Pharmacokinetics and efficacy of epidural oxycodone

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DISSERTATIONS | PANU PIIRAINEN | PHARMACOKINETICS AND EFFICACY OF EPIDURAL OXYCODONE | No 636

PANU PIIRAINEN

PHARMACOKINETICS AND EFFICACY OF EPIDURAL OXYCODONE

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

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PHARMACOKINETICS AND EFFICACY OF EPIDURAL

OXYCODONE

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Panu Piirainen

PHARMACOKINETICS AND EFFICACY OF EPIDURAL OXYCODONE

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

Kuopio University Hospital, Kuopio on August 20^th, 2021, at 1 o’clock PM

Publications of the University of Eastern Finland Dissertations in Health Sciences

No 636

Department of Anaesthesiology and Intensive Care, Kuopio University Hospital/

Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, 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 Oy

Kuopio, 2021

ISBN: 978-952-61-4270-8 (print/nid.) ISBN: 978-952-61-4271-5 (PDF)

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

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Author’s address: Department of Anaesthesiology and Intensive Care/Institute of Clinical Medicine/School of Medicine

University of Eastern Finland KUOPIO, FINLAND

Doctoral programme: Doctoral programme of Clinical Research Supervisors: Docent Hannu Kokki, MD, Ph.D.

School of Medicine

University of Eastern Finland KUOPIO, FINLAND

Docent Merja Kokki, MD, Ph.D.

Department of Anaesthesiology and Intensive Care Kuopio University Hospital

KUOPIO, FINLAND

Reviewers: Docent Tuomas Lilius, MD, Ph.D.

INDIVIDRUG Research Program and Department of Pharmacology, Faculty of Medicine

University of Helsinki

Finnish Poison Information Center, Department of Emergency Medicine and Services

HUS Helsinki University Hospital HELSINKI, FINLAND

Docent Timo Salomäki, MD, Ph.D.

Department of Anaesthesiology University of Oulu

OULU, FINLAND

Opponent: Professor Teijo Saari, Ph.D.

Department of Anesthesiology and Intensive Care University of Turku

TURKU, FINLAND

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Piirainen, Panu

Pharmacokinetics and efficacy of epidural oxycodone Kuopio: University of Eastern Finland

Publications of the University of Eastern Finland Dissertations in Health Sciences 636. 2021, 255 p.

ISBN: 978-952-61-4270-8 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4271-5 (PDF) ISSN: 1798-5714 (PDF)

ABSTRACT

Oxycodone is a commonly used opioid for postoperative analgesia but data on epidural administration of oxycodone are scarce.

The aims of this thesis were to review the recent literature on the pharmacology of oxycodone, to study the efficacy of epidural oxycodone in patients undergoing gynaecological surgery, and to construct a population pharmacokinetic model for epidural and intravenous oxycodone.

The literature review (Publication I) indicated that oxycodone has a high analgesic efficacy in various pain conditions. With careful dosing and follow-up, oxycodone is well-tolerated across a variety of patient populations. Experimental data indicate that oxycodone has active influx at the blood-brain barrier and that oxycodone accumulates in the spinal cord after epidural administration. Analgesia is based primarily on the parent drug because concentrations of active

metabolites are low. Oxycodone is mainly metabolised in the liver via CYP3A4/5 and CYP2D6 into active metabolites; thus, delineating their drug-drug interactions is central for safe and effective oxycodone use. Preliminary data indicate that oxycodone may be feasible for epidural use, with transmucosal buccal and sublingual being feasible administration routes in acute pain management.

The efficacy of epidural oxycodone was evaluated in two double-blind, double- dummy randomised controlled trials, in which a single bolus of oxycodone 0.1 mg kg^–1 was administered either epidurally or intravenously for postoperative

analgesia after gynaecological laparotomy (Publication II, n=30) or laparoscopy (Publication III, n=60). Paracetamol and dexketoprofen were used as multimodal background analgesia. Primary outcome measure was the need for rescue i.v.

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fentanyl during the first 4 h postoperatively. For population pharmacokinetic analysis, one blood sample and one CSF sample per patient (n=60) were obtained by a single puncture at alternating time points.

The need for rescue fentanyl was lower with epidural oxycodone relative to intravenous oxycodone, regardless of surgical approach. All patients required rescue fentanyl after gynaecological laparotomy. Following laparoscopy, most patients in the epidural-group required no or only one dose of rescue fentanyl.

Pruritus was more common in the epidural-group; but otherwise epidural oxycodone was well tolerated. The population pharmacokinetic model indicated that initially 60% of oxycodone injected into the epidural space enters into CSF and 40% is absorbed into the systemic circulation.

In publication IV, population pharmacokinetic model was developed and found to describe oxycodone time-concentration data in CSF and plasma with high precision and accuracy.

In summary, oxycodone is efficacious and well tolerated in many clinical settings and patient groups with carefully considered dosing and follow-up.

Oxycodone readily penetrates the blood-brain barrier and spinal meninges after epidural administration. After gynaecological surgery, epidural oxycodone is more efficacious than the same dose delivered intravenously. A single dose of epidural oxycodone 0.1 mg kg^–1 appears insufficient for analgesia after laparotomy but appears sufficient for analgesia during the first h post-laparoscopy as a part of multimodal analgesia. For assessing oxycodone-induced analgesia, the developed population pharmacokinetic model can act as a key component for future

pharmacokinetic-pharmacodynamic modelling.

Keywords: postoperative pain, laparoscopy, laparotomy, epidural analgesia, oxycodone, population pharmacokinetics

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Piirainen, Panu

Oksikodonin farmakokinetiikka ja teho epiduraalisen annon jälkeen Kuopio: Itä-Suomen yliopisto

Publications of the University of Eastern Finland Dissertations in Health Sciences 636. 2021, 255 s.

ISBN: 978-952-61-4270-8 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4271-5 (PDF) ISSN: 1798-5714 (PDF)

TIIVISTELMÄ

Oksikodoni on yleisesti käytetty opioidi leikkauksen jälkeisessä kivunhoidossa, mutta oksikodonin epiduraalisesta annosta tiedetään vain vähän.

Tämän väitöskirjatyön tavoitteena oli tehdä kirjallisuuskatsaus viimeisimmistä oksikodonin farmakologiaa käsittelevistä julkaisuista, tutkia epiduraalisesti annetun oksikodonin tehokkuutta gynekologisten alavatsaleikkausten jälkeen ja kehittää populaatiofarmakokineettinen malli epiduraalisesti ja laskimonsisäisesti annetulle oksikodonille.

Kirjallisuuskatsauksessa (Osatyö I) todettiin, että oksikodoni on tehokas voimakkaan kivun hoidossa. Kun annostus ja seuranta toteutetaan huolellisesti, oksikodoni on turvallinen monissa eri potilasryhmissä. Kokeelliset tutkimukset ovat osoittaneet, että oksikodoni läpäisee veri-aivoesteen aktiivisen kuljetuksen avulla. Epiduraalisen annon jälkeen oksikodonipitoisuudet keskushermostossa ovat korkeita. Kipua lievittävä vaikutus perustuu lähinnä itse oksikodoniin eikä niinkään metaboliitteihin, joiden pitoisuudet ovat matalia. Oksikodoni

metaboloituu maksassa CYP3A4/5- ja CYP2D6 -entsyymien vaikutuksesta

aktiivisiksi metaboliiteiksi, joten yhteisvaikutukset muiden lääkkeiden kanssa tulee ottaa huomioon tehokkaan ja turvallisen käytön mahdollistamiseksi.

Vaihtoehtoisista antotavoista epiduraalinen anto saattaa olla tehokas, kielen alle ja posken limakalvolle annettuna oksikodoni imeytyy limakalvon läpi ja on

käyttökelpoinen akuutin kivun hoidossa.

Epiduraalisesti annetun oksikodonin tehokkuutta tutkittiin kahdessa satunnaistetussa kaksoissokkotutkimuksessa, joissa annettiin yksi bolus

oksikodonia 0.1 mg kg^–1 joko epiduraalisesti tai laskimonsisäisesti gynekologisen

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laparotomian (n=30, osatyö II) tai –laparoskopian (n=60, osatyö III) jälkeiseen kivunhoitoon. Potilaat saivat multimodaalisena taustakipulääkityksenä parasetamolia ja deksketoprofeenia. Populaatiofarmakokineettistä analyysiä varten 60 potilaalta otettiin kertapistolla yksi verinäyte ja yksi likvornäyte vaihtelevina ajankohtina.

Fentanyylin tarve oli vähäisempää epiduraali-ryhmissä verrattuna laskimoanto- ryhmiin leikkaustekniikasta riippumatta. Laparotomian jälkeen kaikki potilaat tarvitsivat fentanyyliä. Laparoskopian jälkeen useimmat potilaat epiduraali- ryhmässä pärjäsivät ilman fentanyyliä tai tarvitsivat sitä ainoastaan yhden annoksen. Kutina oli yleisempää epiduraalisen annon jälkeen mutta muuten epiduraalisesti annettu oksikodoni oli hyvin siedetty.

Populaatiofarmakokineettisen mallin mukaan epiduraalitilaan annetusta oksikodonista 60% pääsee alussa likvoriin ja 40 % verenkiertoon.

Osatyössä IV kehitettiin populaatiofarmakokineettinen malli, joka ennusti tarkasti oksikodonipitoisuuksia plasmassa ja likvorissa.

Yhteenvetona voidaan todeta, että oksikodoni on tehokas ja turvallinen monissa potilasryhmissä ja tilanteissa, kun annostus ja seuranta toteutetaan huolellisesti. Oksikodoni läpäisee hyvin veriaivoesteen ja epiduraalisen annon jälkeen myös selkäydinkalvot. Epiduraalitilaan annettu oksikodoni on tehokkaampi kuin sama annos laskimonsisäisesti annettuna gynekologisen kirurgian

yhteydessä. Yksi epiduraalinen 0.1 mg kg^–1 annos oksikodonia ei vaikuta olevan riittävän tehokas laparotomian jälkeiseen kivunhoitoon mutta laparoskopian jälkeisessä kivunhoidossa se riittää hyvin ensimmäisten tuntien ajan osana multimodaalista kivunhoitoa. Kehitettyä populaatiofarmakokineettistä mallia voidaan käyttää jatkossa oksikodonin farmakokinetiikan ja farmakodynamiikan samanaikaiseen mallinnukseen.

Avainsanat: leikkauksen jälkeinen kipu, laparoskopia, laparotomia, epiduraalinen kivunhoito, oksikodoni, populaatiofarmakokinetiikka

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ACKNOWLEDGEMENTS

This work was carried out at the School of Medicine, University of Eastern Finland and Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, between 2015–2021.

I wish to express my greatest gratitude to my principal supervisor Docent Hannu Kokki. The research ideas of Docent Kokki are the foundation of this thesis and he has kindly guided me in every phase of this project. Docent Kokki’s

enthusiasm, vast experience and insightful advice have helped me to become a better researcher and clinician. I am also deeply grateful to my second supervisor Docent Merja Kokki for practical teaching in clinical research and tremendous support in the making of this study. I thank both my supervisors for their enormous trust in me; it has given me confidence to push forward despite challenges and setbacks.

I wish to warmly thank MSc Marko Lamminsalo, PhD Pyry Välitalo, PhD Veli- Pekka Ranta, Professor Catherijne Knibbe, Professor Brian Anderson and PhD Jacqueline Hannam for their invaluable expertise in pharmacology and conducting population pharmacokinetic modelling. Without your effort, a considerable part of this thesis would not have been possible to carry out. I am very grateful to my colleague and co-author PhD Mari Kinnunen for her support and great effort to the literature review. Rarely have I worked with such a friendly and hard-working team player. I would also like to thank my other co-authors BM Pauliina Lammi and MSc Heidi Hautajärvi for collaboration. I am forever grateful to Petri Toroi RN for helping me with the study participant and gathering the research data. Your help has been indispensable. I wish to also thank information specialist Tuula Snicker for providing research articles that were otherwise unobtainable.

The reviewers of this work, Docent Timo Salomäki and Docent Tuomas Lilius, are warmly acknowledged for their insightful and constructive comments. Their expertise in anaesthesiology and clinical pharmacology was extremely helpful for improving this thesis.

I wish to thank my dear friends for support and filling my life with joy. Many thanks to my colleagues at Kainuu Central Hospital for your friendship and teaching in clinical anaesthesiology. In addition, I send my most sincere thanks to all our study participants.

Finally, I can never thank enough my family. Thank you my mother Pia and my father Lassi for your love and encouragement to pursue my dreams. I am also very

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grateful to my father Lassi on beautiful artwork for this thesis. I present my

warmest thanks to my brother Pauli and his family, Meri and Minttu, thank you for your love and support. I would also like to thank my parents-in-law Virpi and Jouni, my brother-in-law Niklas and his fiancée Anna for your support. Special thanks go to my little boy Lauri, you make me proud every day. Daddy loves you.

Annika, our PhD projects have been a great adventure. You have stood by me through all my absences and impatience. I would not have been able to finish this thesis without your endless support. Thank you for your love and respect. I am happy to share my life with you.

This work was financially supported by the Olvi Foundation, Iisalmi, Finland, Governmental VTR fund, the Hospital District of Northern Savo, Kuopio, Finland and the Finnish Cultural Foundation, Helsinki, Finland, which are gratefully acknowledged.

Kajaani, July 15^th 2021 Panu Piirainen

Sleep (c. 1771) by Jean Bernard Restout (French, 1732-1797). Adapted and drawn by Lassi Piirainen.

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LIST OF ORIGINAL PUBLICATIONS

This dissertation is based on the following original publications:

I Kinnunen M*, Piirainen P*, Kokki H, Lammi P, Kokki M. Updated clinical pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacokinet.

2019;58(6):705-725. doi:10.1007/s40262-018-00731-3.

II Piirainen P, Kokki H, Hautajärvi H, Ranta VP, Kokki M. The analgesic efficacy and pharmacokinetics of epidural oxycodone after gynaecological

laparotomy: a randomized, double-blind, double-dummy comparison with intravenous administration. Br J Clin Pharmacol. 2018;84(9):2088-2096.

doi:10.1111/bcp.13643

III Piirainen P, Kokki H, Anderson B, Hannam J, Hautajärvi H, Ranta VP, Kokki M.

Analgesic efficacy and pharmacokinetics of epidural oxycodone in pain management after gynaecological laparoscopy - a randomised, double blind, active control, double-dummy clinical comparison with intravenous

administration. Br J Clin Pharmacol. 2019;85(8):1798-1807.

doi:10.1111/bcp.13971

IV Lamminsalo M, Piirainen P, Kokki H, Knibbe CAJ, Ranta VP, Välitalo P, Kokki M.

Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration. Expert Opin Drug Deliv.

2019;16(6):649-656. doi:10.1080/17425247.2019.1618267

*equal contribution

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

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ABBREVIATIONS

AH Abdominal hysterectomy AUC Area under curve

BBB Blood-brain barrier BMI Body mass index CL Apparent total body

clearance from plasma Cmax Maximum (peak)

concentration

CNS Central nervous system CPSP Chronic postsurgical pain CR Controlled-release CSF Cerebrospinal fluid CI Confidence interval i.m. Intramuscular IR Immediate-release i.t. Intrathecal

i.v. Intravenous

LH Laparoscopic hysterectomy

PBPK Physiology-based pharmacokinetic

PCA Patient-controlled analgesia PD Pharmacodynamics

PK Pharmacokinetics p.o. Per os, by mouth

PONV Postoperative nausea and vomiting

RCT Randomised controlled trial s.c. Subcutaneous

SD Standard deviation tmax Time to maximum (peak)

concentration t½ Half-life

VAS Visual analog scale Vd Apparent volume of

distribution

VH Vaginal hysterectomy

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1 INTRODUCTION

Acute pain is a common post-surgical outcome—more than four out of five

patients have postoperative pain necessitating postoperative analgesic use, 75% of whomreport moderate or severe pain. Despite advances in postoperative

analgesia, poorly managed acute postoperative pain remains an intractable clinical problem (Apfelbaum et al., 2003, Gerbershagen et al., 2013, Sommer et al., 2008, Wu, Raja, 2011). Poorly controlled pain is distressing to patients, causes unwanted physiologic effects, increases the incidence of postoperative complications and delays ambulation and rehabilitation (Prabhakar et al., 2014). Severe acute postoperative pain is also associated with persistent postoperative pain which causes morbidity and decreases quality of life on the short and long term (Glare, Aubrey & Myles, 2019, Kehlet, Jensen & Woolf, 2006, Taylor et al., 2013).

Open abdominal surgery has been recognized as one of the most painful procedures. In abdominal surgery, especially procedures involving upper

abdomen are associated with higher pain scores and analgesic requirements than lower abdominal incisions (Ip et al., 2009, Mimica et al., 2007). Nowadays

laparoscopic techniques are widely adapted to intra-abdominal surgery but there are only a few prospective studies comparing laparoscopic surgery to open laparotomy regarding intensity of postoperative pain (Aspinen, Harju, Juvonen, Kokki et al., 2014, Aspinen, Harju, Juvonen, Karjalainen et al., 2014, Aspinen et al., 2016, Harju et al., 2006, Harju et al., 2010, Harju, Aspinen et al., 2013, Harju, Juvonen et al., 2013, Sjövall, Kokki & Kokki, 2015). In fact, in some types of surgery, early postoperative pain can be even more severe after laparoscopy than after laparotomy (Ekstein et al., 2006). Laparotomy can be performed mini-invasively, which may reduce tissue trauma and postoperative pain. In cholecystectomy, for example, minilaparotomy and laparoscopic approaches have been shown to improve recovery compared to conventional open cholecystectomy (Keus, Gooszen & van Laarhoven, 2010). In minilaparotomy, when vertical incisions through the rectus abdominis muscle are used, acute postoperative pain is similar or less compared to laparoscopic approach (Harju et al., 2006, Harju et al., 2010, Harju, Juvonen et al., 2013). Tissue trauma and acute postoperative pain may also be decreased by retracting the rectus abdominis muscle laterally rather than cutting through the muscle (Tyagi et al., 1994).

Over the last three decades, epidural analgesia has been frequently used in major open abdominal surgery and this approach seems to provide appropriate

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early postoperative pain relief in most patients (Gerbershagen et al., 2013, Salomäki et al., 1996). In contrast, after laparoscopy, epidural analgesia is less frequently used, and pain management is often based on non-opioid analgesics and low doses of opioids, therefore, pain may be undertreated (Gerbershagen et al., 2013).

Epidural analgesia is an effective method for managing postoperative pain after major surgery. The analgesic efficacy of epidural analgesia is superior to that of intravenous (i.v.) opioids (Block et al., 2003). Epidural analgesia may also decrease morbidity and mortality after major surgery (Pöpping et al., 2014, Li, Y. W. et al., 2021). Epidural solutions containing local anaesthetics and opioids appear to have better analgesic efficacy than either drug alone (Guay, Nishimori & Kopp, 2016).

Some data indicate that adjuvants (e.g., epinephrine and clonidine) may be useful components in epidural mixtures (Bernard, Kick & Bonnet, 1995, De Kock et al., 1993, Förster, Rosenberg, 2004, Mogensen et al., 1992, Niemi, Breivik, 2002, Paech et al., 1997).

The pharmacokinetics (PK) and pharmacodynamics (PD) of epidural opioids are complex, with large differences between opioids in onset and duration of effects (Bernards, 2004). Thus, the choice of epidural opioid depends on the clinical context. Considering the invasiveness, labour-intensiveness and high cost of epidural analgesia, it is imperative to have empirical data that the drugs administered epidurally actually are more efficacious compared to i.v.

administration of the same compound before implementation to routine clinical use (van Zuylen et al., 2019).

Oxycodone is a commonly used opioid. In Finland oxycodone has been the most used opioid analgesic in postoperative pain management for decades, and during the past two decades, in many countries, the use of oxycodone has surpassed that of morphine (Pain & Policy Studies Group, 2018). Oxycodone is often administered by mouth (per os, p.o.), i.v., subcutaneously (s.c.),

intramuscularly (i.m.), or transmucosally, but data on epidural administration of oxycodone are scarce (Bäcklund et al., 1997, Kokki, H., Kokki & Sjövall, 2012, Kokki, M. et al., 2014, Olczak et al., 2017, Sng et al., 2016, Yanagidate, Dohi, 2004, Zhong et al., 2020). Oxycodone appears to relieve visceral pain more effectively than does morphine and may, therefore, constitute one of the most feasible opioids for abdominal surgery (Kalso et al., 1991, Lenz et al., 2009).

The first aim of the present study was to review the recent literature on the PK and PD of oxycodone. The second aim was to assess the analgesic efficacy of oxycodone after epidural compared to i.v. administration in intra-abdominal

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gynaecological surgery in patients undergoing open surgery and in those undergoing laparoscopic surgery. The third aim was to develop a population PK model for epidural and i.v. oxycodone.

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2 REVIEW OF THE LITERATURE

2.1 PAIN AFTER LAPAROSCOPY

2.1.1 Terminology

The International Association for the Study of Pain (IASP) has recently revised their definition of pain as: “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors. Pain and nociception are different phenomena.

Pain cannot be inferred solely from activity in sensory neurons. Through their life experiences, individuals learn the concept of pain. A person’s report of an

experience as pain should be respected. Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well- being. Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.” (Raja et al., 2020)

Pain has been classified as nociceptive, neuropathic or nociplastic. “Nociceptive pain is pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors.” Nociceptive pain projection is into

damaged part of the body or at a different site but related to spinal segments and referred within a dermatome of painful origin (referred pain). Pain caused by a lesion or disease of the somatosensory nervous system is called neuropathic pain.

In neuropathic pain projection is into innervation area of the body. A third

category of pain, nociplastic pain, has been recently introduced and it is described as “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.” In nociplastic pain. the CNS interpretation of somatosensory information is altered and/or there is a sensitisation in the nociceptive system. This sensitisation can occur at multiple levels including peripheral nerves, spinal cord and brain. (Raja et al., 2020)

However, the three pain types commonly overlap; thus, a fourth category of pain—mixed pain— has been recently proposed. “Mixed pain is a complex overlap of the different known pain types (nociceptive, neuropathic, nociplastic) in any

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combination, acting simultaneously and/or concurrently to cause pain in the same body area. Either mechanism may be more clinically predominant at any point of time. Mixed pain can be acute or chronic.” (Freynhagen et al., 2019)

2.1.2 Mechanisms and consequences of pain after laparoscopy

Pain is a frequent complaint after laparoscopy and. if severe, may impair early convalescence. Severe pain causes detrimental physiological and psychological effects, which may contribute to postoperative complications (Table 2.1). Elevated heart rate increases myocardial oxygen demand, which may lead to myocardial ischaemia and infarction. Surgery of the thorax and abdomen—especially of the upper abdomen — decreases lung volumes and coughing, which,in turn, may lead to hypoxaemia, atelectasis and pneumonia. Acute pain also increases the risk of postoperative ileus and urinary retention. Ambulation may be delayed if pain is untreated and, when combined with the aforementioned problems, prolongs the hospital admission. Moreover, if patients are unable to ambulate, venous stasis of lower extremities may cause deep venous thromboses. Uncontrolled pain

distresses patients and may worsen existing anxiety, depression, fear, insomnia and fatigue. (Bisgaard et al., 2001, Prabhakar et al., 2014)

Severe acute postoperative pain may sensitize the nervous system to subsequent noxious stimuli, which can contribute to development of persistent postoperative pain. Persistent postoperative pain causes morbidity and decreases quality of life on the short and long term. (Glare, Aubrey & Myles, 2019, Kehlet, Jensen & Woolf, 2006, Taylor et al., 2013)

Early pain is often more severe after laparoscopy than after laparotomy (Ekstein et al., 2006, Sjövall, Kokki & Kokki, 2015). Furthermore, some types of laparoscopic surgeries, such as laparoscopic appendectomy (Lintula, Kokki &

Vanamo, 2001), cholecystectomy (Harju, Juvonen et al., 2013, Piirainen et al., 2015), extrauterine pregnancy (Joo, Moon & Moon, 2019), salpingo-oophorectomy and myomectomy (Gerbershagen et al., 2013), are associated with high postoperative pain intensities during the early recovery phase. However, despite severe pain after laparoscopy, no or only low doses of opioids are administered to patients.

Consequently, pain may be undertreated in many cases that exclusively use non- opioid analgesics and non-pharmacological approaches (Gerbershagen et al., 2013).

Acute postoperative pain after laparoscopy has multiple etiologies, with tissue trauma from incision sites being the main origin of pain after laparoscopy.

Nociceptive pain is caused by injury to tissues of the abdominal wall (somatic pain)

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and abdominal organs (visceral pain). Further, if nerves are injured, neuropathic pain can result. Pain after pneumoperitoneum is also multifactorial.

Pneumoperitoneum causes distension of the abdominal wall and irritation of the intraperitoneal cavity, and most patients report shoulder pain if gas remains. The higher the volume of subdiaphragmatic gas, the more severe the postoperative pain the patient may have. Postoperative pneumoperitoneum has been shown to resolve within two days in most patients. Patients with an elevated body mass index (BMI) or a low initial volume of free gas had the shortest duration of pneumoperitoneum. Inflammatory response associated with tissue damage sensitises peripheral and central neuronal structures, which further increases the intensity and duration of postoperative pain in laparoscopy. (Nielsen, K. T. et al., 1997, Sjövall, Kokki & Kokki, 2015, Song, Kim & Lee, 2017)

Different laparoscopic procedures seem to result in substantial variations in postoperative pain. For example, after laparoscopic cholecystectomy, incisional pain usually dominates over visceral pain during early recovery. However, if visceral pain dominates over incisional pain after laparoscopic cholecystectomy, there is an increased risk for persistent postoperative pain (Blichfeldt-Eckhardt et al., 2014). A recent study showed that, unlike after cholecystectomy, visceral pain after laparoscopic hysterectomy (LH) usually dominates over incisional pain during the first 24 h postoperatively. Thereafter, visceral— and especially incisional pain—

decline to lower levels. However, the course of shoulder pain differs developing in 90% of patients after LH. Shoulder pain is most intense at 24 h after surgery and can, thereafter, be more severe than either visceral or incisional pain. Shoulder pain remained fairly constant from 24h postoperatively until the end of the 72-h follow-up and the pain intensity was similar at rest and during movement.

Conversely, visceral and incisional painwere more severe during movement than at rest. Most patients (92%) also had perineal pain during the first 24 h

postoperatively, and in one third of the patients, perineal painwas more severe than abdominal pain and was aggravated by a urinary catheter (Choi, J. B. et al., 2016).

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Table 2.1. Unwanted physiological effects and complications of postoperative pain.

Modified from (Prabhakar et al., 2014, Schug, S. et al., 2020).

2.1.3 Acute pain after hysterectomy

Hysterectomy is one of the most common gynaecological procedures in non- pregnant women worldwide (Kovac, 2014). In Finland, the rate of hysterectomies has been declining since 2002, reaching the rate of other Nordic Countries between 2008–2011 (Jokinen, E. et al., 2015). In 2018, 4700 women underwent hysterectomy in Finland (National Institute for Health and Welfare 2018, b). During the past decades not only the rate of, but also surgical approach used in

hysterectomy has changed; the proportion of abdominal hysterectomy (AH) and vaginal hysterectomy (VH) has declined whereas LH has become more common (Figure 2.1)(Brummer et al., 2009, National Institute for Health and Welfare 2018, b).

Respiratory Inability to cough, reduced lung volumes, sputum retention, atelectasis, ventilation-perfusion abnormalities, hypoxaemia

and infection

Circulatory Tachycardia, increased cardiac contractility and peripheral vascular resistance, increased blood pressure and myocardial

oxygen demand, reduced myocardial oxygen supply, myocardial ischaemia and/or infarction, arrhythmias, altered

regional blood-flow

CNS Exacerbation of postoperative delirium, central sensitization, chronic postsurgical pain

Genitourinary Urinary retention

Gastrointestinal Decreased gastrointestinal motility, ileus, increased risk of bacterial transgression of bowel wall

Neuroendocrine Increased catabolic hormones: glucagon, growth hormone, vasopressin, aldosterone, renin and angiotensin Reduced anabolic hormones: insulin, testosterone Metabolic Hyperglycemia, increased protein breakdown, negative

nitrogen balance, impaired wound healing Musculoskeletal Muscle spasm, immobility, muscle wasting, deep vein

thrombosis

Psychological Increasing anxiety and fear, inability to sleep, demoralisation, a feeling of helplessness, loss of control, and an inability to

think and interact with others

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Figure 2.1. The annual rates of hysterectomies performed in public care in Finland.

Data were obtained from non-psychiatric specialized health care 2018 tables, National Institute of Health and Welfare.

The surgical approach affects postoperative pain, and open abdominal surgery has been recognized as one of the most painful procedures (Ip et al., 2009).

However, epidural analgesia is frequently used in major open abdominal surgery, which may explain why postoperative pain is often deemed mild in these

procedures (Gerbershagen et al., 2013). The surgical technique has been shown to affect acute postoperative pain after hysterectomy also (Aarts et al., 2015)

A recent Cochrane review concluded that the need for analgesics and postoperative pain scores are lower after VH and LH relative to AH (Aarts et al., 2015). However, only a few randomised controlled trials (RCTs) have evaluated postoperative pain as the primary outcome in different surgical approaches to hysterectomy. Two decades ago, a RCT on postoperative pain as the primary outcome reported fewer analgesic requirements and less postoperative pain after laparoscopy-assisted vaginal hysterectomy (LAVH) compared to AH (Ellström et al., 1998). In two more recent studies, the need for pain medication after total

laparoscopic hysterectomy (TLH) or VH was lower than after AH (Miskry, Magos, 2003, Mourits et al., 2010). However, in these trials, postoperative pain was a secondary outcome, and the anaesthetic regimen was not standardised. In a large multicentre trial, pain scores were lower after LH relative to AH. There were no differences in pain scores between LH and VH. However, postoperative pain was a

0 1 000 2 000 3 000 4 000 5 000 6 000 7 000

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Abdominal hysterectomy Laparoscopic hysterectomy

Vaginal hysterectomy Total

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secondary outcome, and the anaesthetic regimen was not standardised (Garry et al., 2004).

When the laparoscopic and vaginal approaches to hysterectomy are compared the results are diverse. Three prospective clinical trials to date have compared postoperative pain and analgesic consumption as primary outcomes between LH/LAVH and VH (Table 2.2). In a randomised prospective trial, pain scores at rest were lower after TLH than after VH. Pain was assessed on a 10-cm visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “unbearable pain”.

Ketorolac and paracetamol were given for background analgesia and morphine 10 mg s.c. was given for rescue analgesia when requested by subjects. Surprisingly, only a few subjects in the LH group (17%) needed rescue analgesics compared to VH group(78%). Dynamic pain was not assessed, and the dose of intraoperative fentanyl were not reported (Ghezzi et al., 2010). These findings were supported by a Finnish clinical trial, in which rescue oxycodone consumption was lower after LH/LAVH compared to VH (20 mg in LH group vs. 23 mg in VH group at 4 h

postoperatively; 24 mg in LH group and 27 mg in VH group at 6 h postoperatively):

in this study, dynamic pain with coughing was assessed, but the study was not randomised (Pokkinen, Kalliomäki et al., 2015). In contrast, a randomised double- blind study found that pain scores on VAS at rest were higher after LAVH than after VH during postoperative days 1–3. On average, pain scores ranged from 1 to 3 in the LAVH group and form 1 to 2 in the VH group on postoperative days 1–3.

Pain scores did not differ on the day of operation. Consumption of piritramide, a strong synthetic opioid, did not differ between groups, (49 mg and 52 mg in LAVH group with and without peritoneal closure, respectively; 46 mg and 48 mg in VH group with and without peritoneal closure, respectively). However, dynamic pain was not assessed, and the difference in pain scores at rest was not clinically relevant (Eggemann et al., 2018).

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Table 2.2. Clinical trials on acute postoperative pain after hysterectomy as primary outcome. Analgesic protocol was standardised in all studies. TLH, total

laparoscopic hysterectomy; VH, vaginal hysterectomy; LH, laparoscopic hysterectomy; LAVH, laparoscopy-assisted vaginal hysterectomy; VH, vaginal hysterectomy; i.v., intravenous; q.i.d., four times a day; s.c., subcutaneous; PCA, patient-controlled analgesia; q.4h, every 4 h; RCT, randomised controlled trial; VAS, visual analog scale.

Variable Study design Intervention Analgesic protocol Outcome

Ghezzi et

al 2010 RCT TLH n=41 vs.

VH n=41

Preoperatively single- dose i.v. ketorolac Intraoperatively i.v.

fentanyl Postoperatively i.v.

paracetamol 1 g q.i.d., rescue analgesia with s.c. morphine 10 mg

Pain scores (VAS) were lower and patients needed

less analgesics after TLH than after VH during

the first postoperative 24

h.

Pokkinen et al 2015

Non- randomised prospective

trial

LH n=74 (TLH n=49 and LAVH n=25) vs VH

n=90

Intraoperatively i.v.

remifentanil and single dose of 0.05 mg i.v.

fentanyl at the end of operation Postoperatively paracetamol 1 g q.i.d.

and i.v. PCA with oxycodone

Cumulative oxycodone consumption was less after LH than after VH at 4-6 h

postoperatively

Eggemann et al 2018

Double- blind, multicenter

RCT

LAVH n=95 vs VH n=97

Postoperatively metamizole 1 g q.4h and

i.v. PCA with piritramide

Pain scores (VAS) were higher after LAVH than after

VH during the first 3 postoperative days. Similar use

of analgesics.

Two meta-analyses have concluded that pain scores are lower after TLH than after VH (Gendy et al., 2011, Sandberg et al., 2017). A meta-analysis of three RCTs comprising 542 patients found that TLH was associated with lower postoperative pain scores (VAS) relative to VH (weighted mean difference [WMD]: –2.1; 95%

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confidence interval (CI) –4.1 to –0.2). However, postoperative pain was a secondary outcome of this meta-analysis, the included studies were heterogeneous and bias could not be tested because of too few trials (Gendy et al., 2011). Another meta- analysis of three RCTs comprising 232 patients found that TLH was associated with lower postoperative pain scores (VAS) relative to VH (WMD –1.1; 95% CI: –1.7 to – 0.4). Again, postoperative pain was a secondary outcome measure of this meta- analysis, and there was evidence of moderate heterogeneity in the included studies (Sandberg et al., 2017). In contrast, a recent meta-analysis of five RCTs comprising 1352 patients found that VH was associated with significantly lower pain scores (VAS) than was LH/LAVH at 24 h after surgery (WMD: –0.53, 95% CI:

−0.70 to −0.35), with low heterogeneity. No differences were found between the two groups on the day of surgery (WMD: 0.80, 95% CI: −0.08 to 1.68) and at 48 h after surgery (WMD: –0.20, 95% CI: −0.61 to 0.22). Postoperative pain was a secondary outcome measure of this meta-analysis and all included studies had a high risk of bias in blinding (Lee, S. H. et al., 2019).

The choice between commonly used general anaesthetic agents, propofol i.v. or sevoflurane inhalation, does not appear to affect need for rescue opioids or pain scores postoperatively (Pokkinen, Yli-Hankala & Kalliomäki, 2014). However, the choice of analgesic technique affects postoperative pain. After laparotomy for gynaecological cancer surgery, postoperative pain may be severe, even if epidural analgesia or i.v. opioid patient-controlled analgesia (PCA) are used. Epidural analgesia provides better analgesia for pain during coughing (Ferguson et al., 2009).

2.1.4 Chronic postsurgical pain after hysterectomy

Chronic pain is defined as pain that persists or recurs for more than 3 months or continues even after the healing of tissue damage despite medication or

treatment (Treede et al., 2015). Chronic pain is classified either as chronic primary pain, which is considered a disease in itself, or as chronic secondary pain, in which pain is symptomatic of an underlying condition. Chronic postsurgical (CPSP) or posttraumatic pain is a subcategory of chronic secondary pain and is defined as

“chronic pain that develops or increases in intensity after tissue trauma (surgical or accidental) and persists beyond the healing process (i.e., ≥3 months)” (Barke, 2019, Schug, S. A. et al., 2019).

CPSP is an increasingly acknowledged complication of surgery (Treede et al., 2015). CPSP was included for the first time in the 11th revision of the International Classification of Diseases (ICD-11), which was adopted by the World Health

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Organization (WHO) in May 2019 and will come into effect in 2022 (World Health Organization, 2021).

Emerging evidence suggests that poorly controlled acute postoperative pain is associated with CPSP (Richebe, Capdevila & Rivat, 2018). CPSP is distressing to patients, increases morbidity and decreases quality of life (Glare, Aubrey & Myles, 2019, Kehlet, Jensen & Woolf, 2006).

CPSP is common after hysterectomy; 10–50% of patients undergoing

hysterectomy for benign indications have persistent pain (Brandsborg et al., 2008, Brandsborg, Nikolajsen, 2018). However, data on CPSP in gynaecological cancer patients are scarce (Hacker, Reynolds & Uppal, 2018). The most consistently reported risk factors for CPSP after hysterectomy are severity and duration of acute postoperative pain, type of hysterectomy, preoperative pain problems in the pelvic region or elsewhere in the body, and psychological factors (Brandsborg, Nikolajsen, 2018).

The prevalence of CPSP appears to be lowest after VH and highest with AH and LH (Brandsborg, Nikolajsen, 2018). In a recent prospective study in Finland, 26% of patients undergoing VH or LH for benign indications had persistent pain six months after surgery. Half of these patients did not have pain before surgery. The severity of pain was mild in most patients and severe in 6.9% of patients. Smoking, severe acute postoperative pain, and laparoscopy were positively associated with persistent postoperative pain (Pokkinen, Nieminen et al., 2015). There were some between individual differences on pain phenotypes reported; persistent pain was neuropathic in nature in over 50% of patients (Pokkinen et al., 2016). Similarly, a prospective study in Denmark found that preoperative pain elsewhere in the body and high intensity of acute postoperative pain were associated with chronic pelvic pain after surgery (Brandsborg et al., 2009).

There are conflicting data on whether CPSP is more common after LH or AH (Table 2.3). A recent systematic review and meta-analysis based on six studies comprising 1041 women indicated that pelvic pain was more common after LH (24.9%) than after AH (11.5%). The prevalence of pelvic pain was similar after subtotal hysterectomy (13.6%) and total hysterectomy (14.4%) (Aleixo et al., 2019).

The prevalence of pelvic pain was the primary outcome in only one of the six studies included in the meta-analysis. In this study (n=59), the prevalence of pelvic pain was similar between subtotal LH (25.0%) and TLH (32.3%) (Berner et al., 2015).

Conversely, a recent prospective cohort study with 406 patients (LH: n=225; AH:

n=181) found similar prevalence rates of CPSP after LH and after AH. Three months after surgery, the prevalence of CPSP was 20.9% in the LH group and

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20.4% in the AH group. Six months after surgery, the prevalence of pain declined to 11.6% in the LH group and to 9.4% in the AH group. At 12 months after surgery, 5.8% in the LH group and 6.1% in the AH group reported persistent pain. A

limitation of their study, however, was that 29.8% of patients in the LH group and 32.0% in the AH group had preoperative pelvic pain and the authors failed to indicate the number of patients in whom chronic pain developed or intensified postoperatively (Jin et al., 2020).

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Table 2.3. Studies on pelvic pain and chronic postsurgical pain after total/subtotal laparoscopic hysterectomy and abdominal hysterectomy. AH, abdominal

hysterectomy; CPSP, chronic postsurgical pain; i.v., intravenous; LH, laparoscopic hysterectomy; PCA, patient-controlled analgesia; RCT, randomised controlled trial;

SAH, subtotal abdominal hysterectomy; SLH, subtotal laparoscopic hysterectomy;

TAH, total abdominal hysterectomy; TLH, total laparoscopic hysterectomy.

Variable Study design Groups Notes Outcome

Berner et

al 2015 Single-blind

RCT TLH (n=31)

SLH (n=31) Analgesic protocol was not described

Primary outcome cyclical pelvic pain

at 12 months postoperatively: no difference between

groups

Aleixo et al

2019 Meta-analysis of six RCTs

TAH n=428 SAH n=424 TLH n=98 SLH n=91

Only one of the six studies (Berner et al 2015) had pelvic pain as a primary

outcome.

Persistence of pelvic pain was

secondary outcome.

Prevalence: TAH 11.9%, SAH 11.1%,

TLH 24.5%, SLH 25.3%

Jin et al 2020

Prospective observational

AH n=181 LH n=225

Analgesic protocol was standardised.

Intraoperatively i.v.

sufentanil and i.v.

parecoxib.

Postoperatively i.v. PCA with tramadol

No difference between prevalence or severity of CPSP between AH and

LH

There are a few data on whether improved acute pain management can

decrease the incidence of CPSP after hysterectomy (Brandsborg, Nikolajsen, 2018).

Interestingly, the data thus far suggest that epidural analgesia could be of benefit to this end. In a case-control study of patients undergoing open abdominal surgery, epidural analgesia was associated with less acute postoperative pain on the day of surgery and on the first postoperative day. CPSP was less frequent at six months after surgery in patients who had epidural analgesia (Bouman et al., 2014).

A small RCT (n=80) in abdominal surgery found improved management of acute postoperative pain and less pain 12 months after surgery with epidural analgesia.

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In that study all patients received i.v. and/or epidural clonidine and i.v. ketamine (Lavand'homme, De Kock & Waterloos, 2005). Whether these data on bowel surgery can be applied to gynaecological surgeries remains unclear. In a

randomised double-blind trial after gynaecological laparotomy (n=141), epidural analgesia improved management of acute postoperative pain relative to patients who received sham epidural and i.v. morphine. Pain disability three weeks after surgery was less in patients who had epidural analgesia, but this benefit was not observed six months after surgery (Katz et al., 2003, Katz, Cohen, 2004).

The potential beneficial effects of epidural analgesia on CPSP have been reported in other types of surgery. A recent Cochrane review of 39 RCTs comprising 3027 patients found that epidural analgesia may reduce the risk of persistent postoperative pain following thoracotomy, caesarean section and breast cancer surgery, yet data regarding abdominal surgery are inconclusive.

(Weinstein et al., 2018)

2.2 EPIDURAL ANALGESIA

Thoracolumbar epidural anaesthesia was first described by Pagés in 1921 and epidural analgesia with morphine was introduced in 1979 by Behar (Behar et al., 1979, Brill, Gurman & Fisher, 2003). In Finland, epidural analgesia has been commonly used in postoperative pain management since the early 1990s

(Salomäki et al., 1996). Nowadays, the main indications for epidural analgesia are major abdominal surgery, thoracotomy and labour (Bos, Hollmann & Lirk, 2017).

Epidural analgesia attenuates the surgical stress response and provides superior analgesic efficacy to i.v. opioid-based regimens in treatment of postoperative pain after major surgery (Block et al., 2003, Pöpping, Zahn et al., 2008, Salomäki et al., 1993, Wheatley, Schug & Watson, 2001, Wu et al., 2005).

Epidural analgesia also improves patient satisfaction and enhances early

postoperative recovery by facilitating mobilization, early food intake and recovery of gastrointestinal function (Ali et al., 2010, Carli et al., 2002). In major surgery, thoracic- and lumbar epidural analgesia with local anaesthetics, with or without opioids, may reduce postoperative mortality and cardiovascular, respiratory, and gastrointestinal morbidity (Pöpping, Elia et al., 2008, Pöpping et al., 2014).

2.2.1 Epidural analgesia in abdominal surgery

After laparoscopic and open abdominal surgery, epidural analgesia reduces the stress response, decreases catabolism, accelerates the recovery of gastrointestinal

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transit, reduces respiratory failure and provides superior analgesia compared to i.v. opioids (Guay, Nishimori & Kopp, 2016, Holte, Kehlet, 2002, Rigg et al., 2002, Sjövall, Kokki & Kokki, 2015). Thoracic epidural analgesia is considered the gold standard in pain control after open abdominal surgery (Feldheiser et al., 2016).

The duration of hospital admission may be shortened after open abdominal surgery when epidural analgesia is used in early phase after surgery for pain management (Guay, Nishimori & Kopp, 2016). In laparoscopic surgery, the use of epidural analgesia must be considered on a case-by-case basis after careful

evaluation of the risks and benefits. Given that patients with epidural analgesia are often bedridden, any prolonged use of epidural analgesia may prolong the

hospital admission after laparoscopic surgery (Sjövall, Kokki & Kokki, 2015).

2.2.2 Epidural local anaesthetics

The most commonly used drugs in epidural analgesia are local anaesthetics and opioids. Numerous adjuvants have also been studied, of which clonidine, an α2- adrenoceptor agonist, and epinephrine are commonly used. (Schug, S. A. et al., 2006)

Local anaesthetics are reversible inhibitors of voltage-gated sodium channels, which are used to block nerve impulses to abolish sensation. After injection into the epidural space, local anaesthetics are considered to act on four levels: the spinal cord, nerve roots, dorsal root ganglia, and spinal nerves. Of these , the nerve roots are considered the primary site of action, despite the fact that

experimental studies on rabbits and sheep show that the cerebrospinal fluid (CSF) bioavailability of epidural local anaesthetics is low (<20%, Table 2.4)(Bromage, 1975, Clement et al., 1999, Clement et al., 2004, Rose et al., 2007). Less attention has been paid on the systemic absorption of local anaesthetics and its effects on pain relief (Weibel et al., 2016).

The long-acting amide local anaesthetics, bupivacaine, levobupivacaine and ropivacaine are commonly used in epidural analgesia (Manion, Brennan, 2011).

Ropivacaine and levobupivacaine have gained popularity in clinical practice

because they are nearly as potent as bupivacaine and less cardiotoxic (Schug, S. A.

et al., 2006).

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Table 2.4. Cerebrospinal fluid (CSF) bioavailability of local anaesthetics after epidural administration. FCSF, CSF bioavailability; tmax-csf, time to maximum concentration in CSF.

Drug Species Fcsf (%) tmax-csf (min) Reference

Lidocaine Rabbit 17.7 7.0 Clément et al 1999

Bupivacaine Rabbit 13.1 6.8 Clément et al 2004

Rabbit 5.5 5.6 Clément et al 1999

Ropivacaine Rabbit 11.3 6.8 Clément et al 2004

Sheep 11.1 12.0 Rose et al 2007

Nerve roots comprise sensory, motor and sympathetic nerve fibres, all of which can be blocked by local anaesthetics. Blocking sensory fibres causes analgesia whereas blocking motor and sympathetic fibres causes adverse effects, such as muscle weakness, urinary retention, and hypotension. However, in thoracic epidural analgesia, sympathetic blockade may actually contribute to reduced gastrointestinal and cardiac morbidity by improving intestinal and myocardial perfusion. (Baldini et al., 2009, Weiss, Pöpping, 2018)

Hypotension is a common adverse effect of epidural local anaesthetics either with or without epidural opioids. Local anaesthetics engender hypotension by blocking sympathetic nerve fibres in spinal nerve roots, which leads to vasodilation and reduced peripheral vascular resistance. Two separate meta-analyses found that the incidence of hypotension was lower when an adjuvant opioid was used but it remained more prevalent than with i.v. opioid-based analgesia (Block et al., 2003, Pöpping et al., 2014). Epidural coadministration of epinephrine and local anaesthetics does not seem to reduce hypotension (Bonica et al., 1971, Tschopp et al., 2018).

Motor blockade of the lower extremities is a common adverse effect of epidural local anaesthetics and may hinder mobilization and impair rehabilitation

(Konigsrainer et al., 2009). The development of motor blockade of the lower extremities is dependent, firstly, on the location of the epidural catheter, because the risk is greater with lumbar catheters than with thoracic catheters (Konigsrainer et al., 2009, Wheatley, Schug & Watson, 2001). Secondly, the dose and

concentration of epidural local anaesthetics affect the risk of lower extremity motor blockade. In patients undergoing lower abdominal surgery with patient- controlled epidural analgesia (PCEA), a lower concentration/higher volume

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coadministration of epidural ropivacaine and fentanyl resulted in comparable analgesia, but less motor blockade than a higher concentration/lower volume admixture of the same drugs. The epidural catheters were inserted in the lumbar or lower thoracic vertebral interspaces (Liu et al., 1999). Another study with patients undergoing gynaecological surgery and PCEA with ropivacaine and fentanyl found that drug consumption required for satisfactory analgesia was lower when a low concentration/high volume admixture was applied (Whiteside et al., 2000). Conversely, in thoracic surgery with high thoracic epidural catheters, no differences in analgesia or adverse effects were found with three levobupivacaine concentrations (1.5, 2.5 and 5 mg mL^–1). A levobupivacaine dose of 10 mg h^–1 and an epidural sufentanil dose of 2.6 µg h^–1 were used in all groups (Mendola et al., 2009).

When only local anaesthetics are used in low thoracic epidurals, motor

blockade of the lower extremities appears dose-dependent rather than dependent on the concentration or volume of the local anaesthetic. After lower abdominal surgery, low thoracic epidural infusion of levobupivacaine (15 mg h^–1) was administered at three concentrations: 1.5, 5, and 7.5 mg mL^–1. Spreading of sensory block was two dermatomes higher, but hypotension and nausea were more common with 1.5 mg mL^–1 levobupivacaine compared to higher

concentration infusions of the same drug (Dernedde et al., 2003). In a similar surgical setting, PCEA with levobupivacaine 15 mg h^–1 background infusion was administered in two different concentrations: 1.5 mg mL^–1and 5 mg mL^–1. No difference in analgesia or adverse effects, including motor blockade of the lower extremities, were noted (Dernedde et al., 2008). The use of PCEA may reduce the dose of epidural local anaesthetic and thereby yield less motor blockade

(Dernedde et al., 2006).

2.2.3 Epidural opioids

Opioids are compounds that bind to opioid receptors, of which there are four subtypes: µ, , , and nociceptin/orphanin FQ opioid peptide receptor (NOP- receptor). Clinically applied opioid analgesics elicit their analgesic effect

predominantly by activating the µ-opioid receptor, and they are usually described as µ-opioid receptor agonists (McDonald J, 2015). In epidural analgesia, opioids are used in combination with local anaesthetics because their combination is more efficacious than either drug alone, especially in dynamic pain, and during

coughing, mobilization, and deep breathing (Block et al., 2003, Wheatley, Schug &

Watson, 2001, Wu et al., 2005).

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Opioid receptors were discovered in nerve tissue in 1973 (Pert, Snyder, 1973, Simon, Hiller & Edelman, 1973, Terenius, 1973). The four opioid receptors were cloned in 1990s and belong to the superfamily of G-protein-coupled receptors (Minami, Satoh, 1995). In the 2010s, the high-resolution crystal structure of the opioid receptors were published, thereby facilitating development of safer novel opioids (Filizola, Devi, 2013).

Yaksh and Rudy (1976) discovered that opioids act directly on the spinal cord (Yaksh, Rudy, 1976). Epidural morphine was introduced in 1979 by Behar and colleagues (Behar et al., 1979). By 1980, opioid receptors were established as being present not only in the brain but also in the substantia gelatinosa in the dorsal horn and in the dorsal root ganglia of the spinal cord (Fields et al., 1980).

Initially, great enthusiasm surrounded epidural morphine, because a single injection could produce long-lasting analgesia without the undesirable effects on motor function that are characteristic of local anaesthetics. However, opioid- related adverse effects, especially late respiratory depression, became a growing concern soon after clinical use in humans began. Thereafter, there was interest in studying other opioids in epidural analgesia (Cousins, Mather, 1984).

Sufentanil and morphine are the two opioids approved for epidural use in Finland, and fentanyl is also commonly used in epidural analgesia (Fischer et al., 1988, Salomäki et al., 1996). After a single injection, the lipophilic opioids (e.g.

sufentanil and fentanyl) have a relatively brief duration of action whereas

hydrophilic opioids (e.g. morphine) have an extended duration of action (Fischer et al., 1988). Both hydrophilic and lipophilic opioids have been administered as continuous infusions, which may result in less respiratory depression with morphine (de Leon-Casasola, Lema, 1996).

Epidural administration of sufentanil and fentanyl have been shown to offer similar analgesia with a lower dose and less adverse effects compared to i.v.

administration (Geller et al., 1993, Guinard et al., 1992, Salomäki, Laitinen &

Nuutinen, 1991, Swenson et al., 1994). However, when sufentanil and fentanyl are used in combination with local anaesthetics, the analgesic effects may be

synergistic (Badner, Bhandari & Komar, 1994, Hansdottir, Bake & Nordberg, 1996, Vercauteren, Meert, 1997). Synergistic enhancement of analgesic efficacy—

particularly in dynamic pain—by combining local anaesthetics with epidural morphine has been demonstrated (Dahl et al., 1992, Kaneko et al., 1994).

Well-known opioid-related adverse effects, such as hypotension, sedation, postoperative nausea and vomiting (PONV), constipation, pruritus, urinary

retention and respiratory depression occur with epidural administration also (van

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Zuylen et al., 2019). Pruritus is more common with the neuraxial route than with other systemic administration routes of opioids (Jannuzzi, 2016). Another

important difference between neuraxial opioids and other systemic administration routes is the risk of late respiratory depression with relatively low doses of

hydrophilic opioids such as morphine. Although recent studies have not found an increased risk for late respiratory depression with epidural morphine compared to other systemic opioids, the potential risk of this severe adverse effect should be kept in mind when hydrophilic neuraxial opioids are used (Sultan, Gutierrez &

Carvalho, 2011).

The adverse effects between epidural opioids can differ; for instance late respiratory depression after epidural morphine is most likely caused by rostral spread of morphine in CSF (Sultan, Gutierrez & Carvalho, 2011). The clearance from the spinal cord and epidural space is more rapid with lipophilic opioids, and epidural fentanyl causes less sedation and respiratory depression than does epidural morphine (Bujedo, Santos & Azpiazu, 2012, Congedo, Sgreccia & De Cosmo, 2009).

When sufentanil and fentanyl are combined with local anaesthetics in thoracic epidural analgesia after major thoracic and abdominal surgery, some studies have found less pruritus, hypotension, urinary retention, and PONV compared to epidural morphine combined with a local anaesthetic (Gianferrari et al., 2001, Kim et al., 2006, Saito et al., 1994). However, not all studies support this discrepancy in adverse effects (Broekema et al., 1998). A recent meta-analysis of 24 RCTs

comparing analgesic efficacy and adverse effects of epidural opioids found that VAS pain scores were similar between morphine, fentanyl and sufentanil. Patients administered epidural morphine consumed slightly less opioid than patients administered epidural fentanyl (1.2 mg of morphine equivalent; 95% CI: 0.27–2.18);

however, this was not clinically relevant. Nausea and pruritus were more common with epidural morphine than with fentanyl. The difference in adverse effects may be explained by cephalad CSF migration of morphine and histamine release caused by morphine (Youssef et al., 2014).

The adverse effects between epidural analgesia and i.v./i.m. opioids also differ.

In two large reviews comprising approximately 120,000 patients, the adverse effects associated with epidural analgesia, i.m. opioid analgesia, and i.v. opioid PCA were compared. Epidural analgesia was associated with less sedation, but urinary retention and hypotension were more common with epidural analgesia than with i.m. opioids or i.v. opioid PCA. Nausea was better alleviated with epidural analgesia than with i.v. PCA (Table 2.5)(Cashman, J. N., Dolin, 2004, Dolin, Cashman, 2005).

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Urinary retention is a common adverse effect of local anaesthetics, and opioids exacerbate the risk of urinary retention, regardless of administration route

(Kowalik, Plante, 2016). Furthermore, adding opioids to epidural local anaesthetics decreases the risk of hypotension (Block et al., 2003, Pöpping et al., 2014).

Pharmacokinetics and efficacy of epidural oxycodone

PANU PIIRAINEN

PHARMACOKINETICS AND EFFICACY OF EPIDURAL OXYCODONE

Dissertations in Health Sciences

PHARMACOKINETICS AND EFFICACY OF EPIDURAL

OXYCODONE

Panu Piirainen

PHARMACOKINETICS AND EFFICACY OF EPIDURAL OXYCODONE

ABSTRACT

TIIVISTELMÄ

ACKNOWLEDGEMENTS

LIST OF ORIGINAL PUBLICATIONS

CONTENTS

ABBREVIATIONS

1 INTRODUCTION

2 REVIEW OF THE LITERATURE

2.1 PAIN AFTER LAPAROSCOPY

2.2 EPIDURAL ANALGESIA