Non-steroidal anti-inflammatory drugs in postoperative pain management : studies in analgesic efficacy, pharmacokinetics and renal safety

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ANNIKA PIIRAINEN

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN POSTOPERATIVE PAIN

MANAGEMENT

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN POSTOPERATIVE PAIN MANAGEMENT

STUDIES IN ANALGESIC EFFICACY, PHARMACOKINETICS AND RENAL SAFETY

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Annika Piirainen

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN POSTOPERATIVE PAIN MANAGEMENT

STUDIES IN ANALGESIC EFFICACY, PHARMACOKINETICS AND RENAL SAFETY

To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Auditorium 1, Kuopio

on August 20^th, 2021, at 9 o’clock am

Publications of the University of Eastern Finland Dissertations in Health Sciences

No 635

Department of Anaesthesia and Intensive Care, Kuopio University Hospital School of Medicine, Anaesthesiology and Intensive Care

University of Eastern Finland, Kuopio 2021

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Series Editors

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences

Professor Tarja Kvist, Ph.D.

Department of Nursing Science Faculty of Health Sciences Professor Ville Leinonen, M.D., Ph.D.

Institute of Clinical Medicine, Neurosurgery Faculty of Health Sciences

Professor Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

Lecturer Veli-Pekka Ranta, Ph.D.

School of Pharmacy Faculty of Health Sciences

Distributor:

University of Eastern Finland Kuopio Campus Library

P.O.Box 1627 FI-70211 Kuopio, Finland

www.uef.fi/kirjasto PunaMusta Media Oyj, 2021 ISBN: 978-952-61-4268-5 (print/nid.)

ISBN: 978-952-61-4269-2 (PDF) ISSNL: 1798-5706

ISSN: 1798-5706 ISSN: 1798-5714 (PDF)

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Author’s address: School of Medicine, Anaesthesiology and Intensive Care University of Eastern Finland

KUOPIO FINLAND

Doctoral programme: Doctoral Programme of Clinical Research Supervisors: Docent Merja Kokki, M.D., Ph.D.

Department of Anaesthesiology and Intensive Care Kuopio University Hospital

University of Eastern Finland KUOPIO

FINLAND

Docent Hannu Kokki, M.D., Ph.D.

Institute of Clinical Medicine University of Eastern Finland KUOPIO

FINLAND

Reviewers: Docent Kirsi-Maija Kaukonen, M.D., Ph.D.

Senior Medical Officer, Finnish Medicines Agency, Fimea HELSINKI

FINLAND

Docent Satu Mäkelä, M.D., Ph.D.

Department of Internal Medicine Tampere University Hospital University of Tampere TAMPERE

FINLAND

Opponent: Professor Ilkka Pörsti, M.D., Ph.D.

Department of Internal Medicine University of Tampere

TAMPERE FINLAND

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Piirainen, Annika

Non-steroidal anti-inflammatory drugs in postoperative pain management—

studies in analgesic efficacy, pharmacokinetics and renal safety Kuopio: University of Eastern Finland

Publications of the University of Eastern Finland Dissertations in Health Sciences 635. 2021, 158 p.

ISBN: 978-952-61-4268-5 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4269-2 (PDF) ISSN: 1798-5714 (PDF)

ABSTRACT

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in

postoperative pain management as part of multimodal analgesia. NSAIDs provide substantial analgesic efficacy after major surgery and have an opioid-sparing effect, thus reducing opioid-related adverse effects. Previously, the analgesic efficacy of NSAIDs and their risk for adverse events have been thought to be dose- dependent; therefore, finding the optimal dose is critical. Though NSAIDs are generally well-tolerated, there are concerns about their effect on perioperative bleeding and risk for acute kidney injury (AKI). These adverse events are, fortunately, rare, but their risk increases in older patients and in patients with particular co-morbidities. Major surgeries are increasingly performed on elderly, and thus, more knowledge on safe and optimal use of NSAIDs is required.

In addition, prevention of AKI by optimising perioperative treatment can improve recognition of patients at high risk for AKI as well as diagnostics of AKI.

Current markers for renal insufficiency are nonspecific and confounded; there is a substantial need for more adequate biomarkers.

In the first study it was found that dexketoprofen doses of 10 mg and 50 mg provided similar analgesic effect after laparoscopic cholecystectomy. Twenty-four patients were randomised to receive 10 mg or 50 mg dose of dexketoprofen 15 minutes before the end of surgery and were given oxycodone doses every 10 minutes as rescue analgesia when clinical pain was > 3/10 at rest or >5/10 at stress until pain reduced under these limits. The minimum effective concentration (MEC) and the minimum effective analgesic concentration (MEAC) of oxycodone were recorded. There was no significant difference in total opioid consumption or MEC and MEAC of oxycodone between the two groups. Based on these results,

dexketoprofen may provide sufficient analgesia with substantially lower dose than that usually advised in clinical practice.

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In the second study, twenty-four patients undergoing total hip arthroplasty (THA) were randomised to receive bodyweight adjusted dose of either intravenous dexketoprofen or oral etoricoxib immediately after surgery. Plasma and

cerebrospinal fluid (CSF) samples were taken up to 24 hours, and the total dose of rescue analgesia and clinical pain were recorded. Dexketoprofen and etoricoxib concentrations were analysed, as well as prostaglandin E2, interleukin 6, interleukin 10, and interleukin 1 receptor antagonist. Both etoricoxib and dexketoprofen readily penetrate into CSF; maximum concentration (Cmax) of dexketoprofen was achieved after 3 hours and Cmax of etoricoxib after 5 hours. During the first postoperative 24 hours, etoricoxib and dexketoprofen had similar effects on pro- and anti-inflammatory markers in plasma and CSF. Total opioid consumption and clinical pain were also similar between the two groups. The data imply that oral etoricoxib and intravenous dexketoprofen provide equally efficient analgesia after THA.

In the third study, fifteen patients undergoing back surgery were given two 200 mg orodispersible ibuprofen tablets the day before surgery and again immediately after anaesthesia and surgery. Each of the patients served as their own control.

Plasma samples were taken up to six hours after administration and we compared the pharmacokinetics of ibuprofen. Anaesthesia and surgery substantially affects the pharmacokinetics of orodispersible ibuprofen; postoperative Cmax was lower compared to preoperative Cmax. However, time to maximum concentration tmax

was not prolonged, therefore orodispersible ibuprofen could be used in

postoperative pain management, but the dose must be optimized to ensure the analgesic concentration of 10 mg/L in plasma.

In the fourth study, I evaluated the utility of novel acute kidney injury biomarkers neutrophil gelatinase associated lipocalin (NGAL), kidney injury

molecule 1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and interleukin 18 (IL-18) to diagnose AKI after total knee arthroplasty (TKA). Thirty patients

undergoing TKA with the use of tourniquet, local infiltration analgesia and perioperative NSAIDs participated. We analysed biomarker concentrations from plasma and urine samples that were taken preoperatively and up to 48 hours postoperatively. Only five patients had a transient decrease in urine output below 0.5 ml/kg/h reflecting mild AKI. In these patients, only plasma NGAL was increased, implying that plasma NGAL could be suitable to detect postoperative AKI.

Keywords: Non-steroidal anti-inflammatory drug, dexketoprofen, etoricoxib, ibuprofen, postoperative pain, pharmacokinetics, inflammatory marker, AKI, NGAL

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Piirainen, Annika

Tulehduskipulääkkeet aikuisten leikkauskivun hoidossa – farmakokinetiikka, teho ja munuaisturvallisuus

Kuopio: Itä-Suomen yliopisto

Publications of the University of Eastern Finland Dissertations in Health Sciences 635. 2021, 158 s.

ISBN: 978-952-61-4268-5 (nid.) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4269-2 (PDF) ISSN: 1798-5714 (PDF)

TIIVISTELMÄ

Tulehduskipulääkkeet kuuluvat osaksi leikkauksen jälkeistä kivun hoitoa, sillä yhdistettynä muihin lääkkeisiin ja kivunlievitysmenetelmiin ne lievittävät kipua tehokkaasti ja vähentävät opioidien tarvetta. Tulehduskipulääkkeet ovat yleensä hyvin siedettyjä, mutta suurten leikkausten yhteydessä niiden käyttöön liittyy verenvuotojen ja akuutin munuaisvaurion riski. Vaikka akuutin munuaisvaurion riski yksittäisen potilaan kohdalla on pieni, toimenpiteitä tehdään suuri määrä, joten vuosittainen haittatapahtumien määrä on merkittävä. Leikattavat potilaat ovat myös yhä vanhempia ja sairaampia, ja näiden potilaiden kohdalla riski lääkehaitoille on erityisen suuri. Koska tulehduskipulääkkeiden haittavaikutusten ajatellaan olevan annosriippuvaisia, on erityisen tärkeää löytää optimaalinen lääkeannos, jotta haittatapahtumien riski vähenisi.

Jotta akuutti munuaisvaurio voitaisiin havaita ja estää lisävaurioiden

kehittyminen, suuressa riskissä olevat potilaat pitäisi tunnistaa ajoissa ja akuutin munuaisvaurion syntyminen pitäisi olla havaittavissa heti ensimmäisistä

vauriomuutoksista. Nykyiset käytössä olevat munuaistoiminnan mittarit ovat epäherkkiä ja ne reagoivat viiveellä. Potilaiden ennusteen parantamiseksi parempia diagnoosivälineitä kaivataan.

Ensimmäisessä osatyössä verrattiin 10 mg:n ja 50 mg:n deksketoprofeeni annosten kivunlievitystehoa laparoskooppisen sappirakon poiston jälkeen.

Tutkimukseen osallistui 24 potilasta, jotka arvottiin saamaan jompikumpi annos deksketoprofeenia ennen leikkauksen päättymistä. Heräämössä potilaat saivat oksikodonia, kun kipu oli numeerisella asteikolla yli 3/10 levossa tai yli 5/10 haavaa painettaessa. Oksikodonia annettiin 10 minuutin välein, kunnes kipu lievittyi alle 3/10 levossa ja alle 5/10 haavaa painettaessa. Tutkimusryhmien välillä ei ollut eroa annetun lisäkipulääkkeen määrässä, todetuissa haittavaikutuksissa, pienimmässä tehokkaassa tai pienimmässä tehokkaassa kipua lievittävässä oksikodonin

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pitoisuudessa. Tämän perusteella arvioitiin, että deksketoprofeeni voisi olla yhtä tehokas pienemmillä annoksilla kuin mikä on tällä hetkellä kliinisessä käytössä.

Toisessa osatyössä 24 elektiiviseen lonkan tekonivelleikkaukseen tulevaa potilasta sai tutkimuslääkkeenä heti leikkauksen jälkeen joko deksketoprofeenia suonensisäisesti tai etorikoksibi- tabletin. Lääke annosteltiin painon mukaan vakioituna. Potilailta kerättiin laskimoveri- ja aivoselkäydinnestenäytteitä 24 tunnin ajan leikkauksen alusta. Niistä määritettiin deksketoprofeeni- ja etorikoksibi- pitoisuudet ja prostaglandiini E2, interleukiini 6, interleukiini 10 ja interleukiini-1 reseptori antagonistin pitoisuudet. Deksketoprofeeni ja etorikoksibi olivat yhtä tehokkaita kivunlievittäjiä lonkan tekonivelleikkauksen jälkeen; tutkimusryhmien välillä ei ollut eroa annetun lisäkipulääkkeen määrässä, tai kivun voimakkuuden arvioissa. Sekä deksketoprofeeni että etorikoksibi läpäisivät veriaivoesteen ja aivoselkäydinnesteessä saavutettiin pitoisuudet, joita aiempien tulosten perusteella pidettiin tehokkaina. Lääkeaineiden vaikutus

tulehduksenvälittäjäaineiden pitoisuuteen oli samankaltainen.

Kolmannessa osatyössä selkäleikkauspotilailta (n=15) määritettiin suussa liukenevan ibuprofeenin farmakokinetiikka ennen ja jälkeen leikkauksen. Potilaat saivat kaksi suussa liukenevaa 200 mg tablettia leikkausta edeltävänä päivänä ja heti leikkauksen jälkeen. Laskimoverinäytteitä otettiin 6 tuntiin asti lääkkeen annostelusta, ja niistä määritettiin lääkeainepitoisuus. Potilaat olivat omia verrokkejaan. Ibuprofeenin maksimipitoisuus plasmassa oli selvästi pienempi leikkauksen jälkeen kuin ennen leikkausta. Maksimipitoisuuden saavuttamiseen kulunut aika ei kuitenkaan pidentynyt, mikä viittaa siihen, että suussa sulavan ibuprofeeni- tabletin käyttö välittömästi leikkauksen jälkeen voisi olla mielekästä, mutta annoksen tulisi olla suurempi, jotta saavutettaisiin kipua lievittävänä pidetty plasmapitoisuus 10 mg/L.

Neljännessä osatyössä arvioitiin uusien akuutin munuaisvaurion

merkkiaineiden, neutrofiilin gelatinaasiin assosioituvan lipokaliinin (NGAL), KIM-1, interleukiini 18 ja L-FABP:n soveltuvuutta akuutin munuaisvaurion toteamiseen potilailla (n=30), joille tehtiin polven tekonivelleikkaus. Itse leikkauksen lisäksi akuutille munuaisvauriolle altistavia tekijöitä olivat verityhjiö, polveen laitettu ketorolaakkia sisältänyt puuduteseos ja muut käytetyt tulehduskipulääkkeet.

Tutkimuksessa todettiin lievä akuutti munuaisvaurio kahdella potilaalla ja yhteensä viidellä potilaalla todettiin ohimenevä virtsanerityksen heikentyminen.

Tutkituista munuaisvaurion merkkiaineista ainoastaan plasman NGAL-pitoisuus oli lievästi koholla neljällä näistä viidestä potilaasta, mikä voisi viitata subkliiniseen munuaisvaurioon. Tutkimustulos viittaa siihen, että NGAL-määrityksen avulla voisi olla mahdollista tunnistaa potilaat, joilla on suurentunut akuutin munuaisvaurion riski leikkauksen jälkeen.

Avainsanat: Tulehduskipulääke, deksketoprofeeni, etorikoksibi, ibuprofeeni, leikkauskipu, farmakokinetiikka, tulehduksen välittäjäaine, akuutti munuaisvaurio, NGAL

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ACKNOWLEDGEMENTS

You are holding a product of hard work of many years. This journey has been nothing but easy, but there have been many moments of joy, inspiration and overcoming myself. It has been a privilege to participate in projects in which I have been able to learn about conducting good quality studies from the start to the end. From these years I have collected important experience which will be utilised in future challenges. I am beyond grateful for this journey, and therefore I want to thank some special people that I have had the privilege to share it with.

This study was carried out at the School of Medicine, University of Eastern Finland and at the Department of Anaesthesiology and Intensive Care, Kuopio University Hospital during the years 2013-2021. I am thankful to professors Matti Reinikainen and Ari Uusaro for providing the facilities for scientific work.

Firstly, I want to thank both of my supervisors: my principal supervisor Docent Merja Kokki and my second supervisor Docent Hannu Kokki. Merja, it has been an utmost privilege to work with you. You have guided me with a firm hand and encouraged me to continue through the hard times. It has always been easy to turn to you with every problem and I could not be more thankful. Hannu, I want to thank you from the bottom of my heart for every shared moment, your guidance and support. Your knowledge and expertise have had a major contribution in taking my thesis to the next level. I am beyond grateful of this given opportunity to work with and learn from both of my supervisors, you have made an impact on me that will last forever.

I wish to thank all of my co-authors who have participated in conducting the studies and writing the papers. It has been a wonderful experience to work with such professionals. I also want to give a special thanks to study nurse Petri Toroi, who has had a major role in the clinical part of the studies.

I want to warmly thank the reviewers of this thesis Docent Maija Kaukonen and Docent Satu Mäkelä. Your constructive feedback and advice have been truly appreciated and has improved the quality of my thesis greatly. Thank you for accepting this laborious task.

I wish to thank all of my co-workes in Kainuu Central Hospital and friends outside of work. Your encouragement and support have had a major importance throughout this project. It has lifted me up especially in those moments, when the workload has felt too heavy.

I want to thank my family: my father Jouni, my mother Virpi, my brother Niklas and my sister-in-law Anna. The safe and supportive environment that you have created has been a good base to build my life and dreams. The work ethics and determination that I have learned from you are qualities that I carry with pride. In addition to my nuclear family, for the last thirteen years I have had the privilege to also call Panu’s family as my own. Lassi, Pia, Pauli and Meri, I am most grateful for

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all of your support. A special thank you to my father-in-law Lassi for the exceptional artwork on page 45.

My last thanks go to my firsts. Panu, you are my endgame. You bring out the best in me and with you I can achieve things I never knew possible. Without you this project would not have met its grande finale. This special journey has been especially great since I have shared it with you. I am so proud of us.

Lauri, the love and joy of my life, mom loves you. I hope that this dissertation project gives you an example of that dreams can come true.

This work was financially supported by the Olvi Foundation, Iisalmi, Finland and the Finnish Cultural Foundation, Helsinki, Finland. Both of these are gratefully acknowledged.

” Success is not final, failure is not fatal: it is the courage to continue that counts.”

- Winston Churchill

In Kajaani, 20^thof July 2021

Annika Piirainen

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LIST OF ORIGINAL PUBLICATIONS

This dissertation is based on the following original publications:

I Piirainen A, Kokki H, Immonen S, Eskelinen M, Häkkinen MR, Hautajärvi H and Kokki M. A Dose-finding study of dexketoprofen in patients undergoing laparoscopic cholecystectomy: a randomized clinical trial on effects on the analgesic concentration of oxycodone. Drugs R D 15: 319-328, 2015.

II Piirainen A, Kokki M, Hautajärvi H, Lehtonen M, Miettinen H, Pulkki K, Ranta VP and Kokki H. The cerebrospinal fluid distribution of postoperatively

administred dexketoprofen and etoricoxib and their effect on pain and inflammatory markers in patients undergoing hip arthroplasty. Clin Drug Investig 36: 545-555, 2016.

III Piirainen A, Kokki M, Lidsle HM, Lehtonen M, Ranta VP and Kokki H.

Absorption of ibuprofen orodispersible tablets in early postoperative phase - a pharmacokinetic study. Curr Med Res Opin 34: 683-688, 2018.

IV Piirainen A, Huopio J, Kokki H, Holopainen A, Pajunen T, Pulkki K and Kokki M.

Novel renal markers for the assessment of renal integrity in patients undergoing knee arthroplasty - a pilot study. J Exp Orthop 25: 40, 2018.

The publications were adapted with the permission of the copyright owners.

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ABBREVIATIONS

ACEi Angiotensin convertase enzyme inhibitor ADH Antidiuretic hormone AKI Acute kidney injury

ARB Angiotensin receptor blocker ASA American Society of

Anesthesiologists physical status classification AUC Area under the curve BBB Blood-brain barrier BMI Body mass index CKD Chronic kidney disease Cmax Maximum concentration CNS Central nervous system COX Cyclo-oxygenase CSF Cerebrospinal fluid CYP Cytochrome P450 CV Coefficient of variation DRG Dorsal root ganglia

etCO2 End-tidal carboxan dioxide GFR Glomerular filtration rate

GI Gastrointestinal

IGFBP-7 Insulin-like growth factor binding protein- 7 IL Interleukin

IL-1ra Interleukin- 1 receptor antagonist

I.v. Intravenous

KIM-1 Kidney injury molecule 1 LCC Laparoscopic

cholecystectomy

LC-MS/MS Liquid chromatography tandem mass spectrometry L-FABP Liver-type fatty acid -binding

protein

MEAC Minimum effective analgesic concentration

MEC Minimum effective concentration

NGAL Neutrophil gelatinase- associated lipocalin NNT Number needed to treat NRS Numeric rating scale NSAID Non-steroidal anti-

inflammatory drug

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PG Prostaglandin RAAS Renin aldosterone

angiotensin system

RRT Renal replacement therapy SD Standard deviation

SpO2 Peripheral saturation T1/2 Elimination half-life Tmax Time to maximum

concentration

THA Total hip arthroplasty TIMP 2 Tissue inhibitor

metalloproteinase 2 TKA Total knee arthroplasty TNF-α Tumor necrosis factor TXA2 Thromboxane A2

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1 INTRODUCTION

Postoperative pain is an expected outcome after surgery, since 50-70% of patients may experience moderate to severe pain postoperatively at rest and even more dynamic pain is reported (Wylde et al., 2011). Surgery involving bones, such as joint arthroplasties (Wylde et al., 2011) and spine surgeries (Puvanesarajah et al., 2015) are among the most painful procedures. Also, other types of surgery, including abdominal surgery, e.g. cholecystectomy, and hysterectomy (Gerbershagen et al., 2013, Kokki, M., Broms, Eskelinen, Rasanen et al., 2012, Piirainen et al., 2018, Piirainen et al., 2019) are associated with a high occurrence of postoperative pain. Appropriate postoperative pain management should be applied since besides causing discomfort, severe pain may increase the risk for adverse effects and lead to prolonged hospitalization (McGrath et al., 2004). The intensity and duration of acute pain is associated with prolonged pain after surgery (Fletcher et al., 2015, Tawfic et al., 2017). This is even more problematic when the indication of the operation has been pain reduction. Therefore,

adequate postoperative pain treatment could be a major contributor in reducing the incidence of persistent postoperative pain (Tawfic et al., 2017).

Multimodal approach is the most efficient method in treating postoperative pain and is in routine use (Buvanendran, Kroin, 2009). Combination of analgesics with different mechanisms and sites of action provide additive or synergistic effect resulting in sufficient analgesia with smaller doses of individual drugs

(Buvanendran, Kroin, 2009). Opioid-related adverse effects are therefore less common and/or less severe with multimodal regimes (Kehlet, Dahl, 1993).

Non-opioid analgesics including non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen), should form the basis of postoperative pain management, because they provide analgesic and opioid-sparing effect. To alleviate breakthrough pain, quick-acting and effective drugs, mainly opioids, are needed. Additionally, local anaesthetic methods can be used in selected situations to further reduce on-site-pain (Spreng et al., 2010).

NSAIDs form the basis of postoperative pain treatment. NSAIDs diminish production of prostaglandin E2 (PGE2)− a key cytokine in inflammatory reaction after surgical procedure. PGE2 is synthetized by cyclo-oxygenase (COX) enzyme-1 and -2 that are up-regulated in both peripheral tissues and in the central nervous system (CNS) (Buvanendran et al., 2006). COX-2 and PGE2 have a major role in the transition of acute to chronic pain (St-Jacques and Ma 2011). Both COX-2 and PGE2

are shown to promote the synthesis of other cytokines, like interleukin-6 (IL-6), that contributes development of neuropathic pain (St-Jacques, Ma, 2011, St- Jacques, Ma, 2014). Blocking both COX-1 and COX-2-enzyme and therefore PGE2

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production already at early phase can reduce the risk of chronic pain conditions (St-Jacques, Ma, 2014).

Dexketoprofen, a dextrorotatory (S (+)) enantiomer of ketoprofen, is a NSAID with both COX-1 and COX-2 inhibition activity (Barbanoj, Antonijoan & Gich, 2001).

Ketoprofen is known to be a potent analgesic in postoperative pain (Kokki, H., 2010). Its analgesic efficacy is mainly due to S (+)-enantiomer and its adverse effects are related to R (-)-enantiomer (Barbanoj, Antonijoan & Gich, 2001), therefore, dexketoprofen is expected to be an even more efficient analgesic.

Studies have shown its analgesic efficacy and opioid-sparing effect in many clinical settings (Hanna et al., 2003, Tunali et al., 2013).

Ibuprofen is extensively used both over the counter and prescribed traditional NSAID in Finland (Finnish Medicines Agency and Social Insurance Institution, 2020) with non-selective COX-inhibition effect (Derry et al., 2009). Ibuprofen is routinely used in postoperative pain, but, for a long, but a lack of intravenous (i.v.)

formulation has prevented its use in the early acute phase. At immediate

postoperative phase after anaesthesia possible lack of bowel mobility, uncertainty of swallowing and supine position can inhibit absorption and efficacy of oral analgesics (Kennedy, van Rij, 2006, Queckenberg, Fuhr, 2009). This has led to the development of new formulations of oral analgesics, which are more easily soluble and could therefore produce faster analgesia also in postoperative setting (Moore, A. R. et al., 2014).

Etoricoxib is a COX-2 –preferential NSAID with a long elimination half-life compared to many other analgesics. Due to its COX-2 –preferential inhibition, etoricoxib is mainly used in treating pain caused by chronic inflammation, e.g.

arthritis (Takemoto et al., 2008). However, the COX-2 –selectivity has raised interest in utilizing these analgesics in treating acute postoperative pain in order to avoid increased risk of complications, which are present in the postoperative setting, e.g.

bleeding, gastrointestinal (GI) ulcerations and acute kidney injury (AKI) (Renner et al., 2012). Etoricoxib has been studied to some extent in orthopaedic surgery, but despite the rather positive outcomes (Clarke, Derry & Moore, 2014), more studies are needed to ensure its role in postoperative pain management.

The main aim of this thesis is to evaluate the efficacy and optimal dosing of dexketoprofen in postoperative pain management in adult patients. The second aim is to compare dexketoprofen’s and etoricoxib’s ability to penetrate into CNS and their effect on both peripheral and central inflammatory reaction in acute pain. The third aim is to assess absorption of orodispersible ibuprofen after low back surgery. The fourth aim is to study the renal safety of dexketoprofen in postoperative setting by assessing the feasibility of novel AKI biomarkers in patients undergoing total knee arthroplasty (TKA).

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2 REVIEW OF THE LITERATURE

2.1 POSTOPERATIVE PAIN

Postoperative pain is a common complaint after surgery (Gerbershagen et al., 2013). In a large observational study in Germany, 22,740 procedures with the highest pain scores were evaluated. Patients reported high pain scores after many minor surgeries, including appendectomy and cholecystectomy which were ranked among the procedures with the highest pain intensities (Gerbershagen et al., 2013). Although multimodal analgesia regimen is a common concept in pain management, there is still a need for improvements in pain treatment. The duration of severe pain in the initial 24 hours postoperatively, instead of the intensity of pain, predicted the chance of developing persistent postoperative pain . For every 10% increase in time spent in severe pain postoperatively, the risk of developing chronic postoperative pain was increased by 30% (Beswick et al., 2012).

2.1.1 Mechanism

The perception of acute incisional pain is a complex process including activation of nociceptors and transmitting painful stimulus from the peripheral site to the CNS.

Nociceptors are a subpopulation of peripheral receptors that are excited by potentially harmful and noxious stimuli. Nociceptors transduce noxious stimuli into electrical activity and transmit this information from the peripheral site to the CNS. The body cells of nociceptors are located in the spinal cord in dorsal root ganglia (DRG), where they synapse with projection neurons (Basbaum et al., 2009).

These furthermore transmit signals to the brainstem and limbic parts and then to different cortical parts of the brain (Renn, Dorsey, 2005). These ascending

pathways are able to forward the painful stimulus but have no ability to modify, intensify or diminish the information. However, the descending pathways create neural network that modulates the pain information transmitted in the ascending pathways. The synapse of nociceptor and projection neuron in DRG is an

important site where noxious signalling can be inhibited (Basbaum et al 2010).

2.1.2 Inflammatory reaction

Noxious stimuli launch inflammatory reaction in both peripheral tissues and central sites. Activated nociceptors and other cells in the damaged tissue promote local release of different proinflammatory mediators including eicosanoids, peptides, neurotransmitters, cytokines and chemokines, which are a vast group of molecules enhancing and inhibiting each other actions (Carvalho, Clark & Angst, 2008). Together with repetitive stimuli, they furthermore activate and sensitize the

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nociceptors. Sensitization includes a decrease in the of action potential threshold and increase in responsiveness to noxious stimuli leading to hyperalgesia and allodynia. In hyperalgesia, a painful stimulus is perceived as more painful than before. In allodynia, a non-painful stimulus becomes painful (Cervero, 2009, Sandkühler, 2009). Additional to peripheral sensitization, repetitive stimulation of afferent nerves leads to central sensitization and usually the first line

phenomenon is wind-up. Wind-up is explained as spinal neurons exhibiting enhanced excitability. This phenomenon outlasts the original stimulus (Cervero, 2009). Sensitization can promote permanent changes both in nociceptors and in spinal cord, which can lead to chronic pain (Woolf, 2011).

Besides the peripheral inflammatory reaction, peripheral tissue damage

induces release of inflammatory mediators in the spinal cord and the brain leading to elevated concentrations of proinflammatory transmitters in cerebrospinal fluid (CSF). The production of inflammatory mediators is positively correlated to pain intensity (Wang, X. M. et al., 2009).

Prostaglandins are produced in all human cells after mechanical trauma or cytokine or growth-factor activation. They act as autocrine and paracrine

mediators and have a significant role in both acute and chronic pain. PGE2 is the most important PG as a pain mediator since it activates the pro-inflammatory cytokine cascade (St-Jacques, Ma, 2011). PGE2 itself also acts as a hyperalgesia mediating agent, as it sensitizes peripheral and central neurons, thus enhancing transduction and transmission of nociceptive information. PG production is regulated by COX enzymes, which act as catalysts in conversion from arachidonic acid to prostanoids, including PGs. Two isoforms of COX-enzymes have been identified. Both isoenzymes are constantly present both in peripheral sites and in CSF, although COX-2 to much lesser extent. The COX-1 has an important role as a house-keeping enzyme, as it contributes to the production of baseline PGs and therefore maintains homeostasis. COX-2 has been found highly inducible enzyme, which has led to theories of its role as the main contributor of PG synthesis in trauma. However, experimental studies have revealed, that both isoenzymes have a major role in acute pain reaction, but there are differences depending on the pain model (Zhu, Conklin & Eisenach, 2005). In acute inflammatory pain, e.g.

arthritis, COX-2 concentration increases rapidly and remains elevated long-term.

Concentration of COX-1 remains stable, which highlights the importance of COX-2.

In contrast, COX-1 concentrations are highly increased in postoperative pain (Prochazkova et al., 2006), though both isoenzymes are upregulated (Kroin et al., 2008).

Besides PGs, cytokines are present in inflammatory reaction in postoperative pain and similarly act as inflammatory mediators. Cytokines consist of different groups of proteins mediating and regulating body functions such as immune defence system and inflammatory reaction (Tayal, Kalra, 2008). They enhance production of other pain mediators and influence the development of signs of inflammation. Cytokines are released locally as cascades in response to painful or

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inflammatory stimuli and they act through binding to specific receptors and thus modulate cell function. This results in sensitization of afferent nerve ends, which in turn, can lead to hyperalgesia. Cytokines also entice migration of white blood cells and thus help create neurogenic inflammation (Beilin et al., 2003). Besides

peripheral cytokine induction, their role in participating to CNS inflammatory reaction has been shown. Cytokines can penetrate the blood brain barrier (BBB) but peripheral inflammation also induces cytokine production in CNS (Bromander et al., 2012).

Cytokines are divided into those with mainly proinflammatory effects and those with anti-inflammatory effects (Bromander et al., 2012). Interleukins (IL) -β, -6 and - 8 and tumour necrosis factor alpha (TNF-α) are considered as major

proinflammatory mediators (Verri et al., 2006).

IL-6 induces release of other inflammatory mediators, but it also enhances expression of COX-2, which results in the release of PGs. Therefore, IL-6 acts as an intermediate hypernociceptive mediator. In addition to acute inflammatory pain, IL-6 also contributes to neuropathic pain (Verri et al., 2006).

IL-6 has been shown to be an important pain mediator both in experimental studies but also in human studies (Wang, X. M. et al., 2009). Pain induces IL-6 synthesis via other inflammatory mediators, such as PGE 2, IL-β, and TNF-α.

Increased IL-6 concentration correlates with the extent of surgery and pain

intensity (De Jongh et al., 2003). Increased concentration also correlates with a risk for surgery related complications and prolonged recovery (Rettig et al., 2016). IL-6 acts through several ways in pain perception; it participates in leukocyte migration, induces production of other cytokines and contributes to pain modulation (Wang, X. M. et al., 2009).

IL-8 and TNF-α are inflammatory mediators that contribute to postoperative pain (Wang, X. M. et al., 2009). Their synthesis is upregulated after surgery and elevated concentrations are detected in peripheral tissues and central sites.

Interestingly, both IL-8 and TNF-α have been connected to neuropsychological postoperative complications, such as delirium−specifically in elderly patients (Wang, X. M. et al., 2009).

Since a properly functioning immune defence system is based on balance, there are anti-inflammatory cytokines to counterbalance effects of

proinflammatory mediators. IL-10 and IL-1 receptor agonist (IL-1ra) are cytokines that mainly have anti-inflammatory properties. Logically, their concentrations in CSF and blood circulation are increased after surgery in order to downregulate the immune response (Bromander et al., 2012).

2.1.3 Postoperative pain after hip arthroplasty

Total hip arthroplasty (THA) is a high-volume procedure; in 2019, 10,443 surgeries were made in Finland and the numbers are growing (Puroharju et al., 2020). The main indications of proceeding to hip replacement are hip arthrosis, pain

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alleviation and improved mobility. This, on top of ethical point of view, motivates pain management optimization even further. The patient population is mostly elderly; 27% of the patients are 75 years or older (Puroharju et al., 2020). This forms a challenge to pain treatment, since older patients are at a greater risk of drug adverse effects, e.g. AKI, bleeding and cognitive disorders, than younger patients (Griffiths et al., 2014).

Total hip arthroplasty is associated with substantial postoperative pain, especially in the early postoperative period, but also 2-4 weeks after discharge from hospital. Approximately 7-20% of THA patients suffer from persistent postoperative pain, and almost 30% of patients use increased amounts of analgesics after surgery (Beswick et al., 2012). Prolonged pain affects negatively the recovery process in several aspects like physical activity, sleep, and cognitive function. This results in an increased use of analgesics, therefore, procedure- specific guidelines for pain treatment are needed (Aasvang, Luna & Kehlet, 2015).

The trend towards fast-track surgery sets its own challenges to postoperative pain treatment. Patients without major complications are currently discharged one to three days after THA in Finland, but in some countries they can be discharged even on the same day (Husted et al., 2021). Thus, the pain treatment must be adapted to allow early discharge. Minimizing the use of opioids should therefore be highlighted particularly in this context, especially during the current global opioid crisis (Raeder, 2020).

Both preoperatively and postoperatively administered NSAIDs have been shown to reduce postoperative pain and opioid-consumption after THA (Fillingham et al., 2020). However, no clinically meaningful difference has been detected between non-selective NSAIDs (Kostamovaara et al., 1998) or between non- selective NSAIDs and COX-2 selective NSAIDs (Chan et al., 2005). However, there has been a trend towards prescribing COX-2 selective NSAIDs, i.e., coxibs for postoperative pain alleviation, especially after joint arthroplasty (Jiang et al., 2020).

This is mainly due to the supposedly better adverse effect profile. Also, no clear evidence for optimal dozing has been presented, even though many drugs are thought to have dose-dependent effect (Fillingham et al., 2020).

2.1.4 Postoperative pain after cholecystectomy

Cholecystectomy is one of the most frequent elective abdominal surgery. In 2018, there were 8,323 laparoscopic cholecystectomies (LCC) and 907 open

cholecystectomies in Finland (Finnish Institute for Health and Welfare, 2019).

Elective cholecystectomy is mainly executed laparoscopically, since the consensus has been that laparoscopy is safer and is associated with less tissue trauma and postoperative pain thus leading to faster recovery than open surgery. However, studies have shown that laparoscopy is associated with substantial postoperative pain that is comparable to open surgery (Aspinen et al., 2016, Bisgaard et al.,

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2001). Persistent pain is the main reason for prolonged hospitalization and readmission after cholecystectomy (Bisgaard et al., 2001, Ko-Iam et al., 2017).

Pain after laparoscopy mainly originates from tissue-trauma at the incision sites, which causes nociceptive pain but can also result in neuropathic pain.

Insufflation of the abdominal cavity with carbon dioxide is another major contributor to postoperative pain after laparoscopy. Pain after

pneumoperitoneum is multi-factorial, resulting from insufflation of gas, type of gas used, volume of residual gas and stretch-induced nerve damage. Surgery also induces systemic inflammatory response. Postoperative pain management should therefore be multifactorial to cover all major components of postoperative pain (Sjövall, Kokki & Kokki, 2015).

Postoperative pain is a major reason for readmission after ambulatory laparoscopic cholecystectomy; therefore, more studies are needed to optimize postoperative pain management (Bisgaard et al., 2001). Paracetamol and NSAIDs are efficient as a part of multimodal pain management regimen and are

recommended for routine use after LCC (Barazanchi et al., 2018). Surgical site infiltration analgesia is also recommended, since it is assumed to reduce pain and need for rescue analgesia (Kaushal-Deep et al., 2018). However, other local

anaesthetic techniques are not routinely recommended, with little or no additional pain relief for basic pain management strategies. Opioids are recommended as a rescue analgesia only in the postoperative setting. They should not be prescribed at discharge, which is in line with the universal opioid-minimising postoperative pain management strategy (Barazanchi et al., 2018).

2.1.5 Postoperative analgesia

After major surgeries, opioids remain the main analgesic used for moderate and severe pain in peri- and postoperative phases. However, opioid-related adverse effects are common and have a negative impact on patient’s outcome; patient morbidity is higher and hospital stay is prolonged (Martinez, Ekman & Nakhla, 2019). Combining different analgesic techniques and analgesics with different mechanisms and sites of action results in additive or synergistic pain relief with fewer individual drug-related adverse effects (Buvanendran, Kroin, 2009). This multimodal approach is the golden standard of perioperative pain management since studies have proven it to be more efficient and safer pain management routine compared to opioids alone (Memtsoudis et al., 2018, Wu et al., 2019). The current recommendation is to combine opioids with paracetamol, NSAIDs, local anaesthetics and possible other adjuncts, with some variations between different types of surgery (Richebé, Brulotte & Raft, 2019). Opioid-free analgesia is of major interest and may represent future trend; however, more studies are needed to establish its efficiency and safety compared to opioid-minimising analgesia (Wu et al., 2019).

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Oxycodone has surpassed other opioids in postoperative pain management. It is a µ-opioid receptor agonist with active metabolites and has been shown to provide sufficient analgesia in different types of surgery (Kinnunen et al., 2019).

Compared to morphine, oxycodone provides better pain alleviation in visceral pain and has similar effect on somatic pain, with less histamine release, pruritus and hypotension. Moreover, oxycodone possibly has lower risk for hallucinations and nightmares. Oxycodone has, however, other well-known opioid-related adverse effects such as nausea, vomiting, ileus, constipation and respiratory depression (Kokki, H., Kokki & Sjövall, 2012).

Nonsteroidal anti-inflammatory analgesic drugs are well-known and

established analgesics in postoperative use. They are especially potent analgesics in orthopaedic surgeries but have shown efficacy in many other types of surgery as well. They have an opioid-sparing effect and are usually well tolerated

(Martinez, Ekman & Nakhla, 2019). The main concerns about their use are risk for excessive bleeding due to platelet dysfunction and AKI, and an increased risk for cardiovascular complications. These risks are highlighted in surgical and elderly populations (Anderson et al., 2020).

Paracetamol is another well-established analgesic and is widely used in both adults and children. It has shown to be opioid sparing when compared to placebo and to provide sufficient analgesia when combined to other analgesics even though the mechanism of action remains partially unresolved. Inhibition of PG synthesis in CNS as well activation of descending serotonergic inhibition system in pain system have been proposed. Opioid, nitric oxide, vanilloid and cannabinoid pathways may also be involved. Paracetamol is well-tolerated and has few adverse effects and contraindications (Hilleman et al., 2020). The role of paracetamol, howver, has been, challenged. Thybo et al. demonstrated that paracetamol did not improve analgesic efficacy when combined with ibuprofen 400 mg compared to ibuprofen 400 mg alone after THA (Thybo et al., 2019). In tonsillectomy patients i.v.

paracetamol combined with i.v. ketoprofen did not reduce the proportion of the patients requiring rescue analgesia, but the number of opioid doses was less in the add-on group (Salonen, Silvola & Kokki, 2009). Moreover, when NSAIDs are contraindicated, paracetamol can be a feasible choice for background analgesia (Kemppainen et al., 2006).

2.2 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Non-steroidal anti-inflammatory drugs are a large group of analgesic compounds with different molecule structures. In addition to the analgesic efficacy, NSAIDs also have alleviating effect on fever and inflammation. They also affect blood platelet functioning.

NSAIDs are one of the most commonly used group of analgesic drugs both in the hospital environment and in self-care (Finnish Medicines Agency and Social Insurance Institution, 2020).

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2.2.1 Mechanism of action of NSAIDs

The mechanism of action of NSAIDs is based on diminished production of PGs and therefore other pro-inflammatory cytokines. PG production is regulated by COX enzymes (COX), which exist in two isoforms, COX-1 and COX-2. COXs act as

catalysts in converting arachidonic acid into PGs. The NSAIDs inhibit up-regulation of COX in reversible competitive manner but can also irreversibly deactivate COX (Burian, Geisslinger, 2005). Among the NSAIDs, there are different molecules with different selectivity for COX isoform inhibition. Traditionally, NSAIDs inhibit both isoforms, however, more specific COX-2 inhibitors have been recently introduced.

Both isoforms of COX have been shown to contribute to PG production in inflammation and nociceptive reaction in peripheral and central sites. COX-1 was, however, earlier considered to be a “house-keeping” isoform. COX-1 is responsible for producing basal concentration of PGs needed for maintenance of different body functions (Burian, Geisslinger, 2005). At the peripheral site, COX-1 has later been shown to be part of PG formation in acute inflammation and moreover, be responsible for the initiative reaction of PG production. COX-2, even though expressed constitutively in low concentrations in kidneys and vascular

endothelium, is highly induced in acute inflammation and is the major contributor to PG production as the inflammation progresses (Burian, Geisslinger, 2005, Mitchell, Kirkby, 2019).

In the central nervous system, both COX-1 and COX-2 are expressed constitutively (Beiche et al., 1998). In experimental works, various stimuli have been shown to increase COX-2 expression, and furthermore increase the PG concentrations in spinal cord (Beiche et al., 1998, Samad et al., 2001). This has also been proved in animal tests in the case of peripheral inflammation, in which peripheral noxious stimuli increases the COX-2 concentration and leads to

increased concentrations of mainly PGE2 (Samad et al., 2001). However, the role of COX-1 has been studied in postoperative setting, and it has been shown to have an important role in enhancing the nociceptive reaction (Zhu, Conklin & Eisenach, 2005).

Since both COX-1 and COX-2 are expressed in peripheral and central sites in acute inflammation, NSAIDs may act in both sites (Vane, 1998).

2.2.2 NSAIDs in postoperative pain treatment

In the postoperative setting, both COX-1 and COX-2 concentrations have been shown to be elevated in peripheral and central tissues (Zhu et al. 2003, Kroin et al.

2004). Elevated concentrations of COX-1 and COX-2 are related to increased PGE2

concentrations in both sites (Kroin et al., 2006). This offers the possibility of using NSAIDs in postoperative pain treatment.

In an experimental study with rats, preoperative administration of non-selective COX-inhibitor ketorolac and COX-2 preferential rofecoxib reduced PGE2

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concentrations in both peripheral tissue and CSF, this reduction was related to decreased pain-related behaviour (Kroin et al., 2006). This effect has been confirmed in other studies with both COX-1 selective inhibitors (Zhu, Conklin &

Eisenach, 2005) and COX-2 selective inhibitors (Peng et al. 2012). In human studies, the effect of NSAIDs on PGE2 and other inflammatory marker concentrations after surgery has mainly focused on tissue fluid (e.g., wound drainage and joint fluid) or plasma concentrations. In these cases, there has been a strong correlation between NSAID administration, reduction in inflammatory marker concentrations and the need for rescue analgesia (Chang et al., 2013, Iohom et al., 2002, Renner et al., 2012). However, there are relatively few studies on the effect of NSAIDs on inflammatory marker concentrations in CSF in humans.

Renner et al. showed that orally administered etoricoxib diminished CSF IL-6 concentration in patients undergoing hip surgery (Renner et al., 2012).

The studies evaluating use of NSAIDs in postoperative pain management have focused on determining their effect on clinical pain and the ability to reduce opioid consumption in postoperative period. NSAIDs have proven to be highly efficient in reducing postoperative pain and have established their status in pain treatment regimens worldwide (Buvanendran, Kroin, 2009). As a part of multimodal analgesia, NSAIDs intensify the efficacy of other analgesics and reduce the need for rescue opioid analgesics (Dahl, Raeder, 2000, Hanna et al., 2003, Rugyte, Kokki, 2007).

The analgesic efficacy of NSAIDs has been thought to be dose-dependent (Clarke, Derry & Moore, 2014, Derry et al., 2009, Gaskell et al., 2017) However, in previous dose-finding studies, the dose-dependency has not been that clear. In a study by Nikanne and colleagues, no difference in efficacy was seen between different doses of ketoprofen in postoperative pain management after adenoidectomy (Nikanne, Kokki & Tuovinen, 1997). A small difference was detected in studies by Kokki et al, where higher doses of intravenous ketoprofen (1.0 or 3.0 mg/kg versus 0.3 mg/kg) provided better analgesia after adenoidectomy and a higher dose of p.o. ketoprofen (0.5 or 1.0 mg/kg versus 0.25 mg/kg) resulted in better analgesic and anti-pyretic effect in children (Kokki, H., Nikanne &

Tuovinen, 1998, Kokki, H., Kokki, 2010). However, the difference favouring higher dose was rather small, therefore more dose-finding studies are needed.

2.2.3 Adverse events of NSAIDs

NSAID’s mechanism of action is based on preventing prostanoid production, and the adverse effects are due to prevention of prostanoids required for maintenance of physiologic functions. Prostanoids participate in maintaining the GI mucosa, renal function and haemostasis (McCrory, Lindahl, 2002). Patients undergoing surgery have a higher risk of adverse events, since the peri- and postoperative period includes various stress factors related to the homeostasis of the body, e.g., operation itself, fluctuation in the fluid balance and patient’s blood pressure,

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fasting, and administration of many other drugs. These adverse effects have been shown to be dose-dependent and to be rather similar between different non- selective COX-inhibitors (Hernández-Díaz, García-Rodríguez, 2001). The urge to diminish the risk of adverse events led to invention of more COX-2-selective NSAIDS. The differences in adverse effects between the two groups are described in section 2.4.3.

In practice, the most common adverse events related to use of NSAIDs are GI irritation and ulcers (McCrory, Lindahl, 2002). PGs, especially PGI2 and PGE2, contribute to mucus production and decrease acid secretion. Thus, inhibiting PG synthesis increases the risk for GI complications. Previously, inhibition of these PGs was merely thought to be COX-1 related, but there is evidence that COX-2 inhibition alone does not protect from GI complications (Wallace, 2000). Indeed, the risk of GI adverse effects is higher in patients taking COX-2 inhibitors

compared to control group (Lin, X. H. et al., 2018). The risk for GI complications is increased particularly in older patients and patients with previous peptic ulcers, as well as in those with medication affecting the haemostasis (Lin, X. H. et al., 2018).

Prostaglandins have a complex effect on renal function, but the main effects are arterial dilatation, which leads to increased renal flow and sodium excretion, renin activation and anti-diuretic hormone suppression (McCrory, Lindahl, 2002).

Inhibition of PGs may also affect renal homeostasis and patients with chronic kidney disease (CKD) are more prone at risk for AKI. Renal adverse effects result in oedema, increased blood pressure as well as electrolyte, acid-base and metabolite imbalance (Curtis et al., 2004). In the perioperative period, patients are exposed to hypovolemia and have a labile blood pressure, which can further enhance the negative renal effects of COX-inhibitors. Patients with normal preoperative renal function have a low risk for COX-inhibitor associated renal adverse effects (Lee et al., 2007). However, growing population of elderly with chronic renal dysfunction are undergoing various surgeries, hence the need for more information on renal safety of NSAIDs in perioperative treatment.

Cyclo-oxygenase-inhibition may also result in haemostasis imbalance.

Thromboxane A2 (TXA2) has a pro-aggregatory effect on blood platelets, and it is regulated mainly by COX-1. On the other hand, PGI2 has an antiplatelet effect, and it is produced by constitutively expressed COX-2 (McCrory, Lindahl, 2002). Non- selective NSAIDs have been related to an increased risk for bleeding in the perioperative period due to platelet dysfunction⎯especially in patients on anticoagulants or antiplatelet medication. Non-selective COX-inhibitors, given orally or i.v., are known to increase bleeding time (Warner, Mitchell, 2008).

However, in large multicentre analyses of patients with no major risk factors for bleeding, there has not been a statistical difference in occurrence of major haemorrhages (Moore, R. A. et al., 2015). In contrast, COX-2 inhibitors have been associated with risk for thrombosis, due to their effect on PGI2 and not on TXA2. The association is not unambiguous, since both non-selective and COX-2 selective

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NSAIDs inhibit COX-2, and the risk for cardiovascular or thrombotic events has been speculated to be similar (Kearney et al., 2006).

2.3 DEXKETOPROFEN

Ketoprofen, (+/-) - (R ,S)-2-(3-benzoylphenyl)-propionic acid, is a chiral 2- arylpropionic acid derivative NSAID with analgesic, antipyretic and anti-

inflammatory effects. Dexketoprofen is the dextrorotatory (S)- (+)- enantiomer of ketoprofen. Both racemic ketoprofen and dexketoprofen are well-known and potent analgesics and have established their role in postoperative pain management (Kokki, M., Broms, Eskelinen, Rasanen et al., 2012).

Table 2.1.Pharmacokinetic parameters of NSAIDs in healthy volunteers (data adapted from Barbanoj, Antonijoan & Gich, 2001, Davies, 1998, Rainsford, 2009, Shi, Klotz, 2008, Takemoto et al., 2008). t_max= time to maximum concentration, Cmax= maximum concentration, AUC= area under curve, t1/2= elimination half-life, CL = Clearance, Vd/F= Apparent volume of distribution after non-intravenous administration. Data are presented as mean values.

Ibuprofen (400 mg p.o.)

Dexketoprofen trometamol (25

mg po)

Etoricoxib (120 mg po)

Plasma tmax (min) 83 30 60

Plasma Cmax (mg/L) 56 2.02 3.16

Bioavailability (%) > 80 81.4 83

Protein binding (%) 98 99 92

Plasma AUC^∞(mg*h/L) 203 4,18 51.5

t1/2 (h) 2.1 1.65 21.0

CL (L/h) 0.048 0.087 3.42

Vd/F (L/kg) 0.14 0.24 1.1-1.8

2.3.1 Mechanism of action of dexketoprofen

Ketoprofen is a highly efficient PG synthesis inhibitor; its analgesic efficacy is mainly due to dexketoprofen, while the levorotatory (R)- (-)- enantiomer levoketoprofen is devoid of such activity (Carabaza et al., 1997, Mauleón et al., 1996). Dexketoprofen is a more potent analgesic than racemic ketoprofen, and equivalent pain reduction can be achieved with half a dose compared to

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ketoprofen (Hanna et al., 2003, Gaskell et al., 2017). The pharmacokinetic properties of oral dexketoprofen trometamol salt are described in Table 2.1.

Ketoprofen is a non-selective COX-inhibitor, and in experimental tests with rats, dexketoprofen has been shown to inhibit both COX-isomers peripherally.

Moreover, dexketoprofen has been shown to be responsible for the main COX-2 inhibition of ketoprofen; the R-enantiomer affected mainly COX-1. This

furthermore confirms dexketoprofen’s role as the main contributor of ketoprofen’s analgesic effect (Carabaza et al., 1997).

The analgesic efficacy in peripheral tissues is known for all NSAIDs, but the possibility of analgesic activity in CNS is affected by the molecule’s ability to penetrate into the CNS. Ketoprofen has small molecular weight and is highly lipophilic, which favour penetrating the BBB and blood-CSF barrier. Ketoprofen is expressed in its ionised form in physiological pH; thus, its lipophilicity is

significantly lowered in circulation. Also, ketoprofen is highly protein bound (>

99%), which even more affects negatively its ability to penetrate into CNS (Kokki, H., 2010). Drug concentrations in CSF are commonly used surrogate measures of CNS exposure of different compounds. Data both in adults (Netter et al., 1985) and in children (Mannila et al., 2006) have shown that ketoprofen can readily penetrate in CSF after i.v. administration. This ability can be assumed with dexketoprofen, implying that dexketoprofen like ketoprofen has two sites of action: peripheral and CNS.

2.3.2 Dexketoprofen in postoperative pain treatment

Dexketoprofen is an efficient analgesic when treating postoperative pain (Gaskell et al., 2017). The analgesic effect is similar compared to other non-selective NSAIDs with recommended doses, and a 20 to 25 mg dose of dexketoprofen provides a number needed to treat (NNT) value of 4.1 with at least 50% pain relief (Gaskell et al., 2017) and a 50 mg dose provides NNT value of 3.3 (Barden et al., 2009). Dosing in the postoperative setting ranges between 25 and 50 mg with 50 mg being the most commonly used dose. Dexketoprofen has provided sufficient analgesia after major orthopaedic, abdominal and gynaecological surgeries (Hanna et al., 2003, Iohom et al., 2002, Jamdade et al., 2011, Moore, R. A., Barden, 2008). An

experimental study with rats showed a synergistic effect between morphine and dexketoprofen (Miranda et al., 2007). In a study by Gaitán and Herrero (Gaitán, Herrero, 2002) dexketoprofen enhanced and extended the analgesic efficacy of fentanyl with subeffective doses. In human studies, perioperative administration of dexketoprofen results in reduced opioid consumption and opioid-related adverse events (Gaskell et al., 2017).

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2.3.3 Adverse events of dexketoprofen

In a recent Cochrane review, no serious adverse events were related to orally administered single doses of dexketoprofen, and the detected adverse events were similar compared to other non-selective NSAIDs (Gaskell et al., 2017).

Previously, dexketoprofen has been associated with a lower risk for adverse events (e.g. GI bleeding) than ketoprofen due to levoketoprofen’s higher COX-1- selectivity. However, this has not been confirmed in later studies (Gaskell et al., 2017). However, their i.v. tolerability makes an exception; Sjövall and associates demonstrated significantly less venous irritation during i.v. administration of dexketoprofen compared to ketoprofen (Sjövall et al., 2015).

Table 2.2. Frequency of dexketoprofen’s adverse effects (Modified from SPC, Ketesse).

>1/100 <1/100 >1/1000 < 1/1000 <1/10000

Kidneys Proteinuria,

renal impairment GI tract Abdominal

pain, reflux, diarrhoea,

nausea

Ulcers and bleeding, stomatitis

Perforation

Heart Arrythmias

Vascular Low blood

pressure High blood pressure

Blood Anaemia Haemolysis,

thrombocytope nia, agranulocytosis

aplastic anaemia

2.4 ETORICOXIB

Etoricoxib, 5-chloro-6’-methyl-3[4-(methylsulfonyl)phenyl]-2,3’-bipyridine, is a potent COX-2-inhibitor and the most recent addition to the group of COX-2- selective NSAIDs. The use of COX-2-inhibitors has been cautious after the withdrawal of rofecoxib due to its high rate of cardiovascular adverse events.

However, studies have shown that currently available COX-2 selective NSAIDs do not have a similar risk for cardiovascular adverse effects (Shi, Klotz, 2008).

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2.4.1 Mechanism of action of etoricoxib

The developmental process of the so-called coxibs, referring to COX-2 selective drugs, was initiated from the observation of adverse events of NSAIDs to be related to COX-1 inhibition (Shi, Klotz, 2008). Etoricoxib has a high COX-2/COX-1 inhibition rate of 106 compared to the other coxibs available on the market, parecoxib and celecoxib that have lower COX-2/COX-1 inhibition rates of 30 and 7.6, respectively (Dallob et al., 2003).

When administered by mouth, etoricoxib is absorbed quickly with a tmax in plasma ranging from 0.5 to 2 hours. Its oral bioavailability is 75%. The elimination half-life is approximately 22 hours, which allows once daily dosing (Table 2.1).

Etoricoxib has a low molecular weight, but is expressed mainly in ionized form in circulation; it is highly (> 99%) protein-bound (Takemoto et al., 2008). This leaves uncertainty on whether etoricoxib is able to pass BBB and blood-CSF barrier and, thus, have a central mechanism of action. However, in two studies conducted by Renner et al, etoricoxib was detected in CSF readily. In the first study already at 1 hour after administration, but the maximum concentration was not reached until 8 hours. In the second study etoricoxib peaked in CSF already at 90 minutes, which refers to faster absorption of etoricoxib when administered preoperatively. These studies failed to demonstrate etoricoxib’s effect on CSF PGE2 concentrations, though it showed reduction of PGE2 and IL-6 concentration in wound fluid (Renner et al., 2010, Renner et al., 2012).

2.4.2 Etoricoxib in postoperative pain treatment

The approved indications for etoricoxib in Europe are inflammatory pain, such as arthritis, gout, rheumatic diseases and postoperative pain after dental surgery (SPC, Arcoxia). However, the possibility of using etoricoxib generally in

postoperative pain management has been studied rather extensively due to its more tolerable adverse effect risk profile compared to non-selective NSAIDs (Clarke, Derry & Moore, 2014).

Etoricoxib has been shown to provide sufficient analgesia after various types of surgery, e.g. orthopaedic, gynaecological, abdominal, thyroid and dental surgeries (Munteanu et al., 2016, Puura et al., 2006, Renner et al., 2012, Smirnov et al., 2008, Toivonen, Pitko & Rosenberg, 2007, Viscusi et al., 2012). Etoricoxib doses range between 30 and 120 mg, and there is no definite recommendation for optimal dosing in postoperative pain management. In dental surgery the recommended dose is 90 mg once daily limited to three days (SPC, Arcoxia, Takemoto et al., 2008).

Also, 90 mg and 120 mg doses of etoricoxib provided equal analgesia after TKA:

total opioid consumption and clinical pain were similar between the two doses during the first seven postoperative days. Moreover, both doses were non-inferior to 1800 mg ibuprofen (Rawal et al., 2013). After third molar extraction, etoricoxib doses 90 mg and 120 mg provided similar analgesia when evaluated by clinical

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pain (Daniels et al., 2011). In another study with patients undergoing dental surgery, etoricoxib 120 mg was superior to 60 mg-dose during the first 24 postoperative hours (Malmstrom et al., 2004).

Etoricoxib reduces the need for rescue analgesia after major surgery, but no clear decrease in opioid related adverse events has been shown. However, in some studies, there has been a tendency towards fewer adverse events in active treatment group compared to placebo (Rawal et al., 2013, Viscusi et al., 2012).

Etoricoxib has been compared to non-selective NSAIDs, with rather consistent results of similar efficacy in postoperative pain treatment (Brown et al., 2013, Rasmussen et al., 2005, Rawal et al., 2013). Studies on the timing of administration have also been concluded, results of which imply to a mild preference of

preoperative administration (Munteanu et al., 2016, Renner et al., 2012). This may be due to the better GI absorption prior to surgery compared to postoperative situation, since in clinical use etoricoxib is only available in tablet form. However, both preoperative and postoperative administration of etoricoxib result in lower opioid-consumption compared to placebo (Puura et al., 2006, Rasmussen et al., 2005, Viscusi et al., 2012).

Recently, a study in which etoricoxib was given both preoperatively and postoperatively to patients undergoing different open abdominal, visceral and gynaecological, and thoracic surgeries, was published (Fleckenstein et al., 2016).

The results were somewhat surprising, since the study concluded that in these surgeries 120 mg dose of etoricoxib once daily had no significant effect on pain or total rescue analgesic consumption during the first 48 postoperative hours compared to placebo. This result is in contrast to previous studies, in which etoricoxib shows rather consistent efficacy throughout the studies. This

unexpected non-efficacy may result from the study design, where the first dose of etoricoxib was administered hours before the surgery. Also, the study included different types of surgeries that are associated with different forms of

postoperative pain, and the authors failed to report the anaesthesia techniques and intraoperative analgesia. Moreover, the study population was small, which may have influenced the results, since the number of patients included did not reach the number suggested by the study power calculations ((Fleckenstein et al., 2016).

2.4.3 Adverse events of etoricoxib

The possible effect of COX-selectivity to the risk of adverse events was one of the main interests to develop more COX-2 preferential NSAIDs. The mucosa of the GI tract is maintained by COX-1 derived enzymes, mainly PGI2. Large studies and meta-analyses have proved that COX-2 inhibitors have significantly better GI tolerability compared to a non-selective NSAIDs. Risk for recurrent ulcer or ulcer complications is similar when non-selective NSAID is combined with proton pump inhibitor compared to COX-2 inhibitor alone (Ray et al., 2007, Lin, X. H. et al., 2018).

Non-steroidal anti-inflammatory drugs in postoperative pain management : studies in analgesic efficacy, pharmacokinetics and renal safety

ANNIKA PIIRAINEN

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN POSTOPERATIVE PAIN

MANAGEMENT

Dissertations in Health Sciences

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN POSTOPERATIVE PAIN MANAGEMENT

Annika Piirainen

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN POSTOPERATIVE PAIN MANAGEMENT

ABSTRACT

TIIVISTELMÄ

ACKNOWLEDGEMENTS

LIST OF ORIGINAL PUBLICATIONS

CONTENTS

ABBREVIATIONS

1 INTRODUCTION

2 REVIEW OF THE LITERATURE

2.1 POSTOPERATIVE PAIN

2.2 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

2.3 DEXKETOPROFEN

2.4 ETORICOXIB