Electronic Supplementary Material

Journal Name Drug Safety

Article Title TheRisk of Ischemic Cardio- and Cerebrovascular Events Associated with Oxycodone/Naloxone and Other Extended-Release High-Potency Opioids: A Nested Case-Control Study

Author Names K Jobski, B Kollhorst, E Garbe, T Schink

Corresponding author:

Kathrin JobskiKathrin Jobski, PhD, MSc

Department of Health Services Research, Carl von Ossietzky University Oldenburg

Ammerländer Heerstrasse 140, 26129 Oldenburg, Germany

E-Mail:

ESM1 Exposure Assessment for Extended-Release High-Potency Opioidsa

Substance / Route of administration / Morphine equivalents b / Range of dosage scheme c
Morphine / Oral / 1 / 1-2 unit(s) per day
Oxycodone / Oral / 1.5 / 2 units per day
Oxycodone/naloxone / Oral / 1.5 / 2 units per day
Hydromorphone / Oral / 7.5 / 1-2 unit(s) per day
Tapentadol / Oral / 0.4 / 2 units per day
Fentanyl / Transdermal / 100 / 1 unit every 3 days
Buprenorphine / Transdermal / 70 / 1 unit every 3 to 7 days

aIncluded in the German Narcotics Drugs Act.

bProvided by the Drug Committee of the German Physicians (AKdÄ)

c Based on the Summary of Products Characteristics (SPC) for the respective brands. For each brand, distinct information regarding the dosage scheme is provided by the respective SPC.

ESM2ICD-10-GM Codes Used for Defining Outcome, Comorbidity, and Indication

Diagnoses / ICD-10-GM code (2011)
Outcome
Myocardial infarction / I21x
Ischemic stroke / I63x, G465, G466
Comorbidity
Hypertensive diseases / I10x-I13x, I15x
Ischemic heart diseases / I20x-I25x
Atrial fibrillation and flutter / I48x
Congestive heart failure / I50x
Atherosclerosis, peripheral vascular disease / I70x, I739
Diabetes / E10x-E14x
Obesity / E66x
Disorders of lipoprotein metabolism / E78x
Cerebrovascular diseases / I63x-I67x
Transient cerebral ischemic attacks and related syndromes / G45x
Indication
Cancer / C00x-C97
Other specific back pain including osteoporosis / M43x-M46x, M48x, M49x, M81x, M82x
Intervertebral disc illnesses / M50x, M51x
Arthrosis / M06x, M13x, M15x-M19x, M25x
Traumatic fractures / S12x, S22x, S32x, S42x, T02x, T08x, T91x
Multimorbidity / L89x, L97, L98x
Neuropathic pain / G50x, G54x-G58x, G62x, G63x, M79x, M89x
Headache / G43x, G44x, R51
Unspecific back pain / M47x, M53x, M54x

ICD-10-GMGermanmodification of the International Classification of Diseases, 10th revision

ESM3ATC Codes Used for Defining Comedication

Substances / ATC code (2011)
Antithrombotic drugs / B01A
Cardiac glycosides / C01A
Vasodilators / C01D
Antihypertensive drugs / C02
Diuretics / C03
Beta blocking agents / C07A
Calcium antagonists / C08
ACE inhibitors / C09A, C09B
Angiotensin II antagonists / C09C, C09D
Laxatives / A06
Methylnaltrexone / A06AH01
Non-steroidal anti-inflammatory drugs (non-selective) / M01A excl. ‘M01AH’
Cox-2selective inhibitors / M01AH
Low potency opioids / N02AA59, N02AA64, N02AA65, N02AA69, N02AX02, N02AX51, N02AX52
Antiepileptic drugs / N03
Conventional antipsychotics / N05AA, N05AB, N05AC, N05AD, N05AF, N05AG, N05AE02, N05AX07, N05AX15, N05CM22, N05CX13, R06AD02, R06AD52, V03AB05
Atypical antipsychotics / N05AH, N05AL, N05AE01, N05AE03, N05AE04, N05AX08, N05AX10, N05AX11, N05AX12, N05AX13
Antidepressants / N06A
Opioid replacement therapy / N07BC01, N07BC02, N07BC05, N07BC51, V70AA01

ACE angiotensin-converting enzyme,ATC anatomical therapeutic chemical,COX-2 cyclooxygenase-2

1

ESM4Further Baseline Characteristics and ER HPO Use of the Study Cohort by Index ER HPO

Total
N = 309 936 (100%) / Morphine
N = 40 919 (13.2%) / Oxycodone
N = 50 414 (16.3%) / Oxycodone/
naloxone
N = 40 254 (13.9%) / Hydromorphone
N = 22 483 (7.3%) / Tapentadol
N = 2500 (0.8%) / Fentanyl
N = 119 132 (38.3%) / Buprenorphine
N = 31 768 (10.2%) / Multiple ER HPOs
N = 2466 (0.8%)
Year of cohort entry
2006 / 88 590 (28.6%) / 14 510 (35.5%) / 19 915 (39.5%) / 1373 ( 3.4%) / 5461 (24.3%) / 0 ( 0.0%) / 39 013 (32.7%) / 7420 (23.4%) / 898 (36.4%)
2007 / 51 884 (16.7%) / 7629 (18.6%) / 7701 (15.3%) / 5742 (14.3%) / 3431 (15.3%) / 0 ( 0.0%) / 20 025 (16.8%) / 6940 (21.8%) / 416 (16.9%)
2008 / 51 957 (16.8%) / 6651 (16.3%) / 7143 (14.2%) / 8153 (20.3%) / 4169 (18.5%) / 0 ( 0.0%) / 19 465 (16.3%) / 5940 (18.7%) / 436 (17.7%)
2009 / 48 832 (15.8%) / 5404 (13.2%) / 6607 (13.1%) / 9791 (24.3%) / 3957 (17.6%) / 0 ( 0.0%) / 17 246 (14.5%) / 5418 (17.1%) / 409 (16.6%)
2010 / 37186 (12.0%) / 3831 ( 9.4%) / 4877 ( 9.7%) / 8515 (21.2%) / 2968 (13.2%) / 593 (23.7%) / 12 746 (10.7%) / 3512 (11.1%) / 144 ( 5.8%)
2011 / 31 487 (10.2%) / 2894 ( 7.1%) / 4171 ( 8.3%) / 6680 (16.6%) / 2497 (11.1%) / 1907 (76.3%) / 10 637 ( 8.9%) / 2538 ( 8.0%) / 163 ( 6.6%)
Physicians’ specialty a
GP/internist / 243 230 (78.5%) / 32 545 (79.5%) / 36 277 (72.0%) / 28 960 (71.9%) / 16 985 (75.5%) / 1422 (56.9%) / 102 236 (85.8%) / 23 028 (72.5%) / 1777 (72.1%)
Anesthesiologist / 16 063 ( 5.2%) / 2305 ( 5.6%) / 3392 ( 6.7%) / 1927 ( 4.8%) / 2075 ( 9.2%) / 444 (17.8%) / 2676 ( 2.2%) / 3091 ( 9.7%) / 153 ( 6.2%)
Orthopedist/orthopedic surgeon / 19 821 ( 6.4%) / 1622 ( 4.0%) / 5486 (10.9%) / 4900 (12.2%) / 885 ( 3.9%) / 253 (10.1%) / 4365 ( 3.7%) / 2231 ( 7.0%) / 79 ( 3.2%)
Surgeon / 2527 ( 0.8%) / 212 ( 0.5%) / 572 ( 1.1%) / 673 ( 1.7%) / 127 ( 0.6%) / 59 ( 2.4%) / 601 ( 0.5%) / 276 ( 0.9%) / 7 ( 0.3%)
Neurologist/psychiatrist/psychotherapist / 2554 ( 0.8%) / 378 ( 0.9%) / 490 ( 1.0%) / 338 ( 0.8%) / 144 ( 0.6%) / 92 ( 3.7%) / 784 ( 0.7%) / 308 ( 1.0%) / 20 ( 0.8%)
Other/unknown/multiple specialties / 25 741 ( 8.3%) / 3857 ( 9.5%) / 4197 ( 8.3%) / 3456 ( 8.6%) / 2267 (10.17%) / 230 ( 9.2%) / 8470 ( 7.1%) / 2834 ( 8.9%) / 430 (17.4%)
Previous use of…
Antithrombotic drugs / 98 423 (31.8%) / 12213 (29.8%) / 14 243 (28.3%) / 11 865 (29.5%) / 7162 (31.9%) / 623 (24.9%) / 41 356 (34.7%) / 10 177 (32.0%) / 784 (31.8%)
Cardiac glycosides / 22 481 ( 7.3%) / 2626 ( 6.4%) / 2623 ( 5.2%) / 1947 ( 4.8%) / 1391 ( 6.2%) / 77 ( 3.1%) / 11173 ( 9.4%) / 2489 ( 7.8%) / 155 ( 6.3%)
Vasodilators / 35 934 (11.6%) / 4359 (10.7%) / 5001 ( 9.9%) / 3769 ( 9.4%) / 2420 (10.8%) / 176 ( 7.0%) / 15 709 (13.2%) / 4269 (13.4%) / 231 ( 9.4%)
Antihypertensive drugs / 14128 ( 4.6%) / 1602 ( 3.9%) / 2197 ( 4.4%) / 1692 ( 4.2%) / 1174 ( 5.2%) / 97 ( 3.9%) / 5598 ( 4.7%) / 1657 ( 5.2%) / 111 ( 4.5%)
Diuretics / 117 678 (38.0%) / 14 819 (36.2%) / 15 620 (31.0%) / 12 622 (31.4%) / 8152 (36.3%) / 685 (27.4%) / 52 479 (44.1%) / 12 452 (39.2%) / 849 (34.4%)
Beta blocking agents / 114 321 (36.9%) / 13 884 (33.9%) / 17 161 (34.0%) / 14 675 (36.5%) / 8447 (37.6%) / 926 (37.0%) / 45 766 (38.4%) / 12 663 (39.9%) / 799 (32.4%)
Calcium antagonists / 66 588 (21.5%) / 8025 (19.6%) / 9909 (19.7%) / 8386 (20.8%) / 4675 (20.8%) / 507 (20.3%) / 27 109 (22.8%) / 7515 (23.7%) / 462 (18.7%)
ACE inhibitors / 109 665 (35.4%) / 13 769 (33.6%) / 16 589 (32.9%) / 13 547 (33.7%) / 7515 (33.4%) / 779 (31.2%) / 45 173 (37.9%) / 11 506 (36.2%) / 787 (31.9%)
Angiotensin-2 antagonists / 47 727 (15.4%) / 4832 (11.8%) / 7560 (15.0%) / 7358 (18.3%) / 3813 (17.0%) / 547 (21.9%) / 17 140 (14.4%) / 6141 (19.3%) / 336 (13.6%)
Non-selective NSAIDs / 180 436 (58.2%) / 23 105 (56.5%) / 31 930 (63.3%) / 25 941 (64.4%) / 13 492 (60.0%) / 1607 (64.3%) / 63 736 (53.5%) / 19 169 (60.3%) / 1456 (59.0%)
COX-2 selective inhibitors / 25 060 ( 8.1%) / 2323 ( 5.7%) / 4623 ( 9.2%) / 4154 (10.3%) / 2222 ( 9.9%) / 393 (15.7%) / 7433 ( 6.2%) / 3705 (11.7%) / 207 ( 8.4%)
Conventional antipsychotics / 22 949 ( 7.4%) / 2664 ( 6.5%) / 2322 ( 4.6%) / 1633 ( 4.1%) / 1306 ( 5.8%) / 97 ( 3.9%) / 12 516 (10.5%) / 2242 ( 7.1%) / 169 ( 6.9%)
Atypical antipsychotics / 12 611 ( 4.1%) / 1201 ( 2.9%) / 1342 ( 2.7%) / 1076 ( 2.7%) / 585 ( 2.6%) / 68 ( 2.7%) / 6946 ( 5.8%) / 1324 ( 4.2%) / 69 ( 2.8%)
Antidepressants / 93 733 (30.2%) / 12 747 (31.2%) / 15 805 (31.4%) / 11 027 (27.4%) / 7138 (31.7%) / 927 (37.1%) / 35 363 (29.7%) / 9923 (31.2%) / 803 (32.6%)
Antiepileptic drugs / 47 653 (15.4%) / 6324 (15.5%) / 8117 (16.1%) / 5954 (14.8%) / 4194 (18.7%) / 709 (28.4%) / 16 663 (14.0%) / 5228 (16.5%) / 464 (18.8%)
Laxatives / 38 442 (12.4%) / 7245 (17.7%) / 5671 (11.2%) / 2271 ( 5.6%) / 3548 (15.8%) / 100 ( 4.0%) / 15 861 (13.3%) / 3208 (10.1%) / 538 (21.8%)
Opioid replacement therapy / 308 ( 0.1%) / 73 ( 0.2%) / 51 ( 0.1%) / 22 ( 0.1%) / 29 ( 0.1%) / 1 ( 0.0%) / 108 ( 0.1%) / 20 ( 0.1%) / 4 ( 0.2%)

Continued

ESM4 Further Baseline Characteristics and ER HPO Use of the Study Cohort by Index ER HPO (continued)

Total
N = 309 936 (100%) / Morphine
N = 40 919 (13.2%) / Oxycodone
N = 50 414 (16.3%) / Oxycodone/
naloxone
N = 40 254 (13.9%) / Hydromorphone
N = 22 483 (7.3%) / Tapentadol
N = 2500 (0.8%) / Fentanyl
N = 119 132 (38.3%) / Buprenorphine
N = 31 768 (10.2%) / Multiple ER HPOs
N = 2466 (0.8%)
Different ER HPO substances during cohort time
Only one ER HPO substance / 22 9051 (73.9%) / 28 776 (70.3%) / 33 915 (67.3%) / 29 884 (74.2%) / 15 507 (69.0%) / 2132 (85.3%) / 96796 (81.3%) / 22041 (69.4%) / 0 ( 0.0%)
Two ER HPO substances / 60 441 (19.5%) / 9202 (22.5%) / 11878 (23.6%) / 7954 (19.8%) / 5169 (23.0%) / 300 (12.0%) / 16984 (14.3%) / 7078 (22.3%) / 1876 (76.1%)
Three or more ER HPO substances / 20 444 ( 6.6%) / 2941 ( 7.2%) / 4621 ( 9.2%) / 2416 ( 6.0%) / 1807 ( 8.0%) / 68 ( 2.7%) / 5352 ( 4.5%) / 2649 ( 8.3%) / 590 (23.9%)
Route of application during cohort time
Only oral ER HPOs / 130 637 (42.1%) / 33 022 (80.7%) / 42 025 (83.4%) / 34 596 (85.9%) / 18 034 (80.2%) / 2349 (94.0%) / 0 ( 0.0%) / 0 ( 0.0%) / 611 (24.8%)
Only transdermal ER HPOs / 124 658 (40.2%) / 0 ( 0.0%) / 0 ( 0.0%) / 0 ( 0.0%) / 0 ( 0.0%) / 0 ( 0.0%) / 99 418 (83.5%) / 25 166 (79.2%) / 74 ( 3.0%)
Oral and transdermal ER HPOs / 54 641 (17.6%) / 7897 (19.3%) / 8389 (16.6%) / 5658 (14.1%) / 4449 (19.8%) / 151 ( 6.0%) / 19 714 (16.5%) / 6602 (20.8%) / 1781 (72.2%)

ACE angiotensin-converting enzyme,COX-2 cyclooxygenase-2,ER extended-release,HPO high-potency opioid,IQR interquartile range,NSAIDs nonsteroidal anti-inflammatory drugs
aRefers to the physician issuing the index ER HPO prescription

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ESM5Characteristics of IncidentUsers aof Oxycodone/Naloxone or Oxycodone

Oxycodone/naloxone
N = 39 152 / Oxycodone
N = 40 395
Age at cohort entry
<30 years / 476 ( 1.2%) / 621 ( 1.5%)
30-39 years / 1038 ( 2.7%) / 1273 ( 3.2%)
40-49 years / 3310 ( 8.5%) / 3761 ( 9.3%)
50-59 years / 5633 (14.4%) / 6232 (15.4%)
60-69 years / 8407 (21.5%) / 9322 (23.1%)
70-79 years / 11 471 (29.3%) / 10 709 (26.5%)
>=80 years / 8817 (22.5%) / 8477 (21.0%)
Sex
Female / 26 570 (67.9%) / 26 826 (66.4%)
Male / 12 582 (32.1%) / 13 569 (33.6%)
Physicians’ specialty b
GP/internist/other / 31 533 (80.5%) / 32870 (81.4%)
Specialist / 7619 (19.5%) / 7525 (18.6%)
Potential indications
Cancer / 9753 (24.9%) / 8999 (22.3%)
Other specific back pain / 15 474 (39.5%) / 15 564 (38.5%)
Intervertebral disc illnesses / 12 635 (32.3%) / 13 294 (32.9%)
Arthrosis / 21 091 (53.9%) / 20 951 (51.9%)
Traumatic fractures / 5046 (12.9%) / 5409 (13.4%)
Multimorbidity / 2650 ( 6.8%) / 2722 ( 6.7%)
Neuropathic pain / 12 777 (32.6%) / 13 042 (32.3%)
Headache / 3904 (10.0%) / 4027 (10.0%)
Unspecific back pain / 27 907 (71.3%) / 28 577 (70.7%)
Year of cohort entry
2006 / 1341 ( 3.4%) / 11 182 (27.7%)
2007 / 5642 (14.4%) / 7467 (18.5%)
2008 / 7963 (20.3%) / 6864 (17.0%)
2009 / 9629 (24.6%) / 6432 (15.9%)
2010 / 8366 (21.4%) / 4736 (11.7%)
2011 / 6211 (15.9%) / 3714 ( 9.2%)
History of…
Hypertensive disease / 26 565 (67.9%) / 25 564 (63.3%)
Ischemic heart disease / 9888 (25.3%) / 9545 (23.6%)
Atrial fibrillation and flutter / 4549 (11.6%) / 4216 (10.4%)
Congestive heart failure / 6688 (17.1%) / 6375 (15.8%)
Atherosclerosis/peripheral vascular disease / 5713 (14.6%) / 5676 (14.1%)
Diabetes / 9929 (25.4%) / 9432 (23.4%)
Obesity / 8357 (21.4%) / 8403 (20.8%)
Disorders of lipoprotein metabolism / 16 868 (43.1%) / 15 771 (39.0%)
Cerebrovascular disease / 5447 (13.9%) / 5192 (12.9%)
Transient cerebral ischemic attacks / 1151 ( 2.9%) / 1078 ( 2.7%)
Opioid abuse/dependence / 120 ( 0.3%) / 167 ( 0.4%)
Other substance use disorders / 1786 ( 4.6%) / 2018 ( 5.0%)
Constipation / 3897 (10.0%) / 3718 ( 9.2%)
Hospitalization in the 7 days before cohort entry / 8134 (20.8%) / 8488 (21.0%)
Previous use of…
Cardiac glycosides / 1903 ( 4.9%) / 2065 ( 5.1%)
Antithrombotic drugs / 11 530 (29.5%) / 11 573 (28.7%)
Vasodilators / 3659 ( 9.4%) / 3833 ( 9.5%)
Other cardiovascular medication c / 26 265 (67.1%) / 26 033 (64.5%)
Non-selective NSAIDS / 25 316 (64.7%) / 26 600 (65.9%)
COX-2 selective inhibitors / 4023 (10.3%) / 3615 ( 9.0%)
Antipsychotics / 2316 ( 5.9%) / 2437 ( 6.0%)
Antidepressants / 10 512 (26.9%) / 10 866 (26.9%)
Antiepileptic drugs / 5632 (14.4%) / 5782 (14.3%)
Laxatives / 1981 ( 5.1%) / 2252 ( 5.6%)

COX-2 cyclooxygenase 2,GP general practitioner,NSAIDs nonsteroidal anti-inflammatory drugs

aNo high-potency opioids dispensed in the six months preceding cohort entry

bRefers to the physician issuing the index ER HPO prescription

cIncludes: antihypertensive drugs, diuretics, beta blocking agents, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin-2 antagonists.

1

ESM6Crude Incidence Rates for Myocardial Infarction/Ischemic Stroke

Overall / IR (95% CI) per 1000 PY
Events / Person time a / IR (95% CI) per 1000 PY / MI / IS / Female / Male / <60 years of age / >=60 years of age / Excluding patients suffering from opioid abuse/dependence
Overall / 12 384 / 635.81 / 19.48 (19.14-19.82) / 8.78 ( 8.56- 9.02) / 10.69 (10.44-10.95) / 18.02 (17.64-18.42) / 23.23 (22.53-23.95) / 5.62 (5.26-5.99) / 24.29 (23.85-24.74) / 19.52 (19.18-19.87)
Morphine / 744 / 39.17 / 19.00 (17.66-20.41) / 9.29 ( 8.36-10.30) / 9.70 ( 8.75-10.73) / 17.50 (15.92-19.18) / 21.94 (19.49-24.62) / 7.26 (5.92-8.81) / 25.56 (23.62-27.62) / 19.17 (17.81-20.61)
Oxycodone / 769 / 42.68 / 18.02 (16.77-19.34) / 8.69 ( 7.83- 9.62) / 9.33 ( 8.43-10.29) / 17.09 (15.64-18.63) / 20.22 (17.82-22.84) / 5.75 (4.59-7.11) / 24.52 (22.71-26.42) / 18.13 (16.87-19.46)
Oxycodone/naloxone / 507 / 26.64 / 19.03 (17.41-20.76) / 8.63 ( 7.55- 9.83) / 10.40 ( 9.21-11.70) / 16.45 (14.69-18.36) / 25.88 (22.32-29.84) / 5.26 (3.75-7.16) / 24.54 (22.37-26.87) / 19.04 (17.41-20.78)
Hydromorphone / 453 / 24.97 / 18.14 (16.51-19.89) / 8.45 ( 7.35- 9.67) / 9.69 ( 8.51-10.99) / 16.76 (14.88-18.81) / 21.16 (18.06-24.64) / 6.69 (5.08-8.65) / 24.23 (21.90-26.74) / 18.12 (16.48-19.88)
Tapentadol / 17 / 1.40 / 12.17 ( 7.09-19.48) / 5.01 ( 2.01-10.32) / 7.16 ( 3.43-13.16) / 7.53 ( 3.25-14.83) / 26.91 (12.31-51.09) / 0.00 (0.00-7.00) / 19.53 (11.38-31.27) / 12.21 (7.11-19.55)
Fentanyl / 2550 / 102.03 / 24.99 (24.03-25.98) / 11.67 (11.02-12.36) / 13.32 (12.62-14.05) / 23.32 (22.25-24.43) / 29.99 (27.91-32.19) / 7.23 (6.03-8.60) / 28.72 (27.59-29.89) / 25.05 (24.09-26.05)
Buprenorphine / 540 / 25.39 / 21.27 (19.51-23.14) / 9.41 ( 8.26-10.69) / 11.86 (10.55-13.27) / 20.15 (18.16-22.29) / 24.38 (20.79-28.41) / 5.67 (3.82-8.09) / 25.38 (23.22-27.68) / 21.33 (19.57-23.22)
No ER HPO / 6804 / 373.55 / 18.21 (17.78-18.65) / 7.96 ( 7.67- 8.25) / 10.26 ( 9.94-10.59) / 16.77 (16.28-17.27) / 21.98 (21.09-22.90) / 5.01 (4.57-5.48) / 22.73 (22.18-23.30) / 18.24 (17.81-18.68)

CI confidence interval,ER extended-release,HPO high-potency opioid,IR incidence rate,IS ischemic stroke,MI myocardial infarction,PY person years

a In 1000 person years

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ESM7Characteristics of Myocardial Infarction/Ischemic Stroke Cases and of Matched Controls

Cases
N = 12 382 / Controls
N = 123 605
Median age at index date (IQR) / 80 (72-85) / 80 (72-85)
Female / 8264 (66.7%) / 82 613 (66.8%)
Morphine equivalents at index date
< 90 mg / 10 636 (85.9%) / 107 440 (86.9%)
>= 90 mg / 1746 (14.1%) / 16 165 (13.1%)
History of…
Hypertensive disease / 9334 (75.4%) / 83 113 (67.2%)
Ischemic heart disease / 5056 (40.8%) / 37 113 (30.0%)
Atrial fibrillation or flutter / 2399 (19.4%) / 16 444 (13.3%)
Congestive heart failure / 3676 (29.7%) / 27 733 (22.4%)
Atherosclerosis/peripheral vascular disease / 2815 (22.7%) / 19 244 (15.6%)
Diabetes / 4234 (34.2%) / 31 083 (25.1%)
Obesity / 2334 (18.8%) / 20 497 (16.6%)
Disorders of lipoprotein metabolism / 5341 (43.1%) / 46 390 (37.5%)
Cerebrovascular diseases / 2817 (22.8%) / 19 618 (15.9%)
Transient cerebral ischemic attacks / 636 ( 5.1%) / 4076 ( 3.3%)
Opioid abuse/dependence / 52 ( 0.4%) / 467 ( 0.4%)
Other substance use disorders / 442 ( 3.6%) / 4059 ( 3.3%)
Constipation / 1341 (10.8%) / 13 016 (10.5%)
Potential indications
Cancer / 2438 (19.7%) / 25 164 (20.4%)
Specific back pain / 5641 (45.6%) / 56 581 (45.8%)
Intervertebral disc illness / 2784 (22.5%) / 30 173 (24.4%)
Arthrosis / 6867 (55.5%) / 71 508 (57.9%)
Traumatic fractures / 1613 (13.0%) / 15 486 (12.5%)
Multimorbidity / 1260 (10.2%) / 9969 ( 8.1%)
Neuropathic pain / 4121 (33.3%) / 37 926 (30.7%)
Headache / 823 ( 6.6%) / 8954 ( 7.2%)
Unspecific back pain / 8254 (66.7%) / 84 153 (68.1%)
Previous use of…
Antithrombotic drugs / 3801 (30.7%) / 26 987 (21.8%)
Cardiac glycosides / 1128 ( 9.1%) / 7109 ( 5.8%)
Vasodilators / 1958 (15.8%) / 11 711 ( 9.5%)
Antihypertensive drugs / 678 ( 5.5%) / 4818 ( 3.9%)
Diuretics / 5347 (43.2%) / 42 293 (34.2%)
Beta blocking agents / 4919 (39.7%) / 38 471 (31.1%)
Calcium antagonists / 2727 (22.0%) / 23 009 (18.6%)
ACE inhibitors / 4501 (36.4%) / 37 771 (30.6%)
Angiotensin-2 antagonists / 1757 (14.2%) / 16 777 (13.6%)
Non-selective NSAIDs / 3442 (27.8%) / 31 773 (25.7%)
COX-2 selective inhibitors / 449 ( 3.6%) / 4146 ( 3.4%)
Conventional antipsychotics / 806 ( 6.5%) / 6800 ( 5.5%)
Atypical antipsychotics / 499 ( 4.0%) / 4398 ( 3.6%)
Antidepressants / 3294 (26.6%) / 29 963 (24.2%)
Antiepileptic drugs / 1930 (15.6%) / 15 560 (12.6%)
Laxatives / 1999 (16.1%) / 18 345 (14.8%)
Opioid replacement therapy / 2 ( 0.0%) / 39 ( 0.0%)
Low-potency opioids / 2493 (20.1%) / 22 319 (18.1%)
Immediate-release HPO / 573 ( 4.6%) / 4901 ( 4.0%)
Methylnaltrexone / 2 ( 0.0%) / 4 ( 0.0%)

ACE angiotensin-converting enzyme,COX-2 cyclooxygenase-2,HPO high-potency opioid,IQR interquartile range,NSAIDs nonsteroidal anti-inflammatory drugs

1

ESM8Recent Switch in Current Users of Oxycodone/Naloxone

Cases
N = 184 / Controls
N = 252 / Adjusted OR
(95% CI) b
Recent switch from any ER HPOa / 4 ( 2.2%) / 6 ( 2.4%) / 0.91 (0.23-3.67)

CI confidence interval,ER extended-release,HPO high-potency opioid,OR odds ratio

a Reference: No switch

b Adjusted for: Hypertensive disease, ischemic heart disease, transient cerebral ischemic attacks, cerebrovascular disease, atherosclerosis/peripheral vascular disease, diabetes, congestive heart failure, other specific back pain, diuretics, beta blocking agents

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