METTE NISSEN
Long-term outcome of spinal cord stimulation in failed back surgery syndrome
Dissertations in Health Sciences
PUBLICATIONS OF
THE UNIVERSITY OF EASTERN FINLAND
LONG-TERM OUTCOME OF SPINAL CORD STIMULATION IN FAILED BACK SURGERY
SYNDROME
Mette Nissen
LONG-TERM OUTCOME OF SPINAL CORD STIMULATION IN FAILED BACK SURGERY
SYNDROME
To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in
Auditorium 1, Kuopio on June 11th, 2021, at 12 o’clock noon
Publications of the University of Eastern Finland Dissertations in Health Sciences
No 623
Department of Neurosurgery University of Eastern Finland, Kuopio
2021
5 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
Grano Oy, 2021
ISBN: 978-952-61-3780-3 (print/nid.) ISBN: 978-952-61-3781-0 (PDF)
ISSNL: 1798-5706 ISSN: 1798-5706 ISSN: 1798-5714 (PDF)
6 Author’s address: Institute of Clinical Medicine, Neurosurgery
University of Eastern Finland KUOPIO
FINLAND
Doctoral programme: Doctoral programme of Clinical Research
Supervisors: Docent Mikael von und zu Fraunberg, M.D., Ph.D.
Department of Neurosurgery Kuopio University Hospital KUOPIO
FINLAND
Professor Ville Leinonen, M.D., Ph.D.
Institute of Clinical Medicine
School of Medicine, Faculty of Health Science University of Eastern Finland
KUOPIO FINLAND
Reviewers: Docent Ville Vuorinen, M.D., Ph.D.
Department of Neurosurgery University of Turku
TURKU FINLAND
Docent Kai Lehtimäki, M.D., Ph.D.
Department of Neurosurgery University of Tampere TAMPERE
FINLAND
Opponent: Professor Maarten Moens, M.D., Ph.D.
Department of Neurosurgery University of Brussels
BRUSSELS BELGIUM
7 Nissen, Mette
Long-term outcome of spinal cord stimulation in failed back surgery syndrome Kuopio: University of Eastern Finland
Publications of the University of Eastern Finland
Dissertations in Health Sciences Number 623. 2021, 121 p.
ISBN: 978-952-61-3780-3 (print) ISSNL: 1798-5706
ISSN: 1798-5706
ISBN: 978-952-61-3781-0 (PDF) ISSN: 1798-5714 (PDF)
ABSTRACT
Failed back surgery syndrome (FBSS) is a challenging condition that lacks a curative treatment. Spinal cord stimulation (SCS) has proven to be a safe, cost-effective and efficacious treatment in selected patients with FBSS. The pharmacological
treatment of FBSS with a predominant neuropathic radicular component is based on the use of gabapentinoids and antidepressants. Opioids are widely used for neuropathic pain, although evidence of efficacy is limited. Opioid overuse is an increasing problem worldwide, as evidenced by an increasing number of overdose deaths. Despite their side effects, opioids are often started before trialing SCS.
We studied the long-term outcomes of SCS as measured by the explantation rate, complications, patient satisfaction and the use of opioids, gabapentinoids and other neuropathic pain medication in 224 consecutive FBSS patients who underwent an SCS trial with surgically implanted leads at Kuopio University
hospital between January 1996 and December 2014. The patients’ satisfaction with treatment was measured through a postal questionnaire at the end of follow-up.
Use of prescribed drugs since 1995 was retrieved from national registries.
After 1-week trial, permanent SCS was implanted in 175 (78%) patients. Of these, 153 (87%) reported satisfactory outcomes after 2 months. During the mean follow-up of 6 years, 34 (19%) of SCS devices were permanently explanted due to inadequate pain relief, and eleven (6%) were explanted for other reasons. One hundred and thirty patients (74%) continued with SCS until the end of follow-up. Of these, 61 (47%) returned the questionnaire, and 42 (69%) reported substantially improved or better outcomes, measured based on Global Perceived Effect using a 7-point Likert scale. Electrode revision due to inadequate pain relief was done for
8 22 patients. In total, 26 complications were reported: seven deep infections, eleven hardware malfunctions, one subcutaneous hematoma, four instances of
discomfort due to the pulse generator, and three electrode migrations.
Higher pre-implantation opioid doses predicted unsuccessful SCS (ROC:
AUC=0.66, p=0.009), with 35 morphine milligram equivalents (MME)/day as the optimal cut-point value. All opioids were discontinued in 23% of patients with successful SCS, but in none of the patients with unsuccessful SCS (p=0.004). Strong opioids were discontinued in 39% of the patients with successful SCS, but in none of the patients with unsuccessful SCS (p=0.04). Mean opioid dose escalated from 18±4 MME/day to 36±6 MME/day with successful SCS and from 22±8 MME/day to 82±21 MME/day with unsuccessful SCS (p<0.001).
Gabapentinoid users had significantly fewer explantations during the two-year follow-up (multivariate Cox regression analysis: HR 0.3, CI 95% 0.094–0.96, p = 0.04). In contrast, patients with strong or intermediate opioid use before implantation had significantly more explantations (HR 3.6, CI 95% 1.3–9.4, p = 0.011). Gabapentinoid users achieved over a 20% reduction of their total opioid dose during the two-year follow-up significantly more often than others (bivariate logistic regression analysis: OR 3.6, CI 95% 1.1–12, p = 0.042). The analyses were adjusted for gender, age, number of previous operations, location and duration of pain, status of instrumented lumbar fusion, use of anxiolytic medication, use of strong or intermediate opioids and use of tricyclic antidepressants.
This study indicates that SCS can provide good outcomes in the treatment of FBSS. Patient selection could be further improved by developing novel predictive biomarkers. Higher pre-implantation opioid doses were associated with SCS failure, suggesting the need for opioid tapering before implantation. With continuous SCS therapy and no explantation or revision due to inadequate pain relief, 39% of FBSS patients discontinued strong opioids, and 23% discontinued all opioids. This indicates that SCS should be considered before detrimental dose escalation. The use of gabapentinoids was associated with a significantly lower spinal cord stimulator explantation rate and a higher chance of an over 20% opioid reduction. This indicates that patients with SCS could benefit from the concomitant use of gabapentinoids. Prospective randomised trials are warranted to verify this hypothesis.
National Library of Medicine Classification: WB 495, WE 720, WE 850, WL 544
Medical Subject Headings: Failed Back Surgery Syndrome; Spinal Cord Stimulation;
Neuralgia; Chronic Pain; Pain Management
9 Nissen, Mette
Selkäydinstimulaation pitkäaikaistulokset selkäleikkauksen jälkeisen kroonisen vaikean alaraajaan säteilevän hermojuurikivun (FBSS) hoidossa.
Kuopio: Itä-Suomen yliopisto
Publications of the University of Eastern Finland Dissertations in Health Sciences 623. 2021, 121 s.
ISBN: 978-952-61-3780-3 (nid.) ISSNL: 1798-5706
ISSN: 1798-5706
ISBN: 978-952-61-3781-0 (PDF) ISSN: 1798-5714 (PDF)
TIIVISTELMÄ
Selkäleikkauksen jälkeinen krooninen vaikea alaraajaan säteilevä hermojuurikipu (Failed Back Surgery Syndrome, FBSS) on hankala kiputila, johon ei ole parantavaa hoitoa. Selkäydinstimulaatio (Spinal Cord Stimulation, SCS) on osoittautunut turvalliseksi ja tehokkaaksi hoidoksi osalle FBSS-potilaista. FBSS:n lääkehoitona käytetään yleisesti gabapentinoideja ja masennuslääkkeitä mutta myös opioideja, vaikkei niiden tehosta ole vakuuttavaa näyttöä. Opioidien liikakäyttö on
maailmanlaajuinen ongelma aiheuttaen yhä useampia yliannostuskuolemia.
Sivuvaikutuksista huolimatta opioidit aloitetaan usein jo ennen SCS:n kokeilua.
Tutkimme SCS:n pitkäaikaistuloksia mitattuna laitteiston poistoilla, kom- plikaatioilla, potilaan tyytyväisyydellä sekä opioidien, gabapentinoidien ja muiden neuropaattisten kipulääkkeiden käytöllä. Aineistona oli 224 FBSS-potilasta, joille kokeiltiin SCS-hoitoa kirurgisesti asennetuilla elektrodeilla Kuopion yliopistollisessa sairaalassa tammikuun 1996 ja joulukuun 2014 välillä. Potilaiden tyytyväisyys hoitoon mitattiin postikyselyllä seurannan lopussa. Reseptilääkkeiden käyttö määritettiin kansallisista rekistereistä vuodesta 1995 lähtien.
Viikon kokeilujakson perusteella pysyvä selkäydinstimulaattori asennettiin 175 (78 %) potilaalle. Heistä 153 (87 %) oli tyytyväisiä tai erittäin tyytyväisiä hoitoon kahden kuukauden jälkeen. Keskimäärin 6 vuoden seurannan aikana 34 (19 %) SCS-laitetta poistettiin riittämättömän kivunlievityksen vuoksi ja 11 (6 %) muista syistä. 130 (74 %) potilasta jatkoi stimulaatiohoitoa seurannan loppuun saakka.
Heistä 61 (47 %) palautti kyselylomakkeen, ja 42 (69 %) ilmoitti 7-portaisella Likert- asteikolla kiputilan olennaisesti tai kokonaan parantuneen. Elektrodin
10 korjausleikkaus puutteellisen kivunlievityksen vuoksi tehtiin 22 potilaalle.
Komplikaatioita sattui yhteensä 26, joista 7 johtui syvästä infektiosta, 11 laitteiston toimintahäiriöstä, 1 ihonalaisesta verenpurkaumasta, 4 pulssigeneraattorin aiheuttamasta kivusta ja 3 elektrodin siirtymisestä.
Selkäydinstimulaation epäonnistumisriski oli suurin potilailla, joilla oli käytössä suuri opioidiannos ennen asennusta (ROC: AUC = 0,66, p = 0,009). Optimaalinen vuorokausiannoksen raja-arvo oli 35 morfiinimilligramman ekvivalenttia (MME).
Opioidien käytön lopetti kokonaan 23 % niistä potilaista, joilla SCS-hoito onnistui, muttei yksikään potilaista, joilta SCS poistettiin tai sitä jouduttiin korjaamaan puutteellisen kivunlievityksen vuoksi (p = 0,004). Vahvojen opiaattien käytön lopetti 39 % potilaista, joilla SCS-hoito onnistui, mutta ei yksikään potilaista, joilla hoito epäonnistui (p = 0,04). Opioidien keskimääräinen vuorokausiannos kasvoi kahden vuoden seurannassa 18±4 MME:sta 36±6 MME:iin onnistuneen SCS-hoidon ja 22±8 MME:sta 82±21 MME:iin epäonnistuneen SCS-hoidon aikana (p <0,001).
Gabapentinoidien käyttö vähensi merkittävästi riskiä SCS-laitteiston poistoon kahden vuoden seurannan aikana (Cox-regressio: HR 0,3, CI 95 % 0,094–0,96, p = 0,04). Sen sijaan vahvan tai keskivahvan opioidin käyttö ennen implantointia lisäsi merkittävästi poistoriskiä (HR 3,6, CI 95 % 1,3–9,4, p = 0,011). Gabapentinoidien käyttäjät pystyivät merkittävästi useammin vähentämään opioidiannosta kuin ei- käyttäjät (logistinen regressio: OR 3,6, CI 95 % 1,1-12, p = 0,042). Analyysit mukautettiin sukupuolen, iän, aikaisempien leikkausten lukumäärän, kivun
sijainnin ja keston, instrumentoidun lannerangan fuusion, anksiolyyttien, vahvojen tai keskivahvojen opioidien ja trisyklisten masennuslääkkeiden käytön perusteella.
Tutkimus osoittaa, että SCS on tehokas ja turvallinen FBSS:n hoito.
Potilasvalintaa tulisi vielä parantaa uusien biomarkkerien avulla. SCS-hoitoa tulisi harkita ennen opioidiannoksen haitallista kasvua: FBSS-potilaista, joilla hoito onnistui eli laitteistoa ei poistettu tai korjattu puutteellisen kivunlievityksen vuoksi, 39 % lopetti vahvojen ja 23 % kaikkien opioidien käytön. Opioidiannoksen
vähentäminen ennen implantointia on suositeltavaa hoitotuloksen
parantamiseksi. Gabapentinoidien käyttöön liittyi huomattavasti pienempi riski stimulaattorin poistoon ja suurempi mahdollisuus yli 20 %:n opioidiannoksen vähentämiseen. Gabapentinoidien hyödyt SCS:n liitännäishoitona tulisi kuitenkin varmentaa satunnaistetulla kontrolloidulla tutkimusasetelmalla.
Luokitus: WB 495, WE 720, WE 850, WL 544
Yleinen suomalainen ontologia: selkä; leikkaushoito; jalat; krooninen kipu; neuropatia selkäydin; stimulointi; kivunhoito
11
12 NÄIN LAULOIN MA KUOLLEELLE ÄIDILLEIN
JA ÄITI MUN YMMÄRSI HETI. HÄN PAINOI SUUKKOSEN OTSALLEIN
JA SYLIHINSÄ MUN VETI:
"KEN USKOVI TOTEEN, KEN UNELMAAN,- SAMA SE, KUN TÄYSIN SA USKOT VAAN! SUN USKOS SE JUURI ON TOTUUTES. USKO TYTTÖNI UNEHES!"
EINO LEINO
13
ACKNOWLEDGEMENTS
This thesis was carried out at the Department of Neurosurgery at the University of Eastern Finland between 2014 and 2021. This project was financially supported by the Foundation of Maire Taponen, the Finnish Association for the Study of Pain, Eastern Finland University and Kuopio University Hospital Research Funds (VTR).
Last two years of writing this thesis have been dramatic in many ways. A pandemic has wiped out a portion of the population, and the scientific field has shifted from on-site conferences to endless webinars and Teams-meetings. Two years ago, I visited Boston and Sydney to present my work, but this is just a distant memory. The end of the pandemic is still to come. However, the academic
profession is not doomed. I wish to express my sincere gratitude to Professor Maarten Moens for agreeing to be my opponent despite these difficult times. Even though traveling is uncertain, modern technology gives us an opportunity for remote participation.
I wish to express my sincere thanks to the pre-examiners of my thesis, adjunct professor Kai Lehtimäki and adjunct professor Ville Vuorinen. Kind words and good discussions made the process smoother.
I am deeply grateful for the support of my supervisors. This was a long and bumpy road. I could not have done this without you. Adjunct professor Mikael von und zu Fraunberg, you gave me both answers and questions day or night. The Poems of Eino Leino will echo in my ears until the day I die. Your guidance led me through the dark times when all the statistics seemed wrong. Professor Ville Leinonen, we share a long research history, even reaching back to the time before I was in medical school. I am glad you could be a part of me becoming a
researcher, and you have always been an inspiration.
The idea of this study came to life after a major change in KUH
neuromodulation. The previous implanters suddenly left, and a new team was constructed. Adjunct professor Jukka Huttunen stepped into his neuromodulation shoes, and a great deal has happened since. Jukka is a valuable surgeon whose vision never stops. He has made groundbreaking changes with Mikael and established the leading neuromodulation protocol in Finland. One of the best changes in KUH neuromodulation occurred when our first neuromodulation nurse, Tiina-Mari Ikäheimo, was hired and trained to be part of the team. At the beginning of her career in neuromodulation, she proved to be the most important part of patient care. With great gratitude, I thank her for her help in planning this
14 thesis and investigating patient records when the work had just begun. I also want to thank Henna-Kaisa Jyrkkänen, MD, PhD, who came to be a part of our team and has provided great value and friendship.
I would like to thank my friends in the OR. They are the best nurses and orderlies a surgeon could ask for. You have made my days a lot funnier and more productive. Also, I wish to appreciate the previous and current staff of the
Department of Neurosurgery. I would especially like to mention Professor Jääskeläinen and Chief Koivisto for the opportunity to become a neurosurgeon.
I want to express my gratitude to my family: dad for supporting me; my brother Hans, who has made me think and grow mentally, and my, godfather, Manu, who has always been so uplifting and shown me the proper way to live. Also, I want to thank my other family in Pieksämäki for making me a part of their family. Of course, t-rex, you motivate me to think above my own field.
Joonas, I could not thank you enough. You have shown me how to be great and loving at the same time. I would not be anything or anyone without my Maria. You have kept me going when all the lights were gone. Words are not enough.
Kuopio, April 12th 2021
15
LIST OF ORIGINAL PUBLICATIONS
This dissertation is based on the following original publications:
I Nissen M, Ikäheimo TM, Huttunen J, Leinonen V, von Und Zu Fraunberg, M.
Long-term outcome of spinal cord stimulation in failed back surgery syndrome: 20 years of experience with 224 consecutive patients.
Neurosurgery. 84: 1011-1018, 2019.
II Nissen M, Ikäheimo T, Huttunen J, Leinonen V, Jyrkkänen H, von und zu Fraunberg, M. Higher pre-implantation opioid doses associated with long- term spinal cord stimulation failure in 211 patients with failed back surgery syndrome. Neuromodulation. 24:102-111, 2020.
III Nissen M, Ikäheimo T, Huttunen J, Leinonen V, Jyrkkänen H, von und zu Fraunberg, M. Gabapentinoids associated with lower explantation rate in 203 patients with Spinal Cord Stimulation for Failed Back Surgery Syndrome. This is a pre-copyedited, author-produced version of an article accepted for publication in Neurosurgery following peer review, 2021.
The publications were adapted with the permission of the copyright owners.
16
17
CONTENTS
ABSTRACT ... 7
TIIVISTELMÄ ... 9
ACKNOWLEDGEMENTS ... 13
1 INTRODUCTION ... 23
2 REVIEW OF THE LITERATURE ... 25
2.1 Pain ... 25
2.1.1 Pain pathophysiology ... 25
2.1.2 Definition of pain ... 25
2.2 Neuropathic pain ... 25
2.2.1 Definition of neuropathic pain ... 25
2.2.2 Pain pathways ... 27
2.2.3 Incidence and prevalence of neuropathic pain ... 27
2.2.4 Why does acute pain become chronic? ... 27
2.2.5 Treatment of neuropathic pain ... 28
2.3 Pharmacological treatment of neuropathic pain ... 29
2.3.1 Opioids ... 29
2.3.2 Gabapentinoids ... 31
2.4 Failed back surgery syndrome ... 32
2.4.1 Definition of FBSS ... 32
2.4.2 Incidence and prevalence of FBSS ... 32
2.4.3 Mechanisms and pathophysiology and risk factors ... 33
2.5 Spinal cord stimulation ... 35
2.5.1 History ... 35
2.5.2 Mechanism of action ... 36
2.5.3 Patient selection ... 38
2.5.4 Spinal Cord Stimulator device... 39
2.5.5 Implantation technique ... 40
2.5.6 Complications ... 43
3 AIMS OF THE STUDY ... 45
4 LONG-TERM OUTCOME OF SPINAL CORD STIMULATION IN FAILED BACK SURGERY SYNDROM: 20 YEARS OF EXPERIENCE WITH 224 CONSECUTIVE PATIENTS... 47
18
4.1 Introduction ... 47
4.2 Methods... 48
4.2.1 Patients ... 48
4.2.2 Clinical evaluation ... 49
4.2.3 SCS implantation ... 49
4.2.4 Statistical analysis ... 50
4.2.5 Ethical issues ... 50
4.3 Results ... 50
4.3.1 FBSS history ... 50
4.3.2 Trial stimulation ... 51
4.3.3 Postoperative outcome ... 54
4.3.4 Explantation rate ... 54
4.3.5 GPE at the end of the follow-up ... 55
4.3.6 Complications and revisions ... 55
4.4 Discussion ... 57
4.4.1 Trial period success ... 57
4.4.2 Long-term success ... 58
4.4.3 Complications and revisions ... 58
4.4.4 Benefits of surgical electrodes ... 58
4.4.5 Limitations of this study ... 59
4.4.6 Strengths of this study ... 59
4.4.7 Suggestions for further research ... 60
4.5 Conclusions ... 60
5 HIGHER PREIMPLANTATION OPIOID DOSES ASSOCIATED WITH LONG-TERM SPINAL CORD STIMULATION FAILURE IN 211 PATIENTS WITH FAILED BACK SURGERY SYNDROME... 61
5.1 Introduction ... 61
5.2 Materials and methods ... 62
5.2.1 Study population ... 62
5.2.2 SCS implantation ... 64
5.2.3 Matched controls ... 64
5.2.4 Opioid purchase data ... 64
5.2.5 Determination of morphine milligram equivalent treshold for SCS failure ... 65
5.2.6 Statistical analysis ... 66
5.3 Results ... 66
5.3.1 Baseline characteristics and opioid use in 211 SCS patients... 66
5.3.2 Opioid use during the follow-up period after SCS implantation... 67
19
5.3.3 Opioid use associated with unsuccessful SCS ... 70
5.3.4 Opioid discontinuation after successful SCS treatment ... 70
5.3.5 Novel use after SCS implantation during the follow-up period after SCS implantation ... 74
5.3.6 Opioid purchase by SCS patients compared to 627 matched controls ... 75
5.3.7 Opioid dose five years after SCS trial or implantation in 147 patients and their 441 matched controls ... 77
5.4 Discussion ... 77
5.5 Conclusions ... 80
6 GABAPENTINOIDS ASSOCIATED WITH LOWER EXPLANTATION RATE IN 203 PATIENTS WITH SPINAL CORD STIMULATION FOR FAILED BACK SURGERY SYNDROME ... 81
6.1 Introduction ... 81
6.2 Methods... 82
6.2.1 Study population ... 82
6.2.2 SCS implantation ... 82
6.2.3 Patient demographics ... 83
6.2.4 Medication data and classes of medicine ... 84
6.2.5 Survival analysis ... 85
6.2.6 Statistical analysis ... 85
6.2.7 Ethical issues ... 85
6.3 Results ... 88
6.3.1 Neuropathic pain medication use during the follow-up ... 88
6.3.2 Gabapentinoid use and SCS explantation... 90
6.3.3 Effect of gabapentin use on opioid dose reduction ... 90
6.4 Discussion ... 94
6.4.1 Limitations of the study ... 95
6.5 Conclusions ... 96
7 DISCUSSION ... 97
7.1 Study design, cohort and data acquisition ... 97
7.2 SCS is a safe and effective treatment of fbss ... 97
7.3 Opioid discontinuation – A GOAL FOR SCS THERAPY? ... 98
7.4 Gabapentinoids improved scs outcome ... 99
7.5 How to improve SCS outcome in FBSS? ... 100
8 FUTURE PERSPECTIVES ... 101
9 SUMMARY AND CONCLUSIONS ... 103
20 REFERENCES ... 105
21
ABBREVIATIONS
ATC anatomical therapeutic chemical
BDI Beck Depression Inventory
CDC United States Centers for Disease Control and Prevention
CI confidence interval
CL central lateral nucleus
CMS Centers for Medicare &
Medicaid Services
CNS central nervous system
CRPS complex regional pain syndrome
DDD defined daily dose
EAA excitatory amino acid
FBSS failed back surgery syndrome
FDA U.S Food and Drug Adminisration
GABA γ-aminobutyric acid
GIC Global Impression of Change
GPE global perceived effect
Hz Hertz
HF SCS High – Frequency SCS
IASP The International Association for the Study of Pain
IPG internal pulse generator
KUH Kuopio University Hospital
LBP low back pain
MDvc ventral caudal part of medial norsal nucleus
MME morphine milligram equivalents
MPQ McGill Pain Questionnaire
NeuPSIG Neuropathic pain special interest group
NHI National Health Insurance
NRS Numeric Rating Scale
NSAID Non-steroidal anti- inflammatory drugs
ODI Oswestry Disability Index
22 PCS Pain Catastrophizing Scale
PNS peripheral nervous system
QOLS Quality of Life Scale
RCT randomized control study
SCS spinal cord stimulation
SII Social Insurance Institution of Finland
SNRI serotonin norepinephrine reuptake inhibitors
SSRI selective serotonin reuptake inhibitor
STT spinothalamic track
TCA tricyclic antidepressant
TD transdermal
VMpo posterior part of the ventral medial nucleus
VPI ventral inferior nucleus
VPL ventral lateral nucleus
WDR wide dynamic range neurons
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1 INTRODUCTION
Pain is a global health problem. Annually, one in ten adults are diagnosed with chronic pain, and it is estimated that closer to 20% of adults suffer from significant chronic pain worldwide (1,2). In a population study performed in Finland, 26% of the responders suffered from chronic pain (3). Chronic pain is associated with psychological co-morbidities, such as depression and anxiety and disturbancies in everyday working life, along with a lower quality of life (4). According to a European concensus report, 36% of patients with chronic pain reported a negative implact on their families and friends, and 27% felt socially lonely and abandoned (5).
Low back pain (LBP) is the single leading cause of disability, with a global prevalence of over 9% in 2010 (6). The prevalence of LBP is highest in Western Europe (15%) and accounts for the largest proportion of lost workdays of all musculoskeletal conditions (7). According to the literature, LBP accounts for 12.5%
to 14% of sick days in Western Europe (7,8). Furthermore, the number of spine surgeries steadily increased until the past decade, with highest increase being observed in patients 65 years and older (9-12).
Failed back surgery syndrome (FBSS) describes persistent or recurrent pain in the lumbar area with or without a sciatic component after one or more lumbar surgeries (13). The incidence of FBSS has reached 20–40%, according to studies, and it has not decreased even though mini-invasive surgical techniques have evolved (14,15).
Spinal cord stimulation (SCS) is a well-established treatment modality for intractable neuropathic pain (16-19). A satisfactory outcome in the spinal cord stimulation trial period predicts a good long-term outcome (20,21), and pain reduction can even improve over time (22). However, in the previous long-term outcome studies, patient cohorts were heterogeneous regarding pain etiology, and many patients were lost before the follow-up visit.
The pharmacological treatment of FBSS with a predominant neuropathic radicular component is widely based on the use of gabapentinoids and antidepressants (23). Gabapentinoids are calcium channel blockers inhibiting neurotransmitter release, and they are likely to have multiple mechanisms of action that are poorly known (24-26). Gabapentinoids are scarcely researched in SCS patients, but in rodent studies, they have been shown to improve SCS’s effect (27). In a study of humans, gabapentinoid with opioid was superior to opioid alone in SCS patients in terms of increasing their quality of life (28).
24 Allthough opioids are not considered the optimal treatment for neuropathic pain and the effect of long-term use is not established, they are widely used, and overuse is an increasing global problem given overdose deaths (29-31). The risk of death in patients taking opioids rises sixfold when they take over 80 mg/day of morphine milligram equivalents (MME) as compared with opioid-naïve patients (32-38). Benzodiazepine use with opioids elevates the risk of trauma, violence- related injuries and overdose-related death (37,38). Opioid use is associated with cardiac insults, as well as endocrinological dysfunction and motor vehicle
accidents (39,40). The prevalence of opioid use increased in Finland from less than 1% to 7% from 1995 to 2016 (41). Long-term opioid use may even increase and prolong neuropathic pain (opioid-induced hyperalgesia) and may activate psychological co-morbidities and addictions, especially in the case of strong opioids (42).
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2 REVIEW OF THE LITERATURE
2.1 PAIN
2.1.1 Pain pathophysiology
Pain is categorised according to its duration and mechanism. Nociceptive pain arises from actual or threatened injury to non-neural tissue due to the activation of sensory neurons called nociceptors. Neuropathic pain arises as a direct sequalae of a lesion or disease affecting the somatosensory system (43).
Pain lasting less than three months is called acute pain, and it is a result from an assault on tissue and represents an adaptive function. After the acute period, pain can become chronic, having no positive influence on the healing process, and moreover, it can lead to a maladaptive response to a previous injury.
2.1.2 Definition of pain
An organism’s survival depends on its ability to feel pain. Animals and humans alike that are born without the ability to perceive pain are predisposed to life- threatening injuries from the birth because accidents, such as burns and cuts, may go unrecognised (44).
Pain is “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”, as defined by the International Association for the Study of Pain (IASP) in 2020. A new definition was needed because of evolving knowledge in the field. The IASP emphasises that the pain reported by the patient should be respected. Chronic pain is defined as persistent or recurrent pain for > 3 months (45).
2.2 NEUROPATHIC PAIN
2.2.1 Definition of neuropathic pain
Chronic neuropathic pain is pain lasting over three months that is caused by an injury or disease affecting the somatosensory nervous system (45). In the absence of pain biomarkers, a diagnosis is made based on clinical characteristics. The diagnosis of neu- ropathic pain includes a wide variety of conditions, including
26 painful neuropathies, nerve root or peripheral nerve injury, complex regional pain syndrome and post-stroke pain.
Neuropathic pain can be characterised as either spontaneous (stimulus- independent) or evoked (stimulus-dependent). Allodynia, pain evoked by non- noxious stimuli, and hyperalgesia, an abnormally low threshold to painful stimuli, can be a part of a neuropathic pain syndrome. Neuropathic pain does not require any receptor stimulation and is caused by a dysfunction in the peripheral or central nervous components of the somatosensory system (46).
Figure 1. Schematic illustration of ascending pain pathways. Laminae IV - V cells decussate and ascend in the anterior spinothalamic track to the thalamus (Central lateral nucleus [CL], ventral lateral nucleus [VPL] and ventral inferior nucleus [VPI]
with connections to cortex. Laminae I cell axons decussate and ascend in the lateral spinothalamic tract to the thalamus (Ventral caudal part of medial dorsal nucleus [MDvc], ventral inferior nucleus [VPI] and posterior part of the ventral medial nucleus [VMpo]) and with further connections to cortical projections.
27 2.2.2 Pain pathways
Nociceptive information is transmitted to the brain via various pathways. The spinotha- lamic track (STT) is the primary pain pathway, encompassing neurons at many levels. The STT can be divided into the lateral pathway and the medial pathway. The STT carries the sensation of nociception, temperature, crude touch and pressure. The lateral pathway is activated by C, Aδ and Aβ fibers. It is formed by the axons of nociceptive-specific and wide-dynamic-range neurons (WDR), which cross the midline of the spinal cord and ascend to the nucleii in the
thalamus, from which it continues to the primary sensory cortex (47). The medial pathway is formed by the axons of neurons of lamina I in the spinal cord, and it projects to the thalamus, from which it ascends to the anterior cingulate and anterior insula. The medial pain pathway encompasses the motivational and affective component of pain, and it is activated by C fibers (Figure 1) (48).
2.2.3 Incidence and prevalence of neuropathic pain
The incidence of neuropathic pain is difficult to measure due to insufficient instruments with which to interpret neuropathic pain based on population-based surveys. According to the literature, the incidence rate could be as high as 7–10%
(46,49,50). The prevalence of neuropathic pain, as a global clinical entity, ranges from 0.9% to 17.9% (46,50). Neuropathic pain is more frequent in women (8% vs 5.7%) and in those over 50 years of age. The most common areas of pain are the lower back, neck and upper and lower limbs (51).
2.2.4 Why does acute pain become chronic?
Normal pain perception involves a peripheral nociceptive stimulus, which is projected through the spinothalamic pain pathway. Pathological changes regulating chronic pain may occur in both the peripheral nervous system (PNS) and central nervous system (CNS). This suggests that chronic pain is a group of nervous system disorders produced by one or multiple anomalous cellular signaling mechanisms.
The somatosensory pathway in the CNS runs in the dorsal horn of the spinal cord, where a network of complex nociceptive processes receives inputs from the peripheral nervous system. These inputs are then modulated and altered by either local or descending control mechanisms (47). The output is transmitted via the ascending pathway and processed in the CNS when this output involves the
28 sensory, emotional, autonomic and motor modalities. In a normal state, the
output would be balanced by excitatory and inhibitory processes. However, in pathological pain states, such as chronic neuropathic pain, the output of the dorsal horn nociceptive network is greatly increased. After peripheral nerve injury,
concentrations of excitatory amino acids (EAA, glutamate and aspartate) become higher in the dorsal column than in a normal state. Simultaneously, GABAergic inhibition is reduced (52). These changes shift the sensory pathway to a state of hyperexcitability, which produces changes from the periphery to the brain and contributes to neuropathic pain becoming chronic (46).
2.2.5 Treatment of neuropathic pain
Treatment algorithms have been proposed in the treatment of neuropathic pain (Figure 2) (53). The cornerstone of treatment is a proper evaluation of pain and a correct diagnosis (54). With pain being more than an unpleasant sensation, factors such as mood, sleep and various aspects of quality of life should also be treated.
The goals of pain management are pain reduction and the improvement of daily functions, while minimising the risk of adverse events (55).
First-line treatment begins with nonpharmacological and noninterventional therapies, such as exercise and physiotherapy, including psychotherapy in some cases. Multidisciplinary care has been shown to decrease pain and improve function, mood, catastrophising and increase pain acceptance (56). If adequate pain relief is not achieved, first-line pharmacotherapy (tricyclic antidepressants (TCA), serotonin and norepinephrine reuptake inhibitors (SNRI), gabapentinoids and tramadol) should be initiated.
For neuropathic pain, no drug is effective for all patients. Tolerance and side- effects limit their use. It is estimated that 45% of patient use more than one medication for their pain (57). Combination therapy may increase efficacy and enable dose reduction, reducing side-effects (54). According to a Cochrane review, gabapentinoids and opioids together provide better pain relief than either alone, but this combination increases the level of adverse events (58). Tramadol is considered a second-line neuropathic pain medication (59).
If the first-line and second-line therapies are inadequate, referral to a special pain clinic is advised (60). Third-line treatment encompasses minimally invasive treatments, such as epidural injections, radiofrequency treatments and
symphatetic blockades. Recommendations for these treatments are, however, weak or inconclusive, and these treatments usually do not have long-term effects (54). Neuromodulation is categorised as a third- or fourth-line treatment (54,61)
29 and has shown efficacy in many randomised controlled trials (RCTs) combating FBSS and other neuropathic pain syndromes (18,62,63).
Strong opioids should be proposed only in the absence of alternative
treatments. The use of opioids should be considered in the context of the current opioid crisis in the US, where the misuse rate and opioid-related mortality are high (34,64). Studies concerning the effect of long-term opioid use are lacking, and in a Cochrane database review, morphine was found to lead to only a moderate (30%) improvement in neuropathic pain (65).
2.3 PHARMACOLOGICAL TREATMENT OF NEUROPATHIC PAIN
The Special Interest Group on Neuropathic Pain (NeuPSIG) of the IASP has published re- commendations for neuropathic pain treatment. According to NeuPSIG, the first- line drugs for neuropathic pain are TCAs, SNRIs, gabapentin and pregabalin.
Tramadol and strong opioids are weakly recommended.
Figure 2. Non-cancer pain analgesic ladder.
2.3.1 Opioids
Opioids can be classified according to their duration of action (long-acting versus short-acting opioids) or their potency, which is used in the WHO pain ladder
30 approach. The pain ladder approach has ladder two for weak opioids and ladder three for strong opioids. The same classification is used in the Controlled
Substance Schedule, which classifies opioids into various control schemes according to their potential for misuse. In the US substance abuse classification, weak and intermediate opioids are class III controlled substances, and strong opioids are in class II (66). In Finland, strong opioids require a controlled prescription, whereas intermediate and weak opioids can be prescribed with a normal prescription.
There is no solid scientific evidence on the effectiveness and harms of long- term opioid therapy for chronic non-cancer pain. Cochrane’s review from 2010 suggested that patients with chronic non-cancer pain may experience clinically significant pain relief if they are able to continue opioid therapy despite adverse effects. However, the impact of long-term opioid therapy on quality of life remains inconclusive (31).
Most opioid trials do not extend beyond 6 weeks and are of limited relevance to long-term pain relief (35). During longer trials, opioids were associated with less pain relief due to opioid tolerance or opioid-induced hyperalgesia (67). This may lead to the prescription of higher opioid doses and consequent harms. Moreover, patients may continue to use opioids after analgesic benefits have waned to avoid withdrawal symptoms.
Long-term opioid therapy may be appropriate for certain pain syndromes or for patients at lower risk of overdose or misuse. Unfortunately, current evidence is in- sufficient to determine how benefits and harms vary in patient subgroups defined by demographic, pain or other clinical characteristics. The US Center for Disease Control and Prevention (CDC) has stated that the decision to start long-term opioid therapy is complex and requires individualised benefit–risk assessments (33).
Weak opioids (codeine, tramadol) are μ-opioid receptor agonists, and in addition, tramadol inhibits the reuptake of serotonin and noradrenalin.
Buprenorphine is a partial μ-opioid receptor agonist and is therefore categorized as an intermediate opioid. With weak opioids, a ceiling effect (a flattening of the dose/effect curve) is clearer than with intermediate or strong opioids. Weak opioids are widely used in combination with paracetamol and non-steroidal anti- inflammatory drugs (68).
The guidelines for non-cancer pain suggest that weak opioids be used in stage two of the treatment algorithm (69). Because of its mechanisms of action
(serotoninergic, noradrenergic action and μ-receptor agonist), tramadol influences both nociceptive and neuropathic pain, which makes it a logical choice in the
31 treatment of pain of mixed origin (70). There is only low-quality evidence to show that weak opioids are more effective than a placebo at reducing pain and
improving functional outcomes (58, 71).
Weak opioids have well-recognised adverse effects (nausea, confusion, constipation), as well as the potential for misuse and physical dependency, but these are less significant that those of their strong counterparts.
Strong opioids are μ-opioid receptor agonists, which are mainly used for acute pain and cancer pain and not recommended for long-term pain treatment.
Oxycodone may also cause κ-receptor antagonism (70). Strong opioids provide only modest short-term relief from pain, and their long-term effectiveness and safety are unknown (72,73). The complications of long-term opioid use include tolerance, hyperalgesia, obstipation, hormonal side effects and addiction (74).
Weak and strong opioids have same side-effect profile, consisting of nausea, vomiting, constipation, dizziness and somnolence, but the use of strong opioids may lead to misuse and overuse, leading to more severe adverse effects. Long- term use may cause immunological changes, physical dependency and misuse or abuse (75).
2.3.2 Gabapentinoids
Gabapentinoids (gabapentin and pregabalin) were originally developed for the treatment of epilepsy. Later, these drugs were recognised as effective in the treatment of neuropathic pain (76). Gabapentinoids are very closely related in terms of their pharmacology. They are derivates of the neurotransmitter γ- aminobutyric acid (GABA) and calcium channel alfa-2-delta ligands, which reduce the release of presynaptic transmitters and hence relieve neuropathic pain (77). A therapeutic dose is dose-dependently associated with a modest increase in the extra-cellular GABA-concentration in the brain tissue (78).
Gabapentinoids are the first-line medication for neuropathic pain, together with tricyclic antidepressants and serotonin-noradrenalin reuptake inhibitor (SNRI) anti- depressants (79). The effect of gabapentinoids with respect to FBSS is not as clear. In two previous studies, gabapentinoids showed no effect on low back pain with radiculopathy (80, 81).
The common side effects experienced with gabapentinoids include dizziness, fatigue, difficulties with concentration and visual disturbances (82). Substance abuse is also reported, with a prevalence rate of 1.6% in the general population, whereas prevalence ranged from 3% to 68% among opioid users (83). Risk factors for misuse include a history of substance use and psychiatric co-morbidities.
32 2.3.3 Tricyclic antidepressants
Tricyclic antidepressants (TCA) have several modes of action, one being serotonin norepinephrine reuptake inhibitors. They have shown moderate efficacy in combating neuropathic pain (70). In fact, TCAs’ pain-relieving component is independent of their antidepressant effect, occurring at 20–30% of the effective antidepressant dose (84).
These TCAs are among the first-line drugs for neuropathic pain, but caution is required, particularly with the elderly, to avoid potential adverse effects, such as falls, cardiac arrythmias and urinary retention due to an anticholinergic effect (54).
2.4 FAILED BACK SURGERY SYNDROME
2.4.1 Definition of FBSS
The term ‘FBSS’ is a controversial one. It was first used by North (13) to describe chronic recurring low back pain with or without a radicular component after lumbar spine surgery (85). A diagnosis is made given persistant back pain or leg pain after lumbar surgery. Its pathophysiology is still unknown, despite extensive research on this topic. Also, FBSS is difficult to treat and resistant to many
conservative treatments. Operations are discouraged due to a lack of nerve compression or instability. Due to the difficulty of treatment, mustering the clinical expertise of multiple professional disclipines is advised (86).
2.4.2 Incidence and prevalence of FBSS
The number of spine surgeries almost doubled from the late 90s to 2012 in the UK (87). At the same time, the rate of FBSS has not decreased. According to a large case series, 10% to 40% of all patients undergoing lumbar surgery develop FBSS (85). The wide range of estimates in reports reflects varying clinical experiences across institutions and the small sample size the se estimates rely on. Pain medication use increases from 21% with normal postope rative recovery to 62%
with FBSS (87). Clearly, FBSS is a long-term problem.
33 Table 1. Etiology of Failed Back Surgery Syndrome.
Preoperative Patient-related factors: psychological, social (88) Operative Surgery-related factors: poor candidate selection,
revision surgery, improper planning (89)
Inadequate decompression of lateral recesses and foramina (90)
Postoperative Instability with excessive decompression (90,91) Incorrect level of surgery (88)
Recurrent disc herniation (92) Adjacent segment disease (93)
Sagittal balance-related problems (94)
Pelvic incidence and lumbar lordosis mismatch (95) Battered root syndrome (88)
Nerve root entrapment syndrome (88) Epidural fibrosis (96)
Postoperative myofascial pain development (97)
2.4.3 Mechanisms and pathophysiology and risk factors
The etiology of FBSS is not yet clear, but several reports agree that its origin is multi- factorial. These factors can be categorised into three groups: preoperative, operative and postoperative factors (Table 1). Preoperative factors are subdivided into patient-related and operative planning-related factors. Risk factors for poor outcomes include patients’ psychological factors, such as depression and anxiety, or social factors, such as low income or litigation (88).
Postoperative causes can be divided into disease progression- and surgery- related problems. The incidence of recurrent disc herniation is shown to be approximately 6%-23% in the same or an adjacent level after microdiscectomy.
Sagittal balance problems play an important role in adjacent-level disc degeneration due to imbalance and compensation (94).
34 Figure 3. Spinal cord stimulation and pain gate theory.
Aβ - fiber
C-fiber Inhibitory interneuron
Projection neuron
Aβ - fiber
C-fiber Inhibitory interneuron
Projection neuron Aβ - fiber
C-fiber Inhibitory interneuron
Projection neuron No input - Gate closed
Large fiber input - Gate closed Small fiber input - Gate open
© Nissen 2020
35
2.5 SPINAL CORD STIMULATION
2.5.1 History
Spinal cord stimulation is defined as the “electrical stimulation of the nervous system for the purpose of modulating or modifying a function, such as the perception of pain”. The first recorded neuromodulation occurred in about 15 AD in ancient Rome, when a Greek physician, Scribonius Largus, observed that gout pain was relieved by accidental contact with Torpedo marmorata (the torpedo ray) (98). He then prescribed electrotherapy for pain relief for various conditions.
In the 1770s, Benjamin Franklin studied the effect of electricity on muscle contraction (99). Galvani demonstrated the electrical contraction of a frog muscle in the 1780s (100). In one hundred years, neuromodulation leaped from a muscle to the brain when Fritsch and Hitzig demonstrated limb movement while
electrically stimulating the motor cortex of a dog (101). The first documented experiment on conscious humans was performed in 1874 by Bartholow. The patient had osteomyelitis in one area on the scalp, and his motor cortex was exposed during the debridement. Muscle contraction was noted on faradic stimulation (102). The first practical intraoperative stimulation was performed by Sir Victor Horsley, who applied electrical stimulation to an occipital encephalocele, causing eye movement, in 1884. Shortly after this, he used stimulation to identify the motor area of the thumb during a local resection in a patient with focal epilepsy (103). The transcutaneous electrical nerve stimulator was the first such device to enter the market at the beginning of the twentieth century.
In the 1940s, stereotactic lesioning procedures took place in the thalamic region. At this time, frontal and transorbital lobotomies were performed to treat severe psychiatric disorders without stereotaxy and, sometimes, with devastating side-effects. Autopsy studies showed the beneficial effect of lobotomy on the dorsomedial nucleus of the thalamus, which became the first target of stereotactic procedures (104). Electric stimulation was used for target localisation. At the same time, Walter Hess experimented by permanently implanting electrodes in
conscious cats. He thought that their stimulation might have the same effect as lesioning but be reversible (105).
Electric stimulation for pain relief advanced in 1965, when Melzack and Wall’s gate control theory was published (106). They proposed that pain perception is affected by small (C-fibers) and large (Aβ fibers) neural fibers. If large, touch- sensitive fibers were stimulated, the pain gate would close, and pain sensation
36 would decrease. Touch sensation could also be stimulated by applying electrical stimulation to the skin.
In 1967, Norman Shealy had an idea to stimulate large-touch nerve fibers in the dorsal column of the spinal cord, where the density of these fibers is high. He designed an implantable stimulator, together with engineering student Thomas Mortimer. The first model required an external power supply. Adapting a
cardiovascular stimulation technique, they designed a fully implantable stimulator device in 1967. This device was implanted in a patient with inoperable
bronchiogenic carcinoma with metastasus in the pleura and liver, yielding pain relief for several months (107). Shealy’s theory on spinal cord stimulation is the basis for current treatment. Modern stimulators use the same target as in 1967, although cancer pain is no longer the primary target of SCS.
2.5.2 Mechanism of action
The gate control theory proposes that specific neurons of the dorsal horn, which project an axon up the spinothalamic track, are excited by both large-diameter Aβ- sensory axons and unmyelinated C-fibers transmitting pain signals. These
projection neurons are also inhibited by an interneuron. This interneuron is both excited by the large Aβ-axon and inhibited by the C-fiber (Figure 3). The activation of the projection neuron by the pain axon allows a nociceptive signal to rise through the spinothalamic pathway to the brain.
Interneurons receive input from large (Aβ) fibers and small (δ and C) fibers. An imbal- ance between small and large fiber input leads to wide dynamic range (WDR) projection neuron transmitting an ascending pain signal (108). With SCS, interneurons become hyperexcitable and restore non-pathologic equilibrium in this pain circuitry (109).
Pain modulation begins with interneurons within the substantia gelatinosa of the spinal cord. Both interneurons and projection neurons are involved with GABAergic synapses (110). A peripheral nerve injury resulting in neuropathic pain has been described as increasing the level of excitatory amino acid (EAA) and decrease the level of GABA in the dorsal horn. With SCS, both EAA and GABA levels normalise (Figure 4).
A new theory has emerged that views glial cells as being a part of SCS’s effect.
Glial cells, for example, those surrounding the synapse cleft, are a major part of the CNS and play an important role in the development and maintenance of neuropathic pain. They provide a functional microenviroment, modulating signal transduction and neuroplasticity (111).
Figure 4. Neurotransmitter model. A. In a normal state Gamma-aminobutyric acid (GABA) and primary excitatory amino acid (EAA) concentrations are balanced. B. In a peripheral nerve injury GABA release is decreased and EAA release is increased, resulting in neuropathic pain. C. In spinal cord stimulation, GABA level is restored (167). 37
38 Nerve injury produces major changes in glial morphology and function, thus altering the synaptic neuron-glia mediator balance. Changes in the concentration and balance of GABA and EAAs contribute to chronic pain. Both GABA and glutamate (one of the EAAs) require glutamine in their synthesis, which is synthesised in glial astrocytes. Also, communication between neurons and glial cells occurs via release of glutamate. Glial cells respond to electrical stimulation with depolarisation and glutamate release, showing amplitude and frequency dependency (112).
2.5.3 Patient selection
Spinal cord stimulation is an expensive and invasive procedure with potential com- plications and the need for a long-term commitment on the part of the patient.
The long-term direct and indirect costs for SCS patients may be significantly
reduced as compared to patients who undergo conventional management, but the initial cost of the device remains high (113). Patient selection is important to maximise treatment outcomes and minimise costs and should be done by a multidisciplinary team.
The primary purpose of SCS is to improve quality of life and physical function in the long term by reducing the severity of pain and its associated characteristics.
Indications for SCS are failed back surgery syndrome, other chronic neuropathic pain, complex regional pain syndrome (CRPS) and ischemic pain conditions (lower extremity claudication and refractory angina pectoris) (114). Selection criteria include a confirmed diagnosis of neuropathic pain without major sensory deafferentation, (2) chronic pain (> 6 months), (3) unresponsiveness to
conventional treatment or major side effects from conventional treatment and (4) an absence of contraindications (114).
Contraindications for SCS include general contraindications for surgery, such as uncontrollable bleeding disorder and systemic shock. Relative contraindications in clude cognitive impairment unless an adequate support system is established for the patient, unresolved psychological disorders and untreated substance abuse (115).
The final decision as to whether the patient is suitable for SCS is made by the im- planting physician. Preoperative imaging of thoraco-lumbar spine MRI is imperative to rule out previously absent pathology and exclude anatomical contraindications for implantation, such as osteophytes, stenosis or disc herniations narrowing the epidural space (117).
39 Once the decision is made to progress with SCS, a trial stimulation is
performed. During a trial of one to two weeks, patient satisfaction and degree of pain relief can be assessed. The decision to begin long-term SCS treatment is made with the patient.
2.5.4 Spinal Cord Stimulator device
The spinal cord stimulator device consists of an electrode (cylindrical or paddle type lead), which is connected to a pulse generator with or without an extension lead. During the trial, an external pulse generator is used and converted to an internal pulse generator, which is implanted under the skin if the pain relief is satisfactory. Cylindrical leads typically have four to eight contacts and are small in diameter. They can be inserted through a Tuohy needle under local anesthesia.
Paddle leads have a flat contact surface and usually have four to 16 contacts in a columnar or diamond-shaped arrangement (Figure 5).
Current is delivered through these contacts, and the field of electricity can be adjusted by activating one or more positive (anode) or negative (cathode) contacts.
The waveform of electrical pulses produced by the pulse generator typically has three parameters: amplitude – the strength of the pulse, measured in volts (V);
pulse width – the length of time a particular pulse is delivered, measured in micro- seconds (ms), and frequency – the number of times per second a pulse is
delivered, measured in Hertz (Hz).
In the last five years, new wave technologies have emerged. Emerging
technologies include Burst-SCS and High-Frequency SCS (HF SCS). Burst-SCS was approved by the US Food and Drug Administration (FDA) in 2016, and HF SCS was approved in 2015. Burst stimulation mimics thalamic bursting within the nervous system, delivering intermittent bursts of electrical pulses to the dorsal column of the spinal cord (118).
In HF SCS, stimulating pulses are given at a rate of > 1 kHz. The FDA-approved stimulation paradigm has a rate of 10 kHz. The pain relief mechanism of HF SCS remains to be discovered, but it has been shown to generate rapid and reversible conduction block in peripheral nerve models (119).
The difference between traditional “tonic” stimulation, in which electrical pulses are given with a specific amplitude, and the novel wave techniques is that tonic stimulation is perceived as paresthetic sensations, commonly described as tingling, pricking or buzzing in the affected area, whereas the novel wave techniques are paresthesia free (120). Various stimulation waveforms may
40 complement one another, and each can be used as a rescue therapy when
another stimulation form fails (121).
Figure 5. Spinal cord stimulation device.
2.5.5 Implantation technique 2.5.5.1 Surgical paddle lead
General anesthesia is used. The patient is prone on the chest rolls on a radiolucent operating table. A fluoroscopic image is obtained to confirm the thoracic level of the incision. In the thoracic region, the mark is place one level below the optimal placement of the surgical paddle-lead. The operation is done under an operating microscope.
A midline incision of 3 to 6 cm is made, and a normal hemilaminotomy approach is used, dissecting the subcutaneurous tissue, fascia and muscle insertions from the side of the approach. The interspinous ligament, processus spinosus and contralateral side remain intact. Hemilaminotomy is performed on the upper lamina. The resection of the yellow ligament should be restricted to fitting the paddle-lead to the epidural space in the region of the hemilaminotomy.
The spinal dura mater is exposed. Decompression is performed above the dura mater, with adequate lateral exposure, as well as further toward the midline and to contralateral side, with an undercutting technique.
The surgical paddle lead is placed into the epidural space from an oblique angle from the side of the surgeon and guided into the midline. The paddle leads’
location should be verified with an anteroposterior fluoroscopy after placement.
41 The paddle lead is then secured to the thoracolumbar fascia with an anchor.
Extensions are attached and externalised through subcutaneous tissue to either flank of the patient for a one-week trial.
2.5.5.2 Percutaneuous lead
Local anesthesia is used. The patient, prone on the chest rolls on a radiolucent operating table. The patient’s position is made as comfortable as possible. An anteroposterior fluoroscopy is used to mark the level of entry and bony landmarks for one upper and one lower vertebrae. A small puncture wound is made 1.5 cm lateral from the midline, and a Tuohy needle is inserted, preferrably at a 45-degree angle, into the posterior epidural space. The electrode lead is inserted through the needle, passing it to the target vertebrae level under fluoroscopic guidance. The level of initial electrode insertion is decided based on the dermatome or
dermatomes on which the patient feels the pain. The lateral placement may be on the midline or laterally offset ipsilateral to the pain location.
After the initial insertion, the affected area is identified, turning the stimulation on. The lead position is revised if necessary to ensure that the paresthesia covers the painful area of the body.
When the electrode is in place and the stimulus coverage is confirmed by the patent, the lead is secured to the thoracolumbar fascia with an anchor. Lateral and anteroposterior fluoroscopy is taken to ensure the correct placement of the lead.
Extensions are attached and externalised through subcutaneous tissue to either flank of the patient for a one-week trial.
2.5.5.3 Pulse generator
After one-week trial, the stimulation effect is evaluated. If the pain relief is sufficient, a permanent pulse generator is implanted under general anesthesia.
The patient is in the prone position. The extension lead is removed. A pocket for the pulse generator is pre- pared in the subcutaneuous tissue in the buttock or lower abdominal area. The electrode lead is tunneled to the prepared pocket and connected to the pulse generator (Figure 6).
42 Figure 6. Surgical electrode and pulse generator in place.
43 2.5.5.4 Programming
The stimulator is programmed with one or more alternative configurations (positive and negative contacts and waveform parameters) at the time of
implantation and at the ward, preferably by a specifically trained neuromodulation nurse (Figure 7) (122). The required stimulating currents vary widely between patients, postures, and lead placements (123). The patient can change the program and stimulation amplitude within a given limit with a remote-control device. By increasing the stimulation amplitude, more dorsal column fibers can be
recruited, which increases the intensity of the perceived paresthesia and enlarges the covered body area (124).
The therapeutic range of the stimulation is, however, limited, because high amplitudes may also activate dorsal root fibers, yielding an uncomfortable and even painful sensation (125).
Figure 7. Programmable elements.
2.5.6 Complications
Spinal cord stimulation is considered safe due to the reversibility of the procedure.
In the past, paddle leads were most often used because they migrated less often than percutaneous leads, keeping the paresthesia area constant. Paddle leads also had lower energy consumption, resulting in longer battery duration (126,127).
Over the years, fixation methods have evolved, and the current trend favors the use of percutaneous leads due to their mini-invasiveness.
Reported incidence of complications in SCS varies between 30 and 40% (128- 130). The most common complications are lead migration, wire fractures, hardware-related pain, infections, allergic reaction to the components,
haematoma and, in rare cases, a new neurological deficit. The lead-migration rate is higher with cylindrical electrodes than with paddle leads. The overall rate varies from 10 to 25%, but figures as high as 60 to 100% have also been reported (131).
Hardware-related problems are more common than biological complications, such as infections and wound breakdown. In the literature, infections leading to the removal of the electrode and pulse generator have an incidence rate of 3.4 to 10% (132,133). Staphylococcus aureus and Staphylococcus epidermidis are, by far, the most common organisms reported in SCS infections, and the pulse generator
44 pocket site is the most commonly infected area. Usually, infection occurs shortly after implantation or revision (133). Smoking, immunosuppressive medication and system diseases, such as diabetes or rheumatoid arthritis, can increase the risk of infections (134). Severe complications, including epidural abscess and irreversible neurological damage, are rare. Only single cases of complications with neurologic sequalae have been reported in the literature (131,135), and they seldom caused long-term morbidity. Removing surgically implanted paddle electrodes is
technically more demanding and riskier than removing percutaneously implanted cylindrical electrodes. Post-surgery anatomical distortion, scar tissue and an incomplete protective layer for the laminar bone increase the overall risk of intraoperative complications, such as dural tear and haematoma. In addition to the exposure of the paddle lead, its removal from the epidural space can cause mechanical trauma (136).
45
3 AIMS OF THE STUDY
I. To evaluate the long-term outcome of SCS in FBSS, as measured by (1) the explantation rate, (2) complications, and (3) patient satisfaction.
II. To study the effect of pre-implantation opioid use on SCS outcome and the effect of SCS on opioid use during a two-year follow-up period.
III. To study the effect of gabapentinoid use on SCS outcome measured by trial success, explantation rate and opioid dose reduction during a two-year follow-up.
46
61
5 HIGHER PREIMPLANTATION OPIOID DOSES ASSOCIATED WITH LONG-TERM SPINAL CORD STIMULATION FAILURE IN 211 PATIENTS WITH FAILED BACK SURGERY SYNDROME
5.1 INTRODUCTION
Opioid overuse is an increasing problem worldwide as evidenced by an increasing number of opioid-related overdose deaths (29,30). The risk of death in patients consuming over 80 mg/day of morphine milligram equivalents (MME) is sixfold, while in patients consuming over 120 MME/day, it is tenfold when compared with opioid-naïve patients (32,37). Concomitant use of benzodiazepines significantly elevates the risk of trauma, violence-related injuries, and overdose-related deaths (34,35). Opioid use is associated with cardiovascular diseases, motor vehicle accidents, and endocrinological dysfunction (39,40,71). In Finland, prevalence of opioid use increased from less than 1% to 7% from 1995 to 2016, which was explained by the change in the treatment of codeine-based opioids (41).
Simultaneously, there was a 68% increase in doctors’ prescriptions of strong opioids from 2012 to 2016 (149). Long-term opioid use may intensify and prolong neuropathic pain and may induce psychological impairment, especially in the case of strong opioids (42).
Failed back surgery syndrome (FBSS) is a difficult pain condition that lacks a curative treatment. For this reason, patients who respond poorly to other pain medications often start opioid treatment. According to current recommendations, these drugs should be used only as a third-line treatment, and the evidence supporting their use in treating neuropathic pain, such as FBSS, is only moderate (13,59,86,150).
An alternative pain relief method for FBSS is spinal cord stimulation (SCS), which has proven to be a safe, cost-effective, and efficacious treatment in selected patients experiencing neuropathic pain (61,126). However, despite the side effects of opioids, they are often started before trialing SCS. Here, we have presented a retrospective analysis of opioid use among FBSS patients treated with SCS in a single institution during a 17-year period. Our objectives were to analyze 1) the prevalence of opioid use among SCS patients compared to a matched sample of
62 the general population, 2) the effect of preimplantation opioid use on SCS
outcome, and 3) the effect of SCS therapy on opioid use, including the discontinuation of strong opioids, during a two-year follow-up period.
5.2 MATERIALS AND METHODS
5.2.1 Study population
Kuopio University Hospital (KUH) is a tertiary center that provides full-time acute and elective neurosurgical services for a catchment containing 850,000 people in Eastern and Central Finland. The study group consisted of all 211 patients who underwent an SCS trial for FBSS with a surgical paddle lead at KUH between January 1, 1997, and March 31, 2014. All patients were followed up for 24 months after the primary trial SCS implantation, and 147 were followed up for 60 months.
A specialist pain physician, neurosurgeon, or orthopedic surgeon made the FBSS diagnosis. Patients had undergone at least one previous lumbar decompressive surgery due to disc herniation or spinal stenosis but suffered from radicular lower limb pain alone or combined with lumbar pain. Initial treatment, including oral analgesics and physical therapy, was provided according to current best practice.
Patients with manifest psychiatric comorbidities were sent to psychiatric
consultation. Untreated depression and other serious psychiatric illnesses were considered a contraindication for SCS. No structured opioid tapering scheme was yet available in the participating pain clinics during the study period.
Patients (n = 211) were divided into three groups, which were as follows 1) SCS trial only with no permanent implantation (n = 47), 2) successful SCS (SCS
implanted and in use throughout the two-year follow-up period, n = 131), and 3) unsuccessful SCS (SCS implanted but later explanted or revised due to inadequate pain relief during the two-year follow-up period, n = 29). Patients who underwent explantation for reasons other than inadequate pain relief (n = 4) were excluded from the overall analysis (Fig. 10). All medical data from hospital records were reviewed for details regarding SCS treatment, complications, and revisions.
Baseline characteristics included age, gender, duration and localization of pain, and previ- ous lumbar surgeries and instrumented fusions. Patients’ reported subjective pain relief at three months was collected retrospectively from patient records.
63 Figure 10. Flow chart of 211 consecutive SCS patients with FBSS treated at Kuopio University Hospital between January 1, 1997, and March 31, 2014, and their opioid use before and during 24-months follow-up after implantation. *Indicates a statistically significant difference (p < 0.05) compared to the successful SCS group in the Fischer´s exact test.
