Piet Waelkens

Emissia Alsabbagh

Axel Sauter

Girish P Joshi

H Ele `ne Beloeil
email: helene.beloeil@chu-rennes.fr

Prof H Ele `ne Beloeil

Po

Pain management after complex spine surgery A systematic review and procedure-specific postoperative pain management recommendations

BACKGROUND Complex spinal procedures are associated with intense pain in the postoperative period. Adequate perioperative pain management has been shown to correlate with improved outcomes including early ambulation and early discharge.

OBJECTIVES We aimed to evaluate the available literature and develop recommendations for optimal pain management after complex spine surgery.

DESIGN AND DATA SOURCES A systematic review using the PROcedure SPECific postoperative pain managemenT methodology was undertaken. Randomised controlled trials and systematic reviews published in the English language from January 2008 to April 2020 assessing postoperative pain after complex spine surgery using analgesic, anaesthetic or surgical interventions were identified from MED-LINE, EMBASE and Cochrane Databases.

RESULTS

Out of 111 eligible studies identified, 31 randomised controlled trials and four systematic reviews met the inclusion criteria. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol, cyclo-oxygenase (COX)-2 specific-inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs), intravenous ketamine infusion and regional analgesia techniques including epidural analgesia using local anaesthetics with or without opioids. Limited evidence was found for local wound infiltration, intrathecal and epidural opioids, erector spinae plane block, thoracolumbar interfascial plane block, intravenous lidocaine, dexmedetomidine and gabapentin.

CONCLUSIONS The analgesic regimen for complex spine surgery should include pre-operative or intra-operative paracetamol and COX-2 specific inhibitors or NSAIDs, continued postoperatively with opioids used as rescue analgesics. Other recommendations are intra-operative ketamine and epidural analgesia using local anaesthetics with or without opioids. Although there is procedure-specific evidence in favour of intra-operative methadone, it is not recommended as it was compared with shorter-acting opioids and due to its limited safety profile. Furthermore, the methadone studies did not use non-opioid analgesics, which should be the primary analgesics to ultimately reduce overall opioid requirements, including methadone. Further qualitative randomised controlled trials are required to confirm the efficacy and safety of these recommended analgesics on postoperative pain relief.

Introduction

Complex spine surgery can be defined as thoracolumbar spine surgery with instrumentation, laminectomy at three or more levels, or scoliosis surgery. Complex spine surgery can improve long-term pain and quality of life in patients with symptomatic back diseases such as idiopathic scoliosis. However, complex spine surgery is associated with significant postoperative pain. [START_REF] Lamperti | Management of complex spine surgery[END_REF] Effective pain control can affect early postoperative rehabilitation and long-term outcomes. [START_REF] Borgeat | Postoperative pain management following scoliosis surgery[END_REF] Although previous reviews stated that multimodal analgesia should be preferred for spine surgery, [START_REF] Devin | Best evidence in multimodal pain management in spine surgery and means of assessing postoperative pain and functional outcomes[END_REF][START_REF] Dunn | Nonopioid analgesics: novel approaches to perioperative analgesia for major spine surgery[END_REF] insufficient evidence did not allow clear recommendations for certain associations of analgesics.

With significant variations in analgesic protocols, a unified approach is necessary to provide standardised interventions on pain reduction. The PROcedure SPECific postoperative pain managemenT (PROSPECT) Working Group is a collaboration of surgeons and anaesthetists working to formulate procedure-specific recommendations for pain management after common but potentially painful operations. The recommendations are based on a procedure-specific systematic review of randomised controlled trials (RCTs) and meta-analyses. The methodology considers clinical practice, efficacy and adverse effects of analgesic techniques. [START_REF] Joshi | Guidelines for perioperative pain management: need for re-evaluation[END_REF] The aim of this systematic review was to evaluate the available literature on the effects of analgesic, anaesthetic and surgical interventions on pain after complex back surgery. The primary outcomes sought were postoperative pain scores and analgesic requirements.

Materials and methods

Search strategy

A systematic review of literature associated with analgesia after complex spine surgery was conducted according to the PROSPECT Methodology. [START_REF] Joshi | on behalf of the PROSPECT Working Group Collaborators. Development of evidence-based recommendations for procedure-specific pain management: PROcedure-SPECific Pain ManagemenT (PROSPECT) methodology[END_REF] The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement was used as a guide for this review. Specific to this study, the Embase, MEDLINE and Cochrane Databases were searched for RCTs published between 1 January 2008 and 18 April 2020. A 10-year period for literature review was chosen because it more likely resembles relevant clinical practice, given that rapid changes occur in peri-operative care including surgical techniques. Of note, the project started in 2018.

The search terms are described in the appendix. Selection criteria for studies include RCTs or systematic reviews of analgesic, anaesthetic and operative interventions, published in the English language assessing pain management for patients undergoing complex spinal surgery. A study was also required to measure pain intensity using a numerical linear scoring system, such as the numerical rating scale (NRS) or visual analogue scale (VAS).

In accordance with the PRISMA checklist, a stepwise process was used, which included screening of abstracts of potential articles. This process was undertaken by two reviewers. Any discrepancies between results were discussed within the working group and a decision was made on inclusion or exclusion by consensus.

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.

Eur J Anaesthesiol 2021; 37:1-10

Criteria employed in the assessment of the quality of eligible studies included allocation concealment, numerical (1 to 5) quality scoring system employed by Jadad to assess randomisation, double blinding and the flow of patients, follow-up of greater or less than 80% of participants, and whether the study met the requirements of the Consolidated Standards of Reporting Trials (CON-SORT) 2010 Statement.

Summary information for each included study was extracted and recorded in data tables. Unless specified otherwise, it was assumed that the pain scores were assessed at rest. The systematic reviews were used to find additional studies via bibliographic screens as well as aid in formulating recommendations.

The included studies were grouped together based upon the analgesic interventions. Within each group, the studies were further placed into subgroups of pre-operative, intra-operative and postoperative interventions.

Pain intensity scores were used as primary outcome measures. We defined a 10% change as clinically important: more than 10 mm on the VAS or 1 point on the NRS. The effectiveness of each intervention for each outcome was evaluated qualitatively, by assessing the number of studies showing a significant difference between treatment arms (P < 0.05 as reported in the study publication). A metaanalysis was not performed due to the limited number of studies with homogeneous design and differences in how results were reported, restricting pooled analysis.

Recommendations are given when at least two congruent studies support an intervention. Recommendations for optimal pain relief are graded A to D according to the overall level of evidence (as determined by the quality of studies included), consistency of evidence and source of evidence (Table 1). The methodology of the PROS-PECT group is unique in that it aims to synthesise clinical evidence while considering risks and benefits of interventions, as well as taking into account study design. Specifically, the group seeks to determine the relevance of study interventions in current peri-operative care practice, and critically evaluate the baseline pain treatment.

The proposed recommendations were sent to the PROS-PECT Working Group for review and comments. A panel discussion took place, which included several rounds of individual comments followed by round-table discussions. Following a round of discussion during the faceto-face meeting, the Working Group unanimously agreed with the proposed recommendations.

Results

The PRISMA flow chart depicting the search strategy is shown in Fig. 1. We included 31 RCTs and four systematic reviews. The methodological quality assessments of the 31 RCTs included for final qualitative analysis are summarised in Supplementary

Analgesic interventions

Pre-operative interventions

The benefit of NSAIDs and COX-2 specific inhibitors was investigated in three studies. Pinar et al. [START_REF] Pinar | Effects of addition of preoperative intravenous ibuprofen to pregabalin on postoperative pain in posterior lumbar interbody fusion surgery[END_REF] compared 800 mg of intravenous (i.v.) ibuprofen 30 min prior to incision versus placebo in patients undergoing multilevel posterior lumbar interbody fusion (PLIF) surgery. The VAS scores and morphine consumption were significantly lower in the ibuprofen group in the first 48 h postsurgery.

In a placebo-controlled study, Jirarattanaphochai et al. [START_REF] Jirarattanaphochai | Effect of parecoxib on postoperative pain after lumbar spine surgery: a bicenter, randomized, double-blinded, placebo-controlled trial[END_REF] compared placebo with the effect of 40 mg parecoxib 30 min before induction of anaesthesia and then every 12 h for 48 h in patients who underwent PLIF surgery. Total morphine requirements over the first 48 h and postoperative pain scores were significantly reduced in the parecoxib group. In a third RCT, the effect of tenoxicam was assessed by Chang et al. [START_REF] Chang | Effect on pain relief and inflammatory response following addition of tenoxicam to intravenous patient-controlled morphine analgesia: a double-blind, randomized, controlled study in patients undergoing spine fusion surgery[END_REF] They compared morphine PCA 1 mg ml À1 vs. PCA morphine 1 mg ml À1 þ tenoxicam 0.6 mg ml À1 vs. a loading dose of 20 mg tenoxicam 30 min before wound closure and a morphine þ tenoxicam PCA. The PCA devices were programmed to deliver a loading dose of 0.05 ml kg À1 , a continuous infusion of 0.005 ml kg À1 h À1 and a bolus dose of Kim et al. [START_REF] Kim | Effective dose of peri-operative oral pregabalin as an adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery[END_REF] compared placebo with two doses of oral pregabalin (75 or 150 mg), 1 h before and 12 h after surgery. Differences in pain scores were not significant, but cumulative morphine i.v. PCA consumption was reduced in the pregabalin 150 mg group after 24 h. The meta-analysis by Yu Lin et al. [START_REF] Yu | Gabapentin and pregabalin in the management of postoperative pain after lumbar spinal surgery[END_REF] demonstrated that, compared with placebo, both gabapentin and pregabalin significantly reduced the postoperative narcotic consumption and postoperative pain scores.

Intra-operative interventions

Murphy et al. [START_REF] Murphy | Clinical effectiveness and safety of intraoperative methadone in patients undergoing posterior spinal fusion surgery: a randomized, double-blinded, controlled trial[END_REF] found a positive analgesic effect of methadone 0.2 mg kg À1 at the start of surgery compared to hydromorphone 2 mg at surgical closure for spinal fusions. Median hydromorphone consumption was significantly reduced in the methadone group and pain scores were lower. This effect was also seen by Gottschalk et al. [START_REF] Gottschalk | Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery[END_REF] when they compared methadone 0.2 mg kg À1 before surgical incision to a sufentanil bolus and continuous infusion in patients undergoing multilevel thoracolumbar spine surgery: following methadone, there was a reduced postoperative opioid requirement by 50% at 48 and 72 h after surgery. Pain sores were also lower by approximately 50% in the methadone group at 48 h postsurgery.

A placebo-controlled trial from Farag et al. showed that i.v. lidocaine infusion (2 mg kg À1 h À1 ) reduced morphine requirements in the first 48 h, but the differences in mean VRS pain scores between the two groups were less than 10%. [START_REF] Farag | Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery[END_REF] Ibrahim et al. 17 also compared i.v. lidocaine infusion (2 mg kg À1 loading and 3 mg kg À1 h À1 infusion) with placebo. Lidocaine significantly reduced the pain scores in the first 48 h postsurgery, the morphine consumption in the first 24 h and the time to the first request for additional analgesia.

The efficacy of ketamine was investigated in six studies. [START_REF] Nielsen | Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blind trial[END_REF][START_REF] Hadi | The influence of anaesthetic drug selection for scoliosis surgery on the management of intraoperative haemodynamic stability and postoperative pain -pharmaceutical care programme[END_REF][START_REF] Loftus | Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery[END_REF][START_REF] Pacreu | The perioperative combination of methadone and ketamine reduces postoperative opioid usage compared with methadone alone[END_REF][START_REF] Urban | Ketamine as an adjunct to postoperative pain management in opioid tolerant patients after spinal fusions: a prospective randomized trial[END_REF][START_REF] Subramaniam | Intra-and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake[END_REF] None of the studies had adequate basic analgesia. [START_REF] Joshi | on behalf of the PROSPECT Working Group Collaborators. Development of evidence-based recommendations for procedure-specific pain management: PROcedure-SPECific Pain ManagemenT (PROSPECT) methodology[END_REF] Bolus doses ranged from high (0.5 mg kg À1 ) [START_REF] Nielsen | Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blind trial[END_REF][START_REF] Loftus | Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery[END_REF][START_REF] Pacreu | The perioperative combination of methadone and ketamine reduces postoperative opioid usage compared with methadone alone[END_REF][START_REF] Subramaniam | Intra-and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake[END_REF] to low (0.1 to 0.2 mg kg À1 ) [START_REF] Hadi | The influence of anaesthetic drug selection for scoliosis surgery on the management of intraoperative haemodynamic stability and postoperative pain -pharmaceutical care programme[END_REF][START_REF] Urban | Ketamine as an adjunct to postoperative pain management in opioid tolerant patients after spinal fusions: a prospective randomized trial[END_REF] and continuous infusion doses ranged from high (up to 10 mg kg À1 min À1 ) [START_REF] Nielsen | Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blind trial[END_REF][START_REF] Hadi | The influence of anaesthetic drug selection for scoliosis surgery on the management of intraoperative haemodynamic stability and postoperative pain -pharmaceutical care programme[END_REF][START_REF] Loftus | Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery[END_REF] to low (1 to 2 mg kg À1 min À1 ). [START_REF] Hadi | The influence of anaesthetic drug selection for scoliosis surgery on the management of intraoperative haemodynamic stability and postoperative pain -pharmaceutical care programme[END_REF][START_REF] Pacreu | The perioperative combination of methadone and ketamine reduces postoperative opioid usage compared with methadone alone[END_REF][START_REF] Urban | Ketamine as an adjunct to postoperative pain management in opioid tolerant patients after spinal fusions: a prospective randomized trial[END_REF][START_REF] Subramaniam | Intra-and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake[END_REF] In patients undergoing major lumbar spinal surgery, Loftus et al. [START_REF] Loftus | Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery[END_REF] demonstrated morphine-sparing effects of intra-operative high-dose ketamine, with decreased pain scores postoperatively and at 6 weeks. Similarly, in patients undergoing lumbar posterior fusions, low-dose ketamine continued for 24 h postoperatively had analgesic, but not opioid-sparing effects. [START_REF] Urban | Ketamine as an adjunct to postoperative pain management in opioid tolerant patients after spinal fusions: a prospective randomized trial[END_REF] Two studies investigated ketamine against the backdrop of intra-operative remifentanil-based analgesia. Hadi et al. [START_REF] Hadi | The influence of anaesthetic drug selection for scoliosis surgery on the management of intraoperative haemodynamic stability and postoperative pain -pharmaceutical care programme[END_REF] found that patients undergoing scoliosis surgery under remifentanil maintenance benefited from ketamine with lower pain scores, reduced morphine consumption and prolonged time to first rescue analgesic. Similarly, Pacreu et al. [START_REF] Pacreu | The perioperative combination of methadone and ketamine reduces postoperative opioid usage compared with methadone alone[END_REF] demonstrated methadone-sparing effects when ketamine infusion was superimposed on a remifentanil maintenance regimen. In chronic pain patients undergoing major spine surgery, Nielsen et al. [START_REF] Nielsen | Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blind trial[END_REF] reported opioid-sparing effects, and reduced opioid-induced sedation, of high-dose ketamine. Sumramaniam et al. [START_REF] Subramaniam | Intra-and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake[END_REF] did not observe additional analgesic benefit of ketamine in patients with pre-operative opioid intake when epidural bupivacaine was used as basic analgesia. Side effects were described by three studies [START_REF] Nielsen | Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blind trial[END_REF][START_REF] Loftus | Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery[END_REF][START_REF] Subramaniam | Intra-and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake[END_REF] : two of these studies found no increase in side effects with ketamine [START_REF] Loftus | Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery[END_REF][START_REF] Subramaniam | Intra-and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake[END_REF] and one study found decreased sedation in the ketamine group. [START_REF] Nielsen | Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blind trial[END_REF] We conclude that intra-operative ketamine has a significant opioid-sparing effect in patients undergoing complex spinal surgery, especially in chronic pain patients.

Dexmedetomidine infusion (0.01 to 0.02 mg kg À1 min À1 ) was compared with remifentanil infusion (0.01 to 0.2 mg kg À1 min À1 ) in patients undergoing PLIF surgery by Hwang et al. [START_REF] Hwang | Dexmedetomidine versus remifentanil in postoperative pain control after spinal surgery: a randomized controlled study[END_REF] The pain scores in the dexmedetomidine group were significantly lower than those in the remifentanil group at the immediate and late postoperative periods (48 h after surgery). The dexmedetomidine group had lower hydromorphone requirements for 48 h after surgery except at time of discharge from PACU. Naik et al. [START_REF] Naik | The effect of dexmedetomidine on postoperative opioid consumption and pain after major spine surgery[END_REF] reported that dexmedetomidine (1 mg kg À1 loading dose followed by 0.5 mg kg À1 h À1 infusion) reduced the intra-operative, but not the postoperative, opioid consumption when compared with placebo in patients undergoing thoracic and/or lumbar spine surgery at three levels or more. There were no differences in pain scores at 24 h postoperatively. A systematic review from Tsaouisi et al., [START_REF] Tsaousi | Dexmedetomidine as a sedative and analgesic adjuvant in spine surgery: a systematic review and meta-analysis of randomized controlled trials[END_REF] with 913 patients included, showed that dexmedetomidine was sedative and allowed an opioidsparing effect intra-operatively. No definite conclusion could be drawn due to the considerable heterogeneity of the available data.

In a study by Jabbour et al., [START_REF] Jabbour | Ketamine and magnesium association reduces morphine consumption after scoliosis surgery: prospective randomised double-blind study[END_REF] patients given magnesium (50 mg kg À1 ) and ketamine (0.2 mg kg À1 bolus with an infusion of 0.15 mg kg À1 h À1 ) showed a significantly lower average cumulative morphine consumption compared with ketamine alone until 48 h postsurgery. VAS scores

Evidence-based pain management after complex spine surgery 5

Eur J Anaesthesiol 2021; 37:1-10

were not significantly different, but quality of sleep and patient satisfaction were better in the magnesium group during the first postoperative night.

Kim et al. [START_REF] Kim | Effective dose of peri-operative oral pregabalin as an adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery[END_REF] compared a multimodal analgesia protocol with celecoxib 200 mg, pregabalin 75 mg, extendedrelease oxycodone 10 mg, acetaminophen 500 mg and IV-PCA morphine with IV-PCA with morphine alone. Pain scores were lower in the multimodal pain management group at all time points (until seven days postoperatively) and opioid consumption was reduced for 48 h after spinal fusion surgery.

A RCT from Maheshwari et al. [START_REF] Maheshwari | Multimodal analgesic regimen for spine surgery. A randomized placebo-controlled trial[END_REF] also investigated the use of a multimodal analgesic pathway in patients at high risk of postoperative pain undergoing multilevel spine surgery. They compared pre-operative acetaminophen and gabapentin, combined with intra-operative infusions of lidocaine and ketamine, with placebo. All patients received epidural analgesia or local wound infiltration. Pain scores, quality of recovery and opioid consumption in the multimodal analgesic group were not superior to the placebo group.

Regional analgesic interventions

The efficacy of epidural infusions was assessed in seven studies. Two RCTs, Park et al. [START_REF] Park | A prospective randomized comparative study of postoperative pain control using an epidural catheter in patients undergoing posterior lumbar interbody fusion[END_REF] and Gessler et al., [START_REF] Gessler | Postoperative patient-controlled epidural analgesia in patients with spondylodiscitis and posterior spinal fusion surgery[END_REF] compared the epidural infusion of 0.2% ropivacaine with IV-PCA opioids. Pain scores were significantly lower in the epidural groups and lower doses of postoperative opioids were required. Two studies compared the combined effects of neuraxial local anaesthetics and opioids with IV-PCA opioid. Prasartritha et al. [START_REF] Prasartritha | A prospective randomized trial comparing epidural morphine through intraoperatively placed epidural catheter and intravenous morphine in major lumbar spinal surgery[END_REF] found that VAS scores in the epidural groups were less than in the i.v. morphine group up to 48 h postoperatively. On the contrary, Kluba et al. [START_REF] Kluba | Efficacy of postoperative analgesia after posterior lumbar instrumented fusion for degenerative disc disease: a prospective randomized comparison of epidural catheter and intravenous administration of analgesics[END_REF] concluded that epidural 0.2% ropivacaine and sufentanil did not lower postoperative pain scores and i.v. sufentanil rescue doses compared with an IV-PCA with piritramide. Epidural bupivacaine 0.125% infusion was compared with 0.2% ropivacaine infusion by Pham-Dang et al. [START_REF] Dang | Epidural analgesia after scoliosis surgery: electrophysiologic and clinical assessment of the effects of bupivacaine 0.125% plus morphine versus ropivacaine 0.2% plus morphine[END_REF] in patients with degenerative or idiopathic scoliosis undergoing multilevel spinal fusion surgery. The VAS scores on mobilisation were lower within the bupivacaine group. Wenk et al. [START_REF] Wenk | Intra-versus postoperative initiation of pain control via a thoracic epidural catheter for lumbar spinal fusion surgery[END_REF] compared an intra-operative epidural infusion of 0.175% bupivacaine and sufentanil 0.5 mg kg À1 with an epidural infusion started after neurological examination on the PACU. They found significantly decreased pain scores in the intra-operative group. Patients in the postoperative group received more intra-operative opioids and postoperative piritramide rescue doses. Early postoperative neurological examination was feasible in all patients in both groups.

There was only one placebo-controlled trial by Choi et al. [START_REF] Choi | The addition of epidural local anesthetic to systemic multimodal analgesia following lumbar spinal fusion: a randomized controlled trial[END_REF] comparing PCEA with 0.1% bupivacaine and hydromorphone with a PCEA 0.9% saline infusion. The mean cumulative opioid consumption was less in the active treatment group, but the difference was statistically not significant. This was the only study that did not favour postoperative epidural techniques over i.v. analgesics.

In a RCT from Offley et al., 37 low (10 mg) and high (15 mg) doses of extended-release epidural morphine were compared. Pain scores in the first 48 h were not significantly different, neither was the total postoperative analgesic consumption.

Ziegeler et al. [START_REF] Ziegeler | Therapeutic effect of intrathecal morphine after posterior lumbar interbody fusion surgery: a prospective, double-blind, randomized study[END_REF] compared the effect of 0.4 mg intrathecal morphine over placebo after posterior lumbar interbody surgery. There was a significantly lower cumulative piritramide requirement in the intrathecal morphine group without any serious increase of opioid-associated side effects. VAS scores were only significantly lower in the morphine group at 4 and 8 h after surgery.

Three studies investigated the effects of local anaesthetic techniques. In a placebo-controlled trial, Greze et al. [START_REF] Greze | Does continuous wound infiltration enhance baseline intravenous multimodal analgesia after posterior spinal fusion surgery? A randomized, double-blinded, placebo-controlled study[END_REF] compared 0.2% ropivacaine (8 ml h À1 ) local wound infusion through a catheter with normal saline after posterior spinal fusion surgery. No additional analgesia or opioid reduction was provided with continuous wound infiltration. Xu et al. [START_REF] Xu | Continuous wound infusion of ropivacaine for the control of pain after thoracolumbar spinal surgery: a randomized clinical trial[END_REF] compared a continuous local wound infusion of 0.33% ropivacaine with flurbiprofen and pentazocine infusion following thoracolumbar spinal surgery. There were no differences in pain scores and rescue analgesia. Chen et al. [START_REF] Chen | Evaluation of ultrasound-guided lateral thoracolumbar interfascial plane Block for postoperative analgesia in lumbar spine fusion surgery: a prospective, randomized, and controlled clinical trial[END_REF] compared the pre-operative placement of a bilateral single shot, ultrasound-guided, lateral thoracolumbar interfascial plane (TLIP) block with a 30 ml bolus of 0.375% ropivacaine at each side to placebo in patients undergoing lumbar spinal fusion surgery. Opioid and anaesthetic consumption in the peri-operative period decreased significantly in the TLIP group compared with the control group. The VAS scores in the TLIP group were lower at 12, 24 and 36 h postoperatively.

Discussion

This systematic review included 31 RCTs with the majority of studies determined to be of high quality based on the CONSORT statement. The strength of our systematic review stems from the PROSPECT methodology, which goes beyond making recommendations based on the simple statistical analysis of the available evidence. On the basis of available evidence and the PROSPECT approach to providing recommendations, combinations of paracetamol and a NSAID or a COX-2 specific inhibitor are recommended pre-operatively or intra-operatively, and they should be continued postoperatively, unless contraindicated. [START_REF] Toms | Single dose oral paracetamol (acetaminophen) for postoperative pain in adults[END_REF][START_REF] Lachiewicz | The role of intravenous acetaminophen in multimodal pain protocols for perioperative orthopedic patients[END_REF][START_REF] Cakan | Intravenous paracetamol improves the quality of postoperative analgesia but does not decrease narcotic requirements[END_REF][START_REF] Khalili | Effect of preemptive and preventive acetaminophen on postoperative pain score: a randomized, double-blind trial of patients undergoing lower extremity surgery[END_REF][START_REF] Sharma | Beyond opioid patient-controlled analgesia: a systematic review of analgesia after major spine surgery[END_REF] Fixed-time interval analgesia has been shown to provide superior pain relief in comparison with on-demand analgesia. [START_REF] Atkinson | Pharmacokinetics and bioavailability of a fixed-dose combination of ibuprofen and paracetamol after intravenous and oral administration[END_REF][START_REF] Yefet | Fixed time interval compared with ondemand oral analgesia protocols for postcaesarean pain: a randomize controlled trial[END_REF] For the intra-operative period, we recommend a low-dose i.v. ketamine infusion. Epidural infusion of local anaesthetic alone or combined with opioids are recommended.

Opioids may be used as postoperative rescue analgesic.

The analgesic benefits and opioid-sparing effects of simple analgesics such as paracetamol and NSAIDs are well described. [START_REF] Joshi | Procedure-specific pain management and outcome strategies[END_REF][START_REF] Martinez | Nonopioid analgesics in adults after major surgery: systematic review with network meta-analysis of randomized trials[END_REF][START_REF] Ong | Combining paracetamol (Acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain[END_REF][START_REF] Chidambaran | Cost-effectiveness of intravenous acetaminophen and ketorolac in adolescents undergoing idiopathic scoliosis surgery[END_REF] Earlier literature suggests concerns that NSAIDs inhibit osteogenesis and increase the rate of nonunion. [START_REF] Li | The effect of ketorolac on thoracolumbar posterolateral fusion: a systematic review and meta-analysis[END_REF] However, more recent studies have reported that NSAIDs appears to have a dose-dependent and duration-dependent effect on fusion rates and their short-term (< 2 weeks) postoperative use is well tolerated. [START_REF] Sivaganesan | The effect of NSAIDs on spinal fusion: a cross-disciplinary review of biochemical, animal, and human studies[END_REF][START_REF] Dodwell | NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies[END_REF] Therefore, short-term use of low-dose NSAIDs around the time of spinal fusion is well tolerated and recommended and does not interfere with osteogenesis or increase the rate of nonunion. [START_REF] Mathiesen | A comprehensive multimodal pain treatment reduces opioid consumption after multilevel spine surgery[END_REF] Patients undergoing spinal surgery in association with peri-operative NSAIDs do not have an increased risk of bleeding. [START_REF] Zhang | Safety of continuing aspirin therapy during spinal surgery: a systematic review and meta-analysis[END_REF][START_REF] Mikhail | Minimizing blood loss in spine surgery[END_REF][START_REF] Chin | Bleeding risk with ketorolac after lumbar microdiscectomy[END_REF] Intra-operative ketamine infusion is recommended due to its significant opioid-sparing effect, especially in opiatedependent chronic pain patients. [START_REF] Loftus | Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery[END_REF][START_REF] Pacreu | The perioperative combination of methadone and ketamine reduces postoperative opioid usage compared with methadone alone[END_REF][START_REF] Urban | Ketamine as an adjunct to postoperative pain management in opioid tolerant patients after spinal fusions: a prospective randomized trial[END_REF][START_REF] Subramaniam | Intra-and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake[END_REF] Negative psychotropic side effects, such as postoperative hallucinations and nightmares, are demonstrated with increasing ketamine doses compared with placebo in the elderly (!60 years old). This was demonstrated in the PODCAST trial. [START_REF] Avidan | Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicenter, double-blind, randomized clinical trial[END_REF] There is insufficient evidence that supports the continuation of ketamine infusion in the postoperative period. It is reasonable to suggest that postoperative ketamine infusion could increase the risk of ketamine-related adverse drug effects. [START_REF] Stoker | Evaluation of clinical factors associated with adverse drug events in patients receiving sub-anesthetic ketamine infusions[END_REF] We conclude that low-dose ketamine infusions (bolus of 0.2 to 0.5 mg kg À1 and continuous infusion of 2 mg kg À1 min À1 ) administered during the intra-operative period improve peri-operative analgesia compared with conventional intra-operative opioid management, [START_REF] Schwenk | Adverse drug effects and preoperative medication factors related to perioperative low-dose ketamine infusions[END_REF] but the ketamine infusions should not be continued in the postoperative period. [START_REF] Schwenk | Adverse drug effects and preoperative medication factors related to perioperative low-dose ketamine infusions[END_REF] The use of epidural analgesia with local anaesthetic, with or without opioids, is recommended as a component of multimodal analgesia. [START_REF] Park | A prospective randomized comparative study of postoperative pain control using an epidural catheter in patients undergoing posterior lumbar interbody fusion[END_REF][START_REF] Gessler | Postoperative patient-controlled epidural analgesia in patients with spondylodiscitis and posterior spinal fusion surgery[END_REF][START_REF] Prasartritha | A prospective randomized trial comparing epidural morphine through intraoperatively placed epidural catheter and intravenous morphine in major lumbar spinal surgery[END_REF][START_REF] Dang | Epidural analgesia after scoliosis surgery: electrophysiologic and clinical assessment of the effects of bupivacaine 0.125% plus morphine versus ropivacaine 0.2% plus morphine[END_REF] Epidural analgesia with opioids alone is not recommended due to lack of evidence. The epidural catheter should be placed under direct visualisation by the surgeon at the end of surgery. Concerns about the use of epidural catheters are loss of sensory function and motor weakness and the possibility of delayed diagnosis of neurological complications. Therefore, low concentrations of local anaesthetics should be used. There were no major adverse effects reported in the literature. [START_REF] Wenk | Intra-versus postoperative initiation of pain control via a thoracic epidural catheter for lumbar spinal fusion surgery[END_REF] Epidural analgesia is recommended, but its use should be individualised.

Methadone given intra-operatively was superior to hydromorphone and sufentanil for lowering postoperative pain scores and opioid requirement. [START_REF] Murphy | Clinical effectiveness and safety of intraoperative methadone in patients undergoing posterior spinal fusion surgery: a randomized, double-blinded, controlled trial[END_REF][START_REF] Gottschalk | Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery[END_REF] However, the benefits of methadone may be related to the duration of action because it was compared with shorter-acting opioids. Furthermore, the methadone studies did not use nonopioid analgesics, which should be the primary analgesics to ultimately reduce overall opioid requirements, including methadone. Importantly, the safety of methadone in the peri-operative period remains a concern. As reported by Dunn et al., [START_REF] Dunn | Safety profile of intraoperative methadone for analgesia after major spine surgery: an observational study of 1,478 patients[END_REF] moderate respiratory depressions, defined as eight or less breaths per minute, can occur following a one-time methadone dose of 0.14 AE 0.07 mg kg À1 in patients scheduled for elective spinal fusion of two or more levels, although the incidence of severe side effects such as reintubation, hypoxaemia and death were not statistically significant. [START_REF] Souza | Intraoperative methadone administration and postoperative pain control: a systematic review and meta-analysis[END_REF] Therefore, i.v. methadone is not recommended currently.

The intra-operative infusion of dexmedetomidine is not recommended due to limited procedure-specific evidence, although intra-operative dexmedetomidine infusion has been reported to reduce peri-operative opioid use and lower postoperative pain scores. [START_REF] Hwang | Dexmedetomidine versus remifentanil in postoperative pain control after spinal surgery: a randomized controlled study[END_REF][START_REF] Tsaousi | Dexmedetomidine as a sedative and analgesic adjuvant in spine surgery: a systematic review and meta-analysis of randomized controlled trials[END_REF] When compared with remifentanil, dexmedetomidine showed fewer side effects such as hypotension, shivering, postoperative nausea and vomiting, and bradycardia. [START_REF] Grape | Intra-operative analgesia with remifentanil vs. dexmedetomidine: a systematic review and metaanalysis with trial sequential analysis[END_REF] Gabapentinoids are not recommended due to limited evidence, although they have an established role in the management of neuropathic pain, which may be a concern in complex spine surgery. [START_REF] Karasch | Wherefore Gabapentinoids? Was there rush too soon to judgment?[END_REF][START_REF] Egunsola | Systematic review of the efficacy and safety of gabapentin and pregabalin for pain in children and adolescents[END_REF][START_REF] Khurana | Postoperative pain and longterm functional outcome after administration of gabapentin and pregabalin in patients undergoing spinal surgery[END_REF] Current evidence does not support the routine use of gabapentinoids as part of a multimodal analgesic regimen in complex spine surgery, and there are concerns regarding side effects such as sedation and respiratory depression. [START_REF] Eipe | Perioperative use of pregabalin for acute pain -a systematic review and meta-analysis[END_REF][START_REF] Calvalcante | Multimodal analgesic therapy with Gabapentin and its association with postoperative respiratory depression[END_REF][START_REF] Myrhe | Pregabalin has analgesic, ventilator and cognitive affects in combination with remifentanil[END_REF][START_REF] Verret | Perioperative use of gabapentinoids for the management of postoperative acute pain: a systematic review and meta-analysis[END_REF] Two studies assessed the benefit of intra-operative i.v. lidocaine. [START_REF] Farag | Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery[END_REF][START_REF] Ibrahim | Effect of intravenous lidocaine infusion on longterm postoperative pain after spinal fusion surgery[END_REF] Only one showed a clinically meaningful reduction in pain scores. [START_REF] Ibrahim | Effect of intravenous lidocaine infusion on longterm postoperative pain after spinal fusion surgery[END_REF] In the study by Farag et al., [START_REF] Farag | Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery[END_REF] the difference in pain scores was less than 10%, and not clinically relevant according to the Prospect methodology. Thus, lidocaine infusion is not recommended due to conflicting evidence.

Intrathecal opioid administration is not recommended due to limited evidence. [START_REF] Ziegeler | Therapeutic effect of intrathecal morphine after posterior lumbar interbody fusion surgery: a prospective, double-blind, randomized study[END_REF] Although intrathecal treatments may be a promising therapeutic option, further studies are needed in adult populations to make proper recommendations. [START_REF] Milbrandt | A comparison of three methods of pain control for posterior spinal fusions in adolescent idiopathic scoliosis[END_REF] Wound infiltration has been shown to reduce postoperative pain after laminectomy and microdisectomy, but not for complex spine surgery in adults. [START_REF] Kjaergaard | Wound infiltration with local anesthetics for postoperative pain relief in lumbar spine surgery: a systematic review[END_REF] Also, data were insufficient to recommend the use of lateral thoracolumbar interfascial plane blocks bilaterally, or a bilateral erector spinae plane block although results from recent publications are promising. [START_REF] Singh | Bilateral ultrasound-guided erector spinae plane block for postoperative analgesia in lumbar spine surgery: a randomized control trial[END_REF] Various multimodal analgesic approaches have been proposed. Kim et al. [START_REF] Kim | Effective dose of peri-operative oral pregabalin as an adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery[END_REF] found lower pain scores and less opioid consumption. There was no significant superiority of multimodal analgesia in the RCT by Maheshwari et al. [START_REF] Maheshwari | Multimodal analgesic regimen for spine surgery. A randomized placebo-controlled trial[END_REF] But there are some biases, as patients received epidural analgesia or local wound infiltration and, in some cases, acetaminophen was continued postoperatively and gabapentin was continued at the discretion of the surgery team.

There are currently no studies in the literature that directly assess the effectiveness of muscle relaxants and nonbenzodiazepines. [START_REF] Van Tulder | Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration[END_REF] We did not find evidence to promote one surgical technique over another. [START_REF] Machado | Effectiveness of surgery for lumbar spinal stenosis: a systematic review and meta-analysis[END_REF] The limitations of this review are related to those of the included studies. There was considerable heterogeneity across the studies, such as the type of surgery. The

Evidence-based pain management after complex spine surgery 7

Eur J Anaesthesiol 2021; 37:1-10 number of vertebrae involved differed between studies and also differed in some populations within a single RCT. There was also heterogeneity in the drug doses administered, the methods of drug administration and the sample sizes. Not all drugs in the RCTs were compared with a multimodal analgesic regimen. One of the major gaps in the literature is the lack of studies assessing analgesic interventions for different types of pain (e.g. neuropathic or radicular pain), or specific patient populations (e.g. opioid-dependent patients or those with major psychiatric disorders).

In summary, major spine surgery with multilevel instrumentation is painful, requiring significant opioid use. This review has identified the analgesic regimen for optimal pain management after complex spine surgery (Table 2). We also identified analgesic interventions that are not recommended (Table 3). We recommend multimodal pain management including pre-or intra-operative paracetamol and NSAIDs or COX-2 specific inhibitors and continued in the postoperative period. Intra-operatively, we recommend the use of a low-dose ketamine infusion. Further, we suggest the use of an epidural catheter, placed under direct visualisation by the surgeon, and postoperative infusion with local anaesthetic alone or combined with opioids. As rescue analgesia postoperatively, we recommend the use of opioids. Well designed procedure-specific studies are necessary to assess the clinical benefits of the recommendations.

2RECOMMENDATIONS 1 .

 1 Waelkens et al. Systemic analgesia should include paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2 specific inhibitors administered pre-operatively or intra-operatively and continued postoperatively. 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.

4

  Waelkens et al.

Fig. 1 35 )

 135 Fig. 1 PRISMA flowchart

  Pre-operative and intra-operative recommendations Oral or i.v. paracetamol (Grade D) Oral or i.v. NSAIDs / COX-2 specific inhibitors (Grade A) i.v. Ketamine infusion (Grade A) Postoperative recommendations Epidural analgesia with local anaesthetics and with or without opioids (Grade B) Oral or i.v. paracetamol (Grade D) Oral or i.v. NSAIDs/COX-2 specific inhibitors (Grade A) Opioids as rescue medication (Grade D) COX, cyclooxygenase; i.v., intravenous.

Table 1

 1 Evidence-based pain management after complex spine surgery 3

	, http://links.lww.-

Table 1

 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.

Eur J Anaesthesiol 2021; 37:1-10 links.lww.com/EJA/A490 and 3, http://links.lww.com/ EJA/A491.

  Search terms: complex spine surgery OR scoliosis surgery OR thoracolumbar instrumentation OR thoracolumbar spine surgery OR spinal fusion AND pain OR pains OR pain management OR postoperative pain OR postoperative pain OR analgesia OR anaesthesia OR VAS OR visual analogue OR VRS OR verbal rating scale OR NRS OR numerical rating scale OR pain rating OR epidural OR neuraxial OR intrathecal OR paravertebral OR spinal OR infiltration OR nerve block OR neural block OR paravertebral block OR field block OR ilioinguinal block OR transversus abdominis plane block OR TAP block OR NSAID OR nonsteroidal anti-inflammatory OR nonsteroidal anti-inflammatory OR cyclo-oxygenase (COX)-2 OR paracetamol OR acetaminophen OR clonidine OR opioid OR ketamine OR corticosteroid OR gabapentin OR pregabalin.PROSPECT is supported by an unrestricted grant from the European Society of Regional Anaesthesia and Pain Therapy (ESRA). In the past, PROSPECT has received unrestricted grants from Pfizer Inc. New York, New York, USA and Grunenthal, Aachen, Germany.Conflicts of interest: Philipp Lirk has no conflicts of interest to declare. Girish P. Joshi has received honoraria from Baxter and Pacira Pharmaceuticals. Francis Bonnet has received honoraria from Pfizer, The Medicine Company, Abbott France and Nordic Pharma France. Henrik Kehlet has received honoraria from Pfizer and Grunenthal. The Anaesthesiology Unit of the University of Western Australia, but not Stephan Schug privately, has received research and travel funding and speaking and consulting honoraria from bioCSL, Eli Lilly, Indivior, iX Biopharma and Pfizer. Narinder Rawal has received honoraria from Baxter and Sintetica. Marc Van de Velde received honoraria from Sintetica, Grunenthal, Vifor Pharma, MSD, Nordic Pharma, Janssen Pharmaceuticals, Heron Therapeutics and Aquettant. H ele `ne Beloeil has received honoraria from Orion, Abbvie and Aspen.Presentations: This systematic review was presented as a poster presentation at the Online SARB (Society for Anesthesia and Resuscitation of Belgium) Graduation Day, 23 of May 2020, Leuven, Belgium.

	Financial support and sponsorship: The PROSPECT Working
	group provided a grant to cover the open access publication costs
	for this article.

Table 2

 2 Overall recommendations for peri-operative pain management in patients undergoing complex spine surgery

Table 3

 3 Analgesic interventions that are not recommended for pain management in patients undergoing complex spine surgery

	Intervention	Reason for not recommending
	Oral gabapentinoids	Significant risk of adverse effects
	i.v. methadone	Significant risk of adverse effects
	Erector spinae plane block	Limited procedure-specific evidence
	Thoracolumbar interfascial	Limited procedure-specific evidence
	plane block
	i.v. lidocaine	Limited procedure-specific evidence
	i.v. glucocorticoid	Lack of procedure-specific evidence
	i.v. dexmedetomidine	Limited procedure-specific evidence
	Epidural opioids	Limited procedure-specific evidence
	Intrathecal opioids	Limited procedure-specific evidence
	Local anaesthetic	Limited and inconsistent procedure-
	wound infusion	specific evidence
	i.v. magnesium	Limited procedure-specific evidence
	Surgical interventions	Limited procedure-specific evidence
	i.v., intravenous.

Eur J Anaesthesiol 2021; 37:1-10

Waelkens et al. Eur J Anaesthesiol 2021; 37:1-10

Eur J Anaesthesiol 2021; 37:1-10

Acknowledgements relating to this article

Assistance with the study: EA and PW Ã equally contributed to this manuscript, and therefore share first authorship. PW and EA conducted the literature search and analysed the retrieved articles with AS, JG and HB. PW and EA wrote the manuscript, which was reviewed and edited by all the other authors who have also participated in the PROSPECT Working Group meetings using the Delphi method and in defining the methodology of the PROSPECT group.

Appendix: PROSPECT working group ÃÃ : E. Albrecht, H. Beloeil, F. Bonnet, A. Delbos, S. Freys, G. P. Joshi, H. Kehlet, P. Lavand'homme, P. Lirk, D. Lobo, E. Pogatzki-Zahn, N. Rawal, J. Raeder, A. Sauter, S. Schug, M. van de Velde