The document discusses postoperative pain management. Effective pain management has humanitarian benefits and can facilitate rapid recovery. It summarizes various pain theories and treatments, including opioids, NSAIDs, and other non-opioid analgesics. It also provides examples of etoricoxib clinical trials that demonstrate its efficacy in reducing postoperative pain with fewer side effects compared to other treatments like ibuprofen and oxycodone.

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

7. Pain is an unpleasent sensorial and emotional experience associated to a real or potential tissue damage International Association for the study of Pain

8. The goals of effective and appropriate pain management are to… Improve quality of life for the patient Facilitate rapid recovery and return to full function Reduce morbidity Allow early discharge from hospital

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

10. Effective pain management is now an integral part of modern surgical practice Postoperative pain management - minimizes patient suffering - can reduce morbidity - facilitates rapid recovery and early discharge from hospital - can reduce hospital costs

11. Pain Theories. Pattern theory Gate control theory Specificity theory

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

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

14. Conditions that Open the Gate Physical conditions Extent of injury Nature of injury Emotional states Anxiety Worry Tension Depression Cognitive states Focusing on the pain

15. Conditions that Open the Gate Physical conditions Extent of injury Nature of injury Emotional states Anxiety Worry Tension Depression Cognitive states Focusing on the pain

16. Conditions that Open the Gate Physical conditions Extent of injury Nature of injury Emotional states Anxiety Worry Tension Depression Cognitive states Focusing on the pain

17. Physical Medication Counterstimulation (e.g. heat, massage) Emotional state Positive emotions (e.g., happiness, optimism) Relaxation Rest Mental state Intense concentration or distraction Involvement and interest in activities Conditions that Close the Gate

18. Providing a warning of tissue damage Inducing immobilization to allow appropriate healing GOOD PAIN… Acute pain plays a useful "positive" physiological role

19. BAD PAIN…. Short term negative effects of acute pain Emotional and physical suffering for the patient Sleep disturbance with negative impact on mood and mobilization Cardiovascular side effects such as hypertension and tachycardia

21. Pain as a Health Problem

22. MOST FREQUENT SCENARIOS Reumathoid Arthritis Osteoarthrosis Chronic Back Pain Postoperative Pain Pain Inflammation Inflammation Pain

23. Accute Gout MOST FREQUENT SCENARIOS Pain Inflammation

24. Pain Treatment Goals Reduce discapacity Improve quality of life Use safe medications that reduce toxic effects Less Time

25. Our most frequent problems Chronic Musculoskeletal Pain

26. Our most frequent problems Postraumatic Pain Postoperative Pain

27. National Institute of Health In a two year period adults age 25 and over sustained nearly 2.3 million sports and recreational injuries - 370,000 recreational sports 331,000 exercising 276,000 playing basketball 231,000 bike riding 205,000 baseball/softball. SOCCER ???

28. The use of analgesics to mask the pain caused by sports injuries is not recommended for long term health. Masking the pain may enable an athlete to continue playing their sport in the short term, but in the longer term, removing the body’s sensory receptors of pain can leave the athlete worse off. .

29. It may also have the effect of significantly impairing their performance.

30. Pain or sports injuries are often the main reasons athletes end up consulting physicians. Instead of merely treating the pain, athletes should be encouraged to treat the cause of the pain

31. Postoperative Pain Pain generates emotional, physiological and psicological responses that affect the final recovery Intensity of pain depends on the operated area: Thorax – Thoracoabdominal Abdomen – Hip & Knee – OBGYN Lower Abdomen Osteoarticular Skin

32. Postoperative Pain Adverse Effects Respiratory Cardiovascular Gastrointestinal Urinary Neuroendocrine Metabolic Psicological

33. Pain Evaluation Measurement of self evaluation VAS – Visual Analogue Scale Numeric verbal score Graphic scales score Observational Measurements Pain Observational Scale Toddlers Pain Scale

34. Pain Assessment

35. Pain Treatment Opioids Systemic Subaracnoid Epidural Non Opioid Analgesics NSAIDS Local Anesthetics Psicological Methods

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

37. 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

38. Opioids Obtained from Opium – Poppy flower (natural) Also Synthetic or semi-synthetic Semi-synthetic are based on morphin or tebain

39. Opioids Synthetic Levorfanol Metadone Pentazocine Phenilpiperidines Phentanil Sufentanil Meperidine Semisynthetic Heroín Dehidromorfin Buprenorfin Natural Morphine Codein Papaverin Tebain

40. Opioid Effects CNS: Powerful analesic action Efective pain control Eliminates emotional side Respiratory: depression Dose dependent Decreases ventilatory response to CO 2

41. Muscle: Increase of muscle tone, dose dependent Cardiovascular low miocardial depresion reduces peripheral vascular resistance increases venous capacity causes bradichardia Opioid Effects

42. Sphincter contracture Abdominal pain Urinary retention Nausea & vomit Increase of GI secretions Myosis Opioid Effects

43. Don’t Forget… Patients must have permanent medical suport Clearly specify dose and schedule Keep record of adverse effects and complications Monitor frequency and depth of respiratory movements

44. Non Opioid Analgesics NSAIDS Paraaminofenols Salicilates

45. Salicilates Sir John Robert Vane 1982 Nobel Prize Effects of Aspirin in Pain

46. Salicilates Ciclooxigenase non reversible inhibition , interfering with prostaglandin synthesis Aspirin is the prototype molecule Effects: control of pain, fever and inflammation Most significative side effect: erosive gastritis and GI bleeding Inhibits platelet function for 7 days Common hypersensitivity and alergic reactions

47. Para-Amino- Phenols Good pain and fever control No anti-inflammatory effects No peripheral ciclooxigenase inhibition Most widely used analgesic in the world High doses or long lasting treatments may cause liver toxicity

48. NSAIDS Non Steroidal Pharmacologic Agents that act on Pain and Inflammation Pathways

49. Inflammation Represents the first step in tissue repair, when the chemical mediators produce increased blood flow, capillary permeability, coagulation, edema, and cell migration These effects stimulate pain nociceptors permanently

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

51. 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.

52. NSAID Facts - Most NSAIDs are weak acids, with a pKa of 3-5 They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (>95%)

53. NSAID Facts Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites which are typically excreted in the urine, although some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.

54. NSAID Facts - Ibuprofen and Diclofenac have short half-lives (2–3 hours) Coxibs have an average half-life of 24 hours - Oxicams have very long half-lives (20–60 hours)

55. NSAIDS by chemical family Propionic acids Ibuprofen Phenoprofen Ketoprofen Phlurbiprofen Naproxen Oxaprozin Pirazolones Phenilbutazone Heteroaril- Acetic Acids Tolmentin Ketorolac Phenilacetics Diclofenac Indolacetic Acids Indomethacin Sulindac Etodolac

56. 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

57. NSAIDS Adverse GI Effects These effects are dose-dependent In many cases severe enough to pose the risk of ulcer perforation / upper GI bleeding / death An estimated 10-20% of NSAID patients experience dyspepsia

58. NSAIDS Adverse GI Effects 2008 FDA DATA Estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the US Represents 43% of drug-related emergency visits Many of these events are avoidable: Unnecessary prescriptions for NSAIDs were written in 42% of visits.

59. 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

60. 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

61. NSAIDS Renal Adverse Effects Changes in renal haemodynamics (blood flow), ordinarily mediated by Prostaglandins Prostaglandins normally cause vasodilation of the afferent arterioles of the glomeruli This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function

62. 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

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

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

66. 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.

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

68. Pain research history 1936 1949 1952 1958 1965 1978 1982 1998 2002 MYOCHRYSINE CORTONE HYDROCORTONE DECADRON INDOCID (Indometacina) DOLOBID (Diflunisal) CLINORIL (Sulindac) VIOXX (Rofecoxib) ARCOXIA (Etoricoxib)

69. Etoricoxib N N Cl S O 2 CH 3 C 3

70. Etoricoxib world clinical program Accute Pain Post dental surgery pain Postoperative pain Gout arthritis accute pain Chronic Pain Osteoarthritis Chronic Low Back Pain Rheumathoid Arthritis

71. 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

72. Lancet. 2006 Nov 18;368(9549):1771-81

73. 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

74. 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 Clin Therapeutics 2004;26:667-672.

75. Anesth Analg 2005;101:1104-11. Act Anaesthesiol Scand 2007;51:316-321. TKR & THR Post Arthroscopy pain Accute Phase: Symilar to Naproxen 1 gm. 2 - 7° day: Better analgesic effect Lower need for other analgesics 120 mg/day PostOp Pain Results Orthopedic Surgery

76. PostOp Pain Results Oxicodone/paracetamol 10/650< mg (n=100) Time (Hours) Post-dose Clin Therapeutics 2004;26:667-672. 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

77. PostOp Pain Results Was “Rescue”medication needed ? % Patients that required rescue medication Clin Therapeutics 2004;26:667-672. *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

78. 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)

79. 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

80. Etoricoxib Metabolism Metabolized by several P450 system enzymes: CYP3A4 (  60%) y CYP2D6, CYP2C9, CYP1A2 y CYP2C19 Elimination : - 70% renal - 20% feces - <2% unaltered Low interaction potential

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

82. Safety Profile % Adverse effects Clin Therapeutics 2004;26:667-672.

83. Safety Profile % Adverse Effects Retired due to AE EA TGI. EA HTA Clin Therapeutics 2004;26:667-672.

84. 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 Clin Therapeutics 2004;26:667-672.

85. 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) Clin Therapeutics 2004;26:667-672.

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

87. Lancet. 2006 Nov 18;368(9549):1771-81

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

89. Contraindications Specific Hypersensitivity or Allergy Gastric Ulcer, GI Bleeding or acido-peptic disease history Congestive Heart Insufficiency or ventricular disfunction Uncontrolled HBP Coronary syndromes – coronary surgeries Severe liver disfunction Pregnancy Children

90. In accute pain 120 mg once a day Etoricoxib

91. In Rheumathoid Arthritis 90 mg once a day Etoricoxib

92. in Osteoarthrosis 60 mg once a day Etoricoxib

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

94. Conclusion Powerful, quick and long lasting analgesic Strong Anti - inflammatory Safe medication Well supported by basic and clinical research Backed up by a well known researcher in the industry Better than any other product I can prescribe An excellent solution for many of my problems… Etoricoxib because…

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

100. CURSO DE INSTRUCCIÓN EN MEDICINA DEL DEPORTE SANTA MARTA, COLOMBIA OCTUBRE 2 & 3 DE 2009 IROTAMA RESORT – GOLF - MARINA