F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S U N I V E R S I T Y O F C O P E N H A G E N

Postoperative pain management in total hip and knee replacement

Doctoral Thesis

Troels Haxholdt Lunn

Department of Anesthesiology and Orthopedic Surgery

Copenhagen University Hospital, Hvidovre

Section for Surgical Pathophysiology Copenhagen University Hospital, Rigshospitalet

The Lundbeck Centre for Fast-track Hip and Knee Arthroplasty

Copenhagen, Denmark 2016

Author Troels Haxholdt Lunn, MD, PhD Members of the assessment committee Professor Johan Ræder, University of Oslo (1. opponent) Professor Nanna Brix Finnerup, University of Aarhus (2. opponent) Professor Jes Bruun Lauritzen, University of Copenhagen (chair of the assessment committee) Professor Henrik S. Thomsen, University of Copenhagen (chair of the defence ceremony) This dissertation was submitted to The Faculty of Health and Medical Sciences at the University of Copenhagen on October 31, 2016. “The Faculty of Health and Medical Sciences at the University of Copenhagen has accepted this dissertation, which consists of the already published dissertations listed on page 3, for public defence for the doctoral degree in Medicine. Copenhagen, September 28, 2017. Ulla Wewer, Head of Faculty” The public defence will take place on February 2, 2018 at 2 pm at Medicinsk Museion, Bredgade 62, 1260 Copenhagen, Denmark. ISBN 978-87-970164-0-4

Contents

Preface and acknowledgements 2 List of papers 3 Papers previously included in academic theses 4 1. Introduction 5

1.1 Setting the scene 5 1.2 The fast-track concept 5 1.3 Multimodal opioid-sparing analgesia 6 1.4 Procedure-specific analgesia 6 1.5 Basic analgesia 7

2. Aim of the thesis 8 2.1 Specific aims and hypotheses 8 2.2 Delimitation and weighting 9 2.3 Scope of the thesis related to my previous PhD thesis 9

3. Non-opioid adjuvant analgesic modalities 10 3.1 Paracetamol, NSAID’s / COX-2-selective inhibitors and their combination 10 3.2 Neuro-axial and peripheral nerve blocks 11 3.3 Local Infiltration Analgesia 12 3.4 Glucocorticoids 14 3.5 Gabapentinoids 17 3.6 Antidepressants 21

4. Preoperative prediction of and risk factors for postoperative pain 24 5. Future research challenges 28

5.1 Basic methodology 28 5.2 Basic pain assessment 28 5.3 Trial designs of analgesic efficacy 29 5.4 Assessment and reporting of adverse events 29 5.5 Challenges in relation to poly-interventional trials 30 5.6 Individual responder analyses 30 5.7 Scientific focus on putative high pain responders 30 5.8 Post-discharge pain – prolonged pain management 31

6. Critical appraisal of the thesis 32 6.1 The thesis review 32 6.2 Exclusion criteria 32 6.3 Statistical considerations 32 6.4 Differences in pain scores 33 6.5 Limitations of thesis papers 33

7. Conclusions 35 8. Summary 38 9. Resumé (Danish summary) 40 10. References 42

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Preface and acknowledgements

The scientific work on which this doctoral is founded started in 2009, where I was employed as a research fellow and PhD student at the Department of Anesthesiology, Copenhagen University Hospital, Hvidovre. After finishing my PhD thesis in 2012, my interest for and scientific work on the topic for this doctoral thesis has continued in parallel with my clinical specialist training as an anesthesiologist. Without the financial support from the Department of Anesthesiology, Copenhagen University Hospital, Hvidovre and the Lundbeck Foundation for Fast-track Hip and Knee Arthroplasty, this work would not have been possible. Further, the final thesis review was written with kind support from the Edgar Schnohr and wife Gilberte Schnohr's Foundation, the Lundbeck Foundation for Fast-track Hip and Knee Arthroplasty, and the Levin’s Foundation. Clinical research, especially conduction of randomized placebo-controlled trials, is demanding, and many people deserve more than thanks – and have been crucial on my way with this work. Particularly, Professor Henrik Kehlet, my previous PhD supervisor, has been of great inspiration and support. His knowledge within the field is enormous and impressive, and I have appreciated our many discussions – and arguments – always with a humorous and respectful tone. Billy Kristensen, my previous PhD co-supervisor, has been a great support, encouraged me and kept my spirits high in difficult times. Claus Lund, Head of Anesthesia, has believed in me and supported me all the way, and Henrik Husted, Head of the Arthroplasty Section, has done a tremendous work, and is a person with a great sense of humor profits. I thank all my co-authors for their invaluable practical and academic contribution – and the statisticians Steen Ladelund and Morten Aagaard Petersen – having had a hand in most trials. It has been a privilege to work with all these dedicated and talented people for the past years. I am indebted to Lissi Gaarn-Larsen, research nurse, for doing an outstanding work, helping me with screening of study patients and with data collection; and the entire staff at the Department of Anesthesiology and Orthopedic Surgery, Copenhagen University Hospital, Hvidovre, have been helpful and dedicated along the way. Also, the staff constituting the Lundbeck Centre Collaboration has done a huge work. I thank the research nurses at multi-center study sites for being dedicated and priceless for data collection: Ulla Hornum (Farsø), Marianne W. Jensen (Grindsted), Brita Pape (Holstebro), Charlotte Troldborg (Vejle) and Stina Bogø (Gentofte). I wish to thank Øivind Jans for being a great sparring partner, Annett Finken for always being helpful with everything and Karen L. Hilsted for skillful support with initiation of multicenter trials. I am grateful to Henrik Kehlet, Claus Lund, Billy Kristensen, Nicolai Bang Foss, Henrik Husted, Jørgen Dahl, Lars Rasmussen, Eske Aasvang, Lasse Andersen, Nicolai Lohse, Øivind Jans, Jacob Lønborg, Ann-Marie Malby Schoos and Iben Luna for encouraging me writing the thesis review. Last but not least, I wish to express my warmest gratitude to Karen Sigrid Jacobsen Lunn, my rock and fortunately also my beautiful wife, my two little daughters Ellen Margrete Lunn and Fanny Marie Lunn, my mother Susanne Lunn, my (step)father Henrik Nepper-Christensen and the rest of my family and family-in-law. Your love, support, and patience not least, enabled me to complete this doctoral thesis. Hopefully, I will succeed in being more present, mentally and physically, in the time to come. The final thesis review was written in the memory of my personal doctors, my father, Henrik Haxholdt and my grandfather, Villars Lunn. Troels Haxholdt Lunn Copenhagen, October 2016

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List of papers

This doctoral thesis is based on the following papers:

1. Husted H, Lunn TH, Troelsen A, Gaarn-Larsen L, Kristensen BB, Kehlet H. 15. Why still in hospital after fast-track hip and knee arthroplasty? Acta Orthop 2011; 82: 679-84.[1]

2. Lunn TH, Husted H, Solgaard S, Kristensen BB, Otte KS, Kjersgaard AG, Gaarn-Larsen L, Kehlet H. Intraoperative local infiltration analgesia for early analgesia after total hip arthroplasty: a randomized, double-blind, placebo-controlled trial. Reg Anesth Pain Med 2011; 36: 424-9.[2]

3. Lunn TH, Kristensen BB, Andersen LØ, Husted H, Otte KS, Gaarn-Larsen L, Kehlet H. Effect of high-dose preoperative methylprednisolone on pain and recovery after total knee arthroplasty: a randomized, placebo-controlled trial. Br J Anaesth 2011; 106: 230-8.[3]

4. Lunn TH, Andersen LØ, Kristensen BB, Husted H, Gaarn-Larsen L, Bandholm T, Ladelund S,

Kehlet H. Effect of high-dose preoperative methylprednisolone on recovery after total hip arthroplasty: a randomized, double-blind, placebo-controlled trial. Br J Anaesth 2013; 110: 66-73.[4]

5. Lunn TH, Gaarn-Larsen L, Kehlet H. Prediction of postoperative pain by preoperative pain

response to heat stimulation in total knee arthroplasty. Pain 2013; 154: 1878-85.[5]

6. Lunn TH, Husted H, Laursen MB, Hansen LT, Kehlet H. Analgesic and sedative effects of perioperative gabapentin in total knee arthroplasty: a randomized, double-blind, placebo-controlled, dose-finding study. Pain 2015; 156: 2438-48.[6]

7. Lunn TH, Frokjaer VG, Hansen TB, Kristensen PW, Lind T, Kehlet H. Analgesic effect of

perioperative escitalopram in high pain catastrophizing patients after total knee arthroplasty: a randomized, double-blind, placebo-controlled trial. Anesthesiology 2015; 122: 884-94.[7]

8. Aasvang EK, Lunn TH, Hansen TB, Kristensen PW, Solgaard S, Kehlet H. Chronic pre-

operative opioid use and acute pain after fast-track total knee arthroplasty. Acta Anaesthesiol Scand 2016; 60: 529-36.[8]

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Papers previously included in academic theses

Paper 3 and 4 were previously part of my PhD thesis High-dose glucocorticoid to improve postoperative recovery in total hip and knee arthroplasty, University of Copenhagen, 2013. Paper 1 and 2 were also included in chief surgeon Henrik Husted’s doctoral thesis Fast-track hip and knee arthroplasty: clinical and organizational aspects, University of Copenhagen, 2012.[9] The fast-track concept as a whole, not postoperative pain management in specific was the primary focus of his thesis.

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1. Introduction

1.1 Setting the scene The International Association for the Study of Pain has had the Year 2016 as their global year campaign against pain in the joints. Joint pain affects millions of people who suffer from a wide variety of clinical conditions. Osteoarthritis is one of them. The incidence of osteoarthritis of the hip and the knee are rising because of an increasingly ageing population and the obesity epidemic.[10;11] Among many inconveniences, osteoarthritis causes pain, functional impairment, sleep disturbances and reduces quality of life. The end stage treatment of advanced osteoarthritis of the hip and knee is surgery, often with implantation of a total artificial hip or knee, a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). THA and TKA are now frequently performed surgical procedures and are growing in number worldwide, thus constituting an important health care challenge.[10;11] Favorable long-term functional outcomes and improved quality of life are reported, although the immediate postoperative phase can be associated with severe pain that hampers rehabilitation.[10;11] In Paper 1, evaluating factors responsible for keeping patient in hospital after THA and TKA, pain, dizziness and general weakness were found to be the main reasons for hospitalization in the early days after both procedures.[1] Although acute pain is most severe after TKA,[12] pain is also clinically significant after THA.[1] Furthermore, pain may be an important reason for patients not meeting discharge criteria in the post anesthesia care unit after both procedures.[13] Thus, efforts to optimize postoperative pain management are paramount in THA and TKA. More generally, it is well-documented from international and national observational surveys that the quality of postoperative pain management has been lagging for decades.[14-18] Thus, it has pinched with implementation of acute postoperative pain management and pain assessment protocols, and if implemented, protocols have not been followed sufficiently, all leading to inadequate pain control and opioid based treatment.[14-18] A humble attempt to contribute to improved postoperative pain management for patients operated with THA and TKA has been the driving force behind the studies making up this doctoral thesis. Some basic concepts initially deserve attention below. 1.2 The fast-track concept The fast-track concept was initially developed within abdominal surgery but has now also been implemented within orthopedic surgery.[9;19] It combines a variety of clinical and organizational features, and involves pre-, intra- and postoperative initiatives. The clinical features include pain management, early and frequent mobilization, physiotherapy, thrombosis-prophylaxis, fluid therapy, anesthetic, surgical and nursing care principles, and utilization of well-defined, standardized, functional discharge criteria.[9;20;21] The organizational features include staff education, thorough information and motivation of patients to be active participants in their own recovery, and revision of traditions.[9;20;21] The fast-track concept is aiming at providing the patients the best available perioperative treatment at any time, and it is a dynamic concept.[9] The ultimate goal is to enhance functional recovery, and to reduce morbidity and mortality, secondarily to reduce length of stay (LOS) in hospital.[9;20;21] Accordingly, LOS after THA and TKA has gradually declined nationwide, from 10-11 days in 2000 to 4 days in 2009,[22] and to ≤ 3 days at present.[23] To my understanding, the fast-track concept has been a rational and admirable attempt to incorporate all aspects of a hospital stay into a patient centered treatment pathway. Especially, it

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has been a precursor of early postoperative mobilization, important in order to enhance functional recovery and to reduce immobility-related complications. So to speak, the concept has changed our approach “from putting patients to bed – to equipping them with a chair and a walking aid”. When that is said, the scientific evidence might be no stronger than the evidence from all what it is made up of – each of its multiple elements – but again (and therefore), the concept is dynamic. The fast-track concept was the setting for all studies included in this thesis. 1.3 Multimodal opioid-sparing analgesia It is widely accepted that insufficient analgesia and side-effects associated with inappropriate analgesic regimes pose a barrier to functional recovery. Contemporary postoperative pain management aims at enhancing pain relief and reducing opioid requirements by combining non-opioid analgesic modalities with different mechanisms of action, so-called multimodal (or balanced) opioid-sparing analgesia.[24-28] Though, the definition of multimodal analgesia is not clear – that means how many analgesic modalities have to be combined for a regime to be “multimodal” – the approach is rational and widely accepted. The American Society of Anesthesiologists Practice Guidelines for Acute Pain Management in the Perioperative Setting state that “whenever possible, anesthesiologists should use multimodal pain management therapy”, but they consider a single non-opioid with morphine i.v. (rescue) as multimodal.[29] The aim of opioid-sparing is to avoid opioid-related side-effects including nausea, vomiting, sedation, dizziness, pruritus, cognitive dysfunction, respiratory and circulatory depression, constipation, ileus, and urinary retention.[25;30] Moreover, although opioids are highly effective in relieving moderate to severe postoperative pain at rest, they are less effective in relieving pain upon mobilization,[30] and raise concern as to tolerance development and opioid-induced hyperalgesia.[31;32] Despite the fact that the multimodal opioid-sparing approach has become the standard of care to reduce postoperative pain[24-28] and the surgical stress response,[20;21] the scientific evidence has recently been demonstrated to be disappointingly limited.[33] Meta-analyses on mono-therapy trials have shown clinically relevant analgesic and opioid-sparing effects of frequently used non-opioid analgesics including paracetamol, NSAIDs, COX-2-inhibitors and gabapentin, but the evidence for the additive or even synergistic analgesic and opioid-sparing effect of various combinations, as originally proposed,[26] is sparse, and no meta-analysis has assessed the effect of poly-intervention combinations of more than two non-opioid analgesic modalities.[33] Furthermore, it is quite clear that adverse effects in relation to application of multimodal analgesia have been poorly assessed and underreported.[34] It has even was been speculated, that patients, on a limited scientific foundation, have been treated with various combinations of analgesics being no more effective than the individual components, which might have introduced escalation of adverse effects only.[33] 1.4 Procedure-specific analgesia There has been general agreement on the usefulness of surgical procedure-specific postoperative pain treatment recommendations, because the efficacy of a particular intervention may vary depending on the type of surgical procedure.[35;36] These recommendations take into account the varying pain characteristics, e.g. pain type, intensity, location and duration, different risk of postoperative morbidity, and surgical and anesthesia technique – all influencing the risk-benefit ratio of an analgesic intervention.[35;36] Procedure-specific postoperative pain treatment recommendations are available on www.postoppain.org, where the PROSPECT Working Group, a

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collaboration of anesthetists and surgeons, publishes its evidence-based consensus recommendations based on systematic reviews of the literature for a particular surgical procedure. Their work has also been published with procedure-specific recommendations for THA and TKA,[37;38] and it has been the intention to update the recommendations regularly. However, the recommendations for THA and TKA need to be updated. The PROSPECT Working Group recommended: For THA (in 2005):[37]

• COX-2-selective inhibitors (grade A) or conventional NSAID’s (grade B) (depending on patient risk factors) + Paracetamol (grade A)

• Weak opioids (grade A) for moderate or low intensity pain • Strong opioids (grade B) for high intensity pain, preferably administered intravenously by

patient-controlled analgesia (grade B) or fixed-interval injection (grade D) • Peripheral neural block (femoral nerve block or posterior lumbar plexus block) continued

after surgery (if initialized intraoperatively in combination with general anaesthesia) for high intensity pain (grade A) in combination with systemic analgesia as required for pain intensity

For TKA (in 2008):[38] • Conventional NSAID’s/COX-2-selective inhibitors (grade A) + paracetamol (grade B) • Weak opioids (grade B), titrated to effect for moderate or low intensity pain • Strong opioids (grade A), titrated to effect for high intensity pain • Femoral nerve block (grade A) in combination with systemic analgesia as required for pain

intensity 1.5 Basic analgesia In daily clinical practice, it might, without detracting the rationale behind the procedure-specific approach, be relevant to complement this approach, with a “basic analgesic” approach (or a “basic recipe”) that can be expanded (including more analgesic modalities) in pain-full procedures, of course, with a procedure-specific adjustment according the specific pain characteristics, anatomical location, and risk of postoperative morbidity.[39] The reason for this is the fact that relatively few analgesic modalities exist,[40] many surgical procedures cause a pain intensity necessitating the use of the same few analgesics, the variability in postoperative pain response is pronounced not only between surgical procedures but also between individuals within a specific procedure, and for organizational arguments.[39]

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2. Aim of the thesis

2.1 Specific aims and hypotheses The papers on which the thesis is based each aimed to provide new knowledge within the topic postoperative pain and its management in total hip and knee replacement. Accordingly, the specific aims and hypotheses of the thesis were: • To explore factors responsible for patients being hospitalized in the early days after THA and

TKA (Paper 1).[1] • To investigate whether intraoperative high-volume local infiltration analgesia (LIA) (with

ropivacaine 0.2%) combined with a multimodal oral analgesic regimen would reduce acute pain after THA. It was hypothesized that LIA would reduce pain during walking 8 h after surgery relative to placebo (Paper 2).[2]

• To investigate the effect of a single preoperative high-dose methylprednisolone, 125 mg i.v., on acute postoperative pain and recovery after TKA. It was hypothesized that methylprednisolone would improve acute postoperative analgesia during walking 24 h after surgery relative to placebo (Paper 3).[3]

• To investigate the effect of a single preoperative high-dose methylprednisolone, 125 mg i.v., on recovery after THA. It was hypothesized that methylprednisolone would reduce time to meet well-defined functional discharge criteria after surgery relative to placebo (Paper 4).[4]

• To investigate whether a simplified preoperative tonic heat pain test paradigm could predict postoperative pain after TKA. It was hypothesized that dependency exists between pain response to preoperative heat pain stimulation and acute postoperative pain (Paper 5).[5]

• To investigate the dose-related effect of gabapentin for 7 days initiated 2 hours preoperatively on acute postoperative pain in opioid-naive patients undergoing TKA. Furthermore, to investigate side effects and severe adverse reactions in detail. It was hypothesized that gabapentin 1300 mg/day would reduce pain upon ambulation 24 h after surgery relative to placebo, but increase sedation 6 h after surgery and, further, that gabapentin 1300 mg/d would be superior to 900 mg/day (Paper 6).[6]

• To investigate the analgesic effect of escitalopram 10 mg daily for 7 days initiated on the day of surgery in high pain catastrophizing patients undergoing TKA. It was hypothesized that escitalopram would reduce pain upon ambulation 24 h after surgery relative to placebo (Paper 7).[7]

• To investigate differences in acute postoperative pain and opioid consumption after TKA in patients with no, low- or high-dose preoperative opioid treatment. It was hypothesized that postoperative pain and opioid consumption would be increased in preoperative opioid users (Paper 8).[8]

The aims of the narrative review were: • To evaluate, with emphasis on the specific topic of each original paper, the current status from

before each paper till now. Further, to summarize the current status on other non-opioid adjuvant analgesic modalities frequently used in recent years, alltogether to discuss the evidence-based conclusions that can be derived in THA and TKA, and to provide basis of a focus specifically directed toward future research challenges.

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2.2 Delimitation and weighting This thesis is made up of eight original papers prepared on the basis of data from eight prospective clinical studies, and of a narrative thesis review. Of the original studies, five were randomized, double-blind, placebo-controlled trials (RCT’s), each trial investigating the effect of a non-opioid adjuvant analgesic modality as part of a multimodal analgesic treatment regimen (LIA in THA, high-dose methylprednisolone in TKA, and in THA, escitalopram in TKA and gabapentin in TKA); and three were observational studies, one dealing with prediction of postoperative pain (using a simple heat pain test paradigm in TKA), one dealing with a potential risk factor for postoperative pain (chronic preoperative opioid use), and one exploring factors responsible for patients remaining hospitalized after THA and TKA – in a way providing the background for the thesis (and referred to in the introduction section). The main thread of the thesis is the original papers all dealing acute postoperative pain after the well-defined surgical procedures, THA and TKA. The reason for dealing with both surgical procedures in the thesis is most importantly, that patients undergoing THA and TKA often are treated by the same clinicians (surgeons and anesthetists). Second, the genesis and indication for surgery is most often the same (advanced osteoarthrosis), and the patients are fairly homogeneous as to demography. The reason for the skewed weighting of included original papers as to surgical procedure, five papers dealing with TKA, two with THA and one with both procedures, reflects the extent of the clinical problem, the fact that acute pain is most severe after TKA as compared with THA.[12] As is apparent, included thesis papers were not restricted to the investigation of a single analgesic modality for instance, and the literature dealing with the topic postoperative pain and its management after THA and TKA is extensive. Consequently, the thesis review is narrative in its nature, by far does not cover all aspects, and is far from being exhaustive. It focuses on the specific topics of included original papers, i.e. specific non-opioid adjuvant analgesic modalities and preoperative prediction of and risk factors for postoperative pain, and also summarizes the current status on other non-opioid adjuvant analgesic modalities in THA and TKA, to discuss the evidence-based conclusions that can be derived, and to provide basis of a focus specifically directed toward future research challenges. The selection of other non-opioid adjuvant analgesic modalities is based on the frequency of usage in clinical practice and investigation in recent years, and on the need to prioritize, but a much large number of modalities are available. Opioid-based analgesic modalities are not included in the review, and the thesis also does not deal with treatment of chronic postoperative pain. The review is primarily based on recent systematic reviews with meta-analyses, procedure-specific reviews and procedure-specific trials in THA and TKA. 2.3 Scope of the thesis related to my previous PhD thesis Whereas my PhD thesis, of which Paper 3 and 4 were part, solely dealt with high-dose glucocorticoid in THA and TKA, the scope of the present doctoral thesis is broadened and includes six new original papers of which three are RCT’s. It is considered inexpedient not to include the two key papers above (both being RCT’s investigating the effect of a potential non-opioid adjuvant analgesic in THA and TKA) in this doctoral thesis with its broadened scope: Postoperative pain management in total hip and knee replacement.

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3. Non-opioid adjuvant analgesic modalities

The optimal analgesic modality relieves pain, have no (minimal) side-effects, promote early mobilization and oral intake, is safe, easy to administer and cheap. However, no such analgesic modality exists, perhaps except for paracetamol (but with only moderate efficacy). In order to optimize postoperative analgesia, minimize the need for rescue opioids and enhance recovery, different non-opioid adjuvant analgesic modalities have been used in clinical practice for THA and TKA patients. At this point, the most frequently used modalities include the following drugs (administered systemically): Paracetamol, NSAID’s, COX-2-inhibitors, glucocorticoids and gabapentinoids – and regional anesthetic techniques: Local infiltration analgesia (LIA), femoral nerve-block, and adductor canal block. However, a much larger number of non-opioid adjuvant analgesic modalities have to a lesser extent (and to varying degrees) been investigated in THA and TKA in recent years. These includes, besides the above mentioned, e.g. antidepressants, ketamine, magnesium, alpha-2 adrenergic agonists (clonidine, dexmedetomidine), sciatic nerve block, obturator nerve block, lumbar plexus block, and lateral femoral cutaneous nerve block – among others. Investigations of these non-opioid adjuvant analgesic modalities have been conducted on top of a basic analgesic regime (poly-therapy trials) or with no basic regime (mono-therapy trials). Due to the innumerable variables in the plethora of studies, including a variety of analgesic modality combinations (drugs and techniques), doses, timing of administration, lack of evidence for and consensus on even a basic regime, outcome heterogeneity, and for other reasons exemplified by the LIA-literature (see Chapter 3.3), comparisons between studies within and between analgesic modalities have been extremely difficult, precluding final conclusions on the ideal combination (gold standard) in THA and TKA so far.[41;42] An additional challenging factor is the pronounced inter-individual variability in postoperative pain response not only between surgical procedures but also within a specific procedure. This may cause some patients to be undertreated and others to be over-treated with a given procedure-specific basic analgesic regime. Consequently, there may be a risk of severe pain and high need for rescue opioid in high pain responders and unnecessary risk in low pain responders. Thus, efforts to preoperatively predict and understand risk factors for postoperative pain responses are critical (see Chapter 4). Below, a narrative review is given on selected non-opioid adjuvant analgesic modalities for postoperative pain management in THA and TKA. The selection is based on the frequency of usage in clinical practice and investigation in recent years according to exiting reviews. 3.1 Paracetamol, NSAID’s / COX-2-selective inhibitors and their combination In accordance with the PROSPECT recommendations,[37;38] a minimum basic recipe combining paracetamol and an NSAID/COX-2-inhibitor in THA and TKA has been widely adapted internationally, although no final consensus has been achieved. However, this has been the minimum basic recipe in the included thesis papers. In a recent topical review, including previous systematic reviews, the evidence for the postoperative analgesic efficacy of the most commonly used systemic non-opioid drugs were scrutinized, including paracetamol, NSAID’s and COX-2-inhibitors, and their combination.[33] In trials of established pain, single-dose oral paracetamol 1 g had a number needed to treat (NNT) of 3.6 (an NNT of 5 for iv administration has later been reported[43]), NSAID’s an NNT of >2 and <4.3 depending on the drug and dosage (e.g. ibuprofen 400 mg an NNT of 2.5), and COX-2-inhibitors

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an NNT of >1.5 and <4.8 depending on the drug and dosage (e.g. celecoxib 400 mg and 200 mg an NNT of 2.5 and 4.2, respectively).[33] In trials of pain prophylaxis (primarily mono-therapy trials), the effect of paracetamol was less convincing, with a mean morphine reduction/24 h of 6.3 to 9.0 mg, not consistently resulting in a reduction of opioid related side-effects.[33] The effect of NSAID’s was more significant on pain intensity, mean morphine reduction/24 h of 10.2 mg, higher with multi-dose regimes, as well as reduction in opioid related side-effects.[33] The effect of COX-2-inhibitors was probably comparable with NSAID’s.[33] On a procedure-specific basis, a recent meta-analysis demonstrated reduced pain and mean morphine reduction/24 h of 14.1 mg with NSAID’s/COX-2-inhibitors in THA patients, but with low quality of evidence (primarily mono-therapy trails, most with high risk of bias).[41] The scientific evidence for an additive or even synergistic effect of the combination of paracetamol and NSAID’s/COX-2-inhibitors was found to be sparse.[33] In trials of established pain, data came from few trials on dental surgery only.[33] An NNT of 5.4 was observed for ibuprofen 400 mg + paracetamol 1000 mg vs. ibuprofen alone, an NNT of 1.5 for the combination vs. placebo, and an NNT of 1.6 for half doses of ibuprofen and paracetamol vs. placebo (with no comparison of the combination vs. paracetamol alone).[44] In trials of pain prophylaxis, most data favored the combination of paracetamol and NSAID vs. each constituent alone, with reduced pain scores and analgesic requirements. However, the efficacy had only been assessed in few qualitative reviews (one which is an updated from previous ones)[45] including different surgical procedures, not quantified in either non-procedure-specific or procedure-specific meta-analyses.[33] The side-effects of paracetamol seem trivial, at least with short-term use.[34] Potential adverse events associated with NSAID’s / COX-2-inhibitors in the perioperative setting have given rise to concerns and continuing controversy. However, data are limited, thus being inconclusive as to mortality, cardiovascular events, surgical bleeding, gastrointestinal-bleeding and renal impairment, but bone healing may not be of concern.[34] Some authors/clinicians recommend e.g. ibuprofen or naproxen (based on thromboembolic cardiovascular risk data from epidemiologic studies), others e.g. celecoxib (in order to potentially reduce surgical and gastrointestinal bleeding). Although, the scientific evidence for a basic recipe combining paracetamol and an NSAID/COX-2-inhibitor is not strong and the adverse effect profile of especially NSAID’s/COX-2-inhibitors not sufficiently assessed in the perioperative setting, a pragmatic approach might at this point still be to recommend short-duration combination therapy for THA and TKA, as long as contra-indications are kept in mind – not least from a consideration that the alternative still largely will be opioids, despite strong evidence of their drawbacks, especially in older patients.[46] However, clinical practice should proceed in parallel with scientific efforts to assess efficacy of combinations of analgesic modalities with improved trial designs, and long-term follow-up to assess potential adverse events (see Chapter 5). In conclusion, combination therapy of paracetamol and an NSAID/COX-2-inhibitor is, with contra-indications kept in mind, recommended for THA and TKA, although no final conclusion can be drawn. 3.2 Neuro-axial and peripheral nerve blocks The fast-track protocols, with increased focus on early postoperative mobilization in order to enhance functional recovery, has limited traditional use of continued lumbar epidural analgesia in THA and TKA, due inherit risk of side-effects (partial motor blockade, urinary retention and hypotension). Thus, continued lumbar epidural analgesia is no longer recommended by the PROSPECT Working Group (for low to medium risk patients).[37;38;47]

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To avoid the side-effects (and risk) associated with neuro-axial blockade, the less invasive peripheral nerve blocks have gained attention. It is widely accepted that peripheral nerve blocks are effective for analgesic treatment.[48] The femoral nerve block has been considered the gold standard and recommended by the PROSPECT Working Group for TKA patients.[38] Analgesic and opioid-sparing effects and reduced opioid related side-effects have been demonstrated with femoral nerve block relative to controls, with mean morphine reduction/24 h of 19.9 mg and 14.7 mg, in two meta-analyses, respectively (primarily mono-therapy trials, most with high or unclear risk of bias).[49;50] The lumbar plexus block has been recommended by the PROSPECT Working Group for THA patients (if initialized intraoperatively in combination with general anaesthesia).[37] In a recent meta-analysis, pain at rest, morphine use and opioid related side-effects were reduced (mean morphine reduction/24 h of 11.9 mg) with lumbar plexus block relative to controls in THA patients, but with very low quality of evidence (only four trials, all with high risk of bias).[41] However, a femoral nerve block, lumbar plexus block (and other nerve blocks, e.g. sciatic nerve block) may impede mobility after THA and TKA, due to inherent risk of motor blockade. Thus, functional rehabilitation might be impaired, making these modalities unattractive on a routine basis. Continuous femoral nerve block and continuous lumbar plexus block have even been associated with risk of falling,[51;52] although this has been questioned by others.[53] In recent years, LIA in THA and TKA (see Chapter 3.3) and the predominantly sensory block, the adductor canal block in TKA have gained attention to preserve quadriceps strength. These techniques have mainly been used and investigated in conjugation with a basic oral analgesic regime. The adductor canal block has been shown to reduce pain after TKA relative to placebo.[54-57] Furthermore, it has indicated “non-inferior” analgesia, and shown superior quadriceps muscle strength compared with femoral nerve block,[58-60] and shown superior quadriceps strength compared with placebo after TKA.[61] The adductor canal block and LIA might even potentially be combined to optimize analgesic efficacy after TKA.[62] However, it is not yet fully clarified if the adductor canal block has a place in the analgesic treatment on a routine basis or for selected patients with severe postoperative pain after TKA. In THA, blockade of the purely sensory nerve, the lateral femoral cutaneous nerve, has recently been investigated – but with limited efficacy (high non-responder rate).[63] In a historical perspective, the focus within regional anesthesia for acute postoperative pain management of THA and TKA patients, thus, has moved towards the periphery.[64] In conclusion, the adductor canal block seems promising in TKA (with comparable analgesic efficacy to the femoral nerve block but without risk of partial motor blockade), but trials are still few and small-sized, making the evidence limited and calling for further studies. 3.3 Local Infiltration Analgesia The Local Infiltration Analgesia (LIA) technique, originally developed by Kerr and Kohan,[65] has gained considerable attention in recent years. The technique covers a systematic intraoperative infiltration of a high-volume analgesic mixture (ropivacaine, ketorolac, and epinephrine) into the surgical wound along with subsequent postoperative injections through an intra-articular placed catheter.[65] Despite the very first positive results were preliminary, arising from an uncontrolled, selected cohort study of 325 patients,[65] LIA gained uncritical widespread acceptance as part of multimodal pain management strategies in THA and TKA, especially in Scandinavia.

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Before Paper 2,[2] few trials had investigated the effect of LIA in THA, all reporting superior analgesia with LIA relative to controls.[66-68] However, methodological inadequacies hindered sufficient interpretation.[2;69] In particular, an LIA mixture combining ropivacaine and ketorolac in the previous studies [66-68] without an NSAID for controls made the interpretation of the local anesthetic component difficult.[2;69] Thus, the analgesic benefit observed might have been due to an analgesic effect of NSAID rather than an effect of the LIA per se,[2;69] as local infiltration of NSAID may have limited additional analgesic efficacy compared with similar systemic administration.[70] Therefore, we investigated whether intraoperative high-volume LIA (with ropivacaine 0.2%) combined with a multimodal oral analgesic regimen would reduce acute pain after THA relative to placebo (Paper 2).[2] In 120 patients (60 in each group), we found no reduction in pain during walking at 8 h with LIA relative to placebo. In exploratory analyses of secondary outcomes, we found no pain reduction the first 8 h (during walking, at rest and upon passive hip flexion) and no opioid-sparing effect. These finding might not exclude a potential effect of LIA but rather be the result of low pain scores (lack of additional efficacy) with the multimodal oral analgesic regime (low assay sensitivity). No severe adverse reactions related to the ropivacaine infiltration were observed.[2] Ten trials have (to my knowledge) later been published on intra- and/or postoperative LIA in THA, like us, solely aiming to investigate the effect of the local analgesic component (with no ketorolac in the LIA-mixture) compared with placebo (saline) or no infiltration. Seven of these trials supported our negative findings,[71-77] whereas three reported on reduced pain and/or opioid-sparing.[78-80] Common, but not unique to the three positive trials, was a less comprehensive systemic analgesic regime. The efficacy of local vs. systemic NSAID has been assessed in few trials of LIA. One study in TKA showed a marginal superior effect in favor of local ketorolac compared with systemic ketorolac.[81] However, in another recent trial on postoperative LIA in THA, with systemic ketorolac as control for local ketorolac in the LIA-mixture, no difference in opioid use was found, but pain during walking was reduced with systemic ketorolac.[82] The overall interpretation of the LIA literature is impeded for several reasons. Generally, many studies have suffered from considerable basic methodological inadequacies, e.g. incomplete blinding, selective reporting, lack of defining a primary outcome, lack of sample-size calculation, being small-sized and underpowered, and having low assay sensitivity.[83] Just as important, is the lack of matched analgesia between groups including lack of systemic control for local NSAID in LIA-mixture (co-intervention bias), insufficient pain assessment, and inclusion of heterogeneous control groups in studies (i.e. no infiltration/saline/epidural analgesia/nerve block/intrathecal morphine etc.).[84;85] These issues, makes it also premature with relevant comparison of LIA with other modalities, e.g. femoral nerve block, although this has been attempted in a recent meta-analysis, showing a small insignificant analgesic effect in favor of LIA in TKA.[86] Recent systematic reviews and meta-analyses on LIA in THA disagree on their conclusions, which might reflect the varying degree of taking the above mentioned concerns into consideration. In TKA the conclusions are more consistent. The latest meta-analysis on intraoperative LIA in THA demonstrated a statistically significant (but questionable clinical relevant) morphine-sparing effect of 7.5 mg/24 h, with no reduction in opioid-related adverse effects, and insignificant pain reduction relative to placebo, with high degree of heterogeneity and low quality of evidence.[41] Only two of the 11 included trials were rated as having low summarized risk of bias[2;74] (both trials with negative findings), but sample-size implicated a moderate risk even in the largest[2] of all trials.[41]

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All trials investigated LIA in conjugation with a basic analgesic regime.[41] As emphasized by the authors, five of the 11 trials used different combinations of drugs in addition to local anesthetics in the LIA-mixture without systemic control for these,[41] thus probably overestimating the already small effect. The latest meta-analysis on LIA in TKA, including 38 trials with a total of 3026 patients, showed reduced pain, opioid consumption (13 mg/24 h) and reduced nausea and vomiting, and higher range of motion with LIA relative to placebo or no injection.[87] The meta-analysis concluded that intraoperative peri-articular but not intra-articular LIA is effective for pain control up to 24 h, and that the effect of postoperative catheter placement is still inconclusive.[87] A recent qualitative systematic review on LIA in THA and TKA concluded that intraoperative LIA provides effective analgesia in the initial period after TKA, but has limited additional analgesic efficiency in THA, when combined with a multimodal analgesic regimen, and that wound catheters did not provide additional analgesia when systemic analgesia was similar.[85] Another meta-analysis on LIA in THA was more positive, and concluded that LIA reduced both pain scores and analgesic consumption on the first day.[88] However, the reduced analgesic consumption was not provided with number of mg/24 h, and the risk of bias evaluation (with the Jadad Score) seems baseless, with risk of bias being underestimated and trial quality overestimated. In conclusion, intraoperative peri-articular LIA seems promising in TKA, but provides no additional clinically relevant analgesic efficacy in THA (where there is less pain to reduce) when combined with a comprehensive multimodal oral analgesic regimen. However, an analgesic effect in THA with use of a less comprehensive oral analgesic regimen or in selected patients (high pain responders) cannot be excluded. Trial quality and heterogeneity make the overall evidence limited, precluding final conclusions. 3.4 Glucocorticoids The effect of low-dose systemic dexamethasone is well-documented for postoperative nausea and vomiting (PONV) prophylaxis.[89-91] For decades, glucocorticoids have also been proposed to have pain relieving properties as demonstrated in a number of topical reviews,[92-94] including major orthopedic surgery.[95] However, the analgesic benefit has not been consistent in all studies.[92] By suppressing the surgical injury-provoked inflammatory response, an important component of the surgical stress response,[20;21;96] it has been suggested that glucocorticoids may exert a wide range of beneficial effects with a potential for improved recovery.[20;21;92;97-99] It has further been speculated that a “high-dose” systemic glucocorticoid might be needed in order to provide postoperative analgesia,[94;100] 1-2 mg/kg methylprednisolone or 0.2-0.4 mg/kg dexamethasone (equipotent doses) suggested by some authors.[100] Before Paper 3[3] and Paper 4,[4] few procedure-specific data from randomized controlled trials existed on the effect of “high-dose” systemic glucocorticoid on postoperative pain in THA and TKA. Actually, only one trial exited in THA[101] and none in TKA. In this single trial including 50 patients (25 in each group), a preoperative dose of dexamethasone, 40 mg i.v., added to a multimodal regime of paracetamol and ibuprofen, was shown to decrease dynamic (standing up) pain at 24 h, reduce the treatment for nausea the first 24 h and to suppress the inflammatory response measured by C-reactive protein (CRP) at 48 h relative to placebo in THA patients.[101] In another a three-armed trial including patients that had undergone mixed orthopedic surgery, a single dose of methylprednisolone, 125 mg i.v., administered to patients with moderate to severe pain 1 day after surgery, was superior to placebo and “equal” to ketorolac, 30 mg i.v., in reducing pain at 24 h (and NNT was 2.8 for both ketorolac and methylprednisolone during the first 4 h).[102]

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Further, the trial suggested a sustained analgesic effect of methylprednisolone superior to both placebo and ketorolac by reducing opioid requirements up to 72 h postoperatively.[102] Also, procedure-specific studies in other surgical procedures, for instance in breast surgery, laparoscopic cholecystectomy and lumbar disc surgery, had shown promising analgesic effects with high-dose systemic glucocorticoid.[103-107] Therefore, we investigated the effect of a single preoperative high-dose of methylprednisolone, 125 mg i.v., added to a comprehensive multimodal oral analgesic regime, on acute postoperative pain and recovery after TKA relative to placebo (Paper 3),[3] and the effect of the same intervention on recovery after THA (Paper 4).[4] In 48 TKA patients (24 in each group), we found significantly lower pain during walking (5 meters) at 24 h with methylprednisolone relative to placebo.[3] In an exploratory analysis of secondary outcomes the following were reduced by methylprednisolone relative to placebo: overall and summarized pain the first 48 h for all pain assessments (during walking, at rest, upon passive hip flexion, and upon passive knee flexion), the CRP-response at 24 h, the number of patients requiring sufentanil in the post anesthesia care unit, rescue oxycodone requirement from 0-24 h, nausea and ondansetron requirement from 0-48 h, and fatigue throughout the day of surgery.[3] Sleep quality, however, was worse on the first postoperative night.[3] In 48 THA patients (24 in each group), we found no significant reduction in time to meet functional discharge criteria by methylprednisolone relative to placebo.[4] In an exploratory analysis of secondary outcomes, overall pain and summarized pain the first 24 h for all pain assessments (during walk, upon rise from chair, at rest, and upon passive hip flexion) and the CRP-response at 24 h were reduced.[4] The only twice daily assessment of the functional discharge criteria may have impaired the possibility to demonstrate a potential difference between groups, since time to meet discharge criteria was already short, thus, representing an issue on assay sensitivity.[4] No serious adverse reactions (especially, no superficial or deep infections) were observed in any of the two trials (follow up till day 30).[3;4] In a later qualitative, approximate but not genuine systematic, review on benefit vs. harm of perioperative glucocorticoid in hip and knee surgery, we arbitrarily divided trial into three groups: systemic glucocorticoid administration analogous to > 10 mg or ≤ 10 mg dexamethasone, and local glucocorticoid administration.[108] Only three trials on high-dose systemic glucocorticoid were found, Paper 3,[3] Paper 4[4] and the THA trial mentioned previously[101] (with a long term follow-up on the same patients).[109] Acute pain was found to be reduced with high-dose systemic and local glucocorticoid, but not with low-dose systemic glucocorticoid. However, the results from local administration studies were flawed by poor trial quality (high risk of bias) and primarily were from minor knee surgical procedures. In low-dose trials, pain related outcomes were not primary outcomes in two of three trials, and pain scores were low, thus trials might have been insensitive to detect a potential analgesic effect.[108] Disappointingly, when repeating this previous search[108] (August 2016), no new trials on the effect of high-dose systemic glucocorticoid (analogous to > 10 mg dexamethasone) was found in THA or TKA. However, analgesic effects of high-dose systemic glucocorticoid have recently been demonstrated in other procedure-specific trials.[110;111] Thus, still very few trials exist in THA and TKA, all being small-sized with consequent inherited risk of imprecision, and confirmatory larger studies are required. Two systematic reviews and meta-analyses have investigated the impact of systemic glucocorticoid on postoperative analgesic efficacy.[112;113] Both of the meta-analyses, including various types of minor to major surgical procedures, showed single-dose perioperative

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dexamethasone to reduce postoperative pain and the need for opioids.[112;113] One of the meta-analysis, including 24 trials with a total of 2751 patients, supported previous speculations, that a certain dose of glucocorticoid might be necessary.[112] Thus, an intermediate dose of dexamethasone (0.11–0.2 mg/kg) was found to reduce both pain at rest and during mobilization, and had a non-specified opioid-sparing effect compared with a low-dose of dexamethasone (≤0.1 mg/kg), but a high-dose dexamethasone (≥0.21 mg/kg) was not superior to the intermediate dose.[112] Thus, dose-finding studies are warranted to define the minimal effective dose to provide postoperative analgesia.[108;112] Also, comparative studies of dexamethasone and methylprednisolone are of interest, dexamethasone with theoretical advantages due to longer biologic half-life. In the other meta-analysis, including 45 trials with a total of 5796 patients, patients receiving dexamethasone in doses between 1.25 and 20 mg had lower pain and used a little less opioid in the first 24 h (mean difference 2.3 mg morphine equivalents/24 h, representing a 10% reduction), compared with controls.[113] Obvious, such a small opioid reduction is of questionable clinical relevance. It must, however, be emphasized that in the studies included in both meta-analyses, pain or opioid consumption were infrequently primary outcomes, dexamethasone was most often administered in doses of 8 mg or less as an adjuvant to other non-opioid analgesics, and the meta-analyses included some of the same trials.[33;112;113] Of special concern in relation to glucocorticoid administration are infection rates and delayed wound healing. Such adverse reactions are well-known to be related to chronic glucocorticoid treatment. In joint replacement surgery, a deep periprosthetic infection is a serious complication increasing morbidity and mortality. Due to the (fortunately) low event rate of this complication, it is a challenging topic to investigate – requiring a substantial number of patients and long-term follow up[108] (but we started, ClinicalTrials.gov ID: NCT02019511). Based on the data from the two meta-analyses discussed above,[112;113] a recent retrospective analysis in THA and TKA,[114] data from cardiac surgery,[115;116] major abdominal surgery,[99;117] mixed major surgery,[98] and from our own qualitative review on hip and knee surgery,[108] the immediate concern for increased infection risk with perioperative systemic single-dose administration, either low- or high-dose, seems not apparent. However, risk of gastrointestinal bleeding was observed to be increased in one meta-analysis.[115] Another concern might be rise in blood sugar. Blood sugar has been shown to be slightly increased in one meta-analysis, based on few studies assessing this issue,[113] and in a large trial on single high-dose dexamethasone in cardiac surgery.[116] There might, however, be no clear evidence for the association between single-dose glucocorticoid administration, raised blood sugar and worsen postoperative outcome,[118] although data are insufficient. All that said, clearly it must be emphasized that the follow-up period in original trials included in meta-analyses mainly has confined to the immediate postoperative period, and that strict follow-up methodology with careful and systematic assessments of adverse reactions has been questionable as best, limiting the validity of the data. Definitely, long-term reporting has been insufficient. Thus, the current safety data are still sparse and incomplete, precluding firm safety conclusions on uncommon severe adverse reactions, and calling for large-scale studies with long-term follow up to clarify the risk.[34;108;119] In conclusion, the results from procedure-specific THA and TKA studies on high-dose systemic glucocorticoid are very promising, but studies are very few and small-sized, making the evidence limited and calling for larger confirmatory efficiency studies. Also, dose-finding and safety studies are required before firm conclusions can be drawn.

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3.5 Gabapentinoids The gabapentinoids, gabapentin and pregabalin, have during the past 10 to 15 years gained considerable attention as a potential component of perioperative multimodal analgesic regimes. The gabapentinoids act on the same receptor (blocking the alpha-2-delta subunit of voltage-sensitive calcium channels in presynaptic afferent neurons), and their analgesic effects are primarily attributed their anti-hyperalgesic properties. Gabapentin has so far been far more frequently studied than pregabalin.[120] Pregabalin has, opposite to gabapentin, linear absorption kinetics, is more potent and obtains faster maximum effect (1-2 h) compared to gabapentin (3-4 h).[121] The side-effect profile might be more pronounced with pregabalin.[34] Before Paper 6,[6] several systematic reviews and meta-analyses across surgical procedures investigating the efficiency of perioperative gabapentin with different dosing regimens on postoperative pain and opioid consumption had been conducted.[122-128] The overall conclusions were that gabapentin reduced acute postoperative pain, provided opioid sparing, attenuated opioid-related side effects as nausea, vomiting and urinary retention, but might increase sedation and dizziness.[122-128] As demonstrated in a topical review based on data from these previous systematic reviews and meta-analyses, the opioid-sparing effect/24 h ranged from 13-32 mg morphine/24 h.[33] The procedure-specific data in TKA were limited and results conflicting.[129-132] Furthermore, the potential adverse effects of gabapentinoids have been of concern, especially in elderly patients. However, such potential adverse effects have usually been insufficiently assessed and underreported in acute postoperative pain trials.[34] Thus, the procedure-specific benefit versus harm had to be have clarified, and information regarding optimal dose was needed.[120] Therefore, we investigated the dose-related effect of gabapentin for 7 days initiated 2 hours preoperatively, in addition to a basic analgesic regime of paracetamol, celecoxib, and intraoperative LIA, on acute postoperative pain in opioid-naive patients undergoing TKA.[6] Furthermore, we investigated side effects and severe adverse reactions in detail (Paper 6).[6] In 300 TKA patients (100 receiving gabapentin 1300 mg/d, 100 receiving gabapentin 900 mg/day and 100 receiving placebo), pain upon ambulation at 24 h was not reduced by gabapentin 1300 or 900 mg/d relative to placebo, but sedation was increased at 6 h by gabapentin 1300 mg/day.[6] In exploratory analyses of other outcomes, no effects on overall pain during well-defined mobilization and at rest from 4 to 48 h or from days 2 to 6 and no opioid-sparing were observed by gabapentin with either dose.[6] More adverse reactions (related to sedation or confusion) were observed in the “high-dose” gabapentin group, of which 5 were characterized as severe due to prolonged hospitalization or readmission.[6] Furthermore, dizziness was more pronounced from days 2 to 6 in the gabapentin “high-dose” group and dizziness tended at an uncorrected level to be more pronounced also in the gabapentin “low-dose” group and from 0 to 48 h in both gabapentin groups. The only benefit observed with gabapentin was an exploratory finding of improved sleep the first to second postoperative night with both doses of gabapentin.[6] Obviously, the results cannot be extrapolated to patients regularly taking opioids prior to TKA, or to TKA patients receiving less comprehensive perioperative multimodal analgesia as discussed.[6] As also discussed, the conflicting results compared with the previous meta-analyses,[122-128] might have arisen from the fact that in the original trials in meta-analyses, gabapentin was most frequently administered as monotherapy (with opioid as rescue).[6] Furthermore, the meta-analyses included many of the same original trials and have been published years ago (not following contemporary recommendations for bias assessment) and currently only representing a fraction of the RCT’s published.[6]

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The most recent meta-analyses on gabapentin for post-operative pain management[133] may have shed new light on all the perioperative gabapentin literature. In this analysis, being the most comprehensive so far, 132 trials with 9498 patients were included for evaluation of benefit, and further 3 trials for evaluation of harm.[133] Gabapentin treatment ranged from 100 to 1200 mg in single-dose trials and from 900 to 2400 mg/d in multi-dose trials. Trials were from various types of minor to major surgical procedures. Only 16 trials had overall low risk of bias, 39 had unclear and 77 had high risk of bias. Only 4 trials included more than 200 patients.[133] In trials with low risk of bias, the mean morphine reduction/24 h was 3.1 mg.[133] In trials with low risk of bias with gabapentin studied as ad on to another non-opioid analgesic regimen, the mean reduction/24 h was 1.2 mg and in trials with gabapentin studied with no non-opioid analgesic regimen 8.0 mg/24 h.[133] The mean morphine reduction/24 h was 7.3 mg in all trial analysis (included independent of the risk of bias assessment) and 4.4 mg/24 and 10.6 mg/h, with gabapentin studied as ad on to another non-opioid analgesic regimen and with no non-opioid analgesic regime, respectively,[133] similar to the results from another recent meta-analysis, showing mean morphine reduction of 8.44 mg/24 h in all trial analysis.[134] In trials with low risk of bias, pain during mobilization was significantly reduced at 6 h postoperatively (mean difference 9 mm), but not at 24 h and not at rest 6 h or 24 h postoperatively (all were reduced in all trials analyses).[133] Risk of nausea, vomiting, sedation and dizziness were not significantly different between groups in trials with low risk of bias, but in all trials analyses nausea and vomiting was reduced, and sedation increased.[133] Only 26 trials reported on incidence of severe adverse events, and the pooled analysis of severe adverse events was inconclusive.[133] However, in trials with low risk of bias, the risk ratio of a severe adverse event was 1.61 with gabapentin relative to placebo, whereas it was 1.14 in all trial analysis.[133] Thus, including all trials independent of the risk of bias evaluation may lead to overestimation of benefits and underestimation of potential harms.[133] This meta-analysis is unique by drawing conclusions from analyses based on reliable high quality, low risk of bias, trials, by differentiating between effects of gabapentin when investigated as ad on to another non-opioid analgesic regimen (poly-therapy trials) or with no non-opioid analgesic regime (mono-therapy trials), and by including analysis of severe adverse events. However, it provides limited information on dose-response and potential procedure-specific differences. The authors conclude that the quality of evidence for perioperative gabapentin treatment is low, that firm evidence for the use of gabapentin in postoperative pain management is lacking, that the clinically relevant beneficial effect seems absent (non-existent as add-on therapy), and that there may be a risk of harm.[133] At best, the “true” opioid-sparing effect of gabapentinoids on a non-procedure specific basis might lie somewhere in between the results from the “low risk of bias” analyses and “all trial” analysis, although this is a rather speculative view. Clearly, information on potential harms, which may be present, is lacking.[6;34;133] Few procedure-specific trials on the effect of gabapentin on postoperative pain in THA and TKA have been conducted. In the most recent and most comprehensive meta-analysis above, four trials in TKA[6;130-132] and two trials in THA[135;136] were included, of which two TKA trials[6;132] and one THA trial[136] met the criteria for low risk of bias, whereas two TKA trials[130;131] had high risk of bias and one THA trial[135] unclear risk of bias.[133] In the other TKA trial with low risk of bias, 101 TKA patients were randomly assigned to either gabapentin 600 mg or placebo preoperatively, followed by gabapentin 200 mg or placebo thrice a day for 2 days added to a multimodal regime of paracetamol and ketorolac.[132] No reduction in 72

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hour morphine consumption (primary outcome) was observed or in pain at rest, with movement, and weight-bearing or knee range of movement.[132] On the other hand, both TKA trials with high risk of bias reported on beneficial effects with gabapentin.[130;131] In one of the trials, 179 TKA patients were randomly assigned to either gabapentin 600 mg or placebo preoperatively, followed by gabapentin 200 mg or placebo thrice a day for 4 days added to a multimodal regime of celecoxib and femoral and sciatic nerve blocks.[130] No improvement in any of several primary outcomes (physical performance tests, patient-reported physical function, or pain score at day 4, and 6 weeks and 3 months) was observed, but morphine consumption at 24 h was reduced and knee range of motion from days 1 to 3 was increased.[130] In the other trial with high risk of bias in TKA patients, these positive findings were supported in an earlier and smaller open-label trial by the same group.[131] In the THA trial with low risk of bias, 102 THA patients were randomly assigned to either gabapentin 600 mg or placebo preoperatively, followed by gabapentin 200 mg or placebo thrice a day for 2 days added to a multimodal regime of paracetamol and ketorolac.[136] No reduction in 72 hour morphine consumption (primary outcome) was observed or in pain or knee range of movement, but patient satisfaction on day 3 was more favorable in the placebo group.[136] In the THA trial with unclear risk of bias, 126 patients were randomly assigned to either gabapentin 600 mg or placebo preoperatively, and a third group to gabapentin 600 mg postoperatively, added to a multimodal regime of paracetamol, celecoxib and dexamethasone (8 mg).[135] No reduction in opioid consumption or pain score the first 48 h and no pain reduction at 6 month were observed with either preoperative or postoperative gabapentin relative to placebo.[135] Based on a scrutiny of the gabapentin literature in THA and TKA in specific, again, including all trials independent of the risk of bias evaluation may lead to overestimation of benefits (both low risk trials in TKA reported no beneficial effects opposite to the two high risk trials). Thus, the procedure-specific evidence for clinically relevant beneficial effects of gabapentin in THA and TKA is even weaker compared with the “non-procedure-specific” evidence. A recent procedure-specific meta-analysis in TKA supports this conclusion.[137] The most recent systematic review with meta-analysis on pregabalin for post-operative pain management included 43 trials with 3378 patients.[138] Trials were from various types of minor to major surgical procedures, and dose of pregabalin treatment ranged significantly with both single-dose trials and multi-dose trials (mainly tested as adjuvant to a basic analgesic regime). Surgical procedures were divided into 3 surgical models: Procedures associated with pronociceptive mechanisms (acute hyperalgesia) (e.g. spine, joint arthroplasty and amputations), procedures not associated with pronociceptive mechanisms (e.g. abdominal laparoscopic surgery, gynecologic procedures, etc.), and procedures with unknown association with pronociceptive mechanisms (e.g. cardiac surgery, dental extraction, etc.).[138] Thirteen studies were rated as low risk of bias (for pain as an outcome). Perioperative pregabalin (150-300 mg/d) resulted in 16 % reduction in analgesic consumption (number of mg not provided), without relation to surgical model, and the sample was underpowered to detect any dose-related effect modification (<150 / 150-300 / > 300 mg/d).[138] A small reduction in pain was observed, primarily restricted to surgery associated with pronociceptive pain. Per 1000 patients, 10 more experienced blurred vision and 41 more sedation with pregabalin relative to placebo.[138] NNT was 11 to prevent one case of nausea and vomiting. The authors emphasize that serious harms and outcomes of enhanced recovery were inadequately assessed in original trials.[138] They conclude that the analgesic effect of pregabalin is largely restricted to surgical procedures associated with pronociceptive mechanisms, and that the clinical significance of these benefits must be weighed against the uncertainties about serious harms.[138]

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Another recent systematic review with meta-analyses on pregabalin for post-operative pain management, being the most comprehensive so far, included 55 trials with 4155 patients.[139] Forty-nine trials investigated acute postoperative pain. Trials were from various types of minor to major surgical procedures, and dose of pregabalin treatment ranged significantly with both single-dose trials (50-300 mg) and multi-dose trials (mainly tested as adjuvant to a basic analgesic regime). The risk of bias assessment was much more optimistic compared with the meta-analyses above, despite including many of the same trials.[139] Pain at rest and during movement at 2 and 24 h were reduced with pregabalin relative to placebo. Opioid consumption was reduced, mean morphine equivalents 8.27 mg/24h (corresponding to 25% reduction).[139] All dose-levels of pregabalin (≤75, 100-150 and 300 mg) resulted in opioid-sparing without significant difference between dose-levels, and between administration of single preoperative dose regimens or multiple postoperative dose regimens. The same was the case for pain outcomes for dose-levels 100-300 mg.[139] PONV was reduced by 38% and pruritus by 51%, whereas sedation was increased by 46%, dizziness by 33% and visual disturbances (3.5 times more likely) relative to placebo. The authors conclude that pregabalin improves postoperative analgesia at the expense of increased sedation and visual disturbances.[139] The opioid-sparing effect of pregabalin relative to placebo, 8.27 mg/24 h,[139] is similar to the effect obtained by gabapentin (all trial analysis by Fabritius et al showing a reduction of 7.3 mg[133] and Doleman et al a reduction of 8.44 mg[134]). Preliminarily, the efficacy of pregabalin might seem a little more pronounced compared with gabapentin, as more trials within the pregabalin literature are poly-therapy (add on) trials compared with more mono-therapy trials in the gabapentin literature, but side-effects might seem more pronounced with pregabalin. However, these potential differences might also relate to different doses, and comparative studies of gabapentin and pregabalin on analgesic efficacy and adverse effects are lacking.[34] Furthermore, no meta-analysis on pregabalin has differentiated between effects of pregabalin in poly- and mono-therapy trials, respectively, severe adverse events have not been assessed, and no meta-analysis with analyses and conclusions only from reliable high quality, low risk of bias, trials exists. Procedure-specific trials on the effect of pregabalin on postoperative pain in THA and TKA have been conducted. In a TKA trial, 240 patients were randomly assigned to either pregabalin 300 mg or placebo preoperatively, followed by pregabalin 150-50 mg twice daily for 14 days added to a multimodal regime of celecoxib, intraoperative LIA, and epidural analgesia.[129] The incidence of chronic “neuropathic” pain (questionnaire) at 3 and 6 months (primary outcomes) were reduced, knee range of motion the first 30 days improved, and in hospital epidural and oral opioid consumption reduced with pregabalin relative to placebo.[129] In addition, early sleep was improved, but early sedation and confusion increased.[129] Early pain recordings (at rest) did not differ between treatment groups; however, according to the study protocol, patients were instructed to keep their NRS score between 2 and 4 with epidural bolus.[129] Unfortunately, no detail on pain during mobilization was reported. In another TKA trial, 120 patients were randomly assigned to either pregabalin 100, 200 or 300 mg or placebo preoperatively, followed by pregabalin 50, 100 or 150 mg or placebo twice a day for 14 days added to a multimodal regime of epidural analgesia, femoral nerve block, oxycodone-paracetamol, and meloxicam (NSAID).[140] No reduction in pain with knee flexion at day 14 (primary outcome), in pain at rest or with ambulation and no opioid-sparing were observed with pregabalin relative to placebo. However, drowsiness was increased and patient satisfaction decreased with pregabalin.[140]

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In a THA trial, 84 patients were randomly assigned to either pregabalin 300 mg or placebo preoperatively (and a third arm received 8 mg dexamethasone in addition to pregabalin) added to a regime of paracetamol and patient-controlled i.v. morphine.[141] Morphine consumption at 24 h (primary outcome) was reduced (not pain or opioid-related side-effects) but sedation increased with pregabalin relative to placebo.[141] In another THA trial, 73 patients were randomly assigned to either pregabalin 150 mg or placebo preoperatively (and a third arm received ketamine and a fourth arm pregabalin plus ketamine) added to no other postoperative regime but patient-controlled i.v. morphine.[142] Morphine consumption at 48 h (primary outcome) was reduced (not pain or opioid-related side-effects) with pregabalin relative to placebo.[142] In a third THA trial, 184 patients were randomly assigned to either pregabalin 150 mg or placebo preoperatively followed by pregabalin 75 mg or placebo twice a day for 7 days added to a regime of celecoxib and patient-controlled i.v. morphine.[143] No reduction in pain or physical function at six weeks or three months (primary outcomes) were observed but morphine consumption the first 24 h and pain and opioid consumption reduced from days 1-7 after discharge with pregabalin relative to placebo.[143] The results from procedure-specific pregabalin trials in THA might seem more positive compared with the gabapentin trials (all three trials of pregabalin reported opioid-sparing in contrast to the two negative trial of gabapentin). However, in the three trials of pregabalin in THA, pregabalin was investigated as monotherapy and as add on to only paracetamol or celecoxib, respectively. In conclusion, there is no firm evidence for a clinical relevant analgesic effect of gabapentin in THA and TKA, especially when added to a multimodal analgesic regime, and potential harmful effects are of concern. Thus, gabapentin may have limited if any role in acute postoperative pain management of these patients and should not be recommended as standard of care. The conclusion as to pregabalin is less clear, but at this point, also pregabalin should not be recommended as standard of care. 3.6 Antidepressants Antidepressants have to a much lesser degree been investigated as potential non-opioid adjuvant analgesics in the treatment of postoperative pain in general and in THA and TKA in specific. Recent reviews, evaluating trials of antidepressants for postsurgical pain, have emphasized that, although there is insufficient evidence to support clinical use of antidepressants (few, mainly older, low quality, heterogeneous trials), positive trials suggest a therapeutic potential for treatment of acute postoperative pain and prevention of persistent postoperative pain with antidepressant drugs.[144;145] Since current treatment of postsurgical pain is often inadequate, and there is a shortage of non-opioid adjuvant analgesics for postoperative pain management, investigations of new drugs and old drugs with additional indications (such as antidepressants) are needed.[144;145] Selective serotonin reuptake inhibitors (SSRI’s) target serotonergic tonus in the central nervous system and are widely used for treatment of major depressive and anxiety disorders. Presynaptic and postsynaptic markers of serotonergic signaling in brain regions relevant to affective cognition have been demonstrated to be associated with tonic pain ratings in healthy volunteers, thus suggesting a role of serotonergic signaling in the modulation and/or the affective appreciation of pain.[146;147] Furthermore, positive effects on basic subconscious processing of negative emotions have been suggested with short-term SSRI treatment, that means, SSRI may dampen the reactivity to negative threat-related and fear-related stimuli as evaluated by functional magnetic

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resonance imaging in an emotional face paradigm.[148-150] Consequently, these acute SSRI effects may translate to a negative stimulus as pain. Before Paper 7,[7] the effect of SSRI’s on well-defined acute postoperative pain had not previously been investigated. In this trial, a novel approach targeting an intervention to a psychosocial risk factor for postoperative pain was used.[7] Thus, an enriched trial design was applied including patients at risk of severe postoperative pain (high pain catastrophizing patients),[151-154] and the effect of escitalopram as a potential targeted, patient-specific analgesic was investigated in this high risk pain population.[7] Furthermore, side-effects and severe adverse reaction were investigated in detail.[7] In 120 TKA patients (60 receiving escitalopram 10 mg/d and 60 receiving placebo, from preanesthesia to postoperative day 6, in addition to a standardized analgesic regime), no pain reduction upon ambulation at 24 h was observed with escitalopram relative to placebo.[7] In exploratory analyses of secondary outcomes, the escitalopram group experienced less overall pain upon ambulation and at rest from days 2 to 6 after surgery, and depressive symptom score was reduced at day 6.[7] No differences in side-effects were observed except for reduced tendency to sweat and prolonged sleep in the escitalopram group, and no severe adverse reactions were observed.[7] Obviously, the small pain reduction observed is of questionable clinical relevance and was observed only in exploratory analyses of secondary outcomes, precluding conclusions. However, one might speculate that an earlier initiation (and/or a higher dose) of the SSRI therapy may exert a significant clinically relevant effect immediately after surgery. Duloxetine, a serotonin and norepinephrine dual reuptake inhibitor (SNRI), recommended for treatment of major depressive and anxiety disorders and for some chronic pain conditions including e.g. diabetic neuropathy, fibromyalgia and musculoskeletal pain, has been investigated for postoperative pain management in TKA.[155;156] In one trial, 106 TKA patients were randomly assigned to either duloxetine 60 mg or placebo preoperatively, followed by duloxetine 60 mg/d or placebo for 14 days, added to a perioperative multimodal regime of epidural analgesia, adductor canal block, dexamethasone (4 mg) and ketorolac – and meloxicam (NSAID) and oxycodone/paracetamol (postoperatively).[155] No reduction in pain with ambulation on day 14 (primary outcome) was observed, but opioid consumption over the postoperative period and nausea (on day 1) was reduced with duloxetine.[155] In another trial, 50 TKA patients were randomly assigned to either duloxetine 60 mg or placebo preoperatively, followed by the same dose on the first postoperative day, added to no other postoperative regime but patient-controlled i.v. morphine.[156] Morphine consumption at 48 h was reduced with duloxetine, but no difference in pain score or opioid-related side-effects were observed.[156] No other recent trials on antidepressants for postoperative pain management in THA and TKA have been published, but in a recent trial on abdominal hysterectomy, duloxetine added to a multimodal regime of ketoprofen, metamizol and morphine, improved quality of recovery and reduced opioid consumption at 24 h.[157] The most recent results from trials on escitalopram[7] and duloxetine[155] in TKA are clearly not uniquely promising, but the explorative secondary findings in these trials might deserve some attention, and trials are still few. On the other hand, although not obvious in the above trials, adverse events with perioperative antidepressant use, such as perioperative bleeding and other morbidities,[158] might be of concern. Thus, patients with psychiatric disorders threated with psychopharmacological drugs for a prolonged period preoperatively have recently been shown to

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have higher risk for prolonged hospital stay and readmission after THA and TKA, but if this is due to the psychiatric disorders per se and/or drug-related adverse events remain unknown.[159] In conclusion, there is currently no evidence to support clinical use of any one specific antidepressant in acute postoperative pain management after TKA and THA. However, trials are few, and although antidepressants might not be “first modalities in the queue”, further trials on efficacy, optimal timing of initiation, dose, and duration of treatment, and detailed assessment of adverse events might be warranted, especially in enriched trials on putative high risk pain responders.

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4. Preoperative prediction of and risk factors for postoperative pain

There is general consensus regarding a pronounced variability in postoperative pain responses not only between surgical procedures but also between individuals within a specific procedure. This procedure-specific pain variability has the unfortunate consequence that some patients might be undertreated and others over-treated with a given procedure-specific basic analgesic regime – with consequent risk of severe pain and great need for rescue opioid in high pain responders and unnecessary risk in low pain responders. Of considerable concern, an association between acute and persistent postsurgical pain exist, although it is uncertain if this relation is causal.[42;160;161] The ability to preoperatively predict the severity of postoperative pain in an individual patient would allow investigations of analgesic modalities in enriched trial designs of high postoperative pain responders. Ultimately, this may result in recommendations of specific more comprehensive analgesic interventions to be administered for high risk pain patients and more minimal analgesic regimes (with lower risk of adverse events) in low risk pain patients – or as highlighted in a recent editorial, a shift in paradigm “from Surgery-specific to Patient-driven Perioperative Analgesic Algorithms”.[162] The rationale behind attempts to preoperatively predict and understand the mechanisms behind differences in postoperative pain responses, thus, are clear cut. However, it has been found to be a difficult task to predict pain responses and obtain usefulness in routine clinical practice, because the predictive methods both need to have sufficient predictive strength and be simple to perform. The pathophysiological mechanisms behind the inter-individual variability in postoperative pain responses are complex and largely remain unsolved. Multiple preoperative, patient-related factors, both somatic and psychological predisposition factors, might be involved in THA and TKA. Also, surgical related factors including nerve injury and tissue damage with inflammation influence postoperative pain intensity.[163] However, the preoperative and at the same time potentially modifiable factors might be of particular interest in order to identify (and stratify) a patient preoperatively. Somatic factors:

• Nociceptive function (sensitization, impaired pain modulation) • Pain intensity • Opioid use • Inflammatory and immunological factors

Psychological factors:

• Pain catastrophizing • Anxiety • Depression

Potential preoperative and at the same time potentially modifiable factors for postoperative pain after THA and TKA. Studies on potential preoperative factors have largely investigated the association with chronic postoperative pain in THA and TKA. The underlying pathophysiological peripheral and central mechanisms leading to transition from acute to persistent postoperative pain are complex and by far fully clarified.[42;160;161] Although, the focus of this thesis is acute postoperative pain, the more comprehensive literature on preoperative prediction of chronic postoperative pain in THA and TKA necessitate a brief inclusion below.

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Nociceptive function assessed by experimental testing (i.e. quantitative sensory testing, QST) has been used for decades to identify different underlying mechanism of pain in different individuals. Trials have suggested that individuals with increased basal pain perception (increased sensitivity / nociceptive response) to experimental physical stimuli (i.e. sensitization) report higher postoperative pain and increased need of analgesics. Thus, a general, non-procedure-specific systematic review has estimated that 4-54% of the variance in postoperative pain experience (mixed acute and chronic postoperative pain outcomes) may be predicted with preoperative pain responses to experimental stimuli.[164] In another general review, pain response to supra-threshold thermal stimuli (i.e. beyond warm and heat pain detection threshold) has been suggested to be the most consistent test modality, but trials have so far generally been limited by their small sample sizes and lack of multivariate statistical analyses.[165] Furthermore, traditional QST is too cumbersome and time consuming to be feasible in routine clinical practice.[162;164] In one of few recent prospective trials investigating preoperative predictors, including experimental pain testing, for acute postoperative pain in TKA, Rakel and colleagues found higher preoperative movement pain, increased widespread sensitivity to von Frey (mechanical stimuli) and heat pain threshold testing (signs of central sensitization) to be significant predictors of moderate or severe postoperative movement pain (active knee range of motion) on day 2 after surgery; and higher preoperative resting pain, depression, and younger age to be significant predictors of moderate to severe postoperative resting pain.[166] The (by far) strongest predictor was severe preoperative movement pain, these patients being 20 times more likely to experience severe postoperative movement pain.[166] In Paper 5, we investigated whether a simplified preoperative tonic heat pain test paradigm could predict acute postoperative pain after TKA, a paradigm that in contrast to previous comprehensive QST protocols might have the ability to translate into clinical practice.[5] However, pain response to heat pain stimulation was not found to be an independent clinical relevant predictor for postoperative pain intensity after TKA, and only anxiety, preoperative pain, and pain catastrophizing were significant explanatory variables, but with weak predictive strength (5-8% of the variance).[5] Recent studies have supported the hypothesis that preoperative sensitization is a risk factor for development of chronic postoperative pain in THA and TKA.[167;168] Especially central sensitization, which is present in about 35% of patients with knee osteoarthrosis,[169;170] seems to play a role. Central sensitization, indicated by widespread sensitivity to pressure pain thresholds and temporal summation, has been found to be associated with pain both before and after THA and TKA.[167;168] It is assumed that preoperative pain (from the joint or elsewhere is the body) may lead to preoperative sensitization and increased risk of postoperative pain, but the association is not fully clarified.[171] Also, altered central pain modulation mechanisms (related to central sensitization) may play a role for the inter-individual variability in chronic joint pain,[172] hopefully stimulating further research assessing these mechanisms in patients undergoing THA and TKA. Preoperative pain intensity has quite consistently been associated with increased risk of postoperative pain and/or analgesic consumption in general[173] and in THA and TKA in specific.[166;167;171;174-179] However, preoperative pain is also the main indication for THA and TKA. Preoperative opioid use is presumably a risk factor for the severity of postoperative pain in orthopedic surgery in general[180;181] and in THA[182] and TKA in specific.[183;184] In Paper 8, we investigated the influence of preoperative opioid use (“low-“ and “high-dose”) compared with no

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opioid use on acute pain and opioid consumption after TKA, ensuring standardized surgical procedure, anesthesia, basic multimodal analgesia along with postoperative continuation of preoperative opioid dosage (in opioid user), and standardized pain assessment.[8] Our result confirmed previous findings that postoperative pain and opioid consumption might be increased in preoperative opioid user.[8] However, the pathogenic mechanisms, e.g. opioid tolerance, sensitization prior to opioid treatment (or opioid-induced hyperalgesia), and if the relationship is causal remain unsolved.[8] Furthermore, a lack of handling the problem persists, as no well-established strategy for perioperative analgesic management of chronic opioid users exists,[42;185] although ketamine might be promising.[186] The degree of intraarticular inflammation has been associated with pain in patients with osteoarthritis.[187;188] Also, a correlation between central sensitization and serologic markers of chronic inflammation has been demonstrated in patients with painful knee osteoarthritis.[189] High preoperative concentration of inflammatory markers in knee synovial fluid (TNF-α and IL-6) have been associated with worse pain outcome two year after TKA.[190] Recently, preoperative patient-specific immune cell state evaluated by single-cell mass cytometry applied to serial whole-blood samples collected prior to surgery was found to predict as much as 50% of the variance in postoperative outcome measures of recovery including functional impairment, pain and fatigue in patients undergoing THA.[191] These findings mirrored previous correlates identified in blood samples collected shortly after surgery.[192] The recent findings may lead to clinical tests using standard flow cytometry to risk-stratify patients based on their predicted recovery profile and afford individualized perioperative management strategies as suggested by the authors.[191] In another novel approach, exploring the nature of neuro-immune interaction, cytokine and chemokine responses (gene expression changes measured by transcription) resulting from preoperative ultraviolet-B (UVB) irradiation of the skin were investigated together with acute postoperative pain responses after TKA. Unfortunately the result from a multiple regression analysis was negative, making the preoperative UVB model unsuitable for prognosis of acute postoperative pain after TKA (submitted data, Lunn TH et al, in collaboration with McMahon SB and others, King’s College London). Overall, a patient’s preoperative inflammatory and immune state, presumably play a role for both preoperative pain and sensitization, and postoperative pain, but the association is complex and by far fully clarified. In a recent general, non-procedure-specific review with meta-analyses on preoperative psychological correlates of acute postoperative pain, pain catastrophizing was found to be the variable most strongly correlated with acute postoperative pain (r=0.41). Also, expectation of pain (r=0.30), anxiety (r=0.27), depression (r=0.25), and optimism (r=0.24) were significant, but less strong correlates.[193] In TKA and in THA (to a lesser extent), pain catastrophizing has most consistently been shown to be associated with higher postoperative pain responses,[151-154;174;179;194;195] but also anxiety[176;178] and depression[166;176] may play a role. These associations have primarily been investigated (and demonstrated) in studies on chronic postoperative pain. A preoperative questionnaire containing survey criteria for fibromyalgia (which by the authors is inferred to as a crude measure of central sensitization) have been shown to predict increased postoperative opioid consumption after THA and TKA.[196] Simple questionnaires assessing psychological factors might easily be incorporated into clinical practice.[162] However, the heterogeneity of studies, e.g. differences in pain assessment tools, criteria for pain (e.g. evaluation as a continuous or dichotomized outcome variable), and follow-up time etc. has varied considerably, precluding firm conclusions on preoperative psychologic factors

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for prediction of postoperative pain. Still, quantification into clinical applicable risk models for high postoperative pain is lacking. In conclusion, preoperative identification of high postoperative pain responders is challenging and no firm conclusion on the exact role of preoperative predictive factors can be drawn in THA and TKA. Multiple factors seem to play a role including preoperative nociceptive function, pain intensity, opioid use, inflammatory and immunological factors, and psychological factors as pain catastrophizing, anxiety and depression. To move forward, we depend upon large-scaled, prospective, observational studies with standardized pain outcomes and standardized analgesic protocols including multiple potential explanatory variables and on close collaboration between clinicians and basic scientists to achieve a better understanding of underlying pathophysiological mechanisms. Only strong algorithm based predictive risk models built on simple clinical applicable tests and questionnaires will bring us closer to the holy grail of individualized perioperative analgesic protocols.

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5. Future research challenges

As emphasized in a recent procedure-specific systematic review with meta-analysis on acute postoperative pain management after THA, still no gold standards exist for THA patients.[41] As appearing from the present narrative review the same might be the case for TKA patients. Thus, far down the road, acute postoperative pain management in THA and TKA remain unsolved,[42] and in many ways we might not have moved as much forward as one could wish after nearly 25 years with multimodal analgesia.[64;197] Several factors might be considered in order to reach a higher level of evidence, of which some must be considered urgent and essential. 5.1 Basic methodology There is general agreement that medical interventions, including treatment of acute postoperative pain, should be evidence-based and rely on results from well-conducted, high quality, low risk of bias, RCT’s[83] and meta-analyses of high scientific quality.[198] However, the basic methodology has not been striking in the postoperative pain literature as illustrated by (but not unique to) trials of LIA and gabapentin.[41;85;133] Thus, in the most recent Cochrane review on single dose intravenous paracetamol or propacetamol for postoperative pain, only five out of 71 trials were rated as having low risk of bias.[43] It should be remembered, however, that there have been major developments on methodology during the last decade, with the risk of judging the past too hard. Also, the perfect trial might presumably not exist, and choices have to be made that strengthens part of the results, but at the expense of other parts. To reach the highest level of evidence, we ultimately depend upon meta-analyses of high scientific quality. Poor meta-analyses, not taking the risk of bias and risk of random errors[199] into account and poling results from mono- and poly-therapy trials (i.e. not considering if a basic non-opioid analgesic regime is applied), will only mislead clinicians. Also, issues as to heterogeneous doses and a mixture of minor to major surgical procedures might generally complicate interpretation.[200] However, no matter how well-conducted a meta-analysis is, it will mirror the limitations from the included trials. Therefore, at first, high quality, low risk of bias, RCT’s are needed. Before we approach these goals, final conclusions on efficacy and safety of analgesic interventions and comparison between analgesic modalities remain difficult – and evidence-based, procedure-specific gold standard almost impossible to define. 5.2 Basic pain assessment Research into pain is challenged by the absence of objective measures. In analgesic trials of acute postoperative pain, sufficient pain assessment is crucial. Pain must be assessed with validated tools, e.g. with the visual analog scale (VAS) or the numeric rating scale (NRS), both being more powerful in detecting changes in pain intensity that the verbal rating scale (VRS).[201;202] Further, pain should be assessed both on well-defined and procedure-relevant movement (important for function and risk of immobility related complication) and at rest (important for comfort). The physical maneuver used to assess pain on movement should be defined and standardized.[203;204] Pain on movement might preferentially be the primary outcome, because it exerts the most direct adverse impact on postsurgical functional recovery.[203;204] Also, application of “matched” analgesia in study groups[205] and inclusion of an outcome of rescue opioid usage should be employed. Unfortunately, application of such basic concepts has often been the exception rather than the rule with many trials not even distinguishing between pain on movement and at rest.[203;204]

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5.3 Trial designs of analgesic efficacy In analgesic trials of postoperative pain, different trial designs might be applied. Common designs are trials of prophylactic pain treatment and trials of established pain.[33] In trials of prophylactic treatment, the analgesic intervention is initiated prior to or during surgery (and possibly continued with multiple doses after surgery). The primary outcome is most often pain intensity or opioid consumption, i.e. difference between active and placebo group.[33] In trials of established pain, the analgesic intervention is initiated after surgery to patients with moderate to severe postoperative pain (most often mono-therapy, single-dose trials). The primary outcome is often number needed to treat (NNT), i.e. number of patients who need to be treated with the active drug for one patient to achieve at least 50% pain relief compared with placebo (who would not have achieved this during a 4-6 h period).[33] Both designs might be useful and complement each other.[206] However, it is important to remember their individual limitations. In trials of prophylactic pain treatment, the baseline pain intensity is hypothetical and unknown at the beginning of the trial.[33] Thus, if pain intensity turns out to be “to low” (in the control group), an important issue on assay sensitivity is present (that is, that a trial should be able to detect a clinical relevant difference, if there is one).[201;207] It is impossible to demonstrate analgesic efficacy with any analgesic, if there is no pain to reduce. Therefore, when a new study is planned, previous or pilot observations on pain and considerations on minimal clinical relevant effects are essential. A three-arm study design with inclusion of an “approximate placebo group” has been suggested to better assess the assay sensitivity in trials comparing efficacy of a new with an established analgesic intervention.[207] In trials of established pain, it is important to remember that NNT is dichotomous, and an effect of less than 50% pain relief might also be substantial and clinically relevant.[208] Also, a pain reduction on the visual analog scale (0-100) from e.g. 10 to 5 is obviously less clinically relevant than a change from 100 to 50.[208] Finally, the NNT might represent a generalized, not procedure-specific approach with NNT values so far primarily been derived from single-dose, mono-therapy interventions in relatively minor surgical procedures not necessarily applicable to major surgical procedure.[35;208] However, estimates of NNT can also be derived from procedure-specific trials including major surgery. 5.4 Assessment and reporting of adverse events As appearing from the present narrative review and as emphasized by others,[34;108;209-211] it is quite clear that acute postoperative pain trials have focused on analgesic efficacy but often with poorly assessed and reported adverse events. The trials have mainly been small-sized, adverse events have not been primary outcomes, and the follow-up period has typically confined to the immediate perioperative period.[34;108;209-211] Noteworthy, the frequency of adverse events might also be underestimated in analgesic trials of acute postoperative pain (compared with the general surgical population), as inclusion and exclusion have been restrictive to homogenize study population and minimize the risk (potentially associated with the analgesic modality under investigation).[34] Widespread improvement with careful and systematic assessment of adverse events is paramount in trials of non-opioid adjuvant analgesic modalities (and their combinations) along with detailed reporting to provide valid safety data.[212] Larger trials with primary outcome measures of adverse effects and long-term follow up are needed.

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Obviously, smaller sized efficacy trials are unpowered to conclude on uncommon adverse events, but if trials do not fulfill basic criteria for assessment and reporting, meta-analyses provide limited information, hindering firm conclusions on potential harmful effects.[133] 5.5 Challenges in relation to poly-interventional trials As previously discussed, different non-opioid adjuvant analgesic modalities have shown clinically relevant analgesic and opioid-sparing effects in meta-analyses of mono-therapy trials (with opioids as escape analgesics).[33] However, the scientific evidence even for a basic recipe of paracetamol and an NSAID/COX-2-inhibitor might not be strong, and the evidence for additive analgesic and opioid-sparing effect of combinations of various other non-opioid adjuvant analgesic modalities even more sparse.[33] Trials on “toping up” a basic (multimodal) analgesic regime, i.e. add on studies (single vs. double or double vs. triple intervention etc.), might pose certain challenges.[33] The effects may not be directly comparable with effects in mono-therapy trials, that means smaller effects of an individual analgesic might be expected in poly-therapy trials (unless true additive effects exist).[213] Thus, larger trial samples are needed in order to evaluate clinical relevant effects from multimodal combinations. Furthermore, improved and more comprehensive methods might be needed to assess the effects of both mono- and poly-interventions, and the interaction among such combinations.[33] Randomized trials with factorial or multi-group designs have been suggested by some authors.[33;41] 5.6 Individual responder analyses Research into postoperative pain is challenged by the inter-individual variability in pain intensity. In trials of analgesic efficacy, the variance is often pronounced and pain relief may often displays a bimodal distribution of either good or poor, which has led to doubt of the relevance of average analgesic efficacy (mean group difference analysis) as a single measure of efficacy.[214] Recently, a new universal dichotomized outcome, “no more than mild pain” (or more than mild pain), has been suggested as a simple and more clinical relevant outcome for the individual patient,[215] and individual responder analyses, i.e. the favorable response rate (comparison of number/percentage of patients fulfilling “no more than mild pain”), suggested to supplement traditional analysis of mean group difference in future pain trials.[214-216] A recent analysis of previous acute postoperative pain trials has shown rather low favorable (no more than mild pain) response rates, especially during mobilization.[217] 5.7 Scientific focus on putative high pain responders At this point, the preoperative stratification to individualized pain treatment is obviously prevented by the lack of reliable and simple methods to identify (predict) the high risk postoperative pain responders. The existing data on preoperative predictive factors have so far not lead to protocols for preoperative screening and risk stratification in clinical practice of THA and TKA patients. Very few trials of prophylactic pain treatment have attempted to investigate efficacy of potential non-opioid adjuvant analgesic modalities in enriched trial samples of putative high postoperative pain responders.[162] Instead, non-opioid adjuvant analgesic modalities have been investigated in an “all or no patient fashion”, most often, however, with exclusion of putative high risk pain responders to homogenize trial samples. Because protocols for preoperative screening and risk stratification are lacking, we still primarily depend on improvement of basic analgesic regimes administered to “all patients” to reduce the

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number of high postoperative pain responders, and trial designs of established pain to investigate potential “rescue” non-opioid analgesic modalities. On the other hand, because trials of prophylactic pain treatment most often exclude putative high risk pain responders, it might also be the time to apply the current preliminary knowledge from predictive trials by conducting more enriched trials of putative high risk pain responders (e.g. high pain catastrophizing patients and chronic opioid users), thereby changing the focus in trials of prophylactic pain treatment – from low risk to high risk postoperative pain patients. 5.8 Post-discharge pain – prolonged pain management The fast-track protocols with short stays in hospital have, despite their many benefits, to a certain degree had the adverse consequence, that the patient has been left without immediate medical attention in case of inadequate analgesia after rapid discharge. Clearly we know that many patients are not pain free after discharge after THA and especially after TKA.[12;218] Research on subacute and long-term pain, and trials evaluating repeated and / or prolonged perioperative dosage of non-opioid analgesics to prolong the immediate short-term effect of single-dose administration are needed. Unfortunately, catheter techniques to prolong the effect of LIA are not conclusive and might pose a concern of infection risk and nerve blocks to be associated with risk of falling.[51;52] Long acting local anesthetics have the potential to revolutionize the whole concept of regional anesthesia in THA and TKA.[64] However, lack of data prevented assessment of the efficacy of liposomal bupivacaine administered for peripheral nerve blocks in a recent systematic review.[219] Pain management after discharge is often still based on paracetamol and an NSAID/COX-2-inhibitor with opioids as escape (with unknown adverse effect profile of especially NSAID’s/COX-2-inhibitors).[34] Analgesic drug consumption might even be increase and be sustained after TKA.[220] Thus, there is a need for an increased and multidisciplinary focus on the post-discharge period to optimize subacute and long-term analgesia and functional outcomes after THA and TKA.[221]

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6. Critical appraisal of the thesis

6.1 The thesis review The literature dealing with the topic postoperative pain and its management after THA and TKA is extensive. Consequently, the thesis review focused on the specific topics of included original papers, but also summarized the current status on other non-opioid adjuvant analgesic modalities frequently used and investigated in recent years. It was narrative, not systematic, in its nature, by far did not cover all aspects, was far from being exhaustive, and might not have provided much evidence per se. However, it may have summarized the current status within the scope of the thesis and thereby provided basis of the focus specifically directed toward future research challenges, which as highlighted in the review need attention to improve evidence. Systematic reviews of the literature covering all aspects of the topic might be a doctoral thesis worthy in itself. 6.2 Exclusion criteria As in most other perioperative trials of analgesic efficacy, inclusion and exclusion were restricted not to compromise the intervention, to homogenize the study population and to minimize the risk of adverse reactions. This might have increased the internal validity, but obviously the exclusion and refusal number limit the extern validity in the general THA / TKA cohort. As emphasized, enriched trials designs must be considered in order to change the focus in trials of prophylactic pain treatment, from low risk to high risk postoperative pain patients (as attempted in Paper 7). 6.3 Statistical considerations In all included RCT’s (Paper 2, 3, 4, 6 and 7), the analytical framework was superiority, and analyses were conducted as per the intention-to-treat principle. Trial designs were all procedure-specific prophylactic pain treatment. Considerations on average pain with standard deviation (from previous trials / pilot observations), minimal relevant difference, type 1 error risk, power (type 2 error risk) and dropout rate served basis for pre-study sample size calculations (for the primary outcome) in all trials. All analyses were performed blinded and were conducted with advice and/or assistance from one of two statisticians. As a supplement to time point specific primary outcome measures, predefined secondary analyses of overall pain with repeated measurement regression and/or summary measures of pain were included. Summary measures have been recommended as a simple and useful method to analyze serial measurements in medical research (with increased sensitivity by including all assessments).[222] The time-frames for overall repeated measurement analyses of outcomes repeatedly assessed were analyzed separately, in hospital and after discharge, respectively, according to different ways of recordings – in hospital with an investigator present and after discharge by diary recordings. Obviously, multiple testing increases the risk of type 1 errors (random errors by repeated testing). Considerations on this matter were done in all RCT’s, and precautions were made to minimize the risk, although a stricter correction might have been used in some instances. However, when having several correlated outcomes as in our case, it is well known that a Bonferroni (and similar) correction taking all tests into account is highly conservative.[223;224] In general, the risk of type 1 errors should always be taking into account when interpreting findings, and it should be remembered that all findings, but the one from the analysis of the primary outcome, are always exploratory in nature (independently of statistical correction method).

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When a significant difference between groups is shown within a trial, this finding in itself demonstrates an outcome to be sufficiently powered (unless due to a type 1 error). However, when no significant difference is observed in trials with superiority design, this might be due to either “true” lack of difference (that no difference exists), or that the trial is underpowered to detect a potential difference (type 2 error), thus being inconclusive (preliminary). As emphasized, this might have been the case for several secondary outcomes in included trials. In Paper 5, the pre-study sample size was calculated based on the number of explanatory variables protocolled for inclusion in the multivariate linear regression analyses (supplemented by logistic regression analyses for the primary outcome). In Paper 1 and 8, no pre-study sample sizes were calculated due to their more explorative nature. Paper 1 was descriptive (epidemiological) in nature. In Paper 8, statistical analyses of both time point specific outcome measures and summary measures were conducted. 6.4 Differences in pain scores Differences in average postoperative pain intensity scores were observed between procedure-specific trials (control groups) in included thesis papers. This might reflect simple sample-variation, but also some trials were single-center and some multi-center trials, thus also might reflect the varying study population (and one trial included only high pain catastrophizing patients). Block-randomization was used in multicenter RCT’s to insure similar group distribution according to center. Also, the basic and rescue analgesic regime changed slightly between trials, reflecting developments along the way. 6.5 Limitations of thesis papers The strengths from included thesis papers include detailed and frequent pain assessment both on well-defined movement and at rest, use of few, trained data collectors ensuring standardized assessment of outcomes, standardized procedures for surgery, anesthesia, analgesia and other perioperative care regimes, few protocol violations, low frequency of missing data being (also after discharge), and the five RCT’s all considered with low risk of bias. However, improved methodology and reporting in included RCT’s might have been observed over time parallel with increased scientific maturity and insight. Individual responder analyses and factorial design, as very recently suggested, were not considered at the time of trial initiation. In the two most recent RCT’s, however, we used a three group (dose-finding) design (Paper 6) and an enriched trial design of putative high risk pain responders (Paper 7), respectively, along with detailed assessment and reporting of adverse events. In relation to some of the individual thesis papers, some limitations should be elaborated below: As to Paper 1,[1] it should be emphasized that the reasons “for not being able to be discharged” are not all strictly objective (but based on patient interview and observation), and that the study is explorative in its nature. However, in a way it may have provided the background for the thesis. The comparison of THA vs. TKA (p-values) might seem a little disruptive in this descriptive study with no predefined hypothesis. As to Paper 2,[2] the assay sensitivity was low as already emphasized, and the sample size calculation might seem (to) optimistic (50% reduction in pain with LIA relative to placebo). However, the number of included patients was substantial – still the largest LIA trial in THA and one of few trials with low risk of bias as appearing from a recent systematic review on procedure-specific postoperative pain treatment after THA.[41] As emphasized, our findings might not exclude

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a potential effect but rather be the result of low pain scores. Therefore, we only conclude on additional efficacy. Also, it might be important to recall that before the trial, LIA was uncritically and widely used in this group of patients on top of a basic oral analgesic regime (at least in Denmark). It could be argued that infiltration with saline is not true placebo, as saline might have a potential analgesic effect, and that a no infiltration control group might have been appropriate. However, the potential effect of saline is considered to be small, and our priority was full blinding (including blinding of the surgeon). The post-hoc power calculation specified in the paper makes little sense. As to Paper 3,[3] a stricter correction for multiple tests (time-point specific tests) could have been used, which, however, would not have changed the overall conclusion (from the overall repeated measurement regression and summary measure analyses). The reporting would have been improved by reporting of mean difference with 95% CI between groups (in addition to the “group data”), for the primary outcome being -32 (-44 – -19). The statistician, Steen Ladelund, involved in the analyses should have been acknowledged. The remark “performance bias” in the paper is misleading (all trial participants, care providers, investigators, and outcome assessors were blinded to allocation). What is meant is that the use of only two data collectors might have ensured standardized assessments of outcomes. As to paper 4,[4] there might be an issue on assay sensitivity as already emphasized – only twice daily assessment of the functional discharge criteria (which is the clinical practice, however) in combination with already short time to meet these criteria. Also, the validity of these criteria might be discussed. However, they are well-defined, considered to be fairly objective, have been used in the clinical practice for a long time, and were assessed by one of two investigators only. Retrospectively however, pain (during walking) might have been a more appropriate primary outcome. Nonetheless, Paper 4[4] is one of few trials with low risk of bias as appearing from a recent systematic review on procedure-specific postoperative pain treatment after THA.[41] As to paper 8,[8] we did not manage to include the planned number of 180 patients, due to the prevalence of patients using opioids (daily for 4 weeks before surgery) was lower than expected. Also, preoperative opioid use was converted into morphine equivalents instead of the original classification of “strong” and “weak” opioids, as the doses taken by the patients overlapped in terms of morphine equivalents. The study did not assess preoperative psychological factors (but psychological disorder and treatment for this was an exclusion criterion) and postoperative opioid-related side-effects, which would have been of interest. It should be specified that the number of opioid naive patients was equally distributed between centers (15 patients included from each center). As emphasized, causality obviously cannot be discerned from our observational design.

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7. Conclusions

According to the specific aims of the thesis, it is concluded that: • The main reasons for not being discharged within 48 h after THA and TKA were pain,

dizziness, and general weakness. Future efforts to enhance recovery should focus on analgesia, orthostatic and muscle function (Paper 1).[1]

• Intraoperative high-volume LIA with ropivacaine 0.2% provides no additional reduction in acute pain after THA when combined with a multimodal oral analgesic regimen consisting of paracetamol, celecoxib, and gabapentin, but does not exclude an analgesic effect with a less comprehensive oral analgesic regimen or in selected patients (high pain responders) (Paper 2).[2]

• A single preoperative high-dose of methylprednisolone, 125 mg i.v., improves acute postoperative analgesia and recovery after TKA even when combined with an extensive multimodal analgesic regime. These findings call for further studies on safety aspects (Paper 3).[3]

• A single preoperative high-dose of methylprednisolone, 125 mg i.v., added to a multimodal oral analgesic regime, does not reduce time to meet functional discharge criteria after THA, despite potential for improved analgesia for the first 24 h (Paper 4).[4]

• Pain response to simple preoperative heat pain stimulation was not an independent clinical relevant predictor for postoperative pain intensity after TKA (Paper 5).[5]

• Pain upon ambulation at 24 h was not reduced with gabapentin (1300 or 900 mg/d), but sedation at 6 hours was increased with gabapentin 1300 mg/d relative to placebo in opioid-naive patients undergoing TKA. Gabapentin may have limited if any role in acute postoperative pain management of these patients and should not be recommended as standard of care (Paper 6).[6]

• Pain upon ambulation 24 h after TKA in preoperative high pain catastrophizing patients was not reduced by escitalopram for 7 days initiated preoperatively on the day of surgery relative to placebo. However, the results of exploratory secondary analyses of pain upon ambulation and at rest from day 2 to 6 may call for future studies on effect, optimal timing of initiation, dose, and duration of SSRI treatment, and detailed assessment on potential side effects (Paper 7).[7]

• Preoperative opioid use might increase acute postoperative pain and opioid consumption after TKA. Further studies are needed to clarify the pathogenic mechanisms (Paper 8).[8]

From the narrative review it might further be concluded that: • No gold standards for postoperative pain management in THA and TKA can be defined at

this point. • Combination therapy of paracetamol and an NSAID/COX-2-inhibitor is, with contra-

indications kept in mind, recommended for THA and TKA, although no final conclusion can be drawn.

• The adductor canal block seems promising in TKA (with comparable analgesic efficacy to the femoral nerve block but without risk of partial motor blockade), but trials are still few and small-sized, making the evidence limited and calling for further studies.

• Intraoperative peri-articular LIA seems promising in TKA, but provides no additional clinically relevant analgesic efficacy in THA (where there less pain to reduce) when

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combined with a comprehensive multimodal oral analgesic regimen. However, an analgesic effect in THA with use of a less comprehensive oral analgesic regimen or in selected patients (high pain responders) cannot be excluded. Trial quality and heterogeneity make the overall evidence limited, precluding final conclusions.

• The results from procedure-specific THA and TKA studies on high-dose systemic glucocorticoid are very promising, but studies are very few and small-sized, making the evidence limited and calling for larger confirmatory efficiency studies. Also, dose-finding and safety studies are required before firm conclusions can be drawn.

• There is no firm evidence for a clinical relevant analgesic effect of gabapentin in THA and TKA, especially when added to a multimodal analgesic regime, and potential harmful effects are of concern. Thus, gabapentin may have limited if any role in acute postoperative pain management of these patients and should not be recommended as standard of care. The conclusion as to pregabalin is less clear, but at this point, also pregabalin should not be recommended as standard of care.

• There is currently no evidence to support clinical use of any one specific antidepressant in acute postoperative pain management after TKA and THA. However, trials are few, and although antidepressants might not be “first modalities in the queue”, further trials on efficacy, optimal timing of initiation, dose, and duration of treatment, and detailed assessment of adverse events might be warranted, especially in enriched trials on putative high risk pain responders.

• Preoperative identification of high postoperative pain responders is challenging and no firm conclusion on the exact role of preoperative predictive factors can be drawn in THA and TKA. Multiple factors seem to play a role including preoperative nociceptive function, pain intensity, opioid use, inflammatory and immunological factors, and psychological factors as pain catastrophizing, anxiety and depression. To move forward, we depend upon large-scaled, prospective, observational studies with standardized pain outcomes and standardized analgesic protocols including multiple potential explanatory variables and on close collaboration between clinicians and basic scientists to achieve a better understanding of underlying pathophysiological mechanisms. Only strong algorithm based predictive risk models built on simple clinical applicable tests and questionnaires will bring us closer to the holy grail of individualized perioperative analgesic protocols.

• Overall interpretation, relevant comparison and firm conclusions have been impeded by methodological shortcomings in RCT’s of analgesic efficacy, trials often being characterized by high/unclear risk of bias, low assay sensitivity, being underpowered, with insufficient pain assessment and lack of matched analgesia between groups, and insufficient assessment and reporting of adverse events. Further, trial heterogeneity has been substantial (e.g. diverse doses, combinations, and timing of administration in the plethora of analgesic modalities investigated, differences in pain assessment tools, diverse pain outcome variables, and diverse basic analgesic regimes, ranging from mono-therapy trials to diverse poly-therapy trials).

• To reach a higher level of evidence: o Trial methodology and reporting must adhere to the highest scientific standards. o Pain assessment must adhere to current recommended standards. o Careful and systematic assessment of adverse events along with detailed reporting is

paramount.

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o Larger trial samples are needed in order to evaluate clinical relevant effects and potential harms with multimodal combinations. Factorial or multi-group designs might be preferable to assess the effects of both mono- and poly-interventions, and the interaction among such combinations.

o A new interesting feature, individual responder analyses, as a supplement to traditional analysis of average analgesic efficacy, might be clinically relevant to assess favorable pain outcome for the individual patient.

o Enriched trials of putative high risk pain responders must be considered in trials of prophylactic pain treatment, thereby changing the focus from low risk to high risk postoperative pain patients.

o Generally, there is a need for an increased and multidisciplinary focus on the post-discharge period to optimize subacute and long-term analgesia and functional outcomes after THA and TKA.

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8. Summary

The incidence of osteoarthritis of the hip and the knee are rising. Among many inconveniences, osteoarthritis causes pain, functional impairment, sleep disturbances and reduces quality of life. The end stage treatment of advanced osteoarthritis of the hip and knee is implantation of a total artificial hip or knee, a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). THA and TKA are now frequently performed surgical procedures and are growing in number worldwide, thus constituting an important health care challenge. Favorable long-term functional outcomes and improved quality of life are reported, although the immediate postoperative phase can be associated with severe pain (especially in TKA) that hampers rehabilitation. Thus, efforts to optimize postoperative pain management are paramount. An additional challenging factor is the pronounced inter-individual variability in postoperative pain response. This may cause some patients to be undertreated and others to be over-treated with a given basic analgesic regime, and therefore, efforts to preoperatively predict and understand risk factors for postoperative pain responses are also needed. Contemporary postoperative pain management aims at enhancing pain relief and reducing opioid requirements and opioid-related side-effects by combining non-opioid analgesic modalities, so-called multimodal opioid-sparing analgesia. This approach is rational and widely accepted, although recent reviews have shed critical light on the scientific evidence. Accordingly, different non-opioid adjuvant analgesic modalities are used and have been investigated in order to optimize postoperative analgesia and enhance functional recovery after THA and TKA. This thesis is made up of eight original papers prepared on the basis of data from eight prospective clinical studies. Five original studies are randomized, double-blind, placebo-controlled trials (RCT’s), each trial aiming to investigate the effect of a non-opioid adjuvant analgesic modality as part of a multimodal analgesic treatment regimen within a well-defined THA and TKA fast-track setup. Three original studies are observational trials, one trial exploring factors responsible for patients remaining hospitalized after THA and TKA, one trial aiming to predict postoperative pain (using a simple heat pain test paradigm preoperatively), and one trial investigating potential differences in postoperative pain responses between preoperative opioid users and opioid naive patients. The principal findings were: The main reasons for hospitalization in the early days after THA and TKA were pain, dizziness, and general weakness (Paper 1). Intraoperative local infiltration analgesia (LIA) with ropivacaine 0.2% provided no reduction in acute pain after THA when combined with a comprehensive oral analgesic regimen (Paper 2). A single preoperative high-dose of methylprednisolone, 125 mg i.v., improved acute postoperative analgesia and recovery after TKA even when combined with an extensive multimodal analgesic regime (Paper 3). The same intervention did not reduce time to meet functional discharge criteria after THA despite improved analgesia (Paper 4). Pain response to simple preoperative heat pain stimulation was not an independent clinical relevant predictor for postoperative pain intensity after TKA (Paper 5). Gabapentin (1300 or 900 mg/d) did not reduce acute postoperative pain, but sedation and dizziness were increased, and more severe adverse reactions were observed with gabapentin 1300 mg/d in opioid-naive patients undergoing TKA (Paper 6). Escitalopram did not reduce acute postoperative pain (but potentially from days 2 to 6) after TKA in preoperative high pain catastrophizing patients (Paper 7). Preoperative opioid use increased acute postoperative pain and opioid consumption after TKA (Paper 8).

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The narrative thesis review focuses on non-opioid adjuvant analgesic modalities and on preoperative prediction of and risk factors for postoperative pain in THA and TKA. Further, a focus is directed toward future research challenges. As it appears, considerable heterogeneity and methodological shortcomings in RCT’s of analgesic efficacy have impeded firm conclusions, and the overall evidence is limited. Thus, no gold standards for postoperative pain management in THA and TKA can be defined at this point. Combination therapy of paracetamol and an NSAID/COX-2-inhibitor is recommended, although no final conclusion can be drawn. The adductor canal block seems promising in TKA, intraoperative LIA seems promising in TKA, but provides no additional clinically relevant analgesic efficacy in THA when combined with a multimodal oral analgesic regimen, and high-dose systemic glucocorticoid seems promising. There is no firm evidence for a clinical relevant analgesic effect of gabapentin, especially when added to a multimodal analgesic regime, and potential harmful effects are of concern. Also, there is currently no evidence to support clinical use of any one specific antidepressant. Preoperative identification of high postoperative pain responders is challenging, and mechanisms behind the inter-individual variability in postoperative pain responses are complex. Multiple factors seem to play a role including preoperative nociceptive function, pain intensity, opioid use, inflammatory and immunological factors, and psychological factors as pain catastrophizing, anxiety and depression. Large-scaled, prospective, observational studies (with standardized pain outcomes) including multiple potential explanatory variables and close collaboration between clinicians and basic scientists are needed to achieve a better understanding of underlying pathophysiological mechanisms, which hopefully will bring us closer to the holy grail of individualized perioperative analgesic protocols. In future trials of analgesic efficacy, methodology and reporting must adhere to the highest scientific standards, pain assessment must adhere to current recommendations, and careful assessment and detailed reporting of adverse events is paramount. Generally, larger trial samples are needed in order to evaluate clinical relevant effects and potential harms with multimodal combinations (factorial or multi-group designs might be preferable). Individual responder analyses (as a supplement to traditional analyses of average analgesic efficacy) might be clinically relevant to assess favorable pain outcome for the individual patient. Finally, enriched trials of putative high risk pain responders must be considered in trials of prophylactic pain treatment, thereby changing the focus from low risk to high risk postoperative pain patients.

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9. Resumé (Danish summary)

Incidensen af slidgigt i hofte- og knæled er stigende. Blandt mange gener forårsager slidgigt smerter, funktionel indskrænkning, søvnforstyrrelse og nedsat livskvalitet. Svær slidgigt i hofte- og knæled behandles kirurgisk, ofte med indsættelse af et helt nyt hofteled (THA) eller knæled (TKA). THA og TKA er nu hyppigt udførte kirurgiske procedurer, som stiger i antal på verdensplan og derfor udgør en stor udfordring for sundhedsvæsenet. De langsigtede resultater er overordnet gode, men smerter er et udtalt problem i den tidlige fase efter operation (især efter TKA), hvilket kan hæmme den funktionelle rehabilitering. Derfor er bestræbelser på at optimere den postoperative smertebehandling afgørende. Hertil kommer, at den inter-individuelle variation i smerterespons efter operation er udtalt. Dette kan medføre, at nogle patienter bliver underbehandlet, mens andre bliver overbehandlet med et givent smertestillende regime. Derfor er bestræbelser på at forudsige og forstå risikofaktorer for sværhedsgraden af det postoperative smerterespons en vigtig opgave. Moderne postoperativ smertebehandling sigter mod at opnå smertelindring og reducere brugen af opioider (og dermed opioid-relaterede bivirkninger) ved at kombinere ”ikke-opioide” smertestillende modaliteter, såkaldt multimodal opioid-besparende analgesi. Denne tilgang er rationel og bredt accepteret, selvom nye oversigtartikler har kastet et kritisk lys over den videnskabelige evidens. Forskellige ”ikke-opioide” smertestillende modaliteter har været brugt og er blevet undersøgt for at optimere den postoperative smertebehandling og forbedre den funktionelle rehabilitering efter THA og TKA. Denne doktorafhandling består af otte originale arbejder udarbejdet på baggrund af data fra otte prospektive kliniske undersøgelser. Fem af disse er randomiserede, dobbeltblindede, placebokontrollerede undersøgelser – hver og én med det formål at undersøge effekten af en ”ikke-opioid” smertestillende modalitet som del af et multimodalt opioid-besparende smertestillende regime i et veldefineret THA og TKA fast-track set up. Tre af undersøgelserne er observationelle – én undersøger faktorer, der er ansvarlige for at patienter forbliver indlagt efter THA og TKA, én har til formål at forudsige det postoperative smerterespons (ved hjælp af en simpel varme-smerte-test inden operation), og én undersøger potentielle forskelle i det postoperative smerterespons mellem patienter, der inden operation er i fast behandling med opioider og patienter, der ikke er. De vigtigste fund var: De primære årsager til forsat indlæggelse i de tidlige dage efter THA og TKA var smerter, svimmelhed, og generel svaghed (artikel 1). Lokal infiltration analgesi (LIA), med ropivacain 0,2%, reducerede ikke akut smerteintensitet efter THA, når det blev kombineret med et omfattende multimodalt smertestillende regime (artikel 2). En enkelt præoperativ høj dosis af methylprednisolon, 125 mg intravenøst, forbedrede akut postoperativ smertelindring efter TKA, selv når det blev kombineret med et omfattende multimodalt smertestillende regime (artikel 3). Den samme intervention reducerede ikke tiden for opfyldelse af funktionelle udskrivningskriterier efter THA på trods af forbedret smertelindring (artikel 4). Smerteresponset under en simpel varme-smerte-test inden operation var ikke en klinisk relevant prædiktor for postoperativ smerteintensitet efter TKA (artikel 5). Gabapentin (1300 eller 900 mg/dag) reducerede ikke akut postoperativ smerteintensitet, men sedation og svimmelhed var øget, og flere alvorlige bivirkninger blev observeret med gabapentin 1300 mg/dag efter TKA (artikel 6). Escitalopram reducerede ikke akut postoperativ smerteintensitet (men potentielt fra dag 2 til 6) efter TKA hos patienter med høj ”smerte-katastrofetænkning” inden operation (artikel 7). Opioidforbrug inden operation øgede akut postoperativ smerteintensitet og opioidforbrug efter TKA (artikel 8).

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Afhandlingsoversigten fokuserer på ”ikke-opioide” smertestillende modaliteter og på forudsigelse af og risikofaktorer for høj postoperativ smerteintensitet efter THA og TKA. Endvidere er der fokus på fremtidige forskningsmæssige udfordringer. Det fremhæves, at betydelig heterogenitet og metodiske mangler i interventionsundersøgelser af smertestillende effekt har umuliggjort endelige konklusioner, og den samlede evidens er begrænset. Derfor kan der på nuværende tidspunkt ikke defineres nogle endegyldige standarder for den postoperative smertebehandling ved THA og TKA. Kombinationsbehandling med paracetamol og en NSAID/COX-2-hæmmer kan anbefales, selvom der ikke kan drages nogen endelig konklusion. Adductor kanal blok er lovende ved TKA, LIA er lovende ved TKA, men giver ingen yderligere klinisk relevant smertestillende effekt ved THA, når det kombineres med et multimodalt oralt smertestillende regime, og højdosis systemisk glukokortikoid er lovende. Der er derimod ingen klar evidens for en klinisk relevant smertelindrende virkning af gabapentin, især ikke når det kombineres med et multimodalt smertestillende regime, og potentielle skadelige virkninger giver anledning til bekymring. Der er på nuværende tidspunkt heller ingen evidens, der støtter klinisk brug af noget antidepressivt middel. Præoperativ identifikation af patienter med højt postoperativt smerterespons er en udfordring, og mekanismerne bag den inter-individuelle variation er komplekse. Flere faktorer synes at spille en rolle, herunder præoperativ nociceptiv funktion, smerteintensitet, forbrug af opioider, inflammatoriske og immunologiske faktorer, og psykologiske faktorer som ”smerte-katastrofetænkning”, angst og depression. Store, prospektive, observationelle studier (med standardiserede smertemål) som inddrager flere potentielle forklarende variable og et tæt samarbejde mellem klinikere og basalforskere er nødvendige forudsætninger for at opnå en bedre forståelse af de underliggende patofysiologiske mekanismer, som forhåbentlig vil bidrage til individualiserede perioperative smertebehandlingsprotokoller i fremtiden. I fremtidige interventionsundersøgelser af smertestillende effekt må metode og rapportering følge de højeste videnskabelige standarder, smertevurdering må overholde gældende anbefalinger, og omhyggelig vurdering og detaljeret rapportering af utilsigtede virkninger er altafgørende. Der er generelt behov for større undersøgelser for at vurdere klinisk relevante virkninger og potentielle skadelige virkninger ved multimodale kombinationer. Individuelle responder analyser (som et supplement til traditionelle analyser af gennemsnitlig smertestillende effekt) kan være klinisk relevante for at vurdere effekten hos den enkelte patient. Endelig må undersøgelser, der tilsigter profylaktisk smertebehandling overveje at benytte sig af et berigede forsøgsdesign, der inkludere formodede problempatienter og dermed retter fokus på højrisiko postoperative smertepatienter fremfor lavrisiko smertepatienter.

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