Constipation and pain management after spine surgery and in pregnancy and postpartum

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DISSERTATIONS | MOONA KURONEN | CONSTIPATION AND PAIN MANAGEMENT AFTER SPINE SURGERY AND IN ... | No 656

MOONA KURONEN

Constipation and pain management after spine surgery and in pregnancy and

postpartum

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

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CONSTIPATION AND PAIN MANAGEMENT AFTER SPINE SURGERY AND IN PREGNANCY AND POST-

PARTUM

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Moona Kuronen

CONSTIPATION AND PAIN MANAGEMENT AFTER SPINE SURGERY AND IN PREGNANCY AND POST-

PARTUM

To be presented by permission of the

Faculty of Health Sciences, University of Eastern Finland

for public examination in Auditorium 1, Kuopio University Hospital, Kuopio on Friday, November 26^th, 2021, at 12 o’clock noon

Publications of the University of Eastern Finland Dissertations in Health Sciences

No 656

Department of Anesthesia 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 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 Lecturer Tarja Välimäki, Ph.D.

Department of Nursing Science Faculty of Health Sciences

PunaMusta Oy Vantaa, 2021

Distributor: University of Eastern Finland Kuopio Campus Library

ISBN: 978-952-61-4358-3 (print/nid.) ISBN: 978-952-61-4359-0 (PDF)

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

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Author’s address: Institute of Clinical Medicine, Anesthesiology and Intensive Care

Faculty of Health Sciences, University of Eastern Finland P.O. Box 100

FI-70029 KUOPIO FINLAND

E-mail: moonak@uef.fi

Doctoral programme: Doctoral programme of Clinical Research

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

Institute of Clinical Medicine University of Eastern Finland KUOPIO

FINLAND

Docent Merja Kokki, M.D., Ph.D.

Department of Anesthesia and Intensive Care Kuopio University Hospital

University of Eastern Finland KUOPIO

FINLAND

Reviewers: Professor Perttu Arkkila, M.D., Ph.D.

Department of Gastroenterology Helsinki University Hospital University of Helsinki HELSINKI

FINLAND

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Professor Päivi Polo-Kantola, M.D., Ph.D.

Department of Obstetrics and Gynecology Turku University Hospital

University of Turku TURKU

FINLAND

Opponent: Docent Maija Kaukonen, M.D., Ph.D.

Department of Anesthesia and Intensive Care FIMEA

HELSINKI FINLAND

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7 Kuronen, Moona

Constipation and pain management after spine surgery and in pregnancy and postpartum

Kuopio: University of Eastern Finland

Publications of the University of Eastern Finland Dissertations in Health Sciences 656. 2021, 258 p.

ISBN: 978-952-61-4358-3 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4359-0 (PDF) ISSN: 1798-5714 (PDF)

ABSTRACT

The present study consists of two populations: spine surgery patients and pregnant and postpartum women. Both groups have an elevated risk for constipation and are therefore clinically relevant.

Opioid analgesics are often needed for moderate to severe pain. In addition to the desired analgesic effect, adverse events, such as nausea or constipation, are also mediated via opioid receptors. Opioids reduce intestinal motility when opioid agonists bind to opioid receptors in the gut. Con- stipation is the main symptom of opioid-induced bowel dysfunction and may lead to discontinuation of opioid therapy and elevated pain. Severe pain is associated with suffering and high risk of persistent pain. Both pain and constipation affect life satisfaction and interfere with daily function.

Patients undergoing cervical or lumbar spine surgery were treated at the Kuopio University Hospital, Kuopio, Finland between 2012 and 2014.

Half of the patients were opioid naïve, and half used opioid analgesics before surgery. Patients were randomized to receive either oxycodone (n = 89) or oxycodone-naloxone (n = 88) controlled released tablets for the first seven postoperative days. Patients completed questionnaires concerning bowel function (Bowel Function Index), pain and pain interference (Brief Pain Inventory), and life satisfaction (LS-scale) before surgery at discharge, one week and three weeks after surgery.

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Pain relief was similar with oxycodone and oxycodone-naloxone. Less constipation was associated with oxycodone-naloxone than with oxycodone. There was a carry-over effect of naloxone on bowel function especially evident in opioid-naïve patients up to three weeks after surgery. Be- fore surgery, patients treated with opioids had more pain interference and lower life satisfaction than opioid-naïve patients. Both groups benefitted from surgery, but on-opioid patients were still more dissatisfied with life than opioid-naïve patients at three weeks after surgery. The majority of on- opioid patients were able to discontinue opioid use three weeks after surgery.

Constipation is the second most common symptom in pregnancy, with a prevalence of 40%. Pregnancy hormones, lifestyle changes and dietary supplements contribute to constipation. Constipation is common after delivery also. Some women experience moderate to severe postpartum pain, and opioid analgesics may contribute to constipation.

Pregnant (n = 474) and delivered (n = 406) women were recruited from Kuopio University Hospital and Central Hospital of Satakunta, Pori, Finland between 2012 and 2014. Pregnant women in their second and third tri- mesters were enrolled during their follow-up visits in antenatal clinics, while postpartum women were from maternal wards. Age-matched, non- pregnant, nonlactating control women (n = 200) were members of staff from the two hospitals. Pregnant women were asked about details of gestation and bowel function. Postpartum women were asked about bowel function, and pain and pain management, while parturient records were searched for delivery data and analgesics in the postpartum period. Post- partum women answered the questionnaires twice, a few days and four weeks after delivery. Constipation was assessed using Rome IV criteria, Bowel Function Index and self-report.

The prevalence of constipation based on Rome IV criteria was two to three times more common during pregnancy, 40%, and in early postpartum, 52%, compared to age-matched controls, 20%. Constipation resolved quickly after delivery, and within weeks, prevalence returned to or below that reported by nonpregnant, nonlactating women. All women used opi-

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9 oid analgesics after cesarean delivery and half after vaginal delivery. Post- partum opioids did not affect the prevalence of constipation in vaginally delivered women.

In conclusion, opioid spine surgery patients have more pain interference and lower life satisfaction than opioid-naïve patients. Spine surgery patients, especially opioid-naïve patients, benefit from the oxycodone-naloxone combination in postoperative pain management with regard to constipation. Constipation during pregnancy and early after delivery was two to three times more common when compared to same-aged, nonpregnant, nonlactating women. Constipation resolved quickly after delivery. Postpar- tum opioid use does not increase the risk for constipation in vaginally delivered women.

Keywords: constipation, opioid-induced constipation, spine surgery, preg- nancy, oxycodone, oxycodone-naloxone

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11 Kuronen, Moona

Ummetus ja kivunhoito selkäkirurgiassa sekä raskauden aikana ja synnytyksen jälkeen.

Kuopio: Itä-Suomen yliopisto

Publications of the University of Eastern Finland Dissertations in Health Sciences 656. 2021, 258 s.

ISBN: 978-952-6 -4358-3 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4359-0 (PDF) ISSN: 1798-5714 (PDF)

TIIVISTELMÄ

Tutkimus käsittelee kahta potilasryhmää ummetukseen liittyen; selkäran- kaleikkauspotilaita sekä raskaana olevia ja synnyttäneitä naisia. Molem- milla ryhmillä on kohonnut riski ummetukselle ja tärkeä kliininen merkitys.

Opioideja tarvitaan usein kohtalaisen ja vaikean kivun hoitoon. Opioidit hidastavat suolen toimintaa, mikä voi joskus olla hyödyllinen vaikutus, ku- ten ripulin ja ärtyvän suolen oireyhtymän hoidossa. Opioidien yleisin maha-suolikanavan haitta on ummetus, joka johtuu opioidien sitoutumi- sesta suolen seinämän opioidi- reseptoreihin. Ummetus voi johtaa lääkityk- sen lopettamiseen, joka taas voi johtaa lisääntyneeseen kipuun. Voimakas kipu aiheuttaa kärsimystä ja on yhteydessä kivun pitkittymiseen. Kipu ja ummetus vaikuttavat elämään tyytyväisyyteen ja päivittäiseen toimintaky- kyyn.

Selkärankaleikkauspotilaat olivat Kuopion Yliopistolliseen Sairaalaan suunniteltuun kaula- tai lannerangan leikkaukseen tulevia potilaita vuosilta 2012–2014. Puolet potilaista käytti kivunhoitoon opioidia ennen leikkausta ja puolet eivät. Potilaat satunnaistettiin saamaan joko oksikodonia (n = 89) tai oksikodonin ja naloksonin yhdistelmää (n = 88) seitsemän leikkauksen jälkeisen päivän ajan. Potilaat vastasivat kyselyyn suolen toiminnasta (Bo- wel Function Index), kivun häiritsevyydestä arjessa (Brief Pain Inventory) ja elämään tyytyväisyydestä (LS-asteikko) ennen leikkausta, kotiutuessa, viikko ja kolme viikkoa leikkauksen jälkeen.

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Kivunlievitys oli vastaava oksikodonin ja oksikodoni-naloksonin välillä.

Yhdistelmälääkkeeseen liittyi vähemmän ummetusta. Erityisesti potilaat, jotka eivät käyttäneet opioidia ennen leikkausta hyötyivät yhdistelmälääk- keestä vielä kolme viikkoa leikkauksesta. Molemmat ryhmät hyötyivät leikkauksesta, molempien ryhmien elämään tyytyväisyys parani ja kivun hait- taavuus väheni. Kuitenkin aiemmin opioidia käyttäneet kokivat enemmän kivun haittaavuutta arjessa ja olivat tyytymättömämpiä elämäänsä ennen leikkausta ja leikkauksen jälkeen verrattuna aiemmin opioidia käyttämättö- miin potilaisiin. Suurin osa aiemmin opioideja käyttäneistä pystyi lopetta- maan opioidien käytön kolmen viikon seuranta-aikana.

Ummetus on toiseksi yleisin raskaudenaikainen oire ja siitä kärsii n. 40

% naisista. Raskaushormonit, elintavat ja ravintolisät voivat altistaa ummetukselle raskaudessa ja synnytyksen jälkeen. Osa naisista kärsii hankalasta kivusta synnytyksen jälkeen ja vahvat opioidi-kipulääkkeet voivat altistaa ummetukselle.

Raskaana olevat (n = 474) ja synnyttäneet (n = 406) naiset rekrytoitiin Kuopion Yliopistollisesta Sairaalasta ja Satakunnan keskussairaalasta vuo- sina 2012–2014. Raskaana olevat naiset osallistuivat tutkimukseen neuvo- lakäyntien yhteydessä ja synnyttäneet sairaaloiden synnytysosastoilla. Ei- raskaana olevat ja ei-imettävät kontrolliryhmän naiset olivat sairaaloiden henkilökuntaa. Naisilta kysyttiin suolen toiminnasta, raskauden ja synnytyksen yksityiskohdista. Synnyttäneiltä naisilta tyytyväisyyttä kipulääkkeisiin ja kivunlievitykseen. Synnyttäneet naiset vastasivat kyselyyn kahdesti: muutama päivä ja kuukausi synnytyksen jälkeen. Ummetusta arvioitiin BFI-in- deksin, Rooma IV-kriteerien ja itsearvion perusteella.

Ummetus on kaksi-kolme kertaa yleisempi raskauden aikana ja synnytyksen jälkeen verrattuna saman ikäisiin verrokkeihin. Ummetuksen esiin- tyvyys oli 40 % raskauden aikana ja 52 % muutama päivä synnytyksen jäl- keen, kun taas 20 % verrokkiryhmän naisista kärsi ummetuksesta Rooma IV- kriteerien mukaan. Suolen toiminta palautui nopeasti synnytyksen jäl- keen samalle tai alemmalle tasolle kuin verrokkinaisilla. Kaikki keisarileik- kauksella synnyttäneet ja puolet alateitse synnyttäneistä naisista käytti opioidia synnytyksen jälkeen. Synnytyksen aikana tai ensimmäisinä päivinä

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13 synnytyksen jälkeen käytetty opioidi ei vaikuttanut ummetuksen esiintyvyy- teen alateitse synnyttäneillä naisilla.

Yhteenvetona voidaan todeta, että selkärankaleikkauspotilailla on kohonnut ummetuksen riski. Etenkin aiemmin opioidia käyttämättömät potilaat hyötyvät oksikodoni-naloksoni-yhdistelmästä. Opioidia ennen leikkausta käyttävillä potilailla on enemmän kivun häiritsevyyttä, ja he ovat tyy- tymättömämpiä elämäänsä kuin opioidia käyttämättömät potilaat. Umme- tus on kaksi-kolme kertaa yleisempää raskauden aikana ja synnytyksen jäl- keen kuin verrokkinaisilla. Suolen toiminta palautuu nopeasti synnytyksen jälkeen. Opioidien käyttö synnytyksen yhteydessä ei lisää ummetuksen il- menemistä alateitse synnyttäneillä naisilla.

Avainsanat: ummetus, opioidien aiheuttama ummetus, selkärankaleik- kaus, raskaus, oksikodoni, oksikodoni-naloksoni

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ACKNOWLEDGEMENTS

This work was carried out at the School of Medicine, University of Eastern Finland and Department of Anesthesia and Intensive Care, Kuopio Univer- sity Hospital, during the years 2016–2021. I wish to express my greatest gratitude to my principal supervisor Docent Hannu Kokki. Docent Kokki has kindly encouraged and guided me through this project. He has always found the time to advise me and polish and refine the manuscripts to the next level. He has also thought me to seeks and find answers myself and sharpened my scientific mind. I wish also show my greatest appreciation to my second adviser Docent Merja Kokki, who has shown me an elegant example how to combine clinical work and research. I only wish I could ac- complish the same with equal devotion. I will be forever grateful to my supervisors for the impact you have had on my research career.

I want warmly thank Docent Sari Sjövall of Pori Central Hospital for her contribution and efforts in this research. I wish to express my gratitude also to Professor Leea Keski-Nisula and MD Leena Alanne for their exper- tise in gynecology and obstetrics. I also wish to warmly thank Docent Sakari Savolainen, Docent Toivo Naaranlahti and MD, PhD Timo Nyyssönen for their collaboration in publications I–II. Docent Sari Hantunen from the Insti- tution of Public Health and Clinical Nutrition of University of Eastern Fin- land has offered her knowledge on the dietary aspects of the thesis. Warm thanks to my colleagues MD Kaisu Vesterinen, MD Cesarina Saukko and MD Ira Snellman (nee. Pikkarainen) for collaboration. I wish to thank Pro- fessor Ari Uusaro and Professor Matti Reinikainen for providing excellent research facilities at Institute of Clinical Medicine, Anesthesiology and In- tensive Care.

The reviewers of this work, Professor Perttu Arkkila and Professor Päivi Polo-Kantola, are warmly acknowledged for their effort and constructive comments. I am thankful for their help to improve the thesis. I want to pro- vide the greatest thanks to all parturients who participated in this study.

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I wish to thank my dear friends and family for supporting me on this journey. You have believed in me relentlessly, even if I did not. My parents, Milla and Tapio have always encouraged me to pursue my dreams and raised me to work hard to achieve my goals. I am forever grateful for their love and support. My friends have offered lots of laugh and understanding, which have giving me the strength to finish the thesis. I especially wish to thank my friend and colleague MD Hanna-Mari Tertsunen for sharing all the obstacles and triumphs of the scientific world.

And finally, I wish to thank my love, Eetu for the unwavering love and support. You have solved my technical issues, helped me with figures and charts and poured one cup of coffee after another to keep me focused in my work. You have been a source of comfort and inspiration during this project.

This work was financially supported by the Finnish Cultural Foundation, Helsinki Finland. The foundation is gratefully acknowledged.

Viitasaari, July 2021 Moona Kuronen

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LIST OF ORIGINAL PUBLICATIONS

This dissertation is based on the following original publications:

I Kokki M, Kuronen M, Naaranlahti T, Nyyssönen T, Pikkarainen I, Savo- lainen S, Kokki H. Opioid-Induced Bowel Dysfunction in Patients Under- going Spine Surgery: Comparison of Oxycodone and Oxycodone-Na- loxone Treatment. Adv Ther. 2017;34:236-51.

II Kuronen M, Kokki H, Nyyssönen T, Savolainen S, Kokki M. Life satisfaction and pain interference in spine surgery patients before and after surgery: comparison between on-opioid and opioid-naïve patients.

Qual Life Res. 2018;27:3013-20.

III Kuronen M, Hantunen S, Alanne L, Kokki H, Saukko C, Sjövall S, Vester- inen K, Kokki M. Pregnancy, puerperium and perinatal constipation - an observational hybrid survey on pregnant and postpartum women and their age-matched non-pregnant controls. BJOG. 2021;128(6):1057- 1064.

IV Kuronen M, Keski-Nisula L, Kokki H, Sjövall S, Kokki M. Pain management and constipation after vaginal delivery and caesarean section.

Submitted.

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

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SPINE SURGERY: COMPARISON OF OXYCODONE AND OXYCODONE- NALOXONE TREATMENT ... 109 4.1 Abstract ... 109 4.2 Introduction ... 110 4.3 METHODS ... 111 4.3.1 Statistics ... 114 4.4 RESULTS ... 115 4.4.1 Opioid-naïve group ... 118 4.4.2 On-Opioid group ... 121 4.5 DISCUSSION ... 122 4.6 CONCLUSION ... 126 5 LIFE SATISFACTION AND PAIN INTERFERENCE IN SPINE SURGERY

PATIENTS BEFORE AND AFTER SURGERY: COMPARISON BETWEEN ON-OPIOID AND OPIOID-NAÏVE PATIENTS ... 129 5.1 ABSTRACT ... 129 5.2 INTRODUCTION ... 130 5.3 METHODS ... 131 5.3.1 Questionnaires ... 133 5.3.2 Statistical analysis ... 134 5.4 RESULTS ... 134 5.4.1 Patient characteristics ... 134 5.4.2 Life satisfaction ... 135 5.4.3 Pain interference... 137 5.4.4 Analgesic use and pain relief ... 138 5.4.5 Adverse effects ... 140 5.5 DISCUSSION ... 142 5.6 Conclusion ... 145

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21 6 PREGNANCY, PUERPERIUM AND PERINATAL CONSTIPATION – AN

OBSERVATIONAL HYBRID SURVEY ON PREGNANT AND POSTPARTUM WOMEN AND THEIR AGE‐MATCHED NON‐PREGNANT CONTROLS147 6.1 ABSTRACT ... 147 6.2 INTRODUCTION ... 148 6.3 METHODS ... 149 6.3.1 Questionnaires ... 151 6.3.2 Statistical analysis ... 152 6.4 RESULTS ... 153 6.4.1 Subject characteristics ... 153 6.4.2 Prevalence of constipation ... 156 6.4.3 Prevalence of other symptoms ... 159 6.5 DISCUSSION ... 161 6.5.1 Main findings ... 161 6.5.2 Strengths and limitations ... 161 6.5.3 Interpretation ... 162 6.6 CONCLUSION ... 164 7 PAIN MANAGEMENT AND CONSTIPATION AFTER VAGINAL AND

CAESAREAN DELIVERY – A COHORT STUDY ... 167 7.1 ABSTRACT ... 167 7.2 Introduction ... 168 7.3 Methods ... 170 7.3.1 Parturient and newborn data ... 171 7.3.2 Postpartum pain ... 172 7.3.3 Postpartum bowel function and abdominal symptoms .... 172 7.3.4 Outcome measures ... 173 7.3.5 Statistical analysis ... 173 7.4 Results ... 174 7.4.1 Subject characteristics ... 174 7.4.2 The primary outcome measure ... 174 7.4.3 Bowel function and abdominal symptoms ... 178 7.4.4 Pain management in women during and after vaginal delivery

182

7.4.5 Pain management in women with cesarean delivery ... 183 7.5 discussion ... 183 7.5.1 Main findings ... 183 7.5.2 Strengths and limitations ... 184

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7.5.3 Interpretation ... 185 7.6 Conclusion ... 187 8 GENERAL DISCUSSION ... 189 8.1 SUMMARY ... 189 8.1.1 Constipation and pain in spine surgery ... 189 8.1.2 Constipation and pain in pregnancy and postpartum ... 192 8.2 LIMITATIONS AND STRENGHTS OF THE PRESENT STUDY ... 195 8.2.1 Constipation and pain in spine surgery ... 195 8.2.2 Constipation and pain in pregnancy and postpartum ... 196 8.3 FUTURE DIRECTIONS ... 197 9 CONCLUSION ... 201 REFERENCES ... 203

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ABBREVIATIONS

BBB Blood Brain Barrier BFI Bowel Function Index BMI Body Mass Index BPI Brief Pain Inventory CNS Central Nervous System COX Cyclooxygenase

CYP Cytochrome P450

ERAS Enhanced Recovery After Surgery

GERD Gastroesophageal Reflux Disease

GI Gastrointestinal

IBD Inflammatory Bowel Dis- ease

IBS Irritable Bowel Syndrome IBS-C Constipation Predomi-

nant Irritable Bowel Syn- drome

NBS Narcotic Bowel Syndrome NMDA N-methyl-D-aspartate

NRS Numerical Rating Scale NSAID Non-Steroidal Anti-In-

flammatory Drug OIBD Opioid-induced Bowel

Dysfunction

OIC Opioid-induced Constipa- tion

PCA Patient Controlled Anal- gesia

PROMIS Patient-Reported Out- comes Measurement In- formation System TRPM Transient Receptor Po-

tential Melastatin

TENS Transcutaneous Electrical Nerve Stimulation

USA United States of America VAS Visual Analogue Scale WHO World Health Organiza-

tion

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1 INTRODUCTION

Back pain is a major health burden and leading cause of disability retire- ment in Finland (Pohjolainen et al., 2014). The prevalence of lower back pain is 30% in both sexes, and for neck pain, it is 24% among men and 37%

among women in the Finnish population (Kaila-Kangas, 2007). For a minor- ity of patients with spinal pain, surgery is indicated. Surgery is needed in patients with severe or progressive neurologic deficits and muscular weak- nesses. Spine surgery might also be performed when conservative treatments do not relieve symptoms and the patient’s pain persists and is disa- bling. In Finland, the annual prevalence for cervical spine surgery is

27.6/100 000 and that for lumbar spine surgery is 107/100 000 (Ponkilainen et al., 2020; Kotkansalo et al., 2019).

Patients undergoing spine surgery have an elevated risk for constipation, since back pain often restricts physical activity (Vlaeyen & Linton, 2000), and patients often use opioid analgesics before surgery (Yerneni et al., 2020). Opioid analgesics are also needed for moderate to severe postsurgical pain. Opioid analgesics are advised for short-term use in non- malignant pain only, as there is a risk for dependence and opioid-use disorder in long-term use (Els et al., 2017). The most common adverse events are opioid-induced bowel dysfunction (OIBD), and the most common symptom is opioid-induced constipation (OIC). Constipation is a result of µ- opioid receptor agonists, such as oxycodone, which binds opioid receptors in the enteric nervous system. Tolerance develops for most opioid-related adverse effects over time but not for OIC (Ueberall & Mueller-Schwefe, 2015; Bell et al., 2009; De Schepper et al., 2004).

The prevalence of postoperative constipation after spine surgery varies between studies ranging from 44 % to 89 % (Jing et al., 2019; Stienen et al., 2014). Due to the mechanism of OIC, laxatives are inadequate for a notable proportion of patients (Coyne et al., 2014; Pappagallo, 2001). Peripherally acting opioid-receptor antagonists were introduced for the treatment of

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OIC a decade ago, and they have become increasingly popular. Naloxone is an opioid receptor antagonist that has been used for OIC. A fixed combination of oxycodone and naloxone 2:1 provided better bowel function and equal analgesia compared to oxycodone alone (Mueller-Lissner et al., 2017;

Kuusniemi et al., 2012; Meissner et al., 2009; Simpson et al., 2008; De Schepper et al., 2004). Severe acute postoperative pain should be treated properly, since it is associated with a risk for the development of chronic pain (Kehlet et al., 2006). However, OIC may lead to discontinuation of opioid therapy and may thus affect surgical outcome (Brock et al., 2012).

The birth rate in Finland is low and has declined during the 2010s. In Fin- land 46 000 babies were born in 2019. The cesarean delivery rate in Fin- land is low, 17.5%, compared to other industrialized countries (Kiuru et al., 2020). Gastrointestinal (GI) symptoms are common in pregnant women, of which heartburn and regurgitation, nausea and vomiting are most fre- quently reported (Cullen et al., 2007). Constipation is also common during pregnancy at 40%, and it is most prevalent in the first and second tri- mesters (Bradley et al., 2007; Derbyshire et al., 2006). During pregnancy, a series of physiological changes occur. Increased progesterone concentrations are associated with constipation. In addition, in later pregnancy, a growing uterus may mechanically cause obstruction. Constipation is also common in the postpartum period, with a reported prevalence of 25%. De- livery mode, perineal trauma, and lifestyle factors contribute to constipation after delivery (Zielinski et al., 2015; Cullen et al., 2007; Bradley et al., 2007; Wald, 2003).

Constipation and other OIBD symptoms after vaginal delivery and cesarean section are important to recognize and treat appropriately because symptoms such as bloating and abdominal pain may delay ambulation, and hard stools and straining apply pressure to the surgical wound and may further delay recovery after surgery. Pregnancy itself increases the risk for constipation, and in addition, some women need opioid analgesics after vaginal delivery and most after cesarean delivery (Komatsu et al., 2017). To decrease opioid-related adverse effects, pain medication after vaginal and cesarean delivery should be based on a multimodal approach,

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27 and nonopioid analgesics are often sufficient for perineal pain and post- partal contractions (Wuytack et al., 2021). In severe postpartum pain, epidural analgesia provides efficient pain relief and enhanced bowel function compared to opioid-based analgesia (Anim-Somuah et al., 2018; Guay et al., 2016).

Chronic constipation is a health care and economic burden for society (Dennison et al., 2005). In the Finnish population, 18% of men and 32% of women have constipation. In men in the 30–49 year age group, the prevalence of self-reported constipation was lower, 9–13%, and was slightly higher in the elderly, more than 20%. In women, the prevalence remains quite con- stant across age groups (Koponen et al., 2018).

Opioid analgesics and pregnancy may cause and aggravate constipation.

Severe constipation may cause complications, such as pelvic floor dysfunction (Shin et al., 2015). Pain and severe constipation may substantially affect everyday life, quality of life, and life satisfaction and are thus important top- ics for research.

The main academic aim of this thesis is to determine the prevalence of constipation in spine surgery patients and in pregnancy and postpartum.

Associations of constipation with opioid use were evaluated. Recovery after spine surgery and delivery, and patient satisfaction are also interests of the thesis.

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2 REVIEW OF THE LITERATURE

2.1 SPINE SURGERY IN FINLAND

Spinal disorders are major health and economic burden. Back pain is the leading cause for disability pensions in Finland (Pohjolainen et al., 2014).

Spine surgery may be indicated in case of disc protrusion, spinal canal stenosis, or foraminal stenosis, and for those who conservative treatment fails. Age adjusted incidence for degenerative cervical spine surgery has increased by 34 % in Finnish population between 2000 and 2015, and in 2015 the operation incidence was 31.7/100 000. (Kotkansalo et al., 2019). In lumbar surgery the increase has been even more substantial. In 2015, the incidence for lumbar spine surgery was 103/100 000, whereas the incidence was 53/100 000 in 2000 based on a Finnish register study, an increase of 94

% (Ponkilainen et al., 2020). The direct cost of lumbar spine surgery was 20 million euros in 2005, when approximately 6000 patients underwent lumbar spine surgery in Finland (Pohjolainen et al., 2007). After degenerative cervical spine surgery, 9.2 % of patients underwent late reoperation between 1999 and 2015 in a Finnish national register-based study. The risk factors for reoperation were male gender, young age, and opioid use. The highest risk for reoperation was in the first six years after surgery.

(Kotkansalo et al., 2021).

2.1.1 Recovery after spine surgery

Recovery after surgery, including spine surgery is multifactorial. Genetics, previous surgeries, several physical and psychosocial factors and lifestyle may affect the outcome. Early, at three months, after lumbar spine surgery two thirds of patients are satisfied with surgery outcome (Sinikallio et al., 2007). Disability, young age, depression and severe symptoms are associated with poorer surgical outcome and dissatisfaction with the surgery (Sinikallio et al., 2020; Järvimäki et al., 2015; Sinikallio et al., 2007).

In Toivonen and colleagues’ study, patients benefitted from lumbar spine fusion surgery after five years. Their disability scores had decreased,

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and mental health had improved compared to baseline. However, compared to general population, spine surgery patients had more disability and lower mental health scores at five years after surgery. Nevertheless, patients with depression benefitted from surgery as did the non-depres- sive patients (Toivonen et al., 2021; Toivonen et al., 2020). In a ten-year follow-up study after lumbar spine surgery, previous lumbar spine surgery and smoking were associated with more pain and disability, and the benefit from surgery declined after five years (Tuomainen et al., 2020). Accord- ing to postal survey conducted in Northern-Finland, outcome after lumbar disc operations were more favorable compared to decompressing or stabi- lizing procedures in terms of pain, quality of life and functional capacity (Järvimäki et al., 2015).

Multimodal pain relief is advised after spine surgery as a part of Early Recovery After Surgery (ERAS) -protocol (Wainwright et al., 2016). Acute postsurgical pain should be treated properly, since it is a risk factor for persistent pain. (Kehlet et al., 2006). Pain affects life satisfaction. Life dissatisfaction is associated with depression and poorer surgical outcome (Pakari- nen et al., 2016; Sinikallio et al., 2009).

2.2 LABOR IN FINLAND

Birth rate has been declining in Finland since 2011. Approximately 46 000 babies were born in 2019, and 99.7 % were born alive. Perinatal mortality, the number of stillbirths and deaths in the first week of life, remained low in Finland, 3.9/1000 births. Vast majority of births take place in a publicly funded hospitals, 99.4 % of all births. (Kiuru et al., 2020).

Delivery by cesarean section is becoming increasingly popular worldwide, especially in developed countries. (Delbaere et al., 2012). The rate for cesarean section ranges between countries, and is high e.g. in the United States and United Kingdom, 30% (Roy et al., 2018; MacDorman et al., 2008) and in China, 40 % (Ming et al., 2019). In Finland, the caesarean section rates are lower, cesarean sections covered 17.5 % of all deliveries in 2019, but the rate has increased by time marginally also in Finland. Caesarean sections were performed more often to nulliparous (21.9%) compared to

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31 multiparous (14.3 %) women. (Kiuru et al., 2020). Operative delivery rate is also low in Finland, in 2019 10 % of vaginal deliveries were operative, and vacuum extraction was the most used method.

In Finland different choices for pain relief during delivery are available to all women with no regards to socioeconomic status. (Räisänen et al., 2014).

Epidural analgesia has been increasingly popular worldwide including Fin- land (Kiuru et al., 2020; Anim-Somuah et al., 2018). In Finland half (53 %) of all vaginally delivered women and 76 % of nulliparous women had epidural analgesia, one out of five (20 %) parturient had spinal analgesia and 40 % non-pharmacological pain relief. (Kiuru et al., 2020). In previous studies epidural analgesia was shown to be associated with better pain control and maternal satisfaction, with no effect on cesarean section rates or neonatal outcomes. However, the quality of evidence is low and further studies are needed. (Anim-Somuah et al., 2018). Pain management and satisfaction to pain relief have a great effect on birthing experience and may have long- term effects on mother`s health status (Christiansen et al., 2002). Anxiety, depression and nulliparity are risk factors for fear of giving birth. Fear of giving birth is associated with more pain during delivery and higher cesarean section rates. (Junge et al., 2018; Nieminen et al., 2009; Rouhe et al., 2009).

2.2.1 Recovery after labor

Postpartum pain is more severe after cesarean section compared to vaginal delivery. In Komatsu and colleagues study resolution of pain was 21 days after cesarean section and 14 after vaginal delivery, respectively. (Ko- matsu et al., 2017).

After caesarean delivery surgical incisional pain is most prevalent, but uterine contraction pain may also occur. After cesarean section 20 % of women experience severe postsurgical pain. (Gamez & Habib, 2018; Eisen- ach et al., 2008). Consistent with other abdominal surgeries, intense pain during the first 24 hours after cesarean section is associated with a risk for persistent pain. (Komatsu et al., 2020; Kainu et al., 2016; Eisenach et al.,

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2008). One year after cesarean section 10% of women suffer from persistent pain in surgical wound area. (Weibel et al., 2016).

After vaginal delivery perineum may be bruised or sutured due to perineal tear or episiotomy. Accordingly, in early postpartum period after vaginal delivery 60–90 % of women with perineal trauma suffer from perineal pain. Moreover, perineal pain is persistent in 40 % of women even without surgical trauma one week postpartum (Macarthur & Macarthur, 2004). Per- sistent pain is common also after vaginal delivery. Komatsu and colleagues found that 17 % of women have perineal pain and dyspareunia one year after vaginal delivery (Komatsu et al., 2020).

Pain after delivery is associated with other postpartum symptoms. Post- operative ileus, pain medication and immobilization all increase the risk for bowel dysfunction after cesarean section (Craciunas et al., 2014). Severe post cesarean pain is associated with three-times higher prevalence in postpartum depression and may delay mother`s recovery. Severe pain after childbirth has negative effect on the early bonding between mother and newborn (Yamada et al., 2021; Niklasson et al., 2015; Eisenach et al., 2008).

Enhanced recovery after surgery (ERAS) model is standardized, operative care program to enhance both clinical and health care system benefits (Gustafsson et al., 2012). This model is widely used in surgical setting, and recently also in cesarean section (Mullman et al., 2020). There is high quality evidence on the benefits of perioperative nutrition care and moderate evidence on multimodal postoperative analgesia and prevention for nausea and vomiting concerning recovery after cesarean section. Among other interventions, e.g., chewing gum is one of the methods to improve bowel function after caesarean section (Macones et al., 2019; Craciunas et al., 2014).

2.3 GASTROINTESTINAL FUNCTION 2.3.1Normal gastrointestinal function

Gastrointestinal system provides digestive, absorptive, storage, immunological and neuroendocrine functions. GI-tract begins in mouth and ends in rectum. Human GI-system is presented in Figure 1.

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33 Figure 1. Human GI-system.

Mouth and esophagus

Nutrient digestion starts in mouth. Saliva contains amylaze-enzyme, which start to digest carbohydrates. Teeth grind the foods, so the digestion surface is greater, and the foods are easier to swallow. Swallowing can be divided into three stages: oral, pharyngeal, and esophageal stage (Matsuo et al., 2009; Goyal et al., 2008). Esophagus is approximately 25 cm long muscular tube and its function is to transfer the foods from pharynx to stomach. Esophagus consists of upper esophageal spinchter (UES), esophageal body and lower esophageal sphincter (LES). The cervical esophagus is com- posed of striated muscle and the thoracic part of smooth muscle. The autonomic nervous system and especially vagus nerve generate the peristaltic movements of esophageal muscles. LES opens as the peristaltic wave begins in pharynx and closes as the peristaltic wave reaches the end of esophagus. LES has a major role in preventing esophageal reflux (Matsuo et al., 2009; Goyal et al., 2008).

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34 Stomach

Stomach is a letter J shaped muscular sack between the esophagus and du- odenum. Stomach has several functions including storage and mechanical and chemical degrading of foods. Stomach consists of four anatomic parts:

cardia, body, antrum, and pylorus. Pyloric sphincter consists of smooth muscle and controls stomach emptying. Peristaltic waves push the chyme trough the pylorus to small intestine. (Soybel, 2005). Stomach mucosa`s epithelial lining consists of mucosal cells that secrete alkaline mucus needed to protect the stomach from acid gastric juice. In addition to these mucosal cells, there are three other kinds of secretory cells in stomach epi- thelium: parietal-, chief- and endocrine cells. Parietal cells produce hydro- chloric acid (HCl) creating a low pH to the gastric juice and intrinsic factor, which is needed for absorption of vitamin B12 in small intestine. Chief cells secrete proenzyme pepsinogen, which is converted to active pepsin. Pepsin degrades amino acids into smaller peptides. Endocrine cells secrete various hormones including gastrin, pepsinogen, secretin, histamine, and serotonin. Secretion of gastric juice is a result of complex coordination of hormonal and neural factors. Autonomic, enteric and central nervous systems (CNS) are all involved in exenteration of the stomach (Hunt et al., 2015;

Schubert 2011).

Small intestine

Small intestine is 5–6 meters long, and most of the digestions and absorption occurs is small intestine. The small intestine can be divided to duode- num, jejunum and ileum. Plicas of the membrane, circular plicas that pro- trude the lumen, which are covered with villas, all multiple the absorption surface of the small intestine. Most of the nutrients are absorbed in the du- odenum or jejunum. However, vitamin B12 and bile acids are absorbed in ileum, at the end of small intestine. Peristaltic movements of small intestine stir and move the chyme along the gut. (Volk & Lacy, 2017). The digestive system is innervated by CNS and enteric nervous system together. En-

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35 teric nervous system consists of myenteric and mucosal plexus, located between circular and longitudinal smooth muscle layers (Rao & Gershon, 2016; Furness et al., 2014). Parasympathetic systems increase gut motility, secretion and absorption, whereas sympathetic systems inhibit these functions (Rao & Gershon, 2016). Pancreas produce enzymes needed to digest the nutrients into absorbable form (Volk & Lacy, 2017).

Small intestine has an important role in both congenital and acquired immune system. Healthy gut membrane serves as a filter that allow the nutrients and certain other molecules to pass through, but prevents absorption of harmful agents, such as viruses, bacteria or other genetically

strange material. There are tight junctions between epithelial cells and specific transporting proteins and ionic channels that act as a barrier between the gut lumen and the rest of the organ system (Habtezion et al., 2017;

Lynch & Pedersen, 2016). Most of our lymphocytes are located in the small intestine and they have a substantial role in acquired immune system. Ac- quired immune system is adaptable, since T- and B-cells may develop specific antibodies to specific antigens and moderate the inflammatory re- sponse. Important feature of acquired immune systems is the ability to create antigen-specific memory-cells. (Habtezion et al., 2017; Lynch &

Pedersen, 2016).

Colon and rectum

Colon consists of cecum, ascending colon, transversal colon, descending colon and sigmoid. At the junction of ileum and caecum, there is a valvula Bauhini, which doses the intestinal content onwards to colon. Colon is 1.3–

1.6 meters long and colon muscles are circular, and the longitudinal muscle is divided into three separate strings, called taenia coli. Rectum is 15 cm long, lowest part of colon located retroperitoneally. Rectum ends in anal canal and anal sphincters. Inner of the two sphincter muscles is involuntary and the outer sphincter consists of striated muscle and is under voluntary control (Andrews & Storr, 2011; Irving & Catchpole, 1992).

Colon has three kinds of functions discovered via radiological imaging:

retrogradial motor function, segmentation, and mass peristaltic function.

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Colon absorbs most of fluids and electrolytes. Rectum and anal sphincters control continence and defection when it is timely or socially convenient.

Pelvic floor muscles and relatively steep 90° angle between rectum and anal canal, the anorectal angle, are important maintaining continence. (An- drews & Storr, 2011; Irving & Catchpole, 1992).

2.3.2Gastrointestinal dysfunction

In this following section the most common GI-symptoms are discussed.

Many diseases, medication, physiological stage such as pregnancy, or other factors may cause GI-dysfunction. Gastrointestinal complaints are common cause for seeking medical attention. Constipation is the main subject of this thesis, and it is thoroughly discussed in chapter 2.4.

Gastroesophageal reflux disease

Esophageal reflux is a condition, where content of the stomach revisits the lower esophagus. This reflux occurs in healthy subjects also, but when the reflux causes tissue damage to esophagus or cause notable symptoms, it is determined as gastroesophageal reflux disease (GERD). The pathophysiol- ogy of GERD is multifactorial, dysfunction of LES, diaphragmatic hernia or individual sensitivity to acid reflux in esophageal surface all affect the clinical stage (Rai et al., 2001). Typical symptoms include heartburn and regurgitation, there may also be extraesophageal symptoms such as cough, dys- phagia or asthma (Richter et al., 2018; Sidhwa et al., 2017). The prevalence of reflux disease is 9–26 % in Europe, but the prevalence varies a lot between studies, since the absence of standard diagnostic criteria (El-Seraq et al., 2014). Genetics and lifestyle affect the pathogenesis. Obesity, genetics, and western lifestyle seem to be a risk factor for reflux disease (Nirwan et al., 2020; Locke et al., 1999). Patients with GERD have more often other functional GI-disorders, such as irritable bowel syndrome (IBS) or functional constipation than individual without GERD (Jung et al., 2007).

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37 If alarming symptoms, such as weight loss, difficulty to swallow, anemia, or vomiting, are absent, treatment-experiment with proton pump inhibitors may be performed. However, if there are any alarming symptoms gas- troscopy is indicated (Gyawali et al., 2018; Mössner, 2016).

Abdominal Pain

Abdominal pain is one of the most common reasons for seeking medical attention. Acute abdominal pain in characterized as severe and novel symptom with a duration less than 72 hours. Acute abdominal pain op- poses a challenge for physician, since the cause may be life-threatening at worst or perfectly banal at best. Most causes for acute abdominal pain are surgical, such as appendicitis, cholecystitis, pancreatitis, bowel obstruction, or diverticulitis. Gynecological infections and other causes such as extrauterine pregnancy, adnex torsion, or endometriosis must be taken into consideration concerning women and testis torsion may cause acute abdominal pain in young males (Flasar & Goldberg, 2006). In addition, many endocrine or infectious diseases may cause abdominal pain. Common causes for acute abdominal pain are presented at Table 1.

Thorough patient history and symptom characteristic as well as clinical status, blood parameters and radiological imaging are often needed to de- terminate the diagnosis. Patient´s vital signs are indicator for urgency. Tak- ing the patient history, medications, illnesses, history of abdominal pain, surgeries, timely development, and relation to food intake, needs to be taken into consideration. Vomiting is an important symptom, as it may revel bowel obstruction. In physical examination measurement of vital signs, abdominal palpation and rectal examination are important (Gans et al., 2015; Flasar & Goldberg, 2006).

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Table 1. Common causes for acute abdominal pain.

Surgical Appendicitis

Cholecystitis Pancreatitis Ileus Perforation Testis torsion

Gynecological Extrauterine pregnancy

Adnexal torsion Myoma

Endometriosis

Pelvic Inflammatory Disease

Metabolic Diabetic ketoacidosis

Uremia

Hemochromatosis Addison`s crisis

Infectious Gastroenteritis

Hepatitis Diverticulitis

Inflammatory Bowel Disease Pyelonephritis

Urological infection: prostatitis, orchitis Herpes Zoster-infection

Referred Cardiac ischemia

Pneumonia Pneumothorax Pericarditis

Renal stone, urolithiasis Congestive heart failure

Immunological Angioneurotic edema

Polyarteritis nodosa Henoch-Schönlein purpura Allergies

Eosinophilic gastroenteritis, colitis or enteritis

Ischemic Atherosclerosis

Thromboembolism Vein thrombosis

Other Abdominal migraine

Anxiety, depression

Nonspecific abdominal pain

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39 Diarrhea

Diarrhea is characterized by increased stool frequency to at least three stools per day, and/or loose stools. For diagnostics purposes, diarrhea is often characterized as bloody or watery stools. If the duration of diarrhea is less than two weeks, it is referred as acute, and four weeks or longer it is referred as chronic. (Fine & Schiller, 1999). Etiology for acute diarrhea is often infectious, whereas etiology of chronic diarrhea heterogeneous. Thor- ough patient history, used medications, illnesses, changes in diet, family history of bowel diseases and travel history are important ques unraveling the diagnosis. Laboratory parameters, physiological status are diagnostic tools, and radiological imaging or endoscopy are indicated in some cases (Schiller et al., 2014; Corinaldesi et al., 2012).

There are multiple mechanisms to diarrhea. In osmotic diarrhea poorly absorbable bowel consistence, for example artificial sweeteners or defect in lactose absorption in lactose intolerance, lead to retention of water, secretion of electrolytes, and changed intestine`s filter capacity. Secretory diarrhea is often caused by inflammation or infection and changed balance of GI-hormones and electrolytes (Corinaldesi et al., 2012). Motility disorders may be primary such as IBS or secondary caused by radiation treatment for cancer or inflammatory bowel disease (IBD) for example (Schiller et al., 2014). Fatty diarrhea may be a result of bowel malabsorption, such as celiac disease, or maldigestion related to exocrine pancreatic insuffi- ciency (Corinaldesi et al., 2012).

Most common causes for acute watery diarrhea are different infection, such as food poisoning or gastroenteritis. Although, some bacteria, for example enterohemorrhagic Escherichia coli, Campylobacter or Shigella, among others, may manifest as watery or bloody stools. Acute diarrhea is often self-limiting (Corinaldesi et al., 2012). Chronic diarrhea may be or- ganic origin, such as celiac disease, lactose intolerance, hyperthyroidism, chronic pancreatitis, IBD or functional. Chronic bloody diarrhea often leads to diagnosis of IBD. Bleeding polyp or tumor in the gut may also manifest as bloody stools. Differential diagnosis for IBD include ischemic and radiation colitis (Corinaldesi et al., 2012).

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Irritable Bowel Syndrome

Irritable bowel syndrome is characterized as abdominal pain, change in bowel function and bloating. IBS is common GI-disorder with the prevalence of 5–10% in most European countries (Lovel et al., 2012). Prevalence of IBS varies a lot between countries and diagnostic criteria. In recent study by Oka and colleagues the prevalence of IBS according to Rome III-criteria was 9.2% whereas using Rome IV-criteria it was 3.8% (Oka et al., 2020). In Finland the prevalence of IBS is similar, 5.1 % based on Rome II-criteria (Hil- lilä & Färkkilä, 2004). Multiple risk factors for IBS have been identified, among others, female sex, young age, prolonged GI infection, lower socioeconomic status, and psychological stress (Enck et al., 2016).

Irritable bowel syndrome has a substantial impact on quality of life. Pa- tients with IBS suffer more often from other GI-syndromes, such as GERD, dyspepsia or pelvic floor dysfunction and extra-GI disorders, such as overactive bladder, fibromyalgia, migraine and higher prevalence of anxiety and depression (Enck et al., 2016; Yarandi et al., 2010; Hillilä et al., 2007;

Whitehead et al., 2007).

The exact etiology of IBS is yet unknown, but combination of secretory and motility disturbances has been proposed. Various factors have a role in pathogenesis, including gut microbiome, immune responses, intestinal permeability, sensitivity of gut enteric nervous system and the gut-brain axis. Despite the similar clinical appearance, IBS may be a very heterogenic state, resulting from different pathogenetic origins (Enck et al., 2016).

Table 2. Rome IV diagnostic criteria for irritable bowel syndrome (Rome-or- ganization, 2016).

Recurrent abdominal pain on average at least 1 day/week in the last 3 months, associated with two or more of the following criteria:

1. Related to defecation

2. Associated with a change in frequency of stool 3. Associated with a change in stool form

Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

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41 Irritable bowel syndrome is diagnosed by symptoms. The diagnostic criteria for IBS according to Rome IV-criteria are presented in Table 2 (Rome- foundation, 2016). IBS can be divided into constipation predominant (IBS- C), diarrhea predominant, and combination forms of IBS. IBS diagnosis is based on symptoms and Rome IV-criteria. However, in diarrhea-predominant IBS celiac disease and IBD should be excluded, and in constipation predominant IBS hypothyroidism and hypercalcemia rolled out. If alarming symptoms are present endoscopy is justified (Enck et al., 2016).

Specific treatment for IBS is not established. Treatment of IBS include managing the symptoms, patient education and support. For a substantial proportion of patients with mild symptoms, dietary and lifestyle counselling, such as low fermentable oligo-di-monosaccharide and polyol -diet, and patient support is sufficient (Enck et al., 2016; Moayyedi et al., 2015).

Some patients experience still moderate to severe symptoms and pharmacological and therapeutic approaches are needed. In diarrhea-predominant IBS symptoms can be successfully treated with µ-opioid agonist loperamide. On the other hand, in IBS-C, opioid-antagonist naloxone had no effect on abdominal pain, bloating or straining. Some studies indicate that k-opioid receptor antagonists relieve abdominal pain and bloating.

Further studies are needed to determine the feasibility to treat IBS-C with opioid antagonists (De Schepper et al.,2004; Hawkes et al., 2002; Dapoigny et al., 1995). Dietary fibers are recommended to treat IBS. In IBS-C soluble fibers may alleviate the symptoms, but insoluble fibers may intensify bloating and abdominal discomfort (Ford et al., 2014). Antispasmodic drugs, menthol and peppermint decrease visceral pain sensation and act as a smooth muscle relaxant relieving abdominal pain and discomfort (Chum- pitazi et al., 2018; Kim et al., 2016). Sometimes low-dose antidepressants, especially selective serotonin uptake inhibitors or cognitive behavioral therapy may be valuable option, if the patient is refractory to antispasmod- ics and dietary changes and symptoms persists (Enck et al., 2016; Fukudo et al., 2015).

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Opioid-induced gastrointestinal symptoms

Opioid analgesics are often needed for pain management in acute trauma or postsurgical pain and in chronic pain among cancer patients and in palli- ative care. Opioids may be used in acute abdominal pain in children and adults, since NSAID is often contraindicated and paracetamol insufficient (Kokki et al., 2005). The intended effect of opioids, analgesia, and adverse events are mediated through opioid receptors. Opioid-associated adverse effects are common, most concern of which are sedation, dizziness, respir- atory depression. Opioids have several adverse effects concerning GI-tract, such as constipation, GERD, abdominal pain and cramping, bloating and nausea. These events are referred as OIBD (Kong et al., 2020; De Schepper et al., 2004). Opioid-induced constipation is discussed further in chapter 2.4.6.

Endogenous opioids and exogenous opioids, such as oxycodone or morphine bind to G-protein mediated opioid receptors. There are four main families of endogenous opioids: β-endorphins, encephalins, dynorphins, and nociceptin/orphanin. These endogenous opioids bind to δ-, k-, and µ- and nociceptin- receptors (Corder et al., 2018). Endogenous opioids have several effects on gut motility and function. Opioid receptors are widely distributed among central and peripheral nervous system. µ-opioid receptors are rich in myenteric and submucosal plexuses in addition to spinal cord and CNS. Opioid effects on GI-tract include reduced gut motility and visceral nociception. δ-receptors are rich in CNS and myenteric plexus and delay GI-transit. k-receptors are mainly located in myenteric plexus and they delay GI-transit and decrease visceral nociception. (De Schepper et al., 2004).

Endogenous opioids have only little effect on esophageal motility or gastric emptying. (Narducci et al., 1986). Exogenous opioids delay gastric emptying by increasing pyloric tone and gastric relaxation. This delayed gastric emptying increases the risk for GERD. Opioids are known to increase contraction of sphincter of Oddi, reducing bile acid duct emptying, and therefore may cause biliary colitis, acute pancreatitis and abdominal discomfort (Kim et al., 2020; Pappagallo, 2001).

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43 Morphine and other opioid analgesics decrease colon transit in small intestine. Delayed transit in small intestine can affect absorption of orally ad- ministered medication. In colon, transit is substantially delayed and therefore content-mucosa contact is longer resulting in increased absorption of fluids causing constipation, bloating and abdominal distension (Pappagallo, 2001). Opioid agonist loperamide is used to treat diarrhea by exploiting this reduction of colon transit (Wingate et al., 2001). Opioids increase the anal sphincter tone and may impair the ability to evacuate stool (Mueller- Lissner et al., 2017; De Schepper et al., 2004; Pappagallo, 2001).

Nausea and emesis are very common complaints in opioid-therapy.

They are believed to be mediated via CNS. Experimental data show that Neurokinin-1 receptors located in the floor of fourth ventricle, in the area postrema, are involved in opioid-induced vomiting. The serotonin type 5 antagonists are effective in treatment for opioid-induced nausea suggest- ing role of area postrema in humans too. Peripheral effects discussed ear- lier may also attribute to experience of nausea (De Schepper et al., 2004).

Less common adverse event of opioid analgesics is narcotic bowel syndrome (NBS). NBS is characterized by increasing abdominal pain associated with opioid treatment, with the prevalence of 5 %, respectively. Opi- oid-induced abdominal pain is often treated with more opioids, which in turn may intensify pain (Kong et al., 2020). The mechanism of NBS is un- clear. Proposed theories include opioid-induced sensitization and development of tolerance (Kong et al., 2020; Keefer et al., 2016). The primary treatment for NBS is gradually decreasing the opioid amounts. However, this is clinically challenging, since reduction of opioids often lead to increasing pain. Solid doctor-patient relationship is the cornerstone of successful treatment in NBS. Tricyclic antidepressants and serotonin uptake inhibitors are proven to be beneficial treating NBS. Serotonin uptake inhibitors have fewer adverse events compared to tricyclic antidepressants, but they may cause constipation in some patients. For withdrawal symptoms after opioid cessation, benzodiazepines or clonidine may be used (Kong et al., 2020).

There are validated questionnaires for diagnosis of OIC, such as bowel function index (BFI), but there are no specific diagnostic tools for OIBD (Mueller-Lissner et al., 2017).

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For treatment of OIBD in addition to decreasing opioid doses if possible, fiber-supplements, prokinetics, and peripheral opioid-antagonists have been suggested. Dietary changes and fiber may alleviate constipation and regulate bowel movement, but the effect on upper GI-disorders is modest.

Prokinetics, such as bisacodyl and sennosides stimulate secretion and they may be effective in more oral segments of the gut. Opioid related GERD is often treated with proton pump inhibitors, although there are no therapeutic trials available. Peripheral opioid-receptor antagonists, such as naloxone or alvimopan relief the symptoms of OIC and OIBD (Mueller-Lissner et al., 2017; Meissner et al., 2009).

Gastrointestinal symptoms in pregnancy

Pregnancy is associated with multiple changes in GI-tract. Gastrointestinal complaints are very common, and most women experience at least one pregnancy-related GI- symptom. These symptoms are part of a normal pregnancy and usually conservative treatments are adequate. However, they can cause substantial stress and discomfort (Zielinski et al., 2015).

Many hormonal and mechanical changes attribute to development of GI-symptoms. Increased pregnancy hormones, estrogen and progesterone have multiple effects. Progesterone inhibits the smooth muscle contractions, which is beneficial as it prevents the uterus from contracting, but progesterone also relaxes smooth muscle in the GI-tract. This increases the risk for GERD, as the LES relaxes, gastric and gallbladder emptying delays.

Transit time through the colon increases causing constipation. Increased estrogen vasodilates blood vessels and softens connective tissue; these al- terations may increase the risk for hemorrhoids. Constipation during pregnancy and postpartum are also major risk factors for hemorrhoids (Ziel- inski et al., 2015).

Growing uterus increases abdominal pressure and pushes the pelvic or- gans upward. Thus, mechanical pressure of colon may also increase constipation (Wald, 2003).

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45 Nausea is the most common GI- symptom in pregnancy, as 50–80 % of women experience nausea and 50% vomiting during pregnancy, most com- monly at the early stages, from 4^th to 6^th gestation weeks up until 20^th gestation weeks (Miller, 2002). The mechanism for nausea and vomiting in pregnancy is not fully understood. Delayed gastric emptying, increased progesterone concentrations, delayed small bowel transit, and multiple psychosocial factors have a role in pathogenesis (Body & Christie, 2016;

Matthews et al., 2015). Hyperemesis gravidum is a rare and severe form of nausea and vomiting with a prevalence of 1.3 % in Finland (Nurmi et al., 2020). In treatment of nausea and vomiting non-pharmacological methods are primary, including patient counselling and lifestyle modifications. Small, frequent meals and adequate fluid intake to prevent dehydration are key (Body & Christie, 2016; Matthews et al., 2015). Antiemetics should be pre- scribed with caution before 12^th to 14^th weeks of gestation (Zambelli- Weiner et al., 2019).

The increased presence on estrogen and progesterone leads to relaxation of LES and increased the risk for dyspepsia and GERD. Delayed gastric motility is also contributing factor. The prevalence of GERD is reported to be between 40 and 80 % (Body & Christie, 2016; Zielinski et al., 2015). Man- agement of symptoms include small proportions and frequent meals, ele- vation of head of bed and increased physical activity (Body & Christie, 2016; Zielinski et al., 2015). If pharmacological treatments are needed, they should be initiated after the first trimester and the first choice of drugs are antacids, which are generally considered safe, with the exception of mag- nesium trisilicates and sodium bicarbonates that may induce metabolic al- kalosis (Richter, 2005).

Constipation is the second most common GI-symptom in pregnancy and is discussed further in chapter 2.4.8.

There is limited data on diarrhea in pregnancy. Most common causes for acute diarrhea in pregnancy are infections, similar to non-pregnant healthy individuals. Causes for persistent diarrhea are IBS, IBD, food intolerance or malabsorption. The diagnostics do not differ greatly from the diagnostic paths of non-pregnant groups, although in pregnancy colonos- copy is performed only with strong indication, and preferably during the

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second trimester (Body & Christie, 2016; Savas, 2014; Bonapace et al., 1998).

2.4 CONSTIPATION

Constipation is a common GI-disorder, which is characterized by infrequent bowel movements, hard or lumpy stools and incomplete bowel evacuation.

Prevalence of constipation in adult population is 16% (Costilla & Foxx-Oren- stein, 2014, Mugie et al., 2011). The prevalence increases with age, 33% of people aged over 60 years suffer from constipation. Bowel movement have a large variation in average population, normal defecation frequency may vary from three times a day or three times a week (Mitsuhashi et al., 2017).

Women are more likely to have constipation than men do, and constipation is more common in lower socioeconomic groups. (Mugie et al., 2011).

According to FinHealth study in 2017, self-reported prevalence of constipation in fertile-aged women (aged 18–49) was 1.3 % (daily constipation) and 27 % (less than daily constipation) during the past month. Among the same-aged men the figures were 0.5 % (daily constipation) and 13 % less than daily constipation (Koponen et al., 2018).

Constipation is not only a discomfort, but also a heath care and economic burden (Dennison et al., 2005). Constipation is often perceived as a minor and easily treated inconvenience. However severe and chronic constipation may lead to complications such as fecal- and urinary incontinence, pelvic organ prolapse or an overactive bladder (Shin et al., 2015).

These complications require medical attention and thus increase hospitali- zation and health care costs. Constipation can also have a negative impact on quality of life (Dennison et al., 2005). Paying attention to prevention and treatment, of direct and indirect constipation-related health care costs can be reduced and patients` life quality improved.

2.4.1Primary constipation

Constipation can be divided into primary and secondary constipation (Fig- ure 2). Primary constipation is further divided into three types: functional,

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47 defecatory disorders and slow transit-constipation (Costilla & Foxx-Oren- stein, 2014). Functional constipation is diagnosed by Rome IV-criteria (Lacy et al., 2016). The Rome IV criteria is discussed further in chapter 2.2.4. It is notable, that IBS-C is a separate condition from functional constipation and often characterized by abdominal pain and change in stool frequency and/or form. (Rome-organization, 2016; Longstreth et al., 2011). However, 90% of patients with IBS-C, also fit the criteria for constipation, and 44%

vice versa (Wong et al., 2010).

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Figure 2. Types of constipation. NSAID= non-steroidal anti-inflammatory drug, MAO= monoamine oxidase inhibitor.

Defecatory disorder is also known as pelvic floor dysfunction or outlet dysfunction. Patients suffering from defecatory disorder have difficulty to expulse stool from rectum. Defecatory disorder may result from reduced rectal pulsative forces or increased resistance. Increased resistance may be due to high anal resting pressure or paradoxical contraction/relaxation of pelvic floor musculature and external anal sphincter. (Bharucha et al.,

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49 2020; Rao et al., 2016). There are number of related conditions such as reduced rectal sensation, rectocele or perineal descent that may be primary or secondary to constipation and further complicate the situation.

(Bharucha, 2020; Prichard et al., 2017). Over time, extensive straining may impair the pudendal nerve and weaken the pelvic floor, increasing the risk for complications, such as urinary or fecal incontinence, perineal descent and pudendal neuropathy. (Bharucha et al., 2020; Snooks et al., 1985).

Slow transit time constipation is characterized by prolonged (over 72 hours) colon transit time. Isolated slow transit constipation may precede colonic motor disorder(s), due to reduction of Cajal cells in GI-track and reduction of colonic intrinsic nerves. (Bharucha & Lacy, 2020; He et al., 2000).

Cajal cells act as a pacemaker of the gut. Patients with slow transit constipation have decreased volume of intestinal Cajal cells compared to healthy individuals (Tong et al., 2004; He et al., 2000). Cajal cells are presented in Figure 3. One-third (37 %) of constipated patients have delayed colon transit and these patients often lack the urge to defecate due to decreased rectal sensation (Bharurcha et al., 2001). Gut-microbiome and dysbiosis have also a role in pathogenesis of slow-transit constipation. In an experimental study, germ-free mice developed slow transit constipation after fecal-microbiome colonization from slow-transit constipated patients. Sero- tonin concentrations are inversely correlated with colon transit, longer transit time, lower serotonin concentrations and decreased bowel motility.

(Cao et al., 2017; Ge et al., 2017).

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Figure 3. Cajal cells of enteric nervous system.

2.4.2Secondary constipation

Secondary constipation is due to an underlying cause, such as medication, underlying illness or diet habits (Figure 2).

Many metabolic diseases may cause constipation. Constipation may be a symptom of hypothyroidism, where the lack of thyroid hormones slows down the GI-function (Chaker et al., 2017). Diabetes mellitus is associated with higher prevalence of chronic constipation among other GI-disorders.

The prevalence of constipation is reported 11–60 % in diabetic patients (Kurniawan et al., 2019; Piper et al., 2017; Enck et al., 1994). GI-disorders

Constipation and pain management after spine surgery and in pregnancy and postpartum

MOONA KURONEN

Constipation and pain management after spine surgery and in pregnancy and

postpartum

Dissertations in Health Sciences

CONSTIPATION AND PAIN MANAGEMENT AFTER SPINE SURGERY AND IN PREGNANCY AND POST-

PARTUM

CONSTIPATION AND PAIN MANAGEMENT AFTER SPINE SURGERY AND IN PREGNANCY AND POST-

PARTUM

ACKNOWLEDGEMENTS

LIST OF ORIGINAL PUBLICATIONS

CONTENTS

ABBREVIATIONS

1 INTRODUCTION

2 REVIEW OF THE LITERATURE