POWER POINT CHOOSING THE BEST NSAID PROF

-

1. MUHAMMAD RAMLI AHMAD CHOOSING THE BEST NSAID

2. HIGHLIGHT OBJECTIVE

3. Intravenous NSAID’s that we know … Ketorolac Intravenous Used in short-term management of moderately severe, acute pain Contraindication: For use >5 days For minor or chronic pain Paediatric patient Patient with active ulcers High risk of bleeding, those with Advanced renal impairment, and Women who are nursing Diclofenac intravenous Contraindicated in patients with known moderate to severe renal insufficiency who may become volume depleted Fever not indicated

4. NSAID’s Analgesic, anti-inflammatory, antipyretic properties Gastrointestinal (GI) and Cardiovascular (CV) risks Cyclo-oxygenase 1 (Cox-1) or COX-2 inhibition Centrally or peripherally acting NSAID’s

5. IBUPROFEN (2RS)-1[4-(2-methyl propyl) phenyl] propionic acid First member of propionic acid derivates to be introduced in 1969 as a better alternative to Aspirin A popular domestic and over the counter analgesic and antipyretic for adults and children Most commonly used and most frequently prescribed NSAID. A non-selective inhibitor of Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) Recommended dose is 400-800 mg i.v. ibuprofen every 6h, Max 3200mg

6. IBUPROFEN Exists in two stereoisomeric forms, S(+) and R(-). Current formulations of the drug are racemic mixtures. The (S)- enantiometer 160 times more potent than (R)- ibuprofen in inhibiting prostaglandin synthesis in vitro Ibuprofen is indicated for the management of mild-to-moderate pain and as an adjunct to opioid analgesics for moderate-to-severe pain in adult patients

7. 60-80% of patients who undergo surgical experience acute postoperative pain Approximately 75% of those report the severity as moderate, severe, or extreme. Physiologically, pain serves to alert individuals to tissue damage and to prevent further harm. In the acute inpatient setting  no useful purpose Pain Activates the symphatetic nervous system, Increasing blood pressure, Cardiac workload and Respiratory rate. Impairs recovery by reducing mobility and physical activity.

8. Ibuprofen: Non-selective inhibitor of COX-1 and COX-2

9. PROSTAGLANDIN IN PERIPHERAL SENSITIZATION Prostaglandins contribute to peripheral sensitization Activation of TTX-R Na + channels Inhibition of voltage-gated potassium currents. Enhancement of the sensitivity of sensory neurons to bradykinin (B2-receptors) Enhancement of the sensitivity to capsaicin by acting on TRPV1-receptors.

10. PROSTAGLANDIN HYPERALGESIC EFFECT IN CENTRAL SENSITIZATION Pre- and Post-synaptic membranes Activation of the presynaptic EP receptors  spinal release of glutamate and neuropeptides  renhanced nociceptive processing At the post-synaptic level  Activate deep dorsal horn neurons via EP-2 like receptors located on dorsal horn neurons and Block inhibitory of glynergic neurotransmission by activation of EP-2-like receptors in the inhibitory neurons.

11. IBUPROFEN – PERIPHERALLY AND CENTRALLY ACTING NSAID Ibuprofen enters the CNS from the bloodstream. The penetration of ibuprofen into spinal and supraspinal structures mainly by passive diffusion (degree of ionization, pH, lipophilicity). After orally administered ibuprofen, both isomers peaked in the CSF at 3 h (Plasma 1.5 h) CSF Concentraions rise rapidly and can exceed the unbound plasma levels of the drug within 90 min The estimated elimination half-lives of (R)- and (S)- ibuprofen were 1.7h and 2.5h in plasma and 3.9h and 7.9h in CSF

12. COX-1 COX-2 Constitutive enzyme Distributed throughout the body Housekeeper role – cell homeostasis Cytoprotection in the GI Tract Platelet function Renal perfusion Inducible enzyme Rapidly unregulated in response to inflammatory stimulies  result of tissue damage, pain, inflammation, fever Cox-1 is inducible under inflammatory conditions in the kidney Cox-2 is constitutively expressed in CNS, kidney, and blood vessels, Cox-1 and Cox-2 inhibitors may contribute to some of the efficacy as well as the side effect profiles

13. ARACHIDONIC ACID PROSTAGLANDIN: CONSTITUTIVE AND INDUCIBLE

14. BLOCK THE PROSTAGLANDIN BY COX INHIBITOR

15. Epidural block Neuro endocrine stress response Humoral stress response Tissue damage induces COX-2 Production Synthesis of prostaglandins Inflammation Peripheral sensitization of nociceptors Increased pain perception Cox-2 induction within spinal cord plays a role in central sensitization PERIPHERAL AND CENTRAL COX EFFECTS

16. BENEFITS OF MULTIMODAL PAIN THERAPY NSAIDs, COXIB, Acetaminophen, nerve blocks, other non-opioid Potentiation Opioids Improved pain relief due to synergistic or additive effects Reduced doses of each analgesics May reduce severity of side effects opioid Kehlet H et al. Anesth Analog. 1993;77: 1048-1056 Gritsenko K, Khelemsky Y, Kaye AD et al. Best Pract Res Clin Anesthesiol . 2014. 28(1):59-79

17. Score Morphine PCA + Ibuprofen 400mg IV (n=134) Morphine PCA + Ibuprofen 800mg IV (n=138) Morphine PCA + placebo (n=134) Pain at rest (VAS*-AUC, mm-h) 1-24 hours Mean (SD) Median LS Mean (SE )+ p ╪ 81.7 (41.7) 82.1 88.5 (4.6) 0.057 73.9 (39.6) 70.6 82.3 (4.4) 0.001 91.0 (46.0) 88.1 97.3 (4.7) - 6-24 hours Mean (SD) Median LS Mean (SE )+ p ╪ 55.6 (32.6) 55.6 59.6 (3.7) 0.013 49.8 (31.4) 48.0 54.9 (3.6) <0.001 65.3 (37.1) 65.0 68.8 (3.8) - 12-24 hours Mean (SD) Median LS Mean (SE )+ p ╪ 34.3 (21.3) 34.0 35.5 (2.5) 0.005 30.6 (21.5) 29.3 32.6 (2.4) <0.001 41.7 (24.7) 41.1 42.5 (2.6) - Table. Patients self assessment of pain at rest and with movement (intent-to-treat population).

18. Postoperative pain  first hour and 24 hour in postoperative periode Fast onset analgesia

19. Parameter 30-min infusion (Hospitalized patients) 5-7min infusion (healthy volunteers) i.v. Ibuprofen (400mg) i.v. Ibuprofen (800mg) Oral Ibuprofen (800mg) Number of patients 31 12 12 AUC ( µg/h/ml) 70.6 + 31.9 190.6 + 35.6 196.4 + 36.2 C max ( µg/ml) 39.8 +17.8 120.3 + 13.5 62.8 + 12.4 T max ( µg/ml) 0.5 + 0.0 0.11 + 0.01 1.5 + 0.6 T 1/2 ( h) 2.26 + 1.0 2.0 + 0.5 1.9 + 0.3 AUC: Area Under the curve; i.v : intravenous Intravenous ibuprofen for postoperative pain. Kroll, Peter.B . Pain Manage. (2012) 2(1), 47-54 RATE OF INFUSION Table. Intravenous ibuprofen pharmacokinetic parameters.

20. SAFETY

21. NSAID safety varies among the many drugs in this class. These selective mechanisms of action are associated with specific risks. Ibuprofen’s balanced selectivity profile between Cox-1 and Cox-2  balanced safety profile Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the same? A Narrative Review. Varrasi , G. Et al. Adv Ther (2020) 37:61-82

22. NSAID AND GI SIDE EFFECTS

23. Cox-1 Cox-2 Serosa Healing of the ulcers  expression of (Cox-2) Epithelial cell migration and proliferation in the mucosal ulcer margin, Angiogenesis in the ulcer bed, Maturation and contraction of the granulation tissue in the ulcer bed, Quality of remodelling

24. All NSAIDs are associated with some degree of risk for upper GI Complications. Dose and duration of therapy At lower dose, compared with other NSAIDs, the risk of GI adverse events is low with ibuprofen, At higher doses, the rate of adverse GI events increases Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis- Henry, Davis. BMJ 1996

25. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project) Jordi Castellsague   1 ,  Nuria Riera-Guardia 1 ,  Brian Calingaert 2 ,  Cristina Varas-Lorenzo 1 ,  Annie Fourrier-Reglat 3 ,  Federica Nicotra 4 ,  Miriam Sturkenboom 5 ,  Susana Perez-Gutthann 1 ,  Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project

26. How About GI Events of intravenous ibuprofen in postoperative pain management settings?

27. 1075 patients Diarrhea, abdominal discomfort, gastritis, etc , occurred at frequencies less than 1% in the IV ibuprofen group. GI events less in iv ibuprofen group. Opioid sparing effect Short duration An integrated safety analysis of intravenous ibuprofen ( Caldolor ®) in adults. Softworth , SR. et al. Journal of Pain Research 2015:8 753-756

28. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain. Softworth , SR. et al.

29. Smith HS, Vos B. Pharmacokinetics of Intravenous Ibuprofen. Drugs. 2012; 72 (3): 327-337 Ibuprofen Intravena

30. NSAID : Imbalance between TxA2 (anticoagulant, COX-1) and PGI ( procoagulant , COX-2) Mytochondrial dysfunction Cardiac cell apoptosis. Hypertension. Cardiac failure.

31. Long term usage : no difference Other studies : The risk is greater to patients with cardiac conditions, such as chronic heart failure In patients without specific CV risks, ibuprofen at 2400 mg/day could slightly increase the risk for coronary events Ibuprofen and CV risk

32. Intravenous Ibuprofen and CV risks There is no report of increasing CV event by using iv ibuprofen in postoperative periode There is a small increased risk of cardiovascular events with high oral doses of ibuprofen (2400 mg per day) Lower dose (1200 mg per day or less) of ibuprofen are not associated with an increased risk of cardiovascular events The overall benefit to risk of harm balance of ibuprofen as well as other non-steroidal anti-inflammatory drugs (NSAIDs) remains positive

33. Strategy Lowest effective dose of ibuprofen should be used for the shortest possible duration Patient requiring high dose ibuprofen therapy should be reviewed regularly to check for efficacy of treatment, adverse effects and the development of cardiovascular risk factor

34. Ibuprofen Intravenous and Bleeding Risk

35. Objectives Intravenous (IV) ibuprofen was approved by the FDA for use in pediatric patients in November 2015. The objective of this study was to compare bleeding rates in pediatric tonsillectomy patients who received intraoperative intravenous ibuprofen versus those who did not. Secondary objectives included analyzing factors that correlated with return to the Emergency Department (ED) for pain or dehydration. Methods Charts were reviewed for all patients 0–18 years of age who underwent a tonsillectomy with or without adenoidectomy at a tertiary care children's hospital from 1/1/2017 through 5/21/2018. Demographic information and perioperative medications including the use of intraoperative intravenous ibuprofen were recorded. ED visits and operating room (OR) returns for bleeding were tracked for up to 30 days after surgery.

36. Results 1085 charts were analyzed. Intraoperative IV ibuprofen was used in 132 cases (12.2%). Primary bleeds, defined as bleeding within 24 h of surgery, occurred in 1 (0.76%) of 132 patients who received IV ibuprofen, and 1 (0.10%) of 953 patients who did not receive IV ibuprofen. Secondary bleeds, defined as bleeds after 24 h from surgery occurred in 2 (1.52%) of 132 patients who received IV ibuprofen and 38 (3.99%) of 953 patients who did not receive IV ibuprofen. No statistical difference was found between the two groups in rates of overall (primary plus secondary) bleeding requiring return to ED (p = 0.759) or return to OR (p = 0.710). Conclusion The observed bleeding rate after pediatric tonsillectomy was not statistically different in patients who received intraoperative IV ibuprofen versus those who did not receive this medication. Level of evidence III.

37. Objective Oral ibuprofen is believed to be safe and effective after pediatric adenotonsillectomy. There has been little study of its use as a preoperative analgesic. We attempt to document its safety in this setting. Methods Children who underwent tonsillectomy or adenotonsillectomy from January 2013 to December 2015 did not receive preoperative ibuprofen. Those who underwent tonsillectomy or adenotonsillectomy from January 2016 to December 2017 received oral ibuprofen 7 mg/kg preoperatively. Pre‐ and postoperative records were reviewed. Intraoperative bleeding > 50 mL or early postoperative bleeding requiring surgical control were outcome measures. Delayed bleeding events were also recorded.

38. Results A total of 217 children met inclusion criteria. Of those, 112 patients did not receive preoperative ibuprofen, and 105 patients did receive preoperative ibuprofen. Mean age was 8.7 years (range: 1–18) in the control/non‐ibuprofen cohort and 8.3 years (range: 1–18) in the ibuprofen cohort. No child experienced significant intraoperative or early postoperative bleeding in the non‐ibuprofen (95% confidence interval [CI] 0–0.027) or in the ibuprofen cohort (95% CI 0– 0.029). Delayed bleeding rates were similar in both groups. Conclusion In this series, children treated with preoperative ibuprofen did not experience increased bleeding during or soon after tonsillectomy compared to controls. Pain control was not studied in these patients. These favorable safety data argue for a future prospective randomized study of preoperative ibuprofen's effectiveness in reducing pain and opioid requirement after pediatric tonsillectomy. Level of Evidence 3b . 

39. Exhibit a spectrum of analgesic, anti-inflammatory, antiplatelet and antipyretic by inhibit COX enxyme Most commonly prescribed analgesic medications in the world. i.e. Metamizole , Ketorolac, Ketoprofen Many used as the sole method of treatment mild to moderate pain Side effect limit their use NsNSAID

40. Selective COX-2 inhibitor Large molecule with side chin fitted the hydrophilic side of COX-2 isoform but did not fit COX-1 isoform COX-2 in peripheral and central nerve system Parecoxib , a water-soluble prodrug of valdecoxib , isa high-selective COX-2 inhibitor that is available for intravenous administration As a part of multimodal analgesia

41. COXIB evidence Coxibs are effective in the treatment of acute postoperative pain (N) (Level I Cochrane Review]) Coxibs were as effective as nsNSAIDs in the management of postoperative pain ( Romsing & Moiniche , 2004 Level I ) Preoperative coxibs reduced postoperative pain and opioid consumption and increased patient satisfaction ( Straube et al, 2005 Level I ) Acute Pain Management: Scientific evicence , 2015

42. Coxibs are as effectives as nsNSAIDs for posopertaive pain (Moore 2015b Level I [Cochrane], =460 RCTs, n=50,000) NNTs are comparable to those for nsNSAIDs for the treatment of moderate to severe acute pain When given as single dose preoperatively, coxibs provide a reduction in mean postoperative analgesic requirements at 24 (MD -0.68; 95% Cl -0,95 to -0,33) ( Nir 2016 Level I [PRISMA[, 13 RCTs, n=1,079)

43. A meta-analysis of perioperative parecoxib found no increase in renal failure vs placebo ( Schug 2017 Level I, 26 RCTs, b=9,282) In acute pain management, short-term use of parecoxib (< 7 d) after noncardiac surgery does not increase the risk of cardiavascular adverse effects ( Schug 2017, Leve I, 26 RCTs, n=9,282) Coxibs , administered at analgesic doses, do not produce bronchospasm in patient with NSAID-exacerbated respiratory disease ( Maroles 2013 Level I [PRISMA], 14 RCTs, n=426) Short-term use (5-7 days) of coxibs results in gastric ulceration rates similar to placebo and lower than nonselective NSAIDs (U) (Level II)

44. The management of acute pain in intensive care requires an individualised multimodal analgesic approach targeted the etiology of acute pain Intensive care unit patients should be provided with appropriate analgesia prior to and during potentially painful procedures, in particular as recall of discomfort, pain and procedures can be a source of post-traumatic stress (S) Analgo -sedation concept as main principle for critically ill patient Non-opioids including NSAIDs and paracetamol improve analgesia in selected intensive care unit patients (S) (Level 1) The risk of NSAIDs in critically ill patients may be overestimated; NSAIDs may provide effective analgesia as a part of multimodal analgesia (N) Pain Management in ICU

45. 40 mg of parecoxib sodium administered intravenously twice daily for 3 consecutive days after surgery significantly improves postoperative pain management by ameliorating analgesic effect and reducing opioid requirement the suplement of parcoxib to opioid analgesia decreased the incidence of ponv parecoxib decreased delirium occurrence and relieved cognitive impairment in elderly patients after surgery, the use of parecoxib improves postoperative analgesia parecoxib decreases the cumulative consumption of morphine parecoxib alleviates the inflammatory response provoked by surgery it is suggested that central inflammation my play an important role in the pathogenesis of delirium and dementia in the erderly Liang MD, et al. Anesthesia & Analgesia: June 2017- Volume 124-Issue 6 Malan TP Jr , et al. Parecoxib Sodium, a Parenteral Cyclooxygenase 2 Selective Inhibitor, Improves Morphine Analgesia and Is Opioid-sparing following Total Hip Arthroplasty . Anesthesiology. 2003;98:950-956 Hubbard RC, et al. Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia . Br J Anaesth . 2003;90:166-172

46. The renal prostaglandins promote vasodilatation which, in turn, promotes renal blood flow NSAIDs affect the homeostasis of renal prostagalndins by inhibiting COX-1 and/ or COX-2 In euvolemic patients, NSAIDs do not cause significant renal effects In geriatric and declined kidney function, higher-than-anticipated free levels of the NSAID and a prolonged half-life was found

47. The Celecoxib Long-Term Arthritis Safety Study (CLASS, n=8059, celecoxib vs ibuprofen vs diclofenac ) Changes in serum creatinin clearance occurred in similar numbers of celecoxib and ibuprofen patients PRECISION study : Risk of renal adverse events was significantly lower in celecoxib than ibuprofen patients (p= 0.004) but the risk was similar between celecoxib and naproxen (p= 0.19) Oral Ibuprofen in longterm therapy

48. Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review. Varrasi , G. et al. Adv Ther (2020) 37:61-82 iv Ibuprofen, postoperative setting In healthy patients underwent orthopedic and abdominal surgery No signifficant diffrence of BUN and serum creatinin value (iv ibuprofen vs placebo, 5 days obsevation )

49. Ibuprofen Intravenous in COVID-19 Patients

50. Assumption : ibuprofen might upregulate ACE-2, thereby increasing the entrance of COVID-19 into the cells An analogy with bacterial soft-tissue infections, where patients receiving NSAIDs had more severe infections because of the immune-depressive actions of NSAIDs of initial symptom suppression Fever is a natural reponse to viral infections and reduces viral activity: antypiretic activity would reduce natural defenses against viruses.

51. The renin-angiotensin-aldosterone system (RAAS) Complex system controls numerous functions in multiple organs. Blood pressure, electrolyte, excretion, and fluid balance Play an important role in regulation of inflammation The ACE2 axis a counter-regulatory pathway anti-inflammatory Oppose ACE and TNF alpha downstream  

52. A narrative review of the potential pharmacological infuence and safety of ibuprofen on coronavirus disease 19 (COVID‑19), ACE2, and the immune system: a dichotomy of expectation and reality. Smart, L. et al. Inflammopharmacology . 28 , 141-1152(2020)

53. CONCLUSIONS Intravenous ibuprofen 800 mg has a good efficacy and safety profile Rapid onset of intravenous ibuprofen might be beneficial in early post operative periode

54. THANK YOU