opioid tolerance and adherence and its pain clinics in
TRANSCRIPT
OPIOID TOLERANCE AND ADHERENCE AND ITS
RELATIONSHIP TO CYTOKINE CONCENTRATIONS
AMONG PATIENTS WITH NON-CANCER PAIN AT
PAIN CLINICS IN THREE TERTIARY HOSPITALS
BY
HUSSAM ABDELJABAR AHMAD MIZHER
A thesis submitted in fulfillment of the requirement for the
degree of Doctor of Philosophy in Pharmaceutical Sciences
(Pharmacy Practice)
Kulliyyah of Pharmacy
International Islamic University Malaysia
AUGUST 2019
ii
ABSTRACT
Introduction: Opioids are strong analgesics that have been used for centuries for the
treatment of pain. The long-term use of opioid in chronic non-cancer pain (CNCP) is
controversial as the available evidence is limited to short term efficacy and side effects.
Several concerns are raised regarding the long-term use of opioids in CNCP, and most
of these concerns were linked to unclear adherence to opioid therapy, increased risks of
opioid tolerance, abuse, addiction, and opioid overdose death. Methods: This
prospective cross-sectional study was conducted among patients with noncancer pain
attending pain clinics at three tertiary hospitals in Malaysia from March 2016 to
February 2017. Patients’ medical records and prescription records were assessed. Blood
samples were also taken for the assessment of pro-inflammatory cytokine interleukin
(IL-6) and anti-inflammatory (IL-10). The opioid plasma concentrations were also
measured using LCMSMS. Patients were categorized into short-term opioid users and
long-term opioid users based on the use of opioids >90 days. For long-term opioid users,
they were further categorized into adherent and non-adherent based on medication
possession ratio (MPR). Prevalence of patients with opioid therapy was also recorded.
Opioid tolerance was investigated based on the significant increment in opioid dose
throughout treatment. This measure of tolerance was then correlated with pro-
inflammatory IL-6 and anti-inflammatory IL-10. Results: Prevalence of opioid use
among 726 pain patients attending the pain clinic during the study period was 11.9%
(n=87/726). Thirty-eight patients were recruited into the study. Of these, 24% (n=9/38)
were short term opioid users, and 76% (n=29/38) were long-term, opioid users. Among
29 patients using opioids for long-term (> 90 days), 62% (n=18/29) of these patients
were adherent to opioid therapy while 38% (n=11/29) of patients showed non-adherence
to opioid therapy. The correlation between both cytokines showed a strong correlation
for long- and short-term users, respectively. The opioid plasma concentrations revealed
that the majority of long- and short-term users had their plasma concentration within
the therapeutic range. Further correlation showed that the plasma concentration measure
and the medication possession ratio have moderate strength correlation. The mean dose
in oral morphine equivalence (OMEQ) for the long-term users was higher (42.8 ± 11.1
mg/day) than with short-term users (13.6 ± 2.7 mg/day) while the small opioid doses of
less than 20 OMEQ was the most common doses prescribed for long- and short-term
users. Opioid tolerance was common in long-term opioid users and to a lesser extent in
short-term users. Moreover, the mean plasma concentration of anti-inflammatory IL-10
was significantly higher among opioid intolerant patients than among opioid-tolerant
patients There was a significant positive correlation between the pro-inflammatory IL-
6 concentration and pain intensity in the tolerant opioid users. Conclusion: The results
of this study demonstrated that most patients used opioids for the long-term for their
non-cancer pain, and the majority of long-term opioid users were adherent to their
opioid therapeutic plan. The indirect measure of adherence using prescription refills
calculated by medication possession ratio was found to be well correlated with the direct
measure of adherence characterized by the opioid plasma concentrations. This study
provides evidence for clinical practice to confidently use the indirect measure of
adherence to assess patients’ behavior to opioid therapy and also further cautions
clinician on the risk of opioid tolerance in patients with long-term opioid therapy.
iii
خلاصة البحث
ائلة أدوية الأفيون من أهم مسكنات الألم والتي بدورها استعملت لعقود لتخفيف الآلام. : تعتبرعالمقدمةيعدّ استعمال الأفيونات في الآلام غير السرطانية طويلة الأمد مثارا للجدل، بسبب نقص الأدلة العلمية
ثثلاالألم في ةد: أجريت هذه الدراسة على مرضى ألم غير سرطاني مزمن مرتادي عياالطريفة. ومحدوديتهاتم تصنيف المرضى إلى مرضى طويلي .2017وشباط 2016في ماليزيا في الفترة بين آذار اتستشفيم
يوم خلال السنة. وتم تصنيف 90الأمد وقصيري الأمد بناء على استعمال المورفينات لمدة تزيد أو تقل عن هذهوتم ربط . على نسبة إمتلاكهم للدواء المرضى طويلي الأمد إلى ملتزمين بالدواء وغير ملتزمين بناء
والسيتوكين مضاد الالتهاب 6-المقاييس للتعود على المورفينات مع السيتوكين المحفز للالتهاب انترلوكينمل دم وتم قياس مستوى السيتوكينات 10. لجميع المرضى المشاركين في الدراسة تم سحب 10-انترلوكين
مريض ارتادوا العيادة خلال فترة الدراسة كان 726استعمال المورفينات ضمن : شيوع النتائج. والمورفينات% طويلي الأمد. 76% قصيري الأمد و 24من المرضى وظفوا في الدراسة، ومنهم %38. 11.9
أظهر التقارب لكلا % غير ملتزمين.38% ملتزمين يالدواء و 62ضمن طويلي الأمد كان هناك تركيز المورفينات في الدم أظهر أن معظم للمرضى طويلي الأجل وقصيري الأجل.السيتوكينات تقاربا قوياً
وأظهر التقارب بين مقياس إمتلاك الدواء المرضى طويلي وقصيري الأمد كانوا ملتزمين بالعلاج بشكل جيد± 42.11) لمورفين كانتلوتركيز المورفينات في الدم تقارياً متوسط القوة. متوسط الجرعة اليومية المكافئة
( مجم مورفين لطويلي وقصيري الأمد على الترتيب، بينما الجرعة الخفيفة بأقل 2.7± 13.06( و )11.1التعود على المورفينات كان أكثر شيوعاً في مجم يومياً كانت الأكثر شيوعا ضمن المجموعتين. 20من
في اليلازما كان أعلى 10-الطويلي الأمد منه في قصيري الأمد، وتركيز السيتوكين مضاد الالتهاب بشكل ملحوظ في المرضى غير المعتادين على المورفينات منه في المعتادين على المورفينات. كان هناك ارتباط
نت نتائج هذه الدراسة : بيّ الخلاصة و شدة الألم في المعتادين على المورفينات. 6-فوي ملحوظ بين الث استعمالهم للمورفينات. وأن معظمهم كانوا ملتزمين بالدواء أن معظم المرضى كانو طويلي الأمد من حي
بشكل جيد. المقياس غير المياشر للالتزام الدوائي أظهر أنه مرتبط بشكل وثيق مع تركيز المورفينات فيزودت هذه الدراسة الدليل العلمي للمارسة السريرية لاستعمال طريفة حساب الالتزام الدوائي البلازما.شرة لمعاينة سلوك المرضى تجاه المورفينات وللفت نظر المعالجين للأخطار المرتيطة لاستعمال المورفينات غير المبا
طويل الأمد.
iv
APPROVAL PAGE
The thesis of Hussam Abdeljabar Ahmad Mizher has been approved by the following:
_____________________________
Che Suraya Bt. Hj. Mohd Zin
Supervisor
_____________________________
Abul Bashar Mohammed Helaluddin
Co-Supervisor
_____________________________
Rozilah @ Abdul Hadi Bin Mohamed
Co-Supervisor
_____________________________
Tariq Abdul Razak
Internal Examiner
_____________________________
Patrick Anthony Ball
External Examiner
_____________________________
Syed Azhar bin Syed Sulaiman
External Examiner
_____________________________
Muhammed Bin Ibrahim
Chairman
v
DECLARATION
I hereby declare that this thesis is the result of my own investigation, except where
otherwise stated. I also declare that it has not been previously or concurrently submitted
as a whole for any other degrees at IIUM or other institutions.
Hussam Abdeljabar Ahmad Mizher
Signature………………………. Date ……………………
vi
INTERNATIONAL ISLAMIC UNIVERSITY MALAYSIA
DECLARATION OF COPYRIGHT AND AFFIRMATION OF
FAIR USE OF UNPUBLISHED RESEARCH
OPIOID TOLERANCE AND ADHERENCE AND ITS
RELATIONSHIP TO CYTOKINE CONCENTRATIONS AMONG
PATIENTS WITH NON-CANCER PAIN AT PAIN CLINICS IN
THREE TERTIARY HOSPITALS
I declare that the copyright holder of this thesis jointly owned by Hussam Abdeljabar
Ahmad Mizher and IIUM.
Copyright ©2019 by Hussam Abdeljabar Ahmad Mizher and International Islamic University
Malaysia. All rights reserved.
No part of this unpublished research may be reproduced, stored in a retrieval system, or
transmitted, in any form or by any means, electronic, mechanical, photocopying,
recording or otherwise without prior written permission of the copyright holder except
as provided below.
1. Any material contained in or derived from this unpublished research may
be used by others in their writing with due acknowledgement.
2. IIUM or its library will have the right to make and transmit copies (print or
electronic) for institutional and academic purposes.
3. The IIUM library will have the right to make, store in a retrieval system and
supply copies of this unpublished research if requested by other universities
and research libraries.
By signing this form, I acknowledged that I have read and understand the IIUM
Intellectual Property Right and Commercialization policy.
Affirmed by Hussam Abdeljabar Ahmad Mizher
……..……..…………… …………..…………..
Signature Date
vii
ACKNOWLEDGEMENTS
This work would never have been possible or completed without the support and
guidance of several people in my life. First, I would like to express my very great
appreciation to my supervisor, Dr Che Suraya Bt. Hj. Mohd Zin for her exemplary
guidance, monitoring and constant support throughout the period of the study, and for
all the valuable advices she provides. I also take this opportunity to express a deep sense
of gratitude to my co-supervisors Dr Abul Bashar Mohammed Helaluddin and Dr
Rozilah @ Abdul Hadi Bin Mohamed.
I would also like to extend my thanks to all the pain clinics medical officers,
nurses, staff for their efforts and supports during samples collection.
I am deeply thankful for International Islamic University Malaysia, and The
Malaysian Ministry of Education for funding this study by the research grants.
Many thanks to my postgraduate friends, who supported and always shared me
valuable advices and experiences.
Finally, this thesis is dedicated to the memory of my beloved father, and to my mother
and family for their invaluable support throughout my life.
viii
TABLE OF CONTENTS
Abstract .......................................................................................................................... ii Abstract in Arabic ......................................................................................................... iii Approval page ............................................................................................................... iv
Declaration ..................................................................................................................... v Copyright ...................................................................................................................... vi Acknowledgements ...................................................................................................... vii Table of Contents ........................................................................................................ viii List of Tables ............................................................................................................... xii
List of Figures ............................................................................................................. xiii
CHAPTER ONE: INTRODUCTION ........................................................................ 1 1.1 Background of study ..................................................................................... 1 1.2 Problem statement ........................................................................................ 3 1.3 Significance of the study .............................................................................. 4 1.4 Objective(s) of the research .......................................................................... 5
1.5 Study summary ............................................................................................. 5
CHAPTER TWO: LITERATURE REVIEW ........................................................... 8 2.1 Pain ............................................................................................................... 8
2.1.1 Chronic pain: Definition and prevalence ........................................... 8
2.1.2 Pathophysiology of chronic pain ........................................................ 9
2.1.3 Pain assessment ................................................................................ 11 2.1.4 Pain management ............................................................................. 12 2.1.5 Opioid in chronic non-cancer pain ................................................... 14
2.2 Opioid adherence ........................................................................................ 15 2.2.1 Medication Possession Ratio (MPR) as a measure of adherence .... 17
2.2.2 Prevalence of non-adherence in chronic non-cancer pain
patients: ..................................................................................................... 19
2.2.3 Factors affecting adherence.............................................................. 19 2.3 Cytokines .................................................................................................... 21
2.3.1 Cytokines in peripheral .................................................................... 22
2.3.2 Glial cells and the cytokines centrally ............................................. 24
2.3.3 Cytokine and opioid ......................................................................... 25 2.3.4 Cytokines analysis ............................................................................ 26
2.4 Opioid tolerance.......................................................................................... 26
2.4.1 Opioid tolerance in chronic pain patients......................................... 28 2.4.2 Assessment of opioid tolerance ........................................................ 29 2.4.3 Assessment of pain intensity and side effects .................................. 31 2.4.4 Blood opioid concentration .............................................................. 31
2.5 Overview of opioids included in the present study .................................... 32
2.5.1 Oxycodone ....................................................................................... 32 2.5.2 Dihydrocodeine ................................................................................ 33 2.5.3 Fentanyl ............................................................................................ 33 2.5.4 Buprenorphine .................................................................................. 34
2.5.5 Morphine .......................................................................................... 34
ix
2.5.6 Overview of opioids pharmacokinetics and therapeutic range ........ 35
CHAPTER THREE: METHODOLOGY ................................................................ 37 3.1 Study design and data source ...................................................................... 37
3.1.1 Study design ..................................................................................... 37 3.1.2 Study site .......................................................................................... 37 3.1.3 Study medications ............................................................................ 37 3.1.4 Study population .............................................................................. 38
3.1.4.1 Inclusion and exclusion criteria ............................................ 39 3.1.5 Patient recruitments .......................................................................... 39
3.1.5.1 Duration of opioid use ........................................................... 41 3.1.5.2 Informed consent forms ......................................................... 41
3.1.6 Patient assessment ............................................................................ 42 3.1.6.1 Patients characteristics ......................................................... 42 3.1.6.2 Prescription for opioids ......................................................... 42
3.1.6.3 Pain intensity ......................................................................... 43 3.1.6.4 Side effects ............................................................................. 44
3.1.7 Blood sampling, analysis, and storage ............................................. 44 3.1.7.1 Sample collection ................................................................... 45
3.2 Quantification of proinflammatory cytokine IL-6 and anti-
inflammatory cytokine IL-10 concentration in plasma using multiplex
assay .................................................................................................................. 46 3.3 Opioid plasma concentration using LCMS/MS .......................................... 49
3.3.1 Materials and methods ..................................................................... 50
3.3.1.1 Chemicals and reagents ........................................................ 50 3.3.1.2 Instruments and devices ........................................................ 50
3.3.2 Bioanalytical method simple optimization and verification ............ 51 3.3.2.1 Preparation of standards stock solutions .............................. 51
3.3.2.2 Optimization of chromatographic conditions ........................ 52 3.3.2.3 Mobile phase optimization .................................................... 53 3.3.2.4 Blank plasma preparation ..................................................... 54
3.3.2.5 Plasma extraction by protein precipitation technique .......... 55
3.3.3 Bioanalytical simple method verification ........................................ 55 3.3.3.1 Selectivity and specificity ...................................................... 55 3.3.3.2 Calibration and linearity ....................................................... 56 3.3.3.3 The lower limit of quantification ........................................... 56
3.3.4 Precision and accuracy ..................................................................... 57 3.3.4.1 Recovery and matrix effect .................................................... 57 3.3.4.2 Stability .................................................................................. 58
3.3.4.3 Statistical analysis for LCMSMS method verification ........... 58 3.4 Quantification of opioid plasma concentrations in patients with short-
and long-term opioid therapy ........................................................................... 59 3.4.1 Optimizing a method of verification for each opioid used in the
study using Liquid Chromatography-Mass Spectrometry-Mass
Spectrometry technique ............................................................................. 59 3.4.1.1 Selectivity and specificity ...................................................... 59 3.4.1.2 Dihydrocodeine ..................................................................... 59 3.4.1.3 Oxycodone ............................................................................. 60
3.4.1.4 Fentanyl ................................................................................. 61
x
3.4.1.5 Buprenorphine ....................................................................... 62
3.4.1.6 Morphine ............................................................................... 63 3.4.2 Calibration and linearity ................................................................... 64
3.4.2.1 Dihydrocodeine ..................................................................... 65 3.4.2.2 Oxycodone ............................................................................. 66 3.4.2.3 Fentanyl ................................................................................. 66 3.4.2.4 Buprenorphine ....................................................................... 67 3.4.2.5 Morphine ............................................................................... 68
3.4.3 Precision and accuracy ..................................................................... 68 3.4.3.1 Dihydrocodeine ..................................................................... 68 3.4.3.2 Oxycodone ............................................................................. 69 3.4.3.3 Fentanyl ................................................................................. 69
3.4.3.4 Buprenorphine ....................................................................... 70 3.4.3.5 Morphine ............................................................................... 71
3.4.4 The lower limit of quantification ..................................................... 71
3.4.5 Recovery and matrix effect .............................................................. 72 3.4.6 Stability ............................................................................................ 72
3.5 Study flow chart .......................................................................................... 73 3.6 Outcome measures ...................................................................................... 74
3.6.1 Prevalence ........................................................................................ 74 3.6.2 Opioid adherence ............................................................................. 74
3.6.3 Plasma concentrations of pro-inflammatory cytokine IL-6 and
anti-inflammatory cytokine IL-10 in adherent and non-adherent
group ......................................................................................................... 75
3.7 Opioid tolerance.......................................................................................... 76 3.7.1 Opioid daily dose in oral morphine equivalence (OMEQ) .............. 76
3.7.2 Documenting opioid tolerance ......................................................... 78 3.8 Ethics approval ........................................................................................... 79
3.9 Statistical analysis ....................................................................................... 79
CHAPTER FOUR: RESULTS AND FINDINGS ................................................... 81 4.1 Patients assessment ..................................................................................... 81
4.1.1 Study subjects and prevalence of opioid use.................................... 81 4.1.2 Patient’s demographics .................................................................... 82 4.1.3 Pain intensity .................................................................................... 84 4.1.4 Side effects ....................................................................................... 85
4.1.4.1 Drowsiness ............................................................................ 86 4.1.4.2 Constipation ........................................................................... 87 4.1.4.3 Other side effects ................................................................... 88
4.2 Outcome measures ...................................................................................... 89 4.2.1 Days covered with opioids ............................................................... 89 4.2.2 Adherence measurement using MPR ............................................... 89
4.2.2.1 Correlation between MPR and pain intensity ........................ 90 4.3 Plasma concentrations of pro-inflammatory cytokine, IL-6 and anti-
inflammatory cytokine, IL-10 in patients with short- and long-term opioid
therapy .............................................................................................................. 91 4.3.1 Plasma concentration of IL-6 and IL-10 in patients with long-
term and short-term opioid therapy ........................................................... 92
xi
4.3.2 Plasma concentration of IL-6 and IL-10 in adherent and non-
adherent groups among patients with long-term opioid therapy ............... 93 4.3.3 Correlation between IL-6 and IL-10 concentrations in patients
with short- and long-term opioid therapy.................................................. 94 4.4 Opioid quantification in plasma samples .................................................... 96
4.4.1 Plasma opioid concentrations in patients with short- and long-
term opioid users ....................................................................................... 98 4.4.2 Correlation between plasma opioid concentration and
medication possession ratio ...................................................................... 99 4.5 Opioid tolerance........................................................................................ 100
4.5.1 Opioid daily dose in oral morphine equivalence (OMEQ) ............ 100 4.5.2 Documenting opioid tolerance ....................................................... 103
4.5.3 Comparison of plasma opioid concentration in tolerant and
intolerant opioid users ............................................................................. 106 4.5.4 Comparison of cytokine concentrations among tolerant and
intolerant opioid patients ......................................................................... 107 4.5.5 Correlation between IL-6 and IL-10 concentrations in tolerant
and intolerant patients among long-term opioid therapy ........................ 109 4.5.6 Correlation of cytokine concentration with pain score and its
relation to opioid tolerance...................................................................... 111
CHAPTER FIVE :DISCUSSION ........................................................................... 114 5.1 Study limitations ....................................................................................... 129
CHAPTER SIX: CONCLUSIONS ......................................................................... 131 6.1 Conclusions .............................................................................................. 131
6.2 Future works ............................................................................................. 133
REFERENCES ......................................................................................................... 134
APPENDIX I: LIST OF PUBLICATION AND CONFERENCES .................... 158
APPENDIX II: PATIENT INFORMATION SHEET .......................................... 160 APPENDIX III: CONSENT FORM ...................................................................... 162
APPENDIX IV: ETHICAL APPROVAL ............................................................. 165 APPENDIX V: CONCOMITANT MEDICATIONS ........................................... 166 APPENDIX VI: CASE REPORT FORM .............................................................. 170
xii
LIST OF TABLES
Table 2-1 The main routes of administration, half-life, and metabolites 35
Table 2-2 Therapeutic and minimal lethal concentration of opioids 36
Table 3-1 List of available opioids at the pain clinic 38
Table 3-2 Assessment of opioid side effect 44
Table 3-3 Stock solution preparation 52
Table 3-4 Mass spectrometry conditions 53
Table 3-5 Mobile phase conditions for dihydrocodeine 54
Table 3-6 Mobile phase conditions for oxycodone 54
Table 3-7 Mobile phase conditions for fentanyl 54
Table 3-8 Precision and accuracy test for dihydrocodeine 69
Table 3-9 Precision and accuracy test for oxycodone 69
Table 3-10 Precision and accuracy test for fentanyl 70
Table 3-11 Precision and accuracy test for buprenorphine 70
Table 3-12 Precision and accuracy test for morphine 71
Table 3-13 Lower limits of quantification 71
Table 3-14 Morphine equivalent dose 77
Table 4-1 Demographic details of recruited patients 83
Table 4-2 Number of patients of each type of side effects of opioids 88
Table 4-3 Details of mean plasma concentration for the study patients 97
xiii
LIST OF FIGURES
Figure 2-1 World Health Organization pain relief ladder 13
Figure 3-1 Patient recruitment procedure 40
Figure 3-2 Visual Analogue Scale (VAS) 43
Figure 3-3 Blood sampling, processing, and storage protocol 45
Figure 3-4 Flowchart for the procedure of Multiplex analysis 48
Figure 3-5 LCMSMS chromatogram of dihydrocodeine for specificity test 60
Figure 3-6 LCMSMS chromatogram of oxycodone for the specificity test 61
Figure 3-7 LCMSMS chromatogram of fentanyl for the specificity test 62
Figure 3-8 LCMSMS chromatogram of buprenorphine for specificity test 63
Figure 3-9 LCMSMS chromatogram of morphine for the specificity test 64
Figure 3-10 Linear curve of dihydrocodeine 65
Figure 3-11 Linear curve of oxycodone 66
Figure 3-12 Linear curve of fentanyl 67
Figure 3-13 Linear curve of buprenorphine 67
Figure 3-14 Linear curve of morphine 68
Figure 3-15 Recovery test 72
Figure 4-1 Study subject flowchart 82
Figure 4-2 Mean pain score for short- and long-term users 84
Figure 4-3 Percentage of patients with mild, moderate and severe pain 85
Figure 4-4 Side effects of opioid therapy 86
Figure 4-5 Drowsiness as a side effect for opioid therapy 87
Figure 4-6 Constipation as a side effect for opioid therapy 88
Figure 4-7 Distribution of Medication Possession Ratio per patient for
long-term 89
Figure 4-8 Percentage of adherent and non-adherent patients among long-term 90
xiv
Figure 4-9 Scatter plots of the relationship between Medication Possession
Ratio (MPR) and pain intensity 91
Figure 4-10 The comparison of IL-6 concentration versus IL-10 concentration
within the same group of short- and long-term users 93
Figure 4-11 The comparison of IL-6 concentration versus IL-10
concentration among adherent and non-adherent long-term
users 94
Figure 4-12 Correlation between IL-6 and IL-10 concentration in long-term
users 95
Figure 4-13 Correlation between IL-6 and IL-10 concentration in short-term
users 95
Figure 4-14 Estimation of the plasma concentration in long-term and short-term
opioid users 98
Figure 4-15 Percentage of adherent and non-adherent patients who have plasma
concentration within or out of therapeutic range 100
Figure 4-16 The mean daily opioid dose for short- and long-term opioid users 101
Figure 4-17 Comparison of opioid dose rank among long-term and short-term
opioid users 102
Figure 4-18 Comparison of opioid dose rank among adherent and non-adherent
opioid users 103
Figure 4-19 Dose increment between the initial dose and last dose in short and
long-term users 104
Figure 4-20 Dose increment between the initial dose and last dose in adherent
and non-adherent long-term opioid users 105
Figure 4-21 Comparison of the plasma concentration among tolerant and
intolerant opioid users 107
Figure 4-22 IL-10 concentration is significantly higher in opioid intolerant
patients than in opioid-tolerant patients 108
Figure 4-23 IL-16 concentration has no significant difference between opioid
intolerant patients and opioid-tolerant patients 108
Figure 4-24 The comparison of IL-6 concentration versus IL-10 concentration
within the same group of opioid tolerant and intolerant 109
Figure 4-25 Correlation between IL-6 and IL-10 concentration in tolerant long-
term users 110
xv
Figure 4-26 Correlation between IL-6 and IL-10 concentration in intolerant
long-term users 110
Figure 4-27 Significant correlation between pain intensity and IL-6
concentration among opioid-tolerant patients 111
Figure 4-28 Lack of significant correlation between pain intensity and IL-6
concentration among opioid intolerant patients 112
Figure 4-29 Lack of significant correlation between pain intensity and IL-10
concentration among opioid-tolerant patients 112
Figure 4-30 Lack of significant correlation between pain intensity and IL-10
concentration among opioid intolerant patients 113
1
INTRODUCTION
1.1 BACKGROUND OF STUDY
Opioids are potent analgesics that have been used for centuries for the treatment of pain.
Opioids such as morphine and codeine were among the first substances initially
discovered from the natural sources of the opium plant. Later, semisynthetic opioids
(e.g., oxycodone and hydromorphone) and fully synthetic opioids (e.g., fentanyl and
hydrocodone) were introduced. Different types of opioids show different levels of
clinical potency because their affinities toward opioid receptors (μ, δ, κ) vary.
Morphine, fentanyl, and oxycodone have high clinical potency and are considered as
potent opioids and commonly known as strong opioids. Codeine and dihydrocodeine
have less clinical potency and are considered as weak opioids.
Opioid use for acute pain following surgery and cancer pain is well established
indications and has been extensively described in the literature (Ahmedzai et al., 2015;
Kang et al., 2015; Lazzari et al., 2015; Mercadante et al., 2015; Porta Sales, Garzón
Rodríguez, Villavicencio Chávez, Llorens Torromé, & González Barboteo, 2016).
However, the long-term use of opioid in chronic non-cancer pain (CNCP) is
controversial as the available evidence is limited to short-term efficacy and side effects
(Laxmaiah Manchikanti, Sairam Atluri, & Hans Hansen, 2014). Some concerns are
raised regarding the long-term use of opioids in CNCP, and the majority of these
concerns were linked to increased risks of opioid tolerance, abuse, addiction, and opioid
overdose death. It is reported that in the United States the opioid overdose deaths has
increased four-fold over the last decade (Jones, Mack, & Paulozzi, 2013).
2
Opioid overdose deaths are commonly associated with the utilization of higher
doses (Y. Liang, Turner, Barbara J, 2015). Opioid doses of 50-99 mg morphine
equivalent dose per day was reported to increase the risk of opioid overdose by 3.7-fold,
while opioid doses of 100 mg or higher per day had increased the overdose risk by 8.9
fold compared with the low doses of 1-20 mg morphine equivalent per day (Dunn et al.,
2010). Similarly, other findings have documented that the risk of opioid overdose death
was higher in patients using doses more than 100 mg morphine equivalent per day
compared with lower doses of less than 20 mg per day (Bohnert et al., 2011). A higher
dose of opioid is required in providing the same amount of pain relief as provided by
previous lower opioid doses is caused by opioid tolerance that occurs following
repeated or prolonged opioid administration (Control & Prevention, 2012).
Opioid tolerance can be documented using opioid blood concentration. Naïve
patients reach adequate analgesia using relatively small opioid doses and at low opioid
plasma concentration; while tolerant patients require much higher opioid doses that
might even be considered as toxic for naïve subjects. Plasma opioid concentration is
relatively considered a novel tool of opioid monitoring which can demonstrate treatment
adherence/compliance and is warranted in problematic situations where optimal opioid
analgesia is challenging to attain. Apart from adherence/compliance, opioid plasma
concentration can also monitor clinical effectiveness and prescribing patterns that are
not available with traditional urine drug testing (UDT). Based on the complexity of both
achieving acceptable outcomes with opioid treatment and the legal and societal issues
at hand, the addition of opioid plasma concentration levels will become the standard of
care in the near future (Starrels et al., 2010).Adherence to opioid treatment is vital in
achieving treatment goals. Poor adherence is accompanied by the increase in morbidity
3
and mortality, treatment cost and worsening in the overall health outcomes (Choudhry,
Denberg, & Qaseem, 2016).
Currently available pharmacological treatment for CNCP which include
opioids, antidepressants and anticonvulsants are all target neurons for pain control. In
the last decades, there has been increasing evidence that cytokines produced by non-
neuronal cells play a crucial role in the establishment and/or maintenance of chronic
pain. Pro-inflammatory cytokines such as the interleukins, IL-1β and IL-6, appear to
exacerbate pain while anti-inflammatory cytokines such as IL-10 appear to ameliorate
pain. The potential role of cytokines in compromising the analgesic effects of opioids
has also been recognized. An improved understanding of the cytokines ability to
modulate opioid analgesia has the potential to improve the clinical utility of opioid
analgesics in the management of chronic pain.
Thus far, opioids have been increasingly used for the treatment of CNCP despite
all the concerns mentioned above. The occurrence of opioid tolerance is not well
characterized, and the effective monitoring tool for opioid tolerance is lacking. The
issue related to opioid adherence is also unclear. As such, this study was prompted to
investigate the occurrence of opioid tolerance and its association with opioid blood and
cytokines concentration in plasma of patients with non-cancer pain receiving short- and
long-term opioid therapy for pain management. Adherence to prescribed opioids will
also be examined and will be correlated with the occurrence of opioid tolerance.
1.2 PROBLEM STATEMENT
Issues related to opioid tolerance are poorly investigated.
Issues linked with adherence to opioid therapy are also unclear.
4
The association between opioid tolerance and adherence to opioid is not well
characterized.
The association between the role of cytokines and opioid blood
concentration with the development of opioid tolerance is not well
understood.
1.3 SIGNIFICANCE OF THE STUDY
The increasing use of opioids for long-term therapy in non-cancer pain has
been linked with an increasing incident of opioid overdose death, and opioid
tolerance is one of the greatest risks contributed to this overdose death
(Rosenquist & Fishman, 2019; W. Zhu, Chernew, Sherry, & Maestas, 2019;
C. S. Zin et al., 2019). The outcomes of this research will provide evidence
on the occurrence of opioid tolerance and how this tolerance associated with
adherence to opioid therapy.
The opioid plasma concentration and the cytokine level included in this
study will further characterize the occurrence of opioid tolerance. The
measure of opioid plasma concentration will further confirm the adherence
that was calculated using the opioid prescription refills. If the finding on the
adherence (calculated using the opioid prescription refills) were found to be
well correlated with the opioid plasma concentration, in future, this method
of adherence assessment could be used in clinical practice without the need
to assess the blood sample from patients. Therefore, opioid tolerance could
be predicted based on prescription-calculated adherence to opioid therapy.
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1.4 OBJECTIVE(S) OF THE RESEARCH
This study aims to investigate the correlation between opioid tolerance and adherence
to opioid therapy and its association with the opioid blood and cytokine concentration
in patients with non-cancer pain using opioids for short- and long-term therapy. The
outcomes between short- and long-term opioid users will be compared.
The specific objectives include:
To evaluate the adherence to opioid therapy using the opioid prescription
records.
To quantify the plasma concentrations of pro-inflammatory cytokines
(IL-6) and anti-inflammatory cytokines (IL-10) using multiplex ELISA
and to correlate the cytokine concentrations with opioid adherence.
To quantify the opioid plasma concentrations using the Liquid
Chromatography-Mass Spectrometry-Mass spectrometry (LC/MSMS)
analysis.
To examine opioid tolerance by evaluating the opioid dose, pain
intensity, and opioid side effects and to correlate the occurrence of
opioid tolerance with the adherence measure
To correlate the levels of opioid and cytokines concentrations in the
plasma with the occurrence of opioid tolerance and adherence to opioid.
1.5 STUDY SUMMARY
This thesis consisted of 6 chapters; introduction, literature review, methods, results and
findings, discussion and conclusion. Chapter one introduces the rationale for the study
and endorse the gap in our knowledge regarding the opioid use in non-cancer pain and
the limited evidence for the safety and efficacy of the opioid use for long-term in this
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population, especially highlighting the lack in our knowledge regarding opioid
adherence and the potential role for the proinflammatory cytokine, IL-6, and the anti-
inflammatory cytokine, IL-10, in developing opioid tolerance.
Chapter two summarizes the available evidence and the published literature to
endorse previous work investigating opioid use in non-cancer pain with a special focus
on the topics of opioid adherence and development of opioid tolerance and how do these
measures correlate with the pro-inflammatory cytokine, IL-6, and the anti-inflammatory
cytokine, IL-10. Further review for plasma opioid concentration in non-cancer pain
patients and the therapeutic range for opioids were then summarized.
Chapter three summarizes the methods applied throughout this thesis; the first
part investigated the prevalence of opioid utilization among chronic pain patients. The
second part recruited 38 current opioid users, and their medical and prescription records
were assessed for demographic information, diagnosis, and history of opioid use, and
they were asked to rank their pain intensity and severity of side effects. After that, a 10
ml blood samples were collected from recruited patients where plasma was extracted
and stored for further quantification of cytokine (by Multiplex ELISA) and opioid
concentrations (by LCMSMS).
After that, the recruited patients were further categorized based on the opioid
use for more than 90 days per year into long- and short-term users. Adherence among
long-term users was calculated using the indirect measure, medication possession
ration.
Opioid tolerance was also examined in recruited patients by exploring any
significant increase in opioid dose over time, where further comparisons among opioid-
tolerant and intolerant patients took place to compare cytokines level, plasma
concentrations, and pain intensity.
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Chapter four presented the results and findings of the study; the first comparison
was made between long- and short- term users in their pain intensity and side effects.
They were followed by investigating opioid adherence among long-term users, and the
correlation between patients’ adherence and pain intensity.
The IL-6 and IL-10 cytokine levels were compared between long- and short-
term opioid users, and between adherent and non-adherent long-term opioid users. After
that, plasma opioid concentration was compared among long- and short-term opioid
users and was correlated with the therapeutic range for each stipulated opioid. The
further correlation was conducted to test the strength of the correlation between
medication possession ratio as a measure of adherence and the opioid plasma
concentration.
The last section of chapter four describes the doses used among long- and short-
term users and assess tolerance development. Furthermore, comparisons between
cytokines levels and opioid plasma concentration were assessed, and correlations of
cytokines level with pain intensity, and it is relation to opioid tolerance were presented.
Chapter 5 discussed and compared the thesis findings with previous literature and
chapter 6 conclude and summarized the main and the significant outcomes and highlighted
the new outcomes.
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LITERATURE REVIEW
2.1 PAIN
Pain is defined by The International Association for the Study of Pain (IASP) as “an
unpleasant sensory and emotional experience associated with actual or potential tissue
damage, or described in terms of such damage” (Loeser & Treede, 2008). Pain is linked
with many health conditions (such as cancer, rheumatoid arthritis, fibromyalgia, and
postherpetic neuralgia, chronic back pain), and pain control remains the top priority for
these conditions.
2.1.1 Chronic Pain: Definition and prevalence
Chronic pain can be defined as the pain that persists for three months, or more and\or
exceed the healing time required for the damaged tissue (Williams & Craig, 2016).
However, acute pain is usually self-limiting and does not persist for longer than three
months compared with chronic pain which can persist for life long (Schug, Palmer,
Scott, Halliwell, & Trinca, 2016). Another pain classification distinguishes types of pain
based on the presence or absence of cancer into cancer pain, the pain due to cancer or
its treatment, and non-cancer pain. The latter can be either inflammatory,
musculoskeletal, or neuropathic (Baron, 2006).
Prevalence of chronic pain varies widely throughout the world. It was reported
as low as 7% and 8.7% in Malaysia and Singapore respectively(Cardosa, Gurpreet, &
Tee, 2008; "Malaysian Association for the Study of Pain," 2015; Yeo & Tay, 2009),
and up to 64.4% in the United States (Watkins, Wollan, Melton III, & Yawn, 2007). In
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the United Kingdom, the prevalence of chronic pain ranges from 35% to 51% (Fayaz,
Croft, Langford, Donaldson, & Jones, 2016). However, chronic pain prevalence was
reported between 10% and 50% in developing countries (Andrew, Derry, Taylor,
Straube, & Phillips, 2014). Another study revealed that 19% of adult European suffer
from moderate to severe pain, and most of them had not seen a pain specialist. While
40% had poor management of their pain (Breivik, Collett, Ventafridda, Cohen, &
Gallacher, 2006).
The reasons behind this massive variation were investigated in an excellent
meta-analysis review published in PAIN recently (Steingrímsdóttir, Landmark,
Macfarlane, & Nielsen, 2017). They concluded that the design of the epidemiological
study affects the outcomes largely, whereas questionnaire data were linked with higher
estimates than interview data.
2.1.2 Pathophysiology of chronic pain
Chronic pain can be classified based on the underlying causes; nociceptive pain is the
pain due to non-neuronal tissue damage, while neuropathic pain is the pain arising
because of nerve damage (Treede et al., 2015).
The classical nociceptive pain pathway starts from the nociceptors where the
pain generated and transferred up to the brain where the pain is perceived. The free
nerve endings, known as nociceptors, are responsible for generating nerve impulses as
a response to tissue damage. Various stimuli such as thermal, mechanical, or chemical
stimulate the nociceptors to depolarize to produce nerve impulse in what is called
transduction (McEntire et al., 2016). The nerve impulse conducted after that through