3 or 6 months.However, the mean pain intensity was generally lowat either time point in both ketamine and placebogroups.

When subanesthetic doses of ketamine wereadministered, rates of ketamine-associated (includ-ing neuro-psychiatric) side effects did not differ between ketamine and placebo for the majority of comparisons, confirming a widely accepted clinicalperception. The single statistically significant differ-ence was observed for the rate of visual distur- bances. However, the data were heterogeneous andmay have reflected differences in definitions of, ormethods of, reporting this adverse event. It appears

that any reductions in opioid use in those treatedwith ketamine were not accompanied by reductionsin opioid-induced side effects. Long-term safetydata were scarce and what were available were notattributed to ketamine administration. Directneurotoxicity of ketamine, particularly with intrath-ecal administration at high doses, has been reportedin animal models.20,51,52 None of the included studiesreported signs of clinical neurotoxicity, eitheracutely or in those patients completing long-termfollow-up.

Overall completeness and applicability of evidenceThe included studies covered a wide variety of sur-geries, but did not include many others associatedwith developing PPSP, such as nephrectomy, chol-ecystectomy or hernia repair. Additionally, adverseevents were rarely monitored beyond the acute

post-operative stage. The clinical relevance of thenumber of patients with ‘any pain’ at study end-points is unclear, but the evidence would undoubt-edly be more applicable if more of the studies hadmeasured pain that was clinically meaningful to apatient. Lastly, it was unclear in many studieswhether patients had pre-existing pain; that is,chronic pain before surgery. Therefore, the efficacyof ketamine in such a population has not been sepa-rately investigated.

Potential biases from the studies and the review

processThe 17 included studies generally had low orunclear risk of bias for the five assessed domains,with high risk occurring only in four studies andonly for attrition and reporting bias. More likely,sources of bias included the low number of partici-pants contributing data and the heterogeneity of reporting of PPSP. For the former, there were amean number of 60 participants (median 42)assigned to receive ketamine in each study and amean number of 46 (median 33) assigned to receiveplacebo, with the number of participants reporting

data dropping substantially at later time points. Asmentioned in the Methods section, we includedstudies where enrolled participants did have, or mayhave had, pre-existing pain of any kind. If we hadincluded only those studies where the authorsexplicitly reported that they excluded patients withpre-existing pain, only five studies would have metthe selection criteria.31–33,42,43

Our search strategies were concise and did notcontain terms for individual surgeries; therefore, it


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is possible that we may have missed relevantstudies. However, all included studies found in ref-erence sections of other papers (original reports orreviews) were also found in at least one of oursearch strategies, suggesting that our searches weresufficiently sensitive. By searching for nonpublisheddata, we believe that our review is not subject topublication bias, but we did not contact studyauthors or manufacturers for unpublished studies.

Comparison with other reviewsSeveral qualitative and quantitative reviews havestudied the acute effects (7 days or less post-operatively) of perioperative ketamine. Findingswere inconsistent both within and between reviews(based on different inclusion criteria for the latter) inthe measured outcomes, which included pain inten-sity, opioid use and opioid-related and ketamine-

related adverse events.

18,53–56

In general, anydifferences in the outcomes studied betweenketamine- and placebo-treated patients were minor.One review of various agents for prevention of chronic pain after surgery employed different inclu-sion criteria to ours and did not perform an analysisof mean pain severity or of adverse events.57 Despitethese differences, the review reported similar minorreductions in the number of patients developingchronic pain when comparing ketamine withplacebo.

As with our analysis, the above reviews discussed

the heterogeneity of included studies and wereunable to recommend an optimal timing or route of administration or dose regimen of ketamine. Directextrapolations of short-term results to long-termeffectiveness are challenging in that acute studiesgenerally assess pain severity or opioid consump-tion, whereas long-term studies generally assessprevalence of pain as their primary outcome.However, many studies included in our reviewdemonstrated short-term efficacy of ketamine thatdid not translate to long-term reductions in PPSP.This suggests that while increased acute pain

appears to be a risk factor for developing PPSP,58

reduction of acute pain intensity may not be directlylinked to reduced prevalence of developing persis-tent pain. Short-term studies may not predict long-term efficacy, but the reduced numbers of participants at later time points also impairs theability to demonstrate a statistically significantresult. In the future, larger studies presenting acutedata for the subset of participants who also reportedlong-term data may clarify this relationship.

Conclusions

In this meta-analysis of all eligible studies, combin-ing intravenous and epidural administration,ketamine did not provide a significant reduction of PPSP at 3 and 6 months. In common with systematicreviews of short-term effects of ketamine on acutepain outcomes, the study data from our review of outcomes at 3 months or later are heterogeneousand suggest efficacy of intravenous ketamine only incomparison with placebo in preventing PPSP at 3and 6 months. There was no evidence to supportepidural ketamine administration for PPSP preven-tion. This may be important as concerns about directketamine neurotoxicity exist.

Highly variable timing and dosing of ketaminein these studies suggest that no unifying effectiveregimen has emerged despite the long history of ketamine in clinical practice. Based on the variabil-

ity of anesthetic and analgesic regimens employed,there may be increased efficacy of ketamine whenused as part of a multimodal regimen. Giventhe multiplicity of neurotransmitters, growthfactors and pathways involved in the transitionfrom acute to chronic pain, it would seem logicalthat a combination of mechanisms should be tar-geted via a variety of approaches in order toincrease the likelihood of inhibiting centralsensitization. It is also unclear whether ketaminemay be more effective in certain surgeries, or inspecific populations, for example, in those who are

opioid tolerant and/or who have pre-existing pain.However, these data suggest that perioperativeketamine is safe; therefore, it may be appropriate inpatients undergoing painful surgeries or who areexpected to require large doses of opioids post-operatively. We found insufficient data to makecomparisons of ketamine with other interventionsused to prevent PPSP.

Future research should focus on clinically rel-evant outcomes; that is, pain that affects functioningor health-related quality of life. Several large studiesrecently addressed the risk factors for PPSP devel-

opment,59,60

and future studies should attempt tostratify populations at high risk for PPSP, to identifywhich patients may benefit the most from specificinterventions. It may be necessary to identifypatients with pre-operative pain and possiblecentral sensitization prior to enrollment. The doseand the duration of perioperative ketamine admin-istration should be adequate to cover the criticalperiod of susceptibility to central sensitization andneural plasticity. Lastly, sufficiently large numbers


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of patients should be enrolled to account for inevi-table loss to follow-up in long-term studies.

Conflicts of interest: No conflicts of interestdeclared.

Funding: The review was funded in part by theRichard Saltonstall Charitable Foundation, USA. Allother funding was departmental.

References1. Macrae WA. Chronic post-surgical pain: 10 years on. Br J

Anaesth 2008; 101: 77–86.2. Haroutiunian S, Nikolajsen L, Finnerup NB, Jensen TS. The

neuropathic component in persistent postsurgical pain: asystematic literature review. Pain 2013; 154: 95–102.

3. Macrae WA. Chronic pain after surgery. Br J Anaesth 2001;87: 88–98.

4. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery: a review of predictive factors. Anesthesiology 2000;93: 1123–33.

5. Macrae WA, Davies HTO. Chronic postsurgical pain, In:Crombie IK, Linton S, Croft P, Von Korff M, LeResche L eds.Epidemiology of pain. Seattle: International Association for

the Study of Pain, 1999: 125–42.6. Johansen A, Romundstad L, Nielsen CS, Schirmer H,

Stubhaug A. Persistent postsurgical pain in a general popu-lation: prevalence and predictors in the Tromsø study. Pain2012; 153: 1390–6.

7. Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM,APM:SE Working Group of theAustralian and New ZealandCollege of Anaesthetists and Faculty of Pain Medicine eds.Acute pain management: scientific evidence, 3rd. Mel- bourne: ANZCA & FPM, 2010.

8. Woolf CJ. Central sensitization: implications for the diagno-sis and treatment of pain. Pain 2011; 152: S2–15.

9. Woolf CJ, Salter MW. Neuronal plasticity: increasing thegain in pain. Science 2000; 288: 1765–8.

10. Colvin LA, Fallon MT. Opioid-induced hyperalgesia: a clini-

cal challenge. Br J Anaesth 2010; 104: 125–7.11. Sandkuhler J. Models and mechanisms of hyperalgesia andallodynia. Physiol Rev 2009; 89: 707–58.

12. Du J, Zhou S, Coggeshall RE, Carlton SM. N-methyl-D-aspartate-induced excitation and sensitization of normaland inflamed nociceptors. Neuroscience 2003; 118: 547–62.

13. Kaneko M, Kaneko T, Kaneko R, Chokechanachaisakul U,Kawamura J, Sunakawa M, Okiji T, Suda H. The role of N -methyl-d-aspartate receptor subunits in the rat thalamicmediodorsal nucleus during central sensitization. Brain Res2011; 1371: 16–22.

14. Richebe P, Rivat C, Laulin JP, Maurette P, Simonnet G.Ketamine improves the management of exaggerated postop-erative pain observed in perioperative fentanyl-treated rats.

Anesthesiology 2005; 102: 421–8.15. Davies SN, Lodge D. Evidence for involvement of N-methylaspartate receptors in ‘wind-up’ of class 2 neu-rones in the dorsal horn of the rat. Brain Res 1987; 424: 402–6.

16. Kovács G, Kocsis P, Tarnawa I, Horváth C, Szombathelyi Z,Farkas S. NR2B containing NMDA receptor dependentwindup of single spinal neurons. Neuropharmacology 2004;46: 23–30.

17. Weinbroum AA. Non-opioid IV adjuvants in theperioperative period: pharmacological and clinical aspectsof ketamine and gabapentinoids. Pharmacol Res 2012; 65:411–29.

18. Bell RF, Dahl JB, Moore RA, Kalso EA. Perioperativeketamine for acute postoperative pain. Cochrane DatabaseSyst Rev 2006; (1): CD004603, doi: 10.1002/14651858.CD004603.pub2.

19. Katz J, Clarke H. Preventive analgesia and beyond: currentstatus, evidence, and future directions, In: Macintyre PE,Walker SM, Rowbotham DJ eds. Clinical pain management:acute pain, 2nd edn. London: Hodder Arnold, 2008: 154–98.

20. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-doseketamine in the management of acute postoperative pain: areview of current techniques and outcomes. Pain 1999; 82:111–25.

21. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant toopioids for cancer pain. Cochrane Database Syst Rev 2012;(11): CD003351, doi: 10.1002/14651858.CD003351.pub2.

22. Hocking G, Cousins MJ. Ketamine in chronic pain manage-ment: an evidence-based review. Anesth Analg 2003; 97:1730–9.

23. White PF, Way WL, Trevor AJ. Ketamine – its pharmacologyand therapeutic uses. Anesthesiology 1982; 56: 119–36.

24. De Kock MF, Lavand’homme PM. The clinical role of NMDAreceptor antagonists for the treatment of postoperative pain.Best Pract Res Clin Anaesthesiol 2007; 21: 85–98.

25. Oye I, Paulsen O, Maurset A. Effects of ketamine onsensory perception: evidence for a role of N-methyl-D-

aspartate receptors. J Pharmacol Exp Ther 1992; 260: 1209–13.

26. Moore RA, Gavaghan D, Tramèr MR, Collins SL, McQuayHJ. Size is everything – large amounts of information areneeded to overcome random effects in estimating directionand magnitude of treatment effects. Pain 1998; 7: 209–16.

27. Review Manager (RevMan) [Computer program]. Version5.2. Copenhagen: The Nordic Cochrane Centre, 2012; TheCochrane Collaboration.

28. Deeks JJ. Issues in the selection of a summary statistic formeta-analysis of clinical trials with binary outcomes. StatMed 2002; 21: 1575–600.

29. Deeks JJ, Higgins JPT, Altman DG. Chapter 9: analysing dataand undertaking meta-analyses, In: Higgins JPT, Green Seds. Cochrane handbook for systematic reviews of interven-

tions. 5.0. Chichester: John Wiley & Sons, 2008: 243–96.30. Crousier M, Cognet V, Khaled M, Gueugniaud P-Y, PiriouV. Effect of ketamine on prevention of postmastectomychronic pain. A pilot study. Ann Fr Anesth Reanim 2008; 27:987–93.

31. Duale C, Sibaud F, Guastella V, Vallet L, Gimbert Y-A, TaheriH, Filaire M, Schoeffler P, Dubray C. Perioperative ketaminedoes not prevent chronic pain after thoracotomy. Eur J Pain2009; 13: 497–505.

32. Joseph C, Gaillat F, Duponq R, Lieven R, Baumstarck K,Thomas P, Penot-Ragon C, Kerbaul F. Is there any benefit toadding intravenous ketamine to patient-controlled epiduralanalgesia after thoracic surgery? A randomized double- blind study. Eur J Cardiothorac Surg 2012; 42: e58–65.

33. Ryu HG, Lee CJ, Kim YT, Bahk JH. Preemptive low-dose

epidural ketamine for preventing chronic postthoracotomypain: a prospective, double-blinded, randomized, clinicaltrial. Clin J Pain 2011; 27: 304–8.

34. Spreng AJ, Dahl V, Raeder J. Effects of perioperative S (+)ketamine infusion added to multimodal analgesia inpatientsundergoing ambulatory haemorrhoidectomy. Scand J Pain2010; 1: 100–5.

35. Bilgen S, Köner O, Türe H, Menda F, Fiçicioglu C, Aykaç B.Effect of three different doses of ketamine prior to generalanaesthesia on postoperative pain following caesarean deliv-ery: a prospective randomized study. Minerva Anestesiol2012; 78: 442–9.


1212


15/16

36. De Kock M, Lavand’homme P, Waterloos H. ‘Balanced anal-gesia’ in the perioperative period: is there a place forketamine? Pain 2001; 92: 373–80.

37. Dullenkopf A, Muller R, Dillmann F, Wiedemeier P, HegiTR, Gautschi S. An intraoperative pre-incision single dose of intravenous ketamine does not have an effect on postopera-tive analgesic requirements under clinical conditions.Anaesth Intensive Care 2009; 37: 753–7.

38. Hayes C, Armstrong-Brown A, Burstal R. Perioperativeintravenous ketamine infusion for the prevention of persis-tent post-amputation pain: a randomized, controlled trial.Anaesth Intens Care 2004; 32: 330–8.

39. Katz J, Schmid R, Snijdelaar DG, Coderre TJ, McCartney CJ,Wowk A. Pre-emptive analgesia using intravenous fentanylplus low-dose ketamine for radical prostatectomy undergeneral anesthesia does not produce short-term or long-termreductions in pain or analgesic use. Pain 2004; 110: 707–18.

40. Mendola C, Cammarota G, Netto R, Cecci G, Pisterna A,Ferrante D, Casadio C, Della Corte F. S+ -ketamine forcontrol of perioperative pain and prevention of post thora-cotomy pain syndrome: a randomized, double-blind study.Minerva Anestesiol 2012; 78: 757–66.

41. Remerand F, Le Tendre C, Baud A, Couvret C, Pourrat X,Favard L, Laffon M, Fusciardi J. The early and delayed anal-gesic effects of ketamine after total hip arthroplasty: a pro-

spective, randomized, controlled, double-blind study.Anesth Analg 2009; 109: 1963–71.

42. Sen H, Sizlan A, Yanarates O, Emirkadi H, Ozkan S, Dagli G,Turan A. The effects of gabapentin on acute and chronic painafter inguinal herniorrhaphy. Eur J Anaesthesiol 2009; 26:772–6.

43. Suppa E, Valente A, Catarci S, Zanfini BA, Draisci G. A studyof low-dose S-ketamine infusion as ‘preventive’ pain treat-ment for cesarean section with spinal anesthesia: benefitsand side effects. Minerva Anestesiol 2012; 78: 774–81.

44. Suzuki M, Haraguti S, Sugimoto K, Kikutani T, Shimada Y,Sakamoto A. Low-dose intravenous ketamine potentiatesepidural analgesia after thoracotomy. Anesthesiology 2006;105: 111–9.

45. Sveticic G, Farzanegan F, Zmoos P, Zmoos S, Eichenberger

U, Curatolo M. Is the combination of morphine withketamine better than morphine alone for postoperativeintravenous patient-controlled analgesia? Anesth Analg2008; 106: 287–93.

46. Wilson JA, Nimmo AF, Fleetwood-Walker SM, Colvin LA. Arandomised double blind trial of the effect of pre-emptiveepidural ketamine on persistent pain after lower limb ampu-tation. Pain 2008; 135: 108–18.

47. Arendt-Nielsen L, Nielsen J, Petersen-Felix S, Schnider TW,Zbinden AM. Effect of racemic mixture and the (S+) isomerof ketamine on temporal and spatial summation of pain. Br JAnaesth 1996; 77: 625–31.

48. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, CleelandCS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD,Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J,

Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, KatzNP, Kehlet H, Kramer LD, Manning DC, McCormick C,McDermott MP, McQuay HJ, Patel S, Porter L, Quessy S,

Rappaport BA, Rauschkolb C, Revicki DA, Rothman M,Schmader KE, Stacey BR, Stauffer JW, von Stein T, White RE,Witter J, Zavisic S. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACTrecommendations. J Pain 2008; 9: 105–21.

49. Xie H, Wang X, Liu G, Wang G. Analgesic effects andpharmacokinetics of a low dose of ketamine preoperativelyadministered epidurally or intravenously. Clin J Pain 2003;19: 317–22.

50. Cousins M, Smith G, Power I. 1996 Labat lecture: pain – apersistent problem. Reg Anesth Pain Med 2000; 25: 6–21.

51. de Lima J, Beggs S, Howard R. Neural toxicity of ketamineand other NMDA antagonists. Pain 2000; 88: 311–2.

52. Malinovsky JM, Lepage JY, Crozian A, Mussini JM, PinaudtM, Souron R. Is ketamine or its preservative responsible forneurotoxicity in the rabbit? Anesthesiology 1993; 78: 109–15.

53. Elia N, Tramer MR. Ketamine and postoperative pain – aquantitative systematic review of randomised trials. Pain2005; 113: 61–70.

54. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematicreview of intravenous ketamine for postoperative analgesia.Can J Anaesth 2011; 58: 911–23.

55. Mathews TJ, Churchhouse AM, Housden T, Dunning J.Does adding ketamine to morphine patient-controlled anal-gesia safely improve post-thoracotomy pain? Interact

Cardiovasc Thorac Surg 2012; 142: 194–9.56. McCartney CJ, Sinha A, Katz J, McCartney CJL, Sinha A,

Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventiveanalgesia. Anesth Analg 2004; 98: 1385–400.

57. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I.Pharmacotherapy for the prevention of chronic pain aftersurgery in adults. Cochrane Database Syst Rev 2013; (7):CD008307, doi: 10.1002/14651858.CD008307.pub2.

58. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain:risk factors and prevention. Lancet 2006; 367: 1618–25.

59. Kaunisto MA, Jokela R, Tallgren M, Kambur O, Tikkanen E,Tasmuth T, Sipila R, Palotie A, Estlander A-M, Leidenius M,Ripatti S, Kalso EA. Pain in 1000 women treated for breastcancer: a prospective study of pain sensitivity and postop-

erative pain. Anesthesiology 2013; 119: 1410–21.60. Deumens R, Steyaert A, Forget P, Schubert M,Lavand’homme P, Hermans E, De Kock M. Prevention of chronic postoperative pain: cellular, molecular, and clinicalinsights for mechanism-based treatment approaches. ProgNeurobiol 2013; 104: 1–37.

Address:Ewan McNicolDepartments of Anesthesiology and PharmacyTufts Medical Center800 Washington Street, Box 420Boston, MA 02111USA

e-mail: [email protected]


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