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Trends in long-term opioid therapy in primary care. Indications for long-term opioid therapy for chronic non-cancer pain. Bafort Jan, Katholieke Universiteit Leuven Promotor: Prof. Dr. Matheï Cathy, Katholieke Universiteit Leuven, ACHG 1

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Page 1: icho-info.be€¦ · Web viewOpioid analgesics and chronic non-cancer pain: A prescription for research in primary care. Fam Pract. 2016;33(6):569-571. 10. Nielsen S, Lintzeris N,

Trends in long-term opioid therapy in primary care. Indications for long-term opioid therapy for chronic non-cancer pain.

Bafort Jan, Katholieke Universiteit Leuven

Promotor: Prof. Dr. Matheï Cathy, Katholieke Universiteit Leuven, ACHG

Master of Family MedicineMasterproef HuisartsgeneeskundeAcademiejaar: 2018 – 2020

Deze masterproef is een examendocument dat niet werd gecorrigeerd voor eventueel vastgestelde fouten. Zonder voorafgaande schriftelijke toestemming van zowel de promotor(en) als de auteur(s) is overnemen, kopiëren, gebruiken of realiseren van deze uitgave of gedeelten ervan verboden. Voor aanvragen tot of informatie i.v.m. het overnemen

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en/of gebruik en/of realisatie van gedeelten uit deze publicatie, wendt u tot de universiteit waaraan de auteur is ingeschreven. Voorafgaande schriftelijke toestemming van de promotor(en) is eveneens vereist voor het aanwenden van de in dit afstudeerwerk beschreven (originele) methoden, producten, schakelingen en programma’s voor industrieel of commercieel nut en voor de inzending van deze publicatie ter deelname aan wetenschappelijke prijzen of wedstrijden.

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TABLE OF CONTENTS

1. ABSTRACT.......................................................................................................................4

2. INTRODUCTION............................................................................................................5

3. METHODS........................................................................................................................6

3.1. DATA COLLECTION.................................................................................................................................6

3.2. STUDY DESIGN........................................................................................................................................6

3.3. STUDY POPULATION...............................................................................................................................6

3.4. CLINICAL CHARACTERISTICS.................................................................................................................6

3.5. DATA ANALYSIS.....................................................................................................................................7

4. RESULTS..........................................................................................................................8

5. DISCUSSION..................................................................................................................13

5.1. MAJOR FINDINGS.................................................................................................................................13

5.2. CONCOMITANT USE OF BZD AND AD.................................................................................................13

5.3. CANCER................................................................................................................................................14

5.4. STRENGTHS AND LIMITATIONS.............................................................................................................14

6. CONCLUSION...............................................................................................................15

7. REFERENCES................................................................................................................16

8. APPENDICES.................................................................................................................18

8.1. ICPC-CODES USED TO DEFINE CANCER................................................................................................18

8.2. PROTOCOL ETHICS COMMITTEE...........................................................................................................19

8.3. APPROVAL ETHICS COMMITTEE...........................................................................................................22

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1. ABSTRACT

Background:

Awareness is raising about the potential harms of long-term opioid therapy. In Europe there is an

increase of opioid consumption for chronic non-cancer pain. There is however a lack of data about

long-term opioid therapy and the underlying pathologies wherefor opioids are prescribed.

Methods:

Data were obtained from Intego, a Belgian general practice-based morbidity network. All patients with

a diagnosis of cancer 5 years prior to the first opioid prescription were excluded. We identified all

patients with 3 or more opioid prescriptions during a period of 365 days. Data were analyzed for the

following subgroups: patients with osteoarthritis and lower back pain. The concomitant use of

benzodiazepines and antidepressants was analyzed.

Results:

The age-standardized prevalence of long-term opioid therapy increased from 0,52% in 2000 to 1,56%

in 2016. For all subgroups an increase in prevalence was noted. The highest raise in prevalence was

noted in patients with lower back pain, without radiation. Of all patients with osteoarthritis or lower

back pain, 36,53% had a concomitant use of benzodiazepines and 37,31% had a concomitant use of

antidepressants in 2016.

Conclusions:

The use of long-term opioid therapy has increased in Belgium from 2000 to 2016, including for

patients with osteoarthritis and lower back pain. There is a high prevalence of concomitant use of

benzodiazepines among patients with osteoarthritis and lower back pain. Those findings are

inconsistent with the current recommendations of the clinical guidelines and with the current evidence

regarding the outcome of long-term opioid therapy. Awareness of the indications and expectations of

long-term opioid therapy should be raised among physicians.

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2. INTRODUCTION

Between 18% and 33% of the population in Western countries is suffering from chronic pain1,2. For

the treatment of chronic pain, pain lasting longer than 3 months, opioids are frequently used. However

long-term opioid therapy (LTOT) isn’t associated with a better pain relief, improved quality of life or

improved functional capacity3. Besides that, the use of opioids as an analgesic leads to a higher risk of

inappropriate use because of its physiological pathway. Opioids bind to the mu-opioid receptors,

which are present in the brain regions responsible for pain perception, but they are also present in the

brain reward regions which leads to the perception of pleasure and well-being. Thus leading to an

association between the analgesic effect and the feeling of well-being4. This effect could be described

as an urge of relief, leading to inappropriate use of opioids4. There is a general fear in the European

countries to head over to an opioid epidemic as seen in the United States, where over 4% of all adults

are misusing opioid prescriptions and with more than 33.000 deaths related to opioid overdose5.

Chronic non-cancer pain (CNCP) is related with a higher consumption of health care services and an

increase in the consumption of health care services associated with the dose of opioids6. LTOT is

associated with a high risk of adverse events, such as addiction, depression, hypogonadism, sleep-

disordered breathing, impaired wound healing, cognitive impairment, falls and a major trauma7,8.

Those are concerning facts, considering the latest evidence of LTOT3 and the prevalence of these

adverse events7.

Benzodiazepines (BZD) and anti-depressants (AD) are frequently co-prescribed with opioids in the

treatment of chronic pain. Evidence proves an association between depression, anxiety and opioid

use1,9. Depression has both been described as a risk factor and as a consequence of LTOT 7. Both BZD

and AD could be used in the treatment of anxiety and depression.

It is known that the concomitant use of BZD and opioids is associated with a higher consumption of

health care services and a greater pain severity10.

The Belgian National Institute for Health and Disability noted that the use of opioids has increased

with 82% between 2006 and 2017. In the same period the number of patients treated with tramadol has

doubled11. In 2017 approximatively 10% of the Belgian population received one prescription for

opioids11.

Consequently, CNCP and the use of opioids are important medical and public health issues.

However little is known about the prevalence of underlying pathologies within CNCP wherefor LTOT

is initiated. This could be an interesting way to raise awareness of the indications and expectations of

LTOT among physicians, thus to prevent an opioid epidemic in Europe. Therefor the aims of this

study are:

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1. To examine trends in the prevalence of LTOT among patients with osteoarthritis (OA) and

lower back pain (LBP).

2. To assess the proportion of OA and LBP within the population of LTOT.

3. To assess the concomitant use of BZD and AD among patients with LTOT and OA or LBP.

3. METHODS

3.1. Data collection

Data were obtained from Intego, Intego is a Belgian general practice-based morbidity network at the

department of General Practice of the University of Leuven. In 2014 48 practices, representing 111

general practitioners, participated to the project. The registry represents the data of approximatively

1,91% of the Flemish population. This population is representative for the Flemish population on age,

gender and average income. The registry contains data about diagnosis, drugs prescribed, laboratory

results and background information12. The diagnosis were classified using the International

Classification of Primary Care (ICPC). The prescribed drugs were classified using the WHO’s

Anatomical Therapeutic Chemical (ATC) classification system.

3.2. Study design

Retrospective, multicentered observational study. There were no patients involved in the research

question. This study was approved by the Research Ethics Committee UZ/KU Leuven on February 26,

2019.

3.3. Study population

All patients who received 3 or more opioid prescriptions within a period of 365 days were included.

Patients aged younger than 18 and patients who received a diagnosis of cancer, 5 years prior to the

first opioid prescription, were excluded from this study.

3.4. Clinical Characteristics

Opioid use

LTOT was defined as receiving 3 opioid prescriptions within a period of 365 days. To establish a

possible causal relationship between the opioid prescription and studied comorbidities, we determined

that the first opioid prescription should be within a period of 1 year after the diagnosis of LBP or OA.

For this study, the use of the three most common used opioids in Belgium was analyzed. Based on

the results of the National Institute of Health and Disability Insurance11, the most common used

opioids in Belgium are Tramadol (ATC-code N02AX02, N02AJ13), Fentanyl (ATC-code N02AB03)

and Oxycodone (ATC-code N02AA05).

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Cancer

We excluded all patients with a diagnosis of cancer 5 years prior to the first opioid prescription. We

used the ICPC-codes as seen in appendix 1.

Chronic lower back pain and osteoarthritis

Chronic LBP and OA are the most common causes of CNCP2,13. Chronic LBP is difficult to define,

because there isn’t a specific ICPC-code for chronic LBP. In addition to the lack of a specific ICPC-

code, the ICPC-codes for LBP are mostly used in acute care settings. Considering those limits, as

described in the report of the Belgian Health Care Knowledge Centre14, we included all patients with a

lower back syndrome with or without radial pain (ICPC-codes L02, L03, L84 and L86).

We used the diagnosis of gon- and/or coxarthrosis to define OA (ICPC-codes L89 and L90).

Comorbidities

In this study we will concentrate on the diagnosis of depression (ICPC-code p67) and anxiety

disorders (ICPC-code p74) as two independent factors.

Comedication

We used the following drugs to identify comedication: AD (ATC-code N06A) and BZD (ATC-code

N05BA and N05CD).

3.5. Data analysis

Prevalence of LTOT was calculated for all patient groups, patients with(out) a diagnosis of cancer 5

years prior to the initiating of opioid therapy, patients with LBP and patients with OA. The prevalence

was reported as a percentage. The rates were age-standardized using the Flemish population in

Belgium as standard population. The reference year was 2000. The trends in age standardized rates

between 2000-2016 were analyzed, using a Joinpoint regression analysis. From this model the annual

percentage change (APC) and average annual percentage change (AAPC) were obtained. The

SEER*Stat software (Joinpoint Trend Analysis software from the Surveillance Research Program of

the US National Cancer Institute) was used to execute the analysis.

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4. RESULTS

Study population

The total study population variated from 79.602 and 125.057 patients in the period between January 1,

2000 and December 31, 2016.

Trends in prevalence of LTOT (2000-2016)

Age-standardized prevalence of LTOT in the general population (in patients with and without a prior

history of cancer) was 0,521% in 2000 and rose to 1,562% in 2016 (AAPC 7,1%; CI 6,7 to 7,4).

Table 1 shows the trends in age standardized prevalence of LTOT for the different populations (i.e.

patients with malignancies 5 years prior to the first opioid prescription, patients without malignancies,

patients with gon- and coxarthrosis, and LBP with or without radiation). The highest raise in

prevalence was noted in patients with LTOT and LBP without radiation. The prevalence rose from

0,075% in 2000 to 0,238% in 2016 ( AAPC 8,4%; CI 7,6 to 9,2).

Opioids, osteoarthritis and lower back pain

The highest proportion of LTOT (without cancer) was noted for patients with LBP without radiation

from 15,59% in 2000 to 17,43% in 2016 (AAPC 1,6%; CI 0,9 to 2,2). There is a significant decrease

of proportion of patients with OA from 4,57% 2000 to 3,59% in 2016 (AAPC -1,6%; CI -2,7 to -0,5).

The trends in proportion of LTOT in patients without malignancies can be found in table 2.

Opioids, benzodiazepines and anti-depressants

Figure 1 and 2 show the evolution of the concomitant use of benzodiazepines and antidepressants.

In 2000, 42,86% of patients with LTOT and OA or LBP had a concomitant use of BZD. The

prevalence decreased to 36,53% in 2016 (AAPC -0,9%; CI -1,6 to -0,2). The use of AD within patients

with LTOT and OA or LBP increased from 32,38% in 2000 to 37,31% in 2016 (AAPC 1,5%; 1,0 to

1,9).

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Figure 1: evolution of the concomitant use of LTOT and Benzodiazepines.

Figure 2: evolution of the concomitant use of LTOT and Antidepressants.

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Gender

In global, the prevalence of opioids is higher within women than men. The differences are most

marked within patients with OA and LBP without radiation, where the prevalence of LTOT in women

is almost twice as high than in men.

Cancer

The proportion of cancer within patients with LTOT rose from 9,27% in 2000 to 12,16% in 20016

(AAPC 1,5%; CI 0,6 to 2,5). When assessing the proportion of cancer for each gender, we noted no

significant raise in prevalence of cancer among male patients with LTOT. The prevalence of LTOT

among male patients with cancer rose from 9,63% in 2000 to 11,81% in 2016 (AAPC 1,06%; CI -0,0

to 2,1%). In contrast the proportion of cancer among female patients rose significantly from 9,09% in

2000 to 12,39% in 2016 (AAPC 1,8%; CI 0,6 to 3,0%).

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Table 1 Trends in age-standardized prevalence of LTOT (2000-2016)Year 2000

Year 2016

AAPC (95% CI) Trend 1Years APC

Trend 2Years APC

Prevalence of LTOT general population (%)

Total 0,521 1,562 7,1 (6,7;7,4)* 2000-2016 7,1 (6,7;7,4)*

Men 0,358 1,285 7,9 (7,3;8,6)* 2000-2016 7,9 (7,3;8,6)*

Women 0,673 1,834 6,6 (6,1;7,0)* 2000-2016 6,6 (6,1;7,0)*

Prevalence of LTOT with malignancies (%)

Total 0,049 0,192 8,8 (7,7;10,0)* 2000-2016 8,8 (7,7;10,0)*

Men 0,035 0,150 9,1 (7,6;10,7)* 2000-2016 9,1 (7,6;10,7)*

Women 0,061 0,230 9,2 (6,9;11,5)* 2000-2014 7,3 (6,0;8,6)* 2014-2016 23,6 (4,4;46,5)*

Prevalence of LTOT without malignancies (%)

Total 0,472 1,370 6,9 (6,5;7,2)* 2000-2016 6,9 (6,5;7,2)*

Men 0,323 1,135 7,8 (7,1;8,4)* 2000-2016 7,8 (7,1;8,4)*

Women 0,611 1,604 6,4 (5,9;6,9)* 2000-2016 6,4 (5,9;6,9)*

Prevalence of LTOT Gon-/Coxarthrosis (%)

Total 0,021 0,049 5,4 (4,4;6,5)* 2000-2016 5,4 (4,4;6,5)*

Men 0,013 0,027 4,4 (1,9;6,8)* 2000-2016 4,4 (1,9;6,8)*

Women 0,029 0,071 5,9 (4,6;7,2)* 2000-2016 5,9 (4,6;7,2)*

Prevalence of LTOT LBP (%)

Total 0,112 0,391 7,9 (7,4;8,4)* 2000-2016 7,9 (7,4;8,4)*

Men 0,083 0,333 7,9 (6,8;9,0)* 2000-2016 7,9 (6,8;9,0)*

Women 0,140 0,451 8,0 (7,3;8,7)* 2000-2016 8,0 (7,3;8,7)*

Prevalence of LTOT LBP with radiation (%)

Total 0,038 0,153 7,1 (6,0;8,2)* 2000-2016 7,1 (6,0;8,2)*

Men 0,030 0,135 7,7 (6,4;9,1)* 2000-2016 7,7 (6,4;9,1)*

Women 0,046 0,171 8,2 (5,8;10,6)* 2000-2005 15,1 (7,1;23,7)* 2005-2016 5,2 (3,7;6,7)

Prevalence of LTOT LBP without radiation (%)

Total 0,075 0,238 8,4 (7,6;9,2)* 2000-2016 8,4 (7,6;9,2)*

Men 0,054 0,198 8,0 (6,6;9,4)* 2000-2016 8,0 (6,6;9,4)*

Women 0,094 0,280 8,8 (7,8;9,8)* 2000-2016 8,8 (7,8;9,8)*

AAPC, average annual percentage change; APC, annual percentage change; LTOT, long term opioid therapy;

LBP, lower back pain.

* Joinpoint regression analysis with p-value < 0,05

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Table 2 Trends in proportions of underlying pathologies in LTOT in patients without malignancies (2000-2016)Year

2000

Year

2016

AAPC (95% CI) Trend 1Years APC

Trend 2Years APC

Trend 3

Years

Trend 4 Years

LBP (%)

Total 23,66 28,61 1,1 (0,7;1,4)* 2000-2016 1,1 (0,7;1,4)*

Men 25,41 29,50 0,1 (-0,6;0,9) 2000-2016 0,1 (-0,6;0,9)

Women 22,80 28,02 1,2 (-0,8; 3,2) 2000-2002 -7,9 (-17,1;2,2) 2002-2005 9,0 (0,3;18,4)* 2005-2008 -2,2 (-8,8;4,8) 2008-2016 2,0 (1,4:2,7)*

LBP with Radiation (%)

Total 8,06 11,18 0,3 (-0,7;1,2) 2000-2016 0,3 (-0,7;1,2)

Men 9,02 12,13 0,0 (-1,1;1,1) 2000-2016 0,0 (-1,1;1,1)

Women 7,60 10,54 0,4 (-0,8;1,5) 2000-2016 0,4 (-0,8;1,5)

LBP without Radiation (%)

Total 15,59 17,43 1,6 (0,9;2,2)* 2000-2016 1,6 (0,9;2,2)*

Men 16,39 17,36 0,2 (-0,8;1,2) 2000-2016 0,2 (-0,8;1,2)

Women 15,20 17,48 1,2 (-1,4;3,9) 2000-2002 -13,4 (-24,7;-0,3)* 2002-2005 8,9 (-2,6; 21,9) 2005-2008 -3,3 (-12,2;6,5) 2008-2016 4,1(3,3;5,0)*

Gon-/Coxarthrosis (%)

Total 4,57 3,59 -1,6 (-2,7;-0,5)* 2000-2016 -1,6 (-2,7;-0,5)*

Men 4,10 2,51 -3,2 (-5,5;-0,9)* 2000-2016 -3,2 (-5,5;-0,9)*

Women 4,80 4,30 -0,9 (-2,1;0,3) 2000-2016 -0,9 (-2,1;0,3)

AAPC, average annual percentage change; APC, annual percentage change; LTOT, long term opioid therapy; LBP, lower back pain.

* Joinpoint regression analysis with p-value < 0,05

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5. DISCUSSION

5.1. Major Findings

This study shows a significant increase in the prevalence of LTOT, independently of the underlying

pathology, since 2000 with an AAPC of 7,1%. In 2016 the prevalence of LTOT for CNCP was

1,562% in Belgium. This prevalence is in line with prior studies in Europe. In Germany the prevalence

of LTOT for CNCP was 1,3% in 20132.

The highest raise in prevalence of LTOT was noted in patients with lower back pain without radiation,

with an AAPC of 8,4%.

Of all patients without a prior history of cancer, to whom LTOT was prescribed , 28% had a prior

diagnosis of LBP.

There is a high prevalence of co-prescribed drugs. Respectively 43% of all patients with OA or LBP

are co-prescribed with BZD and 37% of all patients with OA or LBP are co-prescribed with AD.

The proportion of LBP without radiation, within patients with LTOT, rose significantly. In contrast the

proportion of OA decreased significantly.

A possible explanation for those findings could be the option of (invasive) treatments like infiltrations

for LBP with radiation and knee- and hip surgery for patients with OA.

The finding of an increase of LTOT in patients with LBP without radiation is concerning, knowing

that there is little evidence that LTOT improves quality of life, function and pain management15,16.

The prevalence of LTOT is remarkably higher for women than men, but little is known about the

underlying reasons for those differences. Except that the difference is often noted in other studies

concerning LTOT. Serdarevic et al gave some possible explanations for this finding 17. First, it is

possible that pain sensitivity differs between gender, with women reporting higher pain scores 17.

Second, women reported more pathologies leading to chronic pain17. Third, men are less likely to seek

medical attention than women17. However more research is needed to comprehend the cause of gender

difference.

5.2. Concomitant use of BZD and AD

Of all patients with LTOT and OA or LBP, 43% are concomitant users of BZD. There is a decrease in

the concomitant use of BZD within men, but there is no change in prevalence of BZD within women.

Overall previous studies have found a lower prevalence of concomitant users of BZD, with prevalence

of 12,2 up to 33,9%. This prevalence is depending on patients characteristics, with women having a

higher concomitant use of BZD18,19. In Denmark the concomitant use of BZD and LTOT has decreased

from 66% in 2000 to 33% in 201320.

Compared to the general population, 9,1% of the Belgian population declared to have used BZD in the

last two weeks in 201321. There is a remarkable difference between the general population and patients

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with LTOT. This finding is consistent with previous studies that found a higher use of BZD among

patients with CNCP20. BZD have also been described as a risk factor for the initiation of LTOT3.

Those are concerning findings, given the potentially dangerous interactions between BZD and opioids,

and a higher risk of opioid overdose10. The concomitant use of LTOT and BZD is also associated with

a higher prevalence of pain, mental disorders (such as depression) and substance abuse among patients

with LTOT10. It is possible that BZD are used to treat anxiety. However those findings are inconsistent

with the currently adopted guidelines on the prescription of LTOT15.

There is an increase of the concomitant use of AD to 37%. These findings are in line with previous

European studies19,22. There are different possible explanations for the raise in concomitant use of AD.

First, evidence is growing that there is an association between depression, anxiety and opioid use 1,9.

Depression and anxiety have been described as risk factors and consequences of the use of opioids 7.

The treatment of a depressive disorder within patients with chronic pain is recommended in clinical

guidelines and helped achieving a higher pain reduction compared to patients without anti-depressive

treatment23. Second, AD could be used to treat neuropathic pain, especially tricyclic antidepressants23.

5.3. Cancer

The increase in LTOT is also present within patients with a prior diagnosis of cancer. Those findings

are consistent with the findings of the Belgian health insurance company, Christian Mutuality 24. In the

study of the Christian Mutuality the global number of patients with cancer and opioid consumption

increased. Contrary to the study of the Christian Mutuality, where the share of cancer as an indication

for opioid therapy remained stable around 8%24; our study shows a significant increase in share of

cancer, within all patients with LTOT, from 9,27% to 12,16%. However, our findings should be

interpreted with caution. First, it is important to remind that this study wasn’t establish to demonstrate

a causal relationship between the diagnostic of cancer and the initiation of opioid therapy, as patients

with a diagnosis of cancer 5 years prior to the first opioid prescription were excluded from this study.

Second, in a period of 5 years it is possible that there are multiple confounding factors. Possible

confounding factors could be LBP, OA and renewal of opioid prescriptions for other causes of CNCP

wherefor opioids were prescribed prior to the diagnostic of cancer. By those means it is possible that

the number of patients was overrated.

5.4. Strengths and limitations

The strengths of this study are the large study population (which represents the Flemish population)

and the possibility to follow a cohort during a long period.

However there are some limitations. First, since this is a registry based study, there is no evidence of

causality between the diagnosis and treatment. Second, the diagnosis of chronic lower back pain is

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impossible to make based on the existing ICPC codes. For this reason, we included all patients with an

ICPC-code of lower back pain.

6. Conclusion

In conclusion, the use of LTOT has increased in Belgium from 2000 to 2016, including for patients

with OA and LBP. The highest increase was noted for patients with LBP without radiation. There is a

high prevalence of concomitant use of BZD amongst patients with OA and LBP. Those findings are

inconsistent with the current recommendations of the clinical guidelines and with the current evidence

regarding the outcome of long term opioid treatment. Awareness of the indications and expectations of

LTOT should be raised among physicians.

15

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journey. Eur J Pain (United Kingdom). 2017;21(9):1516-1527.

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mitigation strategies. N Engl J Med. 2016;374(13):1253-1263.

5. Skolnick P. The Opioid Epidemic: Crisis and Solutions. Annu Rev Pharmacol Toxicol.

2018;58(1):143-159.

6. Hansen AB, Skurtveit S, Borchgrevink PC, et al. Consumption of and satisfaction with health

care among opioid users with chronic non-malignant pain. Acta Anaesthesiol Scand.

2015;59(10):1355-1366.

7. Davis MP, Mehta Z. Opioids and Chronic Pain: Where Is the Balance? Curr Oncol Rep.

2016;18(12).

8. Bedson J, Chen Y, Ashworth J, et al. Risk of adverse events in patients prescribed long-term

opioids: A cohort study in the UK Clinical Practice Research Datalink. Eur J Pain (United

Kingdom). 2019;23(5):908-922.

9. Scherrer JF, Schneider FD, Lustman PJ. Opioid analgesics and chronic non-cancer pain: A

prescription for research in primary care. Fam Pract. 2016;33(6):569-571.

10. Nielsen S, Lintzeris N, Bruno R, et al. Benzodiazepine Use among Chronic Pain Patients

Prescribed Opioids: Associations with Pain, Physical and Mental Health, and Health Service

Utilization. Pain Med (United States). 2015;16(2):356-366.

11. Willems H, De Mooter E. Verbruik en mogelijk misbruik van opioïden in België. Rijksinst

voor Ziekte- en Invaliditeitsverzekering. 2018;(11):709-716.

12. Truyers C, Goderis G, Dewitte H, et al. The Intego database: Background, methods and basic

results of a Flemish general practice-based continuous morbidity registration project. BMC

Med Inform Decis Mak. 2014;14(1):1-9.

13. Elliott AM, Smith BH, Penny KI, et al. The epidemiology of chronic pain. Pain.

2016;157(12):2877.

14. Nielens H, Van Zundert J, Mairiaux P, et al. Chronische lage rugpijn. Good Clinical practice

(GCP). Brussel: Federaal Kenniscentrum voor de gezondheidszorg (KCE); 2006. KCE reports

48 A.

15. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain-

United States, 2016. JAMA - J Am Med Assoc. 2016;315(15):1624-1645.

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16. De Leon-Casasola OA. Opioids for chronic pain: New evidence, new strategies, safe

prescribing. Am J Med. 2013;126(3 SUPPL. 1):S3.

17. Mirsada Serdarevic, Catherine W Striley LBC. Gender differences in prescription opioid use.

Curr Opin Psychiatry. 2017;30(4):238-246.

18. Torrance N, Mansoor R, Wang H, et al. Association of opioid prescribing practices with

chronic pain and benzodiazepine co-prescription: a primary care data linkage study. Br J

Anaesth. 2018;120(6):1345-1355.

19. Wertli MM, Held U, Signorell A, et al. Opioid prescription in Switzerland: Appropriate

comedication use in cancer and noncancer pain. Pain Physician. 2019;22(6):537-548.

20. Birke H, Kurita GP, Sjøgren P, et al. Chronic non-cancer pain and the epidemic prescription of

opioids in the Danish population: Trends from 2000 to 2013. Acta Anaesthesiol Scand.

2016;60(5):623-633.

21. Gisle L. Geestelijke gezondheid. In: Van der Heyden J, Charafeddine R (ed.).

Gezondheidsenquête 2013. Rapport 1: Gezondheid en Welzijn. WIV-ISP, Brussel, 2014.

22. Mellbye A, Svendsen K, Borchgrevink PC, et al. Concomitant medication among persistent

opioid users with chronic non-malignant pain. Acta Anaesthesiol Scand. 2012;56(10):1267-

1276.

23. Scottish Intercollegiate Guidelines Network (SIGN). Management of chronic pain. Edinburgh:

SIGN; 2013. (SIGN publication no. 136). [December 2013].

24. Lebbe C, Ntahonganyira R-M, Avalosse H, et al. Opioïden zijn niet ongevaarlijk voor onze

gezondheid. 2019; (september 2016).

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8. APPENDICES

8.1. ICPC-codes used to define cancer

The following ICPC codes were used to define cancer: malignancy not otherwise specified (NOS)

(ICPC code A79), Hodgkin’s disease/lymphoma (ICPC code B72), leukemia (ICPC code B73),

malignant neoplasm blood other (ICPC code B74), malignant neoplasm stomach (ICPC code D74),

malignant neoplasm colon/rectum (ICPC code D75), malignant neoplasm pancreas (ICPC code D76),

Malignant neoplasm digest other/NOS (ICPC code D77), neoplasm of eye/adnexa (ICPC code F74),

neoplasm of ear (ICPC code H75), neoplasm cardiovascular (ICPC code K72), malignant neoplasm

musculoskeletal (ICPC code L71), malignant neoplasm nervous system (ICPC code N74), neoplasm

nervous system NOS (ICPC code N76), malignant neoplasm bronchus/lung (ICPC code R84), other

malignant neoplasm respiratory (ICPC code R85), neoplasm respiratory unspecified (ICPC code R92),

malignant neoplasm of skin (ICPC code S77), malignant neoplasm thyroid (ICPC code T71),

neoplasm endocrine NOS (ICPC code T73), malignant neoplasm of kidney (ICPC code U75),

malignant neoplasm of bladder (ICPC code U76), malignant neoplasm urinary tract (ICPC code U77),

neoplasm urinary tract NOS (ICPC code U79), malignant neoplasm relate to pregnancy (ICPC code

W72), malignant neoplasm cervix (ICPC code X75), malignant neoplasm breast female (ICPC code

X76), genital neoplasm NOS (ICPC code X81), malignant neoplasm prostate (ICPC code Y77), and

malignant neoplasm male genital NOS (ICPC code Y78).

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8.2. Protocol Ethics Committee

Masterproef: De evolutie van het voorschrijven van opioïde pijnstillers in de huisartsenpraktijk.

Indicatiestelling voor het voorschrijven van opioïde pijnstillers bij chronische niet kanker

gerelateerde pijn.

1. Background and rationale

Steeds vaker wordt er in België aan de alarmbel getrokken over het gebruik van opioïde pijnstillers. In

een recent verslag van het RIZIV, waarin het gebruik en mogelijk misbruik van opioïde pijnstillers in

België aan het licht gesteld wordt, ziet men een globale stijging van niet alleen het aantal voorschriften

maar ook van het aantal voorgeschreven dagdosissen en de kostprijs van de opioïde pijnstillers. Bij

ongeveer 10% van de bevolking wordt er op jaarbasis minstens een voorschrift voor opioïde

pijnstillers afgeleverd. Er bestaan tot op heden echter geen gegevens over de onderliggende chronische

niet kanker- gerelateerde pathologieën waarvoor opioïde pijnstillers voorgeschreven worden. Dit kan

potentieel een interessant aanknopingspunt zijn om ons als arts, maar ook als bevolking te

sensibiliseren en te informeren omtrent de wetenschappelijke evidentie over het gebruik van deze

pijnstillers voor de behandeling van chronische niet-kanker gerelateerde pijn.

2. Study objectives

De opzet van deze studie bestaat uit het identificeren van de onderliggende chronische niet-kanker

gerelateerde aandoeningen waarvoor opioïde pijnstillers voorgeschreven worden.

Een bijkomend doel van deze studie is om binnen deze chronische niet-kanker gerelateerde

aandoeningen het type opioïd te identificeren, alsook de duur van de behandeling en de

voorgeschreven dosissen.

3. Research method

Descriptieve, retrospectieve, multicentrische en niet-interventionele studie. De onderliggende

aandoeningen waarbij opioïde pijnstillers worden voorgeschreven zullen op basis van een vooraf

geformuleerde vraagstelling uit de INTEGO-databank gehaald worden. Daarna zal er voor de drie

meest voorkomende aandoeningen een nieuwe zoekvraag geformuleerd worden om het type opioïd, de

voorgeschreven dosis en de duur van de behandeling te achterhalen.

4. Data collection

Er zal gebruik gemaakt worden van de reeds bestaande ‘INTEGO’-databank. De intego-databank

bestaat uit de medische gegevens van 46 huisartsenpraktijken in Vlaanderen, het betreft de informatie

van 440 140 verschillende patiënten. Deze patiëntenpopulatie is representatief voor de Vlaamse

bevolking op vlak van leeftijd, geslacht en gemiddeld inkomen.

5. Analysis

Beschrijvende, bivariate en multivariate statistische analyses zullen worden uitgevoerd.

6. Data handling and management

a. Data storage and management

De gebruikte data is volledig geanonimiseerd.

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b. Declaration of Confidentiality and Careful Management of Information and

Personal Data

In the framework of his / her Master's thesis, the student(s) will have access to all kinds of data,

information, results and documents, including personal data which is not exclusively limited to patient

data (the "Information"). In order to ensure the confidentiality of this Information and the privacy of

those involved, within the framework of his / her Master's thesis the student(s) should always deal

with the Information with the greatest care and discretion.

Data collected in the framework of a Master’s thesis, in particular research related to patients and

including the collection and analysis of personal data, requires the utmost of care and discretion.

Therefore, at all times the student must observe complete confidentiality with respect to the

Information he / she has collected during the course of his / her Master’s thesis.

In performing this research, the student(s) commit(s) him/herself to the following confidentiality

obligations:

He/

sheaccepts,duringandafterthecompletionoftheMaster'sthesis,theobligationtostrictlyobservethe

confidentiality of the Information he / she has collected and the activities to which he / she has

participated, and regarding the patients, healthy volunteers and the staff members with whom

he / she comes into contact;

He/shewillonlyprocessandcollectdatathatisrelevantandnecessaryforhis/herMaster'sthesis;

He/shewillnotshareinformationwithpersonsnotdirectlyinvolvedwithintheframeworkofhis/

herresearch;

He/

shewilltakeallnecessarystepstoprotecttheconfidentialityofInformationandtheprivacyofthoseinv

olved;

He/shewillhandlewithcareandresponsibilitytheInformationandtheaccessgrantedtohim/

hertoinformation systems and digital media.

All investigators shall treat all information and data relating to the study as confidential and shall not

disclose such information to third parties or use such information for any purpose other than the

performance of the study. The collection, processing and disclosure of personal data, such as

participants’ health and medical information, is subject to compliance with applicable personal data

protection legislation.

7. Approval

Hereby we confirm that data collection is performed with approval of the head of the respective unit(s)

or department(s) where data collecting is taking place.

8. Publication policy

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Publications will be coordinated by the Principal Investigator. Authorship to publications will be

determined in accordance with the requirements published by the International Committee of Medical

Journal Editors and in accordance with the requirements of the respective journal.

9. Direct access to source data and documents

The investigator(s) and the institution(s) will permit study-related monitoring, audits, ethical review

and regulatory inspections (where appropriate) by providing direct access to source data.

10. References

Willems H, De Mooter E. Verbruik en mogelijk misbruik van opioïden in België. Rijksinst voor

Ziekte- en Invaliditeitsverzekering. 2018;(11):709-716.

Truyers C, Goderis G, Dewitte H, et al. The Intego database: Background, methods and basic results

of a Flemish general practice-based continuous morbidity registration project. BMC Med Inform Decis

Mak. 2014;14(1):1-9.

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8.3. Approval Ethics Committee

Dear Cathy Matheï Dear Jan Bafort

The Research Ethics Committee UZ/KU Leuven hereby grants favourable advice to the proposed study, as it was described in the protocol. The Commission is of the opinion that from an ethical standpoint there are no objections to the proposed study. The study was approved on 26-02-2019

De Commissie heeft geen bezwaren bij de aanvraag en keurt deze goed.

Given that the study takes the form of a Master's thesis within the Group Biomedical Science, the application to the Research Ethics Committee UZ/KU Leuven was submitted to the Educational- Support Committee.

The Committee has no objection to the project on the basis of confidential treatment of the data and compliance with the Belgian legislation concerning privacy. The Research Ethics Committee UZ/KU Leuven wishes for the head researcher / promoter of the study to be aware of their responsibilities with regard to the privacy of personal / patient details, when in contact with living persons, patients, and / or contained within electronic medical records, including the correct implementation by employees and students.

This favorable advice concerns the submission of 12-02-2019 and is given for the duration of the Master's thesis of the student(s) concerned. Any amendment to the protocol will invalidate this favorable advice. In that case, you must submit an amendment for advice to the committee that previously approved your file.

The Committee confirms that they work in accordance with the ICH-GCP principles (International Conference on Harmonisation Guidelines on Good Clinical Practice), with the most recent verison of the Helsinki Declaration, and with applicable laws and regulations.

The Committee confirms that in case of a conflict of interest, the members concerned have not participated in decision regarding the study.

Kind regards,

Prof. dr. Minne CasteelsPresident / ChairpersonResearch Ethics Committee UZ/KU Leuven

Prof. dr. Pascal BorryPresident / ChairpersonEducation-Support Committee for Medical Ethics KU Leuven

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