Current concepts in Postoperative Pain Management, by Prof. Dr. Carlos Leal MD - Bosque University Orthopedics, Bogota

1. Carlos Leal M.D. Director Orthopedic Research Laboratory Director of Knee Surgery & Sports Medicine Fellowship Bosque University Orthopedic Department Bogotá DC, Colombia Current Management of Postoperative Pain

6. Effective postoperative pain management has a humanitarian role, But there are additional medical and economic benefits for rapid recovery and discharge from hospital.

9. INJURY GATE Various factors: physical, emotional, cognitive or behavioural open or close the gate PAIN experienced depending on how far gate open or closed

16. Pain as a Health Problem

20. Our most frequent problems Chronic Musculoskeletal Pain

25. Pain Assessment

27. IASP Postop Pain Protocols International Association for the Study of Pain

28. Ablation surgery IV Morphine Tens Nerve/Spinal Block Opioid derivates NSAIDS + Codein NSAIDS Aspirin Acetaminophen Pain Intensity Scale Treatment International Association for the study of Pain

41. Pain and Inflammation Pathways Tissue Damage Pro-Inflammatory Response COX Araquidonic Acid Prostaglandins Pain Fever Inflammation

42. NSAID Actions Most NSAIDs act as non-selective inhibitors of the ciclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid Prostaglandins act (among other things) as messenger molecules in the process of inflammation.

47. The widespread use of NSAIDs has meant that the adverse effects of these relatively safe drugs have become increasingly prevalent. Gastrointestinal Renal Cardiovascular Other… NSAIDS Adverse Effects

50. NSAIDS Cardiovascular Adverse Effects Kearney et al., BMJ 2006;332:1302–1308 A recent meta-analysis of all trials comparing NSAIDs found an 80% increase in the risk of myocardial infarction with both newer COX-2 antagonists and high dose traditional anti-inflammatories compared with placebo All NSAIDs are associated with a doubled risk of symptomatic heart failure in patients without a history of cardiac disease

51. NSAIDS Cardiovascular Adverse Effects In patients with such a history, use of NSAIDs was associated with more than 10-fold increase in heart failure If this link is found to be causal NSAIDs are estimated to be responsible for up to 20% of hospital admissions for congestive heart failure

53. NSAIDS Renal Adverse Effects In renal failure the kidney is trying to maintain renal perfusion pressure by elevated Angiotensin II levels Angiotensin II also constricts the afferent ateriole into the glomerulus in addition to the efferent arteriole it normally constricts

55. NSAIDS are good, but more research is needed to improve safety and increase efficacy

56. Discovery of COX-2 Selective inhibition of COX-2 results in anti-inflammatory action without disrupting gastroprotective prostaglandins. Daniel L. Simmons Brigham Young University

57. Discovery of COX-2 COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes COX-2 is an enzyme expressed in inflammation and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.

58. Discovery of COX-2 OXICAMS and COXIBS Proved Efficacy and Safety FDA and EMEA approval under revision due to validation of Cardiovascular Adverse Effects

59. MSD: pain research tradition 1936 1949 1952 1958 1965 1978 1982 1998 2002 MYOCHRYSINE CORTONE HYDROCORTONE DECADRON INDOCID (Indometacina) DOLOBID (Diflunisal) CLINORIL (Sulindac) VIOXX (Rofecoxib) ARCOXIA (Etoricoxib)

60. Etoricoxib ARCOXIA N N Cl S O 2 CH 3 CH 3

62. Etoricoxib world clinical program Phase I / Pharmacology : 651 subjects Phase II / Clinical: OA, RA : 4888 patients. EDGE: GI tolerance: 2 studies OA: 3953 patients, 90 mg RA: 2032 patients, 90 mg. MEDAL: CV safety OA: 8940 patients (6769:60mg; 2171: 90mg) RA: 2846 patients, 90 mg. >30.000

63. PostOp Pain Results Max Pain Relief Score 5 4 3 2 1 0 6 7 8 12 24 Time (hr) Cambio promedio con ± EE Initial Analgesic Effect with Etoricoxib 120 mg= 24 min Initial Analgesic Effect with Ibuprofen 400 mg.= 32 min Clin Therapeutics 2004;26:667-672. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Placebo Ibuprofen 400 mg ETORICOXIB 60 mg ETORICOXIB 120 mg

64. PostOp Pain Results Average Pain Relief Score 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ETORICOXIB 120 mg Naproxen 550 mg Paracetamol 600mg /codeín 60 mg Placebo Time (Hours) Post-dose Puntuación promedio de AD ± EE 0 1 2 3 4 5 6 7 8 10 12 20 24

66. PostOp Pain Results Oxicodone/paracetamol 10/650< mg (n=100) Time (Hours) Post-dose 10 8 6 4 2 0 12 14 16 20 24 Puntuación ±EE 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Placebo (n=25) ETORICOXIB120 mg (n=100) 18 22

67. PostOp Pain Results Was “Rescue”medication needed ? % Patients that required rescue medication *p<0.010 para Etoricoxib vs. oxicodona/paracetamol; p<0.001para Etoricoxib vs. placebo **p<0.010 para oxicodona/paracetamol vs. placebo Porcentaje ±SE 90 80 70 60 50 40 30 20 10 0 Oxicodone/Paracetamol 10/650 mg (n=100) Etoricoxib 120 mg (n=100) Placebo (n=25) 41.0** 22.0* 72.0 100

68. Tolerance Profile Vs. Oxicodone Adverse effects results Oxicodone/ Etoricoxib paracetamol 120 mg 10/650 mg Placebo (%) patients (n=100) (n=100) (n=25) Any AE 32 (32.0)** 71 (71.0) 6 (24.0) AE related to treatment 9 (9.0)** 64 (64.0) 2 (8.0) Common AE Dizziness 2 (2.0) 38 (38.0) 1 (4.0) Nausea 4 (4.0)** 33 (33.0) 0 (0.0) Vomit 0 (0.0)** 20 (20.0) 0 (0.0) Drowsiness 0 (0.0) 19 (19.0) 1 (4.0) Post Op Alveolitis 15 (15.0) 15 (15.0) 2 (8.0) Headache 3 (3.0) 6 (6.0) 0 (0.0)

69. Etoricoxib Farmacokinetics Linear Kinetics Dose Dose Concentration Concentration Max. 1h Biodisponibility 100% Effects Lasts 24 hs (72%) Effect Starts at 24 Minutes (50%) Not affected by food intake Stable after 7 days

71. Medication Interaction INR ↑ Dose Microdosis Monitor MTX Monitor BP

72. Safety Profile % Adverse effects

73. Safety Profile % Adverse Effects Retired due to AE EA TGI. EA HTA

74. GI Adverse Effects *p<0.001 para placebo y etoricoxib vs. naproxeno Incidencia (%) 0 Etoricoxib 120 mg (n=236) 10 20 30 40 70 100 80 22.7* 72.0 50 60 90 Naproxeno 1000 mg (n=235) Etoricoxib 120 mg (n=216) 17.4* 58.7 Ibuprofeno 2400 mg (n=218) Incidencia (%) 0 10 20 30 40 70 100 80 50 60 90 AR - OA OA Placebo (n=229) 23.2* Placebo (n=221) 19.7* Patients with gastric ulcers or erosions diagnosed with endoscopy 12 weeks treatment

75. Endoscopy studies comparing Etoricoxib in OA & RA *p<0.001 vs. naproxeno; **p<0.001 vs. ibuprofeno; ***p=0.007 vs. ibuprofeno Datos en Archivo, MSD. Incidence of GI Ulcers  3 mm - 12 weeks 25 Incidencia Acumulada, porcentaje (± IC 95%) Incidencia Acumulada, porcentaje (± IC 95%) 0 OA o AR 5 10 15 20 25 35 30 Etoricoxib 120 mg (n=251) 7.42* 25.27 Naproxeno 1000 mg (n=244) Placebo (n=247) 1.35* OA 0 5 10 15 20 8.12*** Etoricoxib 120 mg (n=221) 17.02 Ibuprofeno 2400 mg (n=226) 1.86** Placebo (n=233)

76. Cardiovascular adverse effects Note: * p<0.05 vs. Pbo

77. Use with caution… Pregnancy: 6-9 month Alergies Severe renal Insufficiency Moderate liver insufficicency Hiperlipidemia, heavy smokers Dehidration

79. In accute pain 120 mg once a day Etoricoxib

80. In Rheumathoid Arthritis 90 mg once a day Etoricoxib

81. in Osteoarthrosis 60 mg once a day Etoricoxib

82. In chronic low back pain 60 mg once a day Etoricoxib

84. I’ve used Etoricoxib on myself….

85. “ In the new world there will be no pain…” Apc 7,17;21,4

86. Thanks !

87. Thanks !

88. Thanks !

89. More Info ? [email_address] chazleal@gmail.com