Pain Management After Complex Spine Surgery A.10

Eur J Anaesthesiol 2021; 38:985–994
REVIEW ARTICLE
Pain management after complex spine surgery

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A systematic review and procedure-specific postoperative pain

management recommendations
lène Beloeil, on behalf of
Piet Waelkens, Emissia Alsabbagh, Axel Sauter, Girish P. Joshi and He
the PROSPECT Working groupMM of the European Society of Regional Anaesthesia and Pain
therapy (ESRA)
BACKGROUND Complex spinal procedures are associated analgesia using local anaesthetics with or without opioids.
with intense pain in the postoperative period. Adequate peri- Limited evidence was found for local wound infiltration,
operative pain management has been shown to correlate intrathecal and epidural opioids, erector spinae plane block,
with improved outcomes including early ambulation and early thoracolumbar interfascial plane block, intravenous lidocaine,
discharge. dexmedetomidine and gabapentin.
OBJECTIVES We aimed to evaluate the available literature CONCLUSIONS The analgesic regimen for complex spine
and develop recommendations for optimal pain management surgery should include pre-operative or intra-operative para-
after complex spine surgery. cetamol and COX-2 specific inhibitors or NSAIDs, continued
postoperatively with opioids used as rescue analgesics.
DESIGN AND DATA SOURCES A systematic review using
Other recommendations are intra-operative ketamine and
the PROcedure SPECific postoperative pain managemenT
epidural analgesia using local anaesthetics with or without
methodology was undertaken. Randomised controlled trials
opioids. Although there is procedure-specific evidence in
and systematic reviews published in the English language
favour of intra-operative methadone, it is not recommended
from January 2008 to April 2020 assessing postoperative
as it was compared with shorter-acting opioids and due to its
pain after complex spine surgery using analgesic, anaes-
limited safety profile. Furthermore, the methadone studies
thetic or surgical interventions were identified from MED-
did not use non-opioid analgesics, which should be the
LINE, EMBASE and Cochrane Databases.
primary analgesics to ultimately reduce overall opioid require-
RESULTS Out of 111 eligible studies identified, 31 random- ments, including methadone. Further qualitative randomised
ised controlled trials and four systematic reviews met the controlled trials are required to confirm the efficacy and
inclusion criteria. Pre-operative and intra-operative interven- safety of these recommended analgesics on postoperative
tions that improved postoperative pain were paracetamol, pain relief.
cyclo-oxygenase (COX)-2 specific-inhibitors or non-steroidal Published online 15 January 2021
anti-inflammatory drugs (NSAIDs), intravenous ketamine infu-
sion and regional analgesia techniques including epidural
From the Department of Anaesthesiology, KU Leuven and University Hospital Leuven, Leuven, Belgium (PW), CHU Rennes, Anesthesia and Intensive Care Department,
Rennes, France (EA), the Department of Anaesthesiology and Pain Management, University of Oslo, Oslo, Norway (AS), the Department of Anaesthesiology and Pain
Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (AS), the Department of Anaesthesiology and Pain Management, University of Texas
Southwestern Medical Center, Dallas, Texas, USA (GPJ), the University Rennes, CHU Rennes, Inserm, INRA, CIC 1414 NuMeCan, Anesthesia and Intensive Care
Department, Rennes, France (HB)
Correspondence to Prof. H
elène Beloeil, Pôle d’Anesth
esie R
eanimation Chirurgicale, CHU Rennes, 2 Rue Henri Le Guilloux, 35033 Rennes Cedex 9, France
Tel: +33 2 99 28 24 22; fax: +33 2 99 28 24 21; e-mail: [email protected]
0265-0215 Copyright ß 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.
DOI:10.1097/EJA.0000000000001448
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to
download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
986 Waelkens et al.
RECOMMENDATIONS
1. Systemic analgesia should include paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) or cyclo-
oxygenase (COX)-2 specific inhibitors administered pre-operatively or intra-operatively and continued post-
operatively.
2. Intra-operative intravenous low-dose ketamine infusion is recommended.
3. Epidural analgesia with local anaesthetics alone or combined with opioids are recommended.
4. Opioids should be reserved as rescue analgesics in the postoperative period.

WHY WAS THIS GUIDELINE DEVELOPED?

Complex spine surgery is associated with significant postoperative pain. Effective pain control can affect early
postoperative rehabilitation. The aim of this guideline is to provide clinicians with an evidence-based approach to
pain management after complex spine surgery to improve postoperative outcomes such as early ambulation
and discharge.
WHAT OTHER GUIDELINES ARE AVAILABLE ON THIS TOPIC?
Pain management recommendations for spine surgery have been published. However, they were not specific for
complex spine surgery. Secondly, the published reviews on postoperative analgesia for major spine surgery do
not critically evaluate available evidence similar to the PROSPECT approach.
HOW DOES THIS GUIDELINE DIFFER FROM OTHER GUIDELINES?
The PROSPECT approach to develop guidelines is unique as the available evidence is critically assessed for
current clinical relevance and the use of simple, non-opioid analgesics such as paracetamol and non-steroidal
anti-inflammatory drugs as baseline analgesics are considered. This approach reports true clinical effectiveness
by balancing the invasiveness of the analgesic interventions and the degree of pain after surgery, as well as
balancing efficacy and adverse effects.
Introduction
Complex spine surgery can be defined as thoracolumbar Materials and methods
spine surgery with instrumentation, laminectomy at three Search strategy
or more levels, or scoliosis surgery. Complex spine sur- A systematic review of literature associated with analgesia
gery can improve long-term pain and quality of life in after complex spine surgery was conducted according to
patients with symptomatic back diseases such as idio- the PROSPECT Methodology.6 The Preferred Reporting
pathic scoliosis. However, complex spine surgery is asso- Items for Systematic Review and Meta-Analysis Protocols
ciated with significant postoperative pain.1 Effective pain (PRISMA-P) 2015 statement was used as a guide for this
control can affect early postoperative rehabilitation and review. Specific to this study, the Embase, MEDLINE
long-term outcomes.2 Although previous reviews stated and Cochrane Databases were searched for RCTs pub-
that multimodal analgesia should be preferred for spine lished between 1 January 2008 and 18 April 2020. A 10-year
surgery,3,4 insufficient evidence did not allow clear period for literature review was chosen because it more
recommendations for certain associations of analgesics. likely resembles relevant clinical practice, given that rapid
changes occur in peri-operative care including surgical
With significant variations in analgesic protocols, a uni-
techniques. Of note, the project started in 2018.
fied approach is necessary to provide standardised inter-
ventions on pain reduction. The PROcedure SPECific The search terms are described in the appendix. Selec-
postoperative pain managemenT (PROSPECT) Work- tion criteria for studies include RCTs or systematic
ing Group is a collaboration of surgeons and anaesthetists reviews of analgesic, anaesthetic and operative interven-
working to formulate procedure-specific recommendations, published in the English language assessing pain
tions for pain management after common but potentially management for patients undergoing complex spinal
painful operations. The recommendations are based on a surgery. A study was also required to measure pain
procedure-specific systematic review of randomised con- intensity using a numerical linear scoring system, such
trolled trials (RCTs) and meta-analyses. The methodol- as the numerical rating scale (NRS) or visual analogue
ogy considers clinical practice, efficacy and adverse scale (VAS).
effects of analgesic techniques.5
In accordance with the PRISMA checklist, a stepwise
The aim of this systematic review was to evaluate the process was used, which included screening of abstracts
available literature on the effects of analgesic, anaesthetic of potential articles. This process was undertaken by two
and surgical interventions on pain after complex back reviewers. Any discrepancies between results were dis-
surgery. The primary outcomes sought were postopera- cussed within the working group and a decision was made
tive pain scores and analgesic requirements. on inclusion or exclusion by consensus.

Evidence-based pain management after complex spine surgery 987
Table 1 Relationship between quality and source of evidence, levels of evidence and grades of recommendation
Study quality
assessments
Statistical Additional Grade of recommendation
analyses assessment (based on overall
and patient of overall study Level of LoE, considering balance of
follow-up Allocation Jadad quality required evidence clinical practice information
Study type assessment concealment scores to judge LoE (LoE) and evidence)
Systematic review with N/A N/A N/A N/A 1 A

homogeneous results
Randomised controlled Statistics reported AND A (1 to 5) N/A 1 A (based on two or more studies or a
trial (RCT) and >80% follow-up single large, well designed study)
OR
B (3 to 5) N/A
OR
B (1 to 2) Yes
Randomised controlled Statistics not AND/OR B (1 to 2) Yes 2 B (or extrapolation from one
trial (RCT) reported or procedure-specific LoE 1 study)
questionable or
<80% follow-up
OR
C (1 to 5) N/A
OR
D (1 to 5) N/A
Nonsystematic review, cohort N/A N/A 3 C
study, case study; (e.g.
adverse effects)
Clinical practice information N/A N/A 4 D
(expert opinion); inconsistent
evidence
Grades A to D (A, adequate; B, unclear; C, inadequate; D, not used), based on overall level of evidence, considering balance of clinical practice information and evidence.
LoE, levels of evidence; NA, not applicable; RCT, randomised controlled trial.
Criteria employed in the assessment of the quality of Recommendations are given when at least two congruent
eligible studies included allocation concealment, numer- studies support an intervention. Recommendations for
ical (1 to 5) quality scoring system employed by Jadad to optimal pain relief are graded A to D according to the
assess randomisation, double blinding and the flow of overall level of evidence (as determined by the quality of
patients, follow-up of greater or less than 80% of parti- studies included), consistency of evidence and source of
cipants, and whether the study met the requirements of evidence (Table 1). The methodology of the PROS-
the Consolidated Standards of Reporting Trials (CON- PECT group is unique in that it aims to synthesise
SORT) 2010 Statement. clinical evidence while considering risks and benefits
of interventions, as well as taking into account study
Summary information for each included study was
design. Specifically, the group seeks to determine the
extracted and recorded in data tables. Unless specified
relevance of study interventions in current peri-operative
otherwise, it was assumed that the pain scores were
care practice, and critically evaluate the baseline
assessed at rest. The systematic reviews were used to
pain treatment.
find additional studies via bibliographic screens as well as
aid in formulating recommendations. The proposed recommendations were sent to the PROS-
PECT Working Group for review and comments. A panel
The included studies were grouped together based upon discussion took place, which included several rounds of
the analgesic interventions. Within each group, the stud- individual comments followed by round-table discus-
ies were further placed into subgroups of pre-operative, sions. Following a round of discussion during the face-
intra-operative and postoperative interventions. to-face meeting, the Working Group unanimously agreed
Pain intensity scores were used as primary outcome mea- with the proposed recommendations.
sures. We defined a 10% change as clinically important:
more than 10 mm on the VAS or 1 point on the NRS. The Results
effectiveness of each intervention for each outcome was The PRISMA flow chart depicting the search strategy is
evaluated qualitatively, by assessing the number of studies shown in Fig. 1. We included 31 RCTs and four system-
showing a significant difference between treatment arms atic reviews. The methodological quality assessments of
(P < 0.05 as reported in the study publication). A meta- the 31 RCTs included for final qualitative analysis are
analysis was not performed due to the limited number of summarised in Supplementary Table 1, http://links.lww.-
studies with homogeneous design and differences in how com/EJA/A489. The characteristics of the included stud-
results were reported, restricting pooled analysis. ies are shown in Supplementary Tables 2, http://

988 Waelkens et al.
Fig. 1 PRISMA flowchart
Records identified through Additional records identified

Identification
database searching through other sources

(n = 800) (n = 53)
Records after duplicates

removed
(n = 823)
Screening
Records screened
(n = 823)
Records excluded based on

title or abstract review
(n = 712)
Eligibility
Full-text articles assessed

for eligibility
(n = 111)
Full-text articles excluded with reason
(n = 76)
Study type (n = 25)

Missing outcome (n = 16)
No full-text (n = 7)
Included
Surgery type (n = 3)
Number of vertebrae (n = 2)
Studies included in
Paediatric studies (n = 23)
qualitative analysis
(n = 35)
links.lww.com/EJA/A490 and 3, http://links.lww.com/ compared placebo with the effect of 40 mg parecoxib

EJA/A491. 30 min before induction of anaesthesia and then every
12 h for 48 h in patients who underwent PLIF surgery.
Analgesic interventions Total morphine requirements over the first 48 h and
Pre-operative interventions postoperative pain scores were significantly reduced in
The benefit of NSAIDs and COX-2 specific inhibitors the parecoxib group. In a third RCT, the effect of
was investigated in three studies. Pinar et al.7 compared tenoxicam was assessed by Chang et al.9 They compared
800 mg of intravenous (i.v.) ibuprofen 30 min prior to morphine PCA 1 mg ml1 vs. PCA morphine 1 mg ml1 þ
incision versus placebo in patients undergoing multilevel tenoxicam 0.6 mg ml1 vs. a loading dose of 20 mg tenox-
posterior lumbar interbody fusion (PLIF) surgery. The icam 30 min before wound closure and a morphine þ
VAS scores and morphine consumption were significantly tenoxicam PCA. The PCA devices were programmed to
lower in the ibuprofen group in the first 48 h postsurgery. deliver a loading dose of 0.05 ml kg1, a continuous
In a placebo-controlled study, Jirarattanaphochai et al.8 infusion of 0.005 ml kg1 h1 and a bolus dose of

0.02 ml kg1 with a 10 min lock-out period. The pain doses ranged from high (up to 10 mg kg1 min1)18–20 to
scores were not significantly different, but morphine low (1 to 2 mg kg1 min1).19,21–23 In patients undergoing
consumption was reduced in both tenoxicam groups. major lumbar spinal surgery, Loftus et al.20 demonstrated
Two meta-analyses support the use of NSAIDs. Zhang morphine-sparing effects of intra-operative high-dose
et al.10 included eight studies in a meta-analysis, with a ketamine, with decreased pain scores postoperatively
total of 408 patients, comparing NSAIDs with placebo and at 6 weeks. Similarly, in patients undergoing lumbar
after lumbar spine surgery. The mean difference of pain posterior fusions, low-dose ketamine continued for 24 h
scores between NSAIDs and placebo groups was signifi- postoperatively had analgesic, but not opioid-sparing
cant during the first 24 h. The meta-analysis by Jiraratta- effects.22 Two studies investigated ketamine against
naphochai et al.11 included 17 RCTs and 789 patients, and the backdrop of intra-operative remifentanil-based anal-
compared pain scores in patients who underwent lumbar gesia. Hadi et al.19 found that patients undergoing scolio-
spine surgery and received either NSAIDs in addition to sis surgery under remifentanil maintenance benefited
opioids, or opioids alone. The NSAIDs group experi- from ketamine with lower pain scores, reduced morphine
enced significantly less pain and had lower morphine consumption and prolonged time to first rescue analgesic.
consumption. No significant difference was found regard- Similarly, Pacreu et al.21 demonstrated methadone-spar-
ing side effects. ing effects when ketamine infusion was superimposed on
a remifentanil maintenance regimen. In chronic pain
Kim et al.12 compared placebo with two doses of oral
patients undergoing major spine surgery, Nielsen
pregabalin (75 or 150 mg), 1 h before and 12 h after
et al.18 reported opioid-sparing effects, and reduced opi-
surgery. Differences in pain scores were not significant,
oid-induced sedation, of high-dose ketamine. Sumrama-
but cumulative morphine i.v. PCA consumption was
niam et al.23 did not observe additional analgesic benefit
reduced in the pregabalin 150 mg group after 24 h. The
of ketamine in patients with pre-operative opioid intake
meta-analysis by Yu Lin et al.13 demonstrated that, com-
when epidural bupivacaine was used as basic analgesia.
pared with placebo, both gabapentin and pregabalin
Side effects were described by three studies18,20,23: two of
significantly reduced the postoperative narcotic con-
these studies found no increase in side effects with
sumption and postoperative pain scores.
ketamine20,23 and one study found decreased sedation
in the ketamine group.18 We conclude that intra-opera-
Intra-operative interventions tive ketamine has a significant opioid-sparing effect in
Murphy et al.14 found a positive analgesic effect of patients undergoing complex spinal surgery, especially in
methadone 0.2 mg kg1 at the start of surgery compared chronic pain patients.
to hydromorphone 2 mg at surgical closure for spinal
Dexmedetomidine infusion (0.01 to 0.02 mg kg1 min1)
fusions. Median hydromorphone consumption was sig-
was compared with remifentanil infusion (0.01 to
nificantly reduced in the methadone group and pain
0.2 mg kg1 min1) in patients undergoing PLIF surgery
scores were lower. This effect was also seen by
by Hwang et al.24 The pain scores in the dexmedetomi-
Gottschalk et al.15 when they compared methadone
dine group were significantly lower than those in the
0.2 mg kg1 before surgical incision to a sufentanil bolus
remifentanil group at the immediate and late postopera-
and continuous infusion in patients undergoing multi-
tive periods (48 h after surgery). The dexmedetomidine
level thoracolumbar spine surgery: following methadone,
group had lower hydromorphone requirements for 48 h
there was a reduced postoperative opioid requirement by
after surgery except at time of discharge from PACU.
50% at 48 and 72 h after surgery. Pain sores were also
Naik et al.25 reported that dexmedetomidine (1 mg kg1
lower by approximately 50% in the methadone group at
loading dose followed by 0.5 mg kg1 h1 infusion)
48 h postsurgery.
reduced the intra-operative, but not the postoperative,
A placebo-controlled trial from Farag et al. showed that opioid consumption when compared with placebo in
i.v. lidocaine infusion (2 mg kg1 h1) reduced morphine patients undergoing thoracic and/or lumbar spine surgery
requirements in the first 48 h, but the differences in mean at three levels or more. There were no differences in pain
VRS pain scores between the two groups were less than scores at 24 h postoperatively. A systematic review from
10%.16 Ibrahim et al.17 also compared i.v. lidocaine infu- Tsaouisi et al.,26 with 913 patients included, showed that
sion (2 mg kg1 loading and 3 mg kg1 h1 infusion) with dexmedetomidine was sedative and allowed an opioid-
placebo. Lidocaine significantly reduced the pain scores sparing effect intra-operatively. No definite conclusion
in the first 48 h postsurgery, the morphine consumption in could be drawn due to the considerable heterogeneity of
the first 24 h and the time to the first request for the available data.
additional analgesia.
In a study by Jabbour et al.,27 patients given magnesium
The efficacy of ketamine was investigated in six stud- (50 mg kg1) and ketamine (0.2 mg kg1 bolus with an
ies.18–23 None of the studies had adequate basic analge- infusion of 0.15 mg kg1 h1) showed a significantly lower
sia.6 Bolus doses ranged from high (0.5 mg kg1)18,20–21,23 average cumulative morphine consumption compared
to low (0.1 to 0.2 mg kg1)19,22 and continuous infusion with ketamine alone until 48 h postsurgery. VAS scores

990 Waelkens et al.
were not significantly different, but quality of sleep and In a RCT from Offley et al.,37 low (10 mg) and high
patient satisfaction were better in the magnesium group (15 mg) doses of extended-release epidural morphine
during the first postoperative night. were compared. Pain scores in the first 48 h were not
significantly different, neither was the total postoperative
Kim et al.28 compared a multimodal analgesia protocol
analgesic consumption.
with celecoxib 200 mg, pregabalin 75 mg, extended-
release oxycodone 10 mg, acetaminophen 500 mg and Ziegeler et al.38 compared the effect of 0.4 mg intrathecal
IV-PCA morphine with IV-PCA with morphine alone. morphine over placebo after posterior lumbar interbody
Pain scores were lower in the multimodal pain manage- surgery. There was a significantly lower cumulative pir-
ment group at all time points (until seven days postoper- itramide requirement in the intrathecal morphine group
atively) and opioid consumption was reduced for 48 h without any serious increase of opioid-associated side
after spinal fusion surgery. effects. VAS scores were only significantly lower in the
morphine group at 4 and 8 h after surgery.
A RCT from Maheshwari et al.29 also investigated the use
of a multimodal analgesic pathway in patients at high risk Three studies investigated the effects of local anaesthetic
of postoperative pain undergoing multilevel spine sur- techniques. In a placebo-controlled trial, Greze et al.39
gery. They compared pre-operative acetaminophen and compared 0.2% ropivacaine (8 ml h1) local wound infu-
gabapentin, combined with intra-operative infusions of sion through a catheter with normal saline after posterior
lidocaine and ketamine, with placebo. All patients spinal fusion surgery. No additional analgesia or opioid
received epidural analgesia or local wound infiltration. reduction was provided with continuous wound infiltra-
Pain scores, quality of recovery and opioid consumption tion. Xu et al.40 compared a continuous local wound infu-
in the multimodal analgesic group were not superior to sion of 0.33% ropivacaine with flurbiprofen and
the placebo group. pentazocine infusion following thoracolumbar spinal sur-
gery. There were no differences in pain scores and rescue
Regional analgesic interventions analgesia. Chen et al.41 compared the pre-operative place-
The efficacy of epidural infusions was assessed in seven ment of a bilateral single shot, ultrasound-guided, lateral
studies. Two RCTs, Park et al.30 and Gessler et al.,31 com- thoracolumbar interfascial plane (TLIP) block with a 30 ml
pared the epidural infusion of 0.2% ropivacaine with IV- bolus of 0.375% ropivacaine at each side to placebo in
PCA opioids. Pain scores were significantly lower in the patients undergoing lumbar spinal fusion surgery. Opioid
epidural groups and lower doses of postoperative opioids and anaesthetic consumption in the peri-operative period
were required. Two studies compared the combined effects decreased significantly in the TLIP group compared with
of neuraxial local anaesthetics and opioids with IV-PCA the control group. The VAS scores in the TLIP group were
opioid. Prasartritha et al.32 found that VAS scores in the lower at 12, 24 and 36 h postoperatively.
epidural groups were less than in the i.v. morphine group up
to 48 h postoperatively. On the contrary, Kluba et al.33
Discussion
concluded that epidural 0.2% ropivacaine and sufentanil
This systematic review included 31 RCTs with the
did not lower postoperative pain scores and i.v. sufentanil
majority of studies determined to be of high quality
rescue doses compared with an IV-PCA with piritramide.
based on the CONSORT statement. The strength of
Epidural bupivacaine 0.125% infusion was compared with
our systematic review stems from the PROSPECT meth-
0.2% ropivacaine infusion by Pham-Dang et al.34 in patients
odology, which goes beyond making recommendations
with degenerative or idiopathic scoliosis undergoing multi-
based on the simple statistical analysis of the available
level spinal fusion surgery. The VAS scores on mobilisation
evidence. On the basis of available evidence and the
were lower within the bupivacaine group. Wenk et al.35
PROSPECT approach to providing recommendations,
compared an intra-operative epidural infusion of 0.175%
combinations of paracetamol and a NSAID or a COX-2
bupivacaine and sufentanil 0.5 mg kg1 with an epidural
specific inhibitor are recommended pre-operatively or
infusion started after neurological examination on the
intra-operatively, and they should be continued postop-
PACU. They found significantly decreased pain scores in
eratively, unless contraindicated.42–46 Fixed-time inter-
the intra-operative group. Patients in the postoperative
val analgesia has been shown to provide superior pain
group received more intra-operative opioids and postopera-
relief in comparison with on-demand analgesia.47,48 For
tive piritramide rescue doses. Early postoperative neurolog-
the intra-operative period, we recommend a low-dose i.v.
ical examination was feasible in all patients in both groups.
ketamine infusion. Epidural infusion of local anaesthetic
There was only one placebo-controlled trial by Choi et al.36
alone or combined with opioids are recommended.
comparing PCEA with 0.1% bupivacaine and hydromor-
Opioids may be used as postoperative rescue analgesic.
phone with a PCEA 0.9% saline infusion. The mean cumu-
lative opioid consumption was less in the active treatment The analgesic benefits and opioid-sparing effects of
group, but the difference was statistically not significant. simple analgesics such as paracetamol and NSAIDs are
This was the only study that did not favour postoperative well described.49–52 Earlier literature suggests concerns
epidural techniques over i.v. analgesics. that NSAIDs inhibit osteogenesis and increase the rate of

nonunion.53 However, more recent studies have reported severe side effects such as reintubation, hypoxaemia and
that NSAIDs appears to have a dose-dependent and death were not statistically significant.64 Therefore, i.v.
duration-dependent effect on fusion rates and their methadone is not recommended currently.
short-term (< 2 weeks) postoperative use is well toler-
The intra-operative infusion of dexmedetomidine is not
ated.54,55 Therefore, short-term use of low-dose NSAIDs
recommended due to limited procedure-specific evi-
around the time of spinal fusion is well tolerated and
dence, although intra-operative dexmedetomidine infu-
recommended and does not interfere with osteogenesis
sion has been reported to reduce peri-operative opioid

or increase the rate of nonunion.56 Patients undergoing
use and lower postoperative pain scores.24,26 When com-
spinal surgery in association with peri-operative NSAIDs

pared with remifentanil, dexmedetomidine showed
do not have an increased risk of bleeding.57–59
fewer side effects such as hypotension, shivering, post-
Intra-operative ketamine infusion is recommended due to operative nausea and vomiting, and bradycardia.65
its significant opioid-sparing effect, especially in opiate-
Gabapentinoids are not recommended due to limited
dependent chronic pain patients.20–23 Negative psycho-
evidence, although they have an established role in the
tropic side effects, such as postoperative hallucinations and
management of neuropathic pain, which may be a con-
nightmares, are demonstrated with increasing ketamine
cern in complex spine surgery.66–68 Current evidence
doses compared with placebo in the elderly (60 years
does not support the routine use of gabapentinoids as part
old). This was demonstrated in the PODCAST trial.60
of a multimodal analgesic regimen in complex spine
There is insufficient evidence that supports the continua-
surgery, and there are concerns regarding side effects
tion of ketamine infusion in the postoperative period. It is
such as sedation and respiratory depression.69–72
reasonable to suggest that postoperative ketamine infusion
could increase the risk of ketamine-related adverse drug Two studies assessed the benefit of intra-operative i.v.
effects.61 We conclude that low-dose ketamine infusions lidocaine.16,17 Only one showed a clinically meaningful
(bolus of 0.2 to 0.5 mg kg1 and continuous infusion of reduction in pain scores.17 In the study by Farag et al.,16
2 mg kg1 min1) administered during the intra-operative the difference in pain scores was less than 10%, and not
period improve peri-operative analgesia compared with clinically relevant according to the Prospect methodol-
conventional intra-operative opioid management,62 but ogy. Thus, lidocaine infusion is not recommended due to
the ketamine infusions should not be continued in the conflicting evidence.
postoperative period.62
Intrathecal opioid administration is not recommended
The use of epidural analgesia with local anaesthetic, with due to limited evidence.38 Although intrathecal treat-
or without opioids, is recommended as a component of ments may be a promising therapeutic option, further
multimodal analgesia.30–32,34 Epidural analgesia with studies are needed in adult populations to make proper
opioids alone is not recommended due to lack of evi- recommendations.73 Wound infiltration has been shown
dence. The epidural catheter should be placed under to reduce postoperative pain after laminectomy and
direct visualisation by the surgeon at the end of surgery. microdisectomy, but not for complex spine surgery in
Concerns about the use of epidural catheters are loss of adults.74 Also, data were insufficient to recommend the
sensory function and motor weakness and the possibility use of lateral thoracolumbar interfascial plane blocks
of delayed diagnosis of neurological complications. bilaterally, or a bilateral erector spinae plane block
Therefore, low concentrations of local anaesthetics although results from recent publications are promising.75
should be used. There were no major adverse effects
Various multimodal analgesic approaches have been pro-
reported in the literature.35 Epidural analgesia is recom-
posed. Kim et al.28 found lower pain scores and less opioid
mended, but its use should be individualised.
consumption. There was no significant superiority of
Methadone given intra-operatively was superior to hydro- multimodal analgesia in the RCT by Maheshwari
morphone and sufentanil for lowering postoperative pain et al.29 But there are some biases, as patients received
scores and opioid requirement.14,15 However, the benefits of epidural analgesia or local wound infiltration and, in some
methadone may be related to the duration of action because cases, acetaminophen was continued postoperatively and
it was compared with shorter-acting opioids. Furthermore, gabapentin was continued at the discretion of the
the methadone studies did not use nonopioid analgesics, surgery team.
which should be the primary analgesics to ultimately reduce
There are currently no studies in the literature that
overall opioid requirements, including methadone. Impor-
directly assess the effectiveness of muscle relaxants
tantly, the safety of methadone in the peri-operative period
and nonbenzodiazepines.76 We did not find evidence
remains a concern. As reported by Dunn et al.,63 moderate
to promote one surgical technique over another.77
respiratory depressions, defined as eight or less breaths per
minute, can occur following a one-time methadone dose of The limitations of this review are related to those of the
0.14 0.07 mg kg1 in patients scheduled for elective spinal included studies. There was considerable heterogeneity
fusion of two or more levels, although the incidence of across the studies, such as the type of surgery. The

992 Waelkens et al.
Overall recommendations for peri-operative pain

Table 2 procedure-specific studies are necessary to assess the
management in patients undergoing complex spine surgery
clinical benefits of the recommendations.
Pre-operative and intra-operative recommendations
Oral or i.v. paracetamol (Grade D)
Oral or i.v. NSAIDs / COX-2 specific inhibitors (Grade A) Acknowledgements relating to this article
i.v. Ketamine infusion (Grade A) Assistance with the study: EA and PW equally contributed to this
Postoperative recommendations manuscript, and therefore share first authorship. PW and EA con-
Epidural analgesia with local anaesthetics and with or without opioids (Grade ducted the literature search and analysed the retrieved articles with
B)
AS, JG and HB. PW and EA wrote the manuscript, which was
Oral or i.v. paracetamol (Grade D)
Oral or i.v. NSAIDs/COX-2 specific inhibitors (Grade A)

reviewed and edited by all the other authors who have also partici-
Opioids as rescue medication (Grade D) pated in the PROSPECT Working Group meetings using the
Delphi method and in defining the methodology of the
COX, cyclooxygenase; i.v., intravenous. PROSPECT group.
Appendix: PROSPECT working group: E. Albrecht, H. Beloeil,
Analgesic interventions that are not recommended for pain
Table 3 F. Bonnet, A. Delbos, S. Freys, G. P. Joshi, H. Kehlet, P. Lavand’-
management in patients undergoing complex spine surgery homme, P. Lirk, D. Lobo, E. Pogatzki-Zahn, N. Rawal, J. Raeder,
A. Sauter, S. Schug, M. van de Velde
Intervention Reason for not recommending
Oral gabapentinoids Significant risk of adverse effects Search terms: complex spine surgery OR scoliosis surgery OR thor-
i.v. methadone Significant risk of adverse effects acolumbar instrumentation OR thoracolumbar spine surgery OR
Erector spinae plane block Limited procedure-specific evidence spinal fusion AND pain OR pains OR pain management OR post-
Thoracolumbar interfascial Limited procedure-specific evidence operative pain OR postoperative pain OR analgesia OR anaesthesia
plane block OR VAS OR visual analogue OR VRS OR verbal rating scale OR
i.v. lidocaine Limited procedure-specific evidence
NRS OR numerical rating scale OR pain rating OR epidural OR
i.v. glucocorticoid Lack of procedure-specific evidence
i.v. dexmedetomidine Limited procedure-specific evidence
neuraxial OR intrathecal OR paravertebral OR spinal OR infiltration
Epidural opioids Limited procedure-specific evidence OR nerve block OR neural block OR paravertebral block OR field
Intrathecal opioids Limited procedure-specific evidence block OR ilioinguinal block OR transversus abdominis plane block
Local anaesthetic Limited and inconsistent procedure- OR TAP block OR NSAID OR nonsteroidal anti-inflammatory OR
wound infusion specific evidence nonsteroidal anti-inflammatory OR cyclo-oxygenase (COX)-2 OR
i.v. magnesium Limited procedure-specific evidence
paracetamol OR acetaminophen OR clonidine OR opioid OR keta-
Surgical interventions Limited procedure-specific evidence
mine OR corticosteroid OR gabapentin OR pregabalin.
i.v., intravenous.
Financial support and sponsorship: The PROSPECT Working
group provided a grant to cover the open access publication costs
for this article.
number of vertebrae involved differed between studies
PROSPECT is supported by an unrestricted grant from the Euro-
and also differed in some populations within a single
pean Society of Regional Anaesthesia and Pain Therapy (ESRA). In
RCT. There was also heterogeneity in the drug doses the past, PROSPECT has received unrestricted grants from Pfizer
administered, the methods of drug administration and the Inc. New York, New York, USA and Grunenthal, Aachen, Germany.
sample sizes. Not all drugs in the RCTs were compared
with a multimodal analgesic regimen. One of the major Conflicts of interest: Philipp Lirk has no conflicts of interest to
declare. Girish P. Joshi has received honoraria from Baxter and
gaps in the literature is the lack of studies assessing
Pacira Pharmaceuticals. Francis Bonnet has received honoraria from
analgesic interventions for different types of pain (e.g. Pfizer, The Medicine Company, Abbott France and Nordic Pharma
neuropathic or radicular pain), or specific patient popula- France. Henrik Kehlet has received honoraria from Pfizer and
tions (e.g. opioid-dependent patients or those with major Grunenthal. The Anaesthesiology Unit of the University of West-
psychiatric disorders). ern Australia, but not Stephan Schug privately, has received
research and travel funding and speaking and consulting honoraria
In summary, major spine surgery with multilevel instru- from bioCSL, Eli Lilly, Indivior, iX Biopharma and Pfizer. Narinder
mentation is painful, requiring significant opioid use. Rawal has received honoraria from Baxter and Sintetica. Marc Van
This review has identified the analgesic regimen for de Velde received honoraria from Sintetica, Grunenthal, Vifor
optimal pain management after complex spine surgery Pharma, MSD, Nordic Pharma, Janssen Pharmaceuticals, Heron
(Table 2). We also identified analgesic interventions that Therapeutics and Aquettant. H elène Beloeil has received honoraria
are not recommended (Table 3). We recommend multi- from Orion, Abbvie and Aspen.
modal pain management including pre- or intra-operative Presentations: This systematic review was presented as a poster
paracetamol and NSAIDs or COX-2 specific inhibitors presentation at the Online SARB (Society for Anesthesia and
and continued in the postoperative period. Intra-opera- Resuscitation of Belgium) Graduation Day, 23 of May 2020,
tively, we recommend the use of a low-dose ketamine Leuven, Belgium.
infusion. Further, we suggest the use of an epidural
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Eur J Anaesthesiol 2021; 38:985–994