British Journal of Anaesthesia, 123 (3): 325e334 (2019)

doi: 10.1016/j.bja.2019.05.043
Advance Access Publication Date: 18 July 2019
Review Article

PAIN

Low-dose ketamine in painful orthopaedic surgery: a systematic

review and meta-analysis
J. Mark Riddell1,2,*, John M. Trummel3 and Igho J. Onakpoya1
1
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford,
UK, 2Southern New Hampshire Medical Center, Nashua, NH, USA and 3Dartmouth-Hitchcock Medical Center, Lebanon,
NH, USA

*Corresponding author. E-mail: John.Riddell@snhhs.org

Abstract
Background: Ketamine is a phencyclidine intravenous anaesthetic that blocks N-methyl-D-aspartate receptors and HCN
channels in the CNS. Lately it has gained acceptance in a low-dose form, with studies showing an analgesic benefit in
orthopaedic surgery. Our goal was to critically appraise and synthesise current evidence regarding use of low-dose ke-
tamine in major, painful orthopaedic surgeries.
Methods: We conducted searches in Medline, Embase, Cochrane, and specialty journals for randomised controlled trials
(RCTs) that compared low-dose ketamine to placebo. Primary outcomes included total opioid use, time to first opioid, and
VAS pain scores. Meta-analyses were undertaken in RevMan software using a random effects model. We rated the
quality of the evidence using the GRADE Working Group criteria.
Results: We included 20 studies across four subgroups for meta-analysis. The overall quality of the evidence was
moderate. Ketamine significantly decreased total opioid use and pain scores (VAS) at 24 and 48 h (Opioid: standardised
mean difference [SMD] e0.82 [e1.24, e0.40], p¼0.0001, and e0.65 [e1.03,e0.27], p¼0.0008; VAS: SMD e0.53 [e0.91, e0.15],
p¼0.006 and e0.60 [e1.05, e0.16], p¼0.008), and delayed the time to first opioid dose (SMD 0.64 [0.01, 1.27], p¼0.05). Results
for nausea and hallucinations were equivocal, whereas results for chronic pain were inconclusive. The most prominent
effects were seen in total joint operations.
Conclusion: Low-dose ketamine is an effective adjuvant that decreases pain and opioid requirements in painful ortho-
paedic procedures, especially in the first 24 h after procedure. Future research should focus on arthroscopic procedures
and the incidence of chronic pain.

Keywords: ketamine; orthopaedics; pain; postoperative; chronic pain; opioids

Pain after major orthopaedic surgery continues to impact pa-

Editor’s key points
 The benefit of low-dose ketamine in reducing pain after
orthopaedic surgery has been unclear, largely due to
significant heterogeneity across studies.
 This meta-analysis of 20 RCTs showed a significant
decrease in opioid use and pain scores at 24 and 48 h,
with an evidence GRADE of moderate, whereas results
for nausea and hallucinations were equivocal.
tient well-being and satisfaction. Orthopaedic surgeons were
the third highest prescribers of opioids in the USA in 2010.1
Orthopaedics has played a role in the opioid epidemic, with
patients reporting an abundance of opioids prescribed after
surgery, and orthopaedic surgeons often neglecting non-
opioid alternatives.2 Also, unclear and conflicting recom-
mendations from US regulatory bodies has led to confusion
among orthopaedic surgeons regarding how to safely treat
their patient’s pain.3 Finally, although many orthopaedic

Editorial decision: 28 May 2019; Accepted: 28 May 2019

© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com

325
 326 - Riddell et al.
surgeries are now performed arthroscopically, recent data
have shown that the pain of arthroscopic shoulder and knee
ligament surgery is equal to or exceeds that of traditional
arthroplasties and back surgeries.4
Ketamine (C13H16ClNO) is a phencyclidine-class intrave-
nous anaesthetic drug that antagonises the excitatory N-
methyl-D-aspartate (NMDA) receptor in the CNS. At low doses
(0.1e0.5 mg kg1), it demonstrates prominent analgesic ef-
fects, and can be used to supplement regional or local anaes-
thesia.5 NMDA receptors may be responsible for the
development of the ‘memory’ of pain in the CNS, so blockade
of the receptor pre-procedure might contribute to the pre-
vention of pain.6,7 The results from previous systematic re-
views showed that low-dose ketamine (<1 mg kg1 IV bolus) is
an effective adjuvant medication to the standard regimen of
opioids and local anaesthetics.8
Several studies and systematic reviews have shown a
benefit from using low-dose ketamine in all surgical patients,
as it appears to have an opioid-sparing effect.9,10 Also, when
used at lower doses, ketamine does not demonstrate un-
wanted side-effects of the drug, specifically hallucinations.11
However, many of the reviews had few orthopaedic studies,
they excluded studies that involved regional anaesthesia (now
standard), and subgroup analyses of orthopaedic patients
were not consistently conclusive.
Although low-dose ketamine has been shown to be
generally beneficial in terms of mitigating pain, it is unclear if
there is a defined benefit in orthopaedics. The objective of this
systematic review was to critically appraise the evidence from
RCTs that used low-dose ketamine in adult patients under-
going painful orthopaedic procedures.
Methods
This review was carried out using guidelines from the
Cochrane Handbook for Systematic Reviews of In-
terventions,12 the University of York/Centres for Review and
Dissemination,13 and the Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA).14 The final
protocol was registered on PROSPERO on January 15, 2018:
http://www.crd.york.ac.uk/PROSPERO/display_record.php?
ID¼CRD42018086054
With assistance from a research librarian at Harvard
Medical School, a collaborative search strategy was devised
using keywords and Medical Subject Subheadings (MeSH).
Ketamine was first synthesised in 1966, so we searched from
that year onwards. No language restrictions were imposed.
Searches were carried out on Medline, EMBASE, Cochrane
Library, Web of Science, BIOSIS, ASA abstracts, CINAHL,
ClinicalTrials.gov, and WHO Trials. Grey Literature was
searched using Google Scholar, OpenGrey, and ProQuest
Database. All initial searches were completed by February 5,
2018, with final updated searches concluded on July 31, 2018.
An example of one search strategy can be seen in Appendix 1.
The references of included trials were hand-searched for
relevant studies. Anesthesiology, Anesthesia and Analgesia, and
British Journal of Anaesthesia were hand searched for eligible
studies from the past 3 yr. A noted expert in the field (Loftus)
was contacted regarding any unpublished studies.
All search results were imported using Mendeley soft-
ware.15 Full-text articles were obtained to determine eligi-
bility, and when necessary, authors were contacted directly.
We considered parallel-design RCTs of low-dose/micro-
dose ketamine in major orthopaedic surgical procedures
occurring in the operating room, excluding crossover or clus-
ter randomised trials. Unpublished studies were evaluated if
there was sufficient evidence to warrant their inclusion.
We excluded studies that did not involve orthopaedics,
studies that used ketamine as an induction agent, and paedi-
atric studies. Studies that used ketamine at doses outside the
specified ranges were excluded. Emergency room studies were
excluded if they did not lead to a procedure in the operating
room. If the surgical procedure was not explicitly stated, the
study was excluded. We also excluded studies if their full texts
were unavailable. Two review authors (JMR, JMT) indepen-
dently screened titles and abstracts.
Population
Adults (18 yr of age) undergoing major, painful orthopaedic
surgery (scheduled and emergent): total joint replacement
(hips, knees), spine surgery, shoulder surgery, arthroscopic
reconstruction, orthopaedic oncology, and trauma.
Intervention
Patients received low-dose ketamine as:
1. An IV bolus (0.1e0.5 mg/kg), before or during the procedure.
2. An infusion of 1e10 mg kg1 min1, terminated at any point
48 h afterwards.
3. Some combination of a bolus and an infusion.
Control
Control individuals comprise those who received a bolus or
infusion of normal saline (NS) or both. Any study that
compared ketamine with another drug (or in combination
with other drugs) without a saline control was excluded.
Primary outcomes
1. The total amount of opioid (mg or mg) used by patients after
operation, given either by nurses (intravenous and oral), or
as part of patient-controlled analgesia (PCA) devices.
2. The time to the first dose of opioid after surgery (minutes). A
longer period to the first dose was considered indicative of
greater pain control.
3. The pain scores at rest using the visual analogue scale (VAS)
at 12, 24, and 48 h. In certain studies, the 11-point Numer-
ical Rating Scale (NRS) was used, where the patient stated a
value for their pain without seeing a visual representa-
tion.16 Studies have demonstrated a correlation between
the two, and one can reliably be substituted for the other.17
Although some studies investigated pain scores with
movement, pain at rest was widely reported, so only those
data were analysed.
Secondary outcomes
1. The effect of ketamine on the incidence of postoperative
nausea and vomiting (PONV).
2. The incidence of hallucinations.
3. Whether or not patients developed chronic pain after sur-
gery, defined as:
a. Pain that developed after a surgical procedure.
b. Of greater than 2 months’ duration.
c. Other causes of pain had been ruled out.18

Two review authors (JMR, JMT) independently extracted the
data onto customised Excel spreadsheets. We used the
Cochrane criteria to assess the risk of bias, and we rated the
overall body of evidence using the GRADE Working Group
criteria.19 The two authors (JMR, JMT) independently assessed
the risk of bias, and disagreements were resolved through
consensus. If a consensus could not be reached, the third
author (IJO) arbitrated.
Review Manager 5.3.5 was used for all analyses and forest
plots.20 All primary outcomes were analysed using an inverse
variance/random effects model, with the standardised mean
difference (SMD) as the effect measure; given heterogeneity in
study design and opioids used, SMD allows for comparisons
independent of specific units of measure. Dichotomous out-
comes were analysed using a random effects/Man-
teleHaenszel model; the effect measure was displayed as a
risk ratio (RR), which was used to calculate a number needed to
treat (NNT). One review author (JMR) entered the data onto
RevMan; these were independently verified by a second review
author (JMT). Forest plots were generated to display effect
estimates. We assessed heterogeneity using the I2 statistic;
values of 25%, 50%, and 75% represented mild, moderate, and
substantial heterogeneity, respectively.21 We used funnel
plots to assess publication bias.
We assessed the robustness of our overall analyses by
performing sensitivity analyses for the following subgroups:
1. Total Joint Arthroplasty (total knee, total hip)
2. Spine Surgery (lumbar laminectomy, lumbar fusion)
3. Arthroscopic Surgery (ACL reconstruction, shoulder surgery)
Results
Our searches identified 3174 citations: 2947 from electronic
database searches and 227 from alternate sources. After du-
plicates were removed, 2109 abstracts were available for
screening by the reviewers. A total of 234 full-text articles were
assessed; ultimately, a total of 38 studies were eligible for in-
clusion in the review and 20 for the meta-analysis. Specific
totals from each database, and reasons for exclusion, can be
found in the PRISMA diagram (Fig. 1).
We included the results of an observational study23 that
was a continuation of an earlier included RCT.24 Multiple
studies looked at comparing ketamine with placebo and
another drug, but only ketamine and placebo data were
analysed.
A total of 1271 patients participated in 19 trials from 2000 to
2014. Six studies examined low-dose ketamine in total joint
replacement, eight addressed spine surgery, and four involved
arthroscopy. Only one trauma study met the criteria for in-
clusion25; no orthopaedic oncology studies met inclusion
criteria.
All patients had general anaesthesia via inhalation gases
or total intravenous anaesthesia (TIVA); some supple-
mented with regional or spinal anaesthesia. Fifteen studies
used a ketamine bolus and infusion; three were bolus-only
and one was infusion-only. All but one of the bolus studies
gave ketamine before incision. Eight terminated the infu-
sion during skin closure, three maintained the drip for 2e24
h, and five maintained the infusion for 48 h. Two-thirds
used a bolus of 0.5 mg kg1 (full range: 0.15e0.5), whereas
the doses of the infusions varied considerably (0.04e10 mg
kg1 min1). A list of the studies and doses can be found in
Table 1.
Low-dose ketamine in painful orthopaedic surgery - 327
Bias assessments
The majority of studies received a ‘low risk’ or an ‘unclear risk’
assessment with regards to randomisation, allocation
concealment, blinding, incomplete outcomes, and selective
reporting. Several studies25,29,30,42 had specific design issues
consistent with a high risk of bias. A graph of the pooled risks
of bias can be seen in Figure 2.
Several studies displayed data as graphs without listing
values, so those data were interpolated using GraphClick and
Engauge Digitizer.43,44 Specific studies had results that fol-
lowed a non-standard distribution, so median and inter-
quartile range data were converted to mean and standard
deviation using the Hozo 2005 formulae.45
Effect of interventions
Opioid use
There was a significant decrease in total opioid use in favour of
ketamine. At 12 h, the SMD was e1.01 [e1.75, e0.28], p¼0.007;
(I2 ¼ 91%), GRADE¼Moderate. The SMD at 24 h between keta-
mine and placebo was e0.82 [e1.24, e0.40], p¼0.0001, (I2¼88%)
in favour of ketamine, GRADE¼High. Finally, the SMD at 48 h
was e0.65 [e1.03, e0.27], p¼0.0008, (I2 ¼83%), GRADE¼Moderate.
In subgroups at 24 h (Fig. 3), SMD is greatest in the total
joints (e1.41 [e2.59, e0.23], p¼0.02), with a lower effect in spine
patients (e0.60 [e1.10, e0.09], p¼0.02); arthroscopy results
were equivocal (e0.13, [e1.13, 0.86], p¼0.79). At 48 h
(Supplementary Fig. S1), the total joints again see the greatest
benefit (SMD e1.07 [e1.83, e0.31], p¼0.006), with a lesser
benefit seen in spine patients (e0.68 [e1.27, e0.09], p¼0.03).
The arthroscopy group was equivocal with regard to opioid use
(SMD e0.10 [e1.11, 0.92], p¼0.85). The GRADE for total joints
and spine patients was Moderate.
Sensitivity analyses that excluded four studies (Aveline and
colleagues24 [large effect size]; Cengiz and colleagues28 [high
infusion dose]; Jaksch and colleagues30 [very low infusion
dose]; and Pacreu and colleagues37 [used methadone as rescue
medication]) resulted in reductions in heterogeneity:
12 h: adjusted SMD e0.44 [e0.84, e0.04], I2¼61%
24 h: adjusted SMD e0.51 [e0.72, e0.30], I2¼44%
48 h: adjusted SMD e0.46 [e0.67, e0.25], I2¼39%
With the time to first opioid/narcotic (Supplementary
Fig. S2), the SMD was 0.64 [0.01, 1.27], p¼0.05, (I2¼83%), GRA-
DE¼Moderate, in favour of a longer time in the ketamine
group.
Pain
There was a significant improvement in pain scores (VAS/NRS)
at 24 and 48 h with ketamine as compared with placebo: SMD
e0.53 [e0.91, e0.15], p¼0.006, (I2¼88%), GRADE¼Moderate, and
SMD e0.60 [e1.05, e0.16], p¼0.008, (I2 ¼ 87%), GRADE¼Mo-
derate. Any attempt to reduce heterogeneity did not make for
an appreciable difference in I2.
At 24 h (Fig. 4), both the total joint and arthroscopy sub-
groups had results that were not significant (Joints: SMD e0.87
[e2.17, 0.43], p¼0.19; Arthroscopy: e0.46 [e1.12, 0.20], p¼0.17).
The spine subgroup had a significant result (e0.34 [e0.61,
e0.06], p¼0.02, GRADE¼Moderate) that favoured ketamine,
and Deng and colleagues25 (trauma) also showed a positive
finding (e0.96 [e1.38, e0.55], p<0.00001). At 48 h
(Supplementary Fig. S3), the total joint subgroup SMD was
e1.65 [e3.13, e0.17], p¼0.03, GRADE¼Moderate. In contrast,
 328 - Riddell et al.

Records idenfied through Addional records idenfied

Identification
database searching through other sources
2947 227
PubMed 362, Embase 1014, Cochrane 209, Google Scholar 203, Open Grey (grey
Web of Science 431, BIOSIS 222, CINAHL 40, literature) 5, Hand-searching 19
Clinical Trials 41, WHO Trials 239, ASA 321,
ProQuest 68

3174 Records
1065 duplicates removed
Screening

Titles and abstracts Records excluded

screened 1875
2109 Not relevant to primary review
queson

Full-text arcles assessed Full-text arcles excluded

for eligibility
Eligibility

196
234 Reasons:
Did not meet eligibility criteria: 104
Did not address review outcome: 10
Book Chapter/Editorial: 11
Narrave/Pracce Review: 41
Case Report: 13
Duplicate Data: 7
Unable to access: 10
Studies included
38
Included

Studies included in
quantave synthesis
(meta-analysis)
20
Total Joint Replacement: 7
Spine surgery: 8
Arthroscopy: 4
Trauma: 1

Fig 1. PRISMA 2009 flow diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.22

both the spine and arthroscopy subgroups showed VAS results
that were not significant (Spine: e0.26 [e0.56, 0.05], p¼0.1;
Arthroscopy: e0.21 [e0.73, 0.32], p¼0.44).
Adverse events
Across 17 studies, the risk for nausea was not significantly
different with ketamine (RR¼0.88 [0.69, 1.13], p¼0.33, (I2¼23%),
NNT¼24 [19, 31]). There was no significant difference in the
risk of hallucinations: RR¼0.87 [0.48, 1.58], p¼0.65, (I2 0%). Also,
there was no significant difference in the risk of chronic pain:
RR¼0.50 [0.16, 1.50], p¼0.21 (I2¼84%).
Discussion
Summary of main findings
Low-dose ketamine significantly decreases the need for opi-
oids in the 24e48 h after orthopaedic surgery, and significantly
prolongs the time to the first request for pain medicine. Based
on VAS/NRS values, ketamine patients report less pain. Low-
dose ketamine does not increase the incidence of either
nausea or hallucinations. There were not enough data to make
a definitive assessment regarding chronic pain. Overall, the
quality of evidence was moderate.
Patients having total joint surgery or spine surgery reported
significant benefits in terms of total opioid use at 24 and 48 h;
in contrast, arthroscopic patients do not appear to benefit
from ketamine in terms of reducing their need for opioid at 24
or 48 h. Using VAS, spine patients report less pain at 24, but not
at 48 h; in contrast, the total joint patients show a VAS benefit
48 h after the procedure. Supplementary Fig. S4 provides a
summary of these findings.
Comparison with existing literature
Whereas several earlier reviews looked at all surgical pro-
cedures, our review focused exclusively on the effect of low-
Table 1 Details of studies included in meta-analysis. 1o Anaes, primary anaesthetic; B, bolus; gtt, infusion; N2O, nitrous oxide used; GA, general anaesthesia; ACL, anterior cruciate
ligament; TIVA, total intravenous anaesthetic; NRS, Numerical Rating Scale; Sp, spinal anaesthesia; IS, interscalene block.

Author Year Surgical procedure 1o Anaes Eligible Type Bolus Infusion (mg Stopped N2O Opioid Pain Chron Comments
(B, gtt) (mg/kg) kg¡1 min¡1) scale pain

Adam and colleagues26 2005 Total knee GA 40 Bþgtt 0.5 3; 1.5 after 48 h Y Morphine VAS No Femoral nerve catheter
arthroplasty operation potentially reducing effect
size
Aveline and 2009 Total knee GA 50 Bþgtt 0.2 2; 1 after 48 h Y Morphine VAS e Large effect size
colleagues24 arthroplasty operation
Aveline and 2014 Total knee GA e e e e e Y VAS Yes Continuation of 2009 study,
colleagues23 arthroplasty examining chronic pain
Baik27 2000 Lumbar fusion GA 60 B 0.15 e e ? Morphine VAS No No English translation
available, unable to assess
bias
Cengiz and colleagues28 2014 Total knee GA 60 gtt e 6 Closure Y Morphine VAS No Questionable blinding, all
arthroplasty results significant
Deng and colleagues25 2009 Lower limb fracture GA 200 Bþgtt 0.5 1.6, 0.8, 0.16 24 h N Remifentanil VAS No Possible protocol breaches, all
results significant
Hong and colleagues29 2016 Rotator cuff repair GA 56 B 0.5 e e Y Fentanyl VAS No Extensive exclusion criteria
Jaksch and colleagues30 2002 Arthroscopic ACL TIVA 30 Bþgtt 0.5 0.033 2h N Morphine VAS No Possible loss of blinding, very
low infusion dose
Kim and colleagues31 2013 Lumbar fusion GA 60 Bþgtt 0.5 1 or 2 48 h Y Fentanyl VAS No No discussion of allocation or
blinding

Low-dose ketamine in painful orthopaedic surgery

Loftus and colleagues32 2010 Lumbar surgery GA 102 Bþgtt 0.5 10 Closure N Morphine VAS Yes Chronic pain evaluated at 6
equivalent weeks
Martinez and 2014 Total hip GA 60 Bþgtt 0.5 3 Closure N Morphine VAS No e
colleagues33 arthroplasty
Menigaux and 2000 ACL repair TIVA 45 B 0.15 e e Y Morphine VAS No Possible loss of blinding
colleagues34
Mitra and colleagues35 2017 Lumbar fusion GA 42 Bþgtt 0.5 4.17 Closure N Fentanyl VAS No e
Nielsen and 2017 Lumbar fusion GA 150 Bþgtt 0.5 4.17 Closure N Morphine VAS Yes e
colleagues36
Pacreu and colleagues37 2012 Lumbar fusion GA 20 Bþgtt 0.5 2.5 Closure N Methadone NRS No Unequal PCA dosing between
treatment groups;
methadone
Perrin and Purcell38 2009 Total knee GAþSp 12 Bþgtt 0.5 4 Closure ? Morphine VAS Yes Low sample size, possible
arthroplasty unblinding, GAþ spinal
Remerand and 2009 Total hip GA 154 Bþgtt 0.5 2 24 h Y Morphine NRS Yes e
colleagues39 arthroplasty
Song and colleagues40 2013 Lumbar fusion GA 50 Bþgtt 0.3 0.04 48 h N Fentanyl VAS No Meperidine used as rescue
opioid; female only study
41
Woo and colleagues 2014 Shoulder GAþIS 40 Bþgtt 0.3 2.5 Closure N Fentanyl NRS No Interscalene block possibly
arthroscopy reducing effect size
Yeom and colleagues42 2012 Lumbar fusion GA 40 Bþgtt 0.2 0.5 48 h Y Fentanyl NRS No Uneven group numbers,
opioid use ’estimated’

-
329
 330 - Riddell et al.

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of High risk of

bias bias

Green represents the percentage of total studies that had a

low risk of bias, red the percentage that had a high risk of
bias. Yellow indicates that there was insufficient data to
make a clear assessment of bias.

Fig 2. Cumulative risks of bias by category.

Fig 3. Forest plot of 24 h opioid use by subgroup. CI, confidence interval; SD, standard deviation.
 Low-dose ketamine in painful orthopaedic surgery
Fig 4. Forest plot of 24 h visual analogue scale by subgroup. CI, confidence interval;
dose ketamine in orthopaedic procedures with significant
pain/morbidity. Our results are consistent with those re-
ported by Laskowski and colleagues,46 showing a benefit in
orthopaedic patients in terms of opioid use and pain control.
In contrast to that review, we included studies that used
regional anaesthesia/peripheral nerve blocks, which are now
standard in orthopaedics. The results of our review also
support those of Bell and colleagues11 which concluded that
ketamine reduced post-surgery opioid use. In contrast to that
review, we restricted our interventions to orthopaedic sur-
gery, and we did not observe a significant reduction in the
frequency of PONV. Our results confirm the findings of
McNicol and colleagues,47 who showed the beneficial effects
of intravenous ketamine at reducing post-surgical pain; in
contrast to that review, we restricted our inclusion criteria to
RCTs of major orthopaedic surgery, with more included
studies (20 vs 2).
Strength and limitations
We executed a thorough search strategy of eleven unique
databases and trial registries and believe that all relevant
studies were identified. We used the Cochrane criteria to
- 331
SD, standard deviation.
assess the risk of bias and GRADE to assess the overall quality
of the evidence (Supplementary Fig. S5). The large number of
studies (n¼20) and subsequent meta-analysis gives us confi-
dence that low-dose ketamine can be an effective adjuvant
medication that decreases opioid requirements and pain
perception after painful orthopaedic surgery, with few side-
effects.
However, we note several limitations. Although there was a
robust number of studies, the quality of several can be ques-
tioned, especially those with low enrolments. Some study
populations were not of a standard distribution, making it
harder to generalise their results to a greater population.
Heterogeneity was high in most of the analyses, possibly
attributable to variations in study designs, differences in time
points for outcome assessments, type of rescue narcotic and
its mode of delivery, and variations in participants’ pain
characteristics at baseline. Because of this heterogeneity, the
only outcome we could analyse was SMD. Of note, our sensi-
tivity analyses resulted in reductions in heterogeneity.
Confounders might also have affected the results. Although
regional anaesthesia might impact results, it would appear
that all efforts were made to minimise bias. Multiple studies
used nitrous oxide and sedatives (propofol and
 332 - Riddell et al.
benzodiazepines) to decrease ketamine-related hallucina-
tions; it is unclear if these medications might potentiate the
benefit seen from ketamine in those studies.
Implications for clinical practice
Low-dose ketamine should be used in painful orthopaedic
surgical procedures, especially total joint replacement, as it
shows an opioid-sparing effect at 24 and 48 h, and decreased
pain perception at 48 h. A suggested dose based on the evi-
dence is 0.5 mg kg1 bolus; longer procedures (>90 min) might
warrant an infusion of 2e5 mg kg1 min1 (stopped at closure).
An amnestic (benzodiazepines, propofol) should be given, and
those using s-ketamine should decrease the dose by 50%. The
use in spine patients is less compelling, but there is still a
benefit. Any benefit in arthroscopic surgery is unclear, as the
effect appears to be equivocal. Multiple promising arthro-
scopic studies did not meet inclusion criteria, so there may
still be a benefit to its use in arthroscopy.
Emerging trends within orthopaedic surgery include
mobilising patients earlier and transitioning them to oral
medications. With lower opioid requirements and lower pain
perception, both goals can be accomplished with greater effi-
cacy. Also, Enhanced Recovery After Surgery (ERAS) protocols
are currently changing orthopaedic practice. However, the
effect of low-dose ketamine as part of the ‘multi-modal opioid-
sparing analgesia’ in many ERAS protocols has not been spe-
cifically studied.
Implications for research
Further studies are needed in the field of arthroscopy. All
studies should re-assess for chronic pain at 3, 6, and 12
months, as there could be a benefit from ketamine. Also, many
studies in this review looked at very low-dose infusions that
demonstrated questionable efficacy; future studies should
focus on higher dose infusions (2e10 mg kg1 min1) paired
with a standard 0.5 mg kg1 bolus.
None of the included studies reflected the fact that many of
these surgeries are now performed as outpatient procedures.
Outpatient total joint arthroplasty is gaining popularity, so
patient selection is a paramount in importance, as is effective
multi-modal postoperative pain control.48 Finally, the use of
low-dose ketamine in the setting of regional anaesthesia
should be an area of future investigation.
Conclusions
The evidence from published RCTs shows that low-dose ke-
tamine significantly decreases total opioid use, the intensity of
pain, and prolongs the time to first opioid requirement in the
first 24e48 h after orthopaedic surgery. Low-dose ketamine
does not significantly increase the risk of hallucinations or
PONV. The quality of the evidence is moderate. Future studies
should focus on the benefits of low-dose ketamine in arthro-
scopic procedures and the incidence of chronic pain.
Authors’ contributions
Writing of the protocol: JMR
Conduct of searches: JMR
Screening and selection of studies: JMR, JMT, IJO
Data extraction: JMR, JMT
Statistical analysis: JMR, JMT
Advised on statistical analysis: IJO
Writing of the manuscript: JMR
Editing of the manuscript: JMT, IJO
Declaration of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
We thank Paul Bain of Countway Library/Harvard Medical
School, Boston, MA, USA, for help with designing and con-
ducting the electronic searches.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bja.2019.05.043.
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Handling editor: J.G. Hardman

Appendix 1. Example of search strategy for

one specific database
Embase (Elsevier)
(’ketamine’/exp OR (ketamine OR ketalar OR ketofol):ab,ti)
AND
((’fracture’/exp OR ’fracture fixation’/exp OR (fracture* OR ’in-
ternal fixation’ OR ’external fixation’):ab,ti OR ((orthopaedic OR
orthopaedic) NEXt/1 trauma*):ab,ti)
OR
(’replacement arthroplasty’/exp OR ((replacement* OR arthro-
plast* OR hemiarthroplast*) NEAR/3 (joint OR knee* OR hip OR
hips OR shoulder* OR ankle* OR elbow* OR disk OR disks OR
disc OR discs)):ab,ti)
OR
(’shoulder surgery’/exp ((shoulder OR ’rotator cuff’) NEAR/3
(surger* OR reconstruction OR repair OR arthroscop*)):ab,ti OR
((’rotator cuff’ OR subacromial) NEXT/1 decompression):ab,ti
OR (’clavicle resection’ OR acrominoplast* OR ’total shoulder’
OR ’slap repair’ OR bankart OR ’weaver dunn’):ab,ti)
OR
(’spine surgery’/exp OR ((spine OR spinal OR disk OR disc OR
vertebral OR scoliosis) NEAR/3 (surger* OR repair* OR fusio-
n*)):ab,ti OR ((lumbar OR thoracic OR cervical) NEAR/3 fusio-
n*):ab,ti OR (corpectom* OR diskectom* OR discectom* OR
laminectom* OR laminotom* OR harrington):ab,ti)
OR
(’anterior cruciate ligament reconstruction’/exp OR ’knee
arthroscopy’/exp OR ((’anterior cruciate ligament’ OR acr)
NEAR/3 (surger* OR repair* OR reconstruction* OR arthroscop*
OR arthroplast*)):ab,ti OR (knee* NEAR/3 arthroscop*):ab,ti))