OPIOID TOLERANCE AND ADHERENCE AND ITS RELATIONSHIP TO CYTOKINE CONCENTRATIONS

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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

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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.

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ثحبلا ةصلاخ

ةمدقملا عبرتعت : .ملالآا فيفختل دوقعل تلمعتسا اهرودب تيلاو لملأا تانكسم مهأ نم نويفلأا ةيودأ ةلئا

ةيملعلا ةلدلأا صقن ببسب ،لدجلل اراثم دملأا ةليوط ةيناطرسلا يرغ ملالآا في تانويفلأا لامعتسا ّدعي اهتيدودمحو ةفيرطلا .

ايع يداترم نمزم نياطرس يرغ لمأ ىضرم ىلع ةساردلا هذه تيرجأ : دة

في لملأا لاث ث

م يفشتس تا راذآ ينب ةترفلا في ايزيلام في 2016

طابشو 2017 . يليوط ىضرم لىإ ىضرلما فينصت تم

نع لقت وأ ديزت ةدلم تانيفرولما لامعتسا ىلع ءانب دملأا ييرصقو دملأا 90

فينصت تمو .ةنسلا للاخ موي

ءانب ينمزتلم يرغو ءاودلاب ينمزتلم لىإ دملأا يليوط ىضرلما ءاودلل مهكلاتمإ ةبسن ىلع

. طبر تمو هذه

ينكولترنا باهتللال زفلمحا ينكوتيسلا عم تانيفرولما ىلع دوعتلل سيياقلما -

6 باهتللاا داضم ينكوتيسلاو

ينكولترنا - 10 بحس تم ةساردلا في ينكراشلما ىضرلما عيملج . 10

تانيكوتيسلا ىوتسم سايق تمو مد لم

تانيفرولماو جئاتنلا .

عويش : نمض تانيفرولما لامعتسا 726

ناك ةساردلا ةترف للاخ ةدايعلا اوداترا ضيرم

11.9 .%

38 مهنمو ،ةساردلا في اوفظو ىضرلما نم 24

و دملأا ييرصق % 76

.دملأا يليوط %

كانه ناك دملأا يليوط نمض 62

و ءاودلاي ينمزتلم % 38

.ينمزتلم يرغ % لاكل براقتلا رهظأ

ًايوق ابراقت تانيكوتيسلا .لجلأا ييرصقو لجلأا يليوط ىضرملل

مظعم نأ رهظأ مدلا في تانيفرولما زيكرت

ديج لكشب جلاعلاب ينمزتلم اوناك دملأا ييرصقو يليوط ىضرلما ءاودلا كلاتمإ سايقم ينب براقتلا رهظأو

ةئفاكلما ةيمويلا ةعرلجا طسوتم .ةوقلا طسوتم ًايراقت مدلا في تانيفرولما زيكرتو ل

تناك ينفرومل (

42.11 ±

11.1 ( و ) 13.06 ±

2.7 لقأب ةفيفلخا ةعرلجا امنيب ،بيتترلا ىلع دملأا ييرصقو يليوطل ينفروم ممج )

نم .ينتعوملمجا نمض اعويش رثكلأا تناك ًايموي ممج 20

في ًاعويش رثكأ ناك تانيفرولما ىلع دوعتلا

باهتللاا داضم ينكوتيسلا زيكرتو ،دملأا ييرصق في هنم دملأا يليوط لا

- 10 ىلعأ ناك امزلايلا في

طابترا كانه ناك .تانيفرولما ىلع نيداتعلما في هنم تانيفرولما ىلع نيداتعلما يرغ ىضرلما في ظوحلم لكشب لا ينب ظوحلم يوف -

6 .تانيفرولما ىلع نيداتعلما في لملأا ةدش و ةصلاخلا

ّيب : ةساردلا هذه جئاتن تن

يح نم دملأا يليوط وناك ىضرلما مظعم نأ ءاودلاب ينمزتلم اوناك مهمظعم نأو .تانيفروملل ملهامعتسا ث

في تانيفرولما زيكرت عم قيثو لكشب طبترم هنأ رهظأ يئاودلا مازتللال رشايلما يرغ سايقلما .ديج لكشب .امزلابلا يئاودلا مازتللاا باسح ةفيرط لامعتسلا ةيريرسلا ةسراملل يملعلا ليلدلا ةساردلا هذه تدوز

ابلما يرغ تانيفرولما لامعتسلا ةطيترلما راطخلأل ينلجاعلما رظن تفللو تانيفرولما هاتج ىضرلما كولس ةنياعلم ةرش

.دملأا ليوط

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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

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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 ………

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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.

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

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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.

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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

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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

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3.4.1.5 Buprenorphine ... 62

3.4.1.6 Morphine ... 63

3.4.2 Calibration and linearity ... 64

3.4.2.2 Oxycodone ... 66

3.4.2.3 Fentanyl ... 66

3.4.2.5 Morphine ... 68

3.4.3 Precision and accuracy ... 68

3.4.3.2 Oxycodone ... 69

3.4.3.3 Fentanyl ... 69

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

3.7.1 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

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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

4.5.1 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

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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

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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

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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

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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

concentration among opioid-tolerant patients 112

concentration among opioid intolerant patients 113

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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).

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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

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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.

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 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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5 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

rheumatoid arthritis,

OPIOID TOLERANCE AND ADHERENCE AND ITS RELATIONSHIP TO CYTOKINE CONCENTRATIONS