Role NSAID in Perioperative Period Pediatric Anesthesia Consultant and Pain ManagementAnesthesiology and Intensive Department Faculty of Medicine Universitas Sumatera Utaradr. Asmin Lubis, DAF, Sp.An, KAP, KMN

What is Pain

An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.

IASP Pain Definition (1994, 2008)

Why Prevent Pain?Basic human right! pain and suffering complications likelihood of chronic pain development patient satisfaction speed of recovery length of stay cost productivity and quality of life

Adverse Effects of Poor Pain ControlRespiratory; increases risk of chest infection/pneumonia.Cardiovascular; Hypertension, tachycardia, platelet aggregation and venous stasis due to poor pain controlGastrointestinal; Nausea and vomitingGenitourinary; Urinary retentionEndocrine; The stress response from pain causes release of hormonesPsychological; anxiety, sleep deprivationSmith J, Acute Pain Management in Surgical Patients, http://www.jjs.me.uk/teaching/acutepain, 2013

When start for controlling pain?We must do the pain management; before, during, and after a procedure that are intended to reduce or eliminate pain before discharge ( Perioperative Pain Management)

ASA Task Force on Acute Pain Management. Practice Guidelines for acute pain management in the Perioperative Setting. Anesthesiology 2012;116:248-73

1d. Preemptivve & Preventive

Methods to Treat PainTreatment based on path physiology of painPharmacologicMedicationsAcetaminophenNSAIDOpioidsGabapentinNMDA antagonistsAlpha-2 agonistsProceduresRegional AnesthesiaLA infiltration at incision siteSurgical InterventionNon-Pharmacologic / Non-Surgical

Multimodal AnalgesiaCombinations of varying agents for pain controlAlways consider multimodal analgesia when treating painDifferent drugs with different mechanisms/sites of action along pain pathwayEach with a lower dose than if used aloneCan provide additive or synergistic effectsProvides better analgesia with less side effects (mainly opiate related S/E)

The use of multimodal analgesia technique offersmultiple benefits for the patient and the healthcaresystem in line with the goals of modern ambulatory(day-case) surgery

NSAID (Non-Steroidal Antiinflammatory Drug)

Have been use for treating pain for decadesNSAID is an all-inclusive term denoting a varied group of drugs possessing analgesic, anti-inflammatory, and antipyretic effectAll NSAIDs, including selective COX-2 inhibitors: Antipyretic, analgesic, and antiinflammatory, with the exception of acetaminophen, which is antipyretic and analgesic but is largely devoid of antiinflammatory activity. Categorized: Conventional non spesific inhibitors of both isoform of COX (ibuprofen, naproxen, aspirin, acetaminofen, ketorolac)COX 2 selective inhibitor (celecoxib, rofecoxib, valdecoxib, parecoxib)

Characteristic of NSAIDs Decrease activation and sensitization of peripheral nociceptorsAttenuate inflammatory responseAbsence of dependence or addiction potentialSynergistic effect with opioidPreemptive analgesia (decrease neural sensitization)Absence of depression of breathingLess nausea and vomiting compared with opioidLong duration of actionLess dose variability compared with opioidNo pupillary change Absence of cognitive effects

Common issues of NSAIDsDifferent chemical familiesDifferent pharmacokinetics and potencyCommon mechanism of action (COX inhibition)Different selectivity to COX-1 and COX-2Common clinical indicationsAnalgesic (CNS and peripheral effect) may involve non-PG related effectsAntipyretic (CNS effect) Anti-inflammatory (mainly by PG inhibition) Effective dose for analgesic anti-inflammatory antipyreticCommon analgesic ceiling effect

Current view in selecting analgesic and anti-inflammatory drugsEfficacy (indication)Safety (side effect)Not only GI toxicityCardiovascular toxicityRenal toxicityBleedingBone healing impairment etcSuitability (contra-indication)AvailabilityPharmacokinetics and drug interactionDaily costEvidence based medicine

Factors to consider when choosing NSAID as pain killerDrug issuesEfficacyTolerability Safety Dosage Cost

Patient issuesType, severityRisk factors: GI, platelet, renal and cerebro-cardiovascular system.Co-prescription. Co-morbidity.Compliance.

BENEFITSefficacyRISKSsafety

PGD2inhibits plateletaggregation,vasodilatorPGE2vasodilator,hyperalgesiaPGF2alfabronchodilatationmyometrial contr.hyperalgesiaPGI2inhibits plateletaggregation,vasodilator,hyperalgesiaTXA2stimulates plateletaggregation,vasoconstriction5-HPETELTA4LTB4chemotaxisLTC4LTD4LTE4brochoconstrictionincreasevascularpermeabilitycyclicendoperoxidesphospholipidsarachidonic acidCOXLOXCOX-1COX-2

COX-1 or COX-2The detrimental effects of some NSAIDs (eg, renal dysfunction, gastrointestinal mucosal compromise, platelet inhibition) are mediated by inhibition COX-1The analgetic effect and anti-inflammatory effects are attributable primarily to inhibition of COX-2Experimental evidence showing that prostaglandin E2 (PGE2), which is generated by the COX-2 pathways, plays a critical role in the induction of both peripheral and central sensitization

OtotoxicBronchospamCHFHepatotoxicUGIBBleedingNephrotoxicTocolyticAllergyColor blindnessAdverse Effects of NSAIDs Mechanism of = Mechanism of therapeutic effects adverse effectsUGIB

plateletaggregation plateletaggregationGIbleeding GIbleeding bleedingplateletaggregationCOX-1inhibitorCOX-2inhibitormore heart attackblood coagulationfewer heart attackhemorrhagic strokeLelo, 2000

COX-1/COX-2 selectivity of NSAIDsnonselectivePref.COX-2COX-2selectiveCOX-1selectivePref.COX-1

anti-inflammationanalgesic

KetorolacKetorolac is a potent analgesic but only a moderately effective antiinflammatory drug. Pharmacokinetics and MetabolismRapid onset of actionHalf life 4-6 hours, Peak plasma 30-60 after IMExtensive protein bindingShort duration of action Oral bioavailability is about 80%. Urinary excretion accounts for about 90% of eliminated drug, with about 10% excreted unchanged and the remainder as a glucuronidated conjugateThe rate of elimination is reduced in the elderly and in patients with renal failureCommon adverse effectsSide effects at usual oral doses include somnolence, dizziness, headache, gastrointestinal pain, dyspepsia, nausea, and pain at the site of injection.

COX 1 SELECTIVEGoodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

KetorolacOnly use < 5 days>65 years: 10 mg every 4-6 hours (not to exceed 40 mg/24 hours)

KetoprofenPharmacokineticsPeak plasma 1-2 hours, Half life 2 hoursProtein binding 98%Half-life in plasma of about 2 hours except in the elderly, in whom it is slightly prolongedConjugated with glucuronic acid in the liver, and the conjugate is excreted in the urine. Patients with impaired renal function eliminate the drug more slowly. DoseAnalgesia: 25 mg (3-4 times/day)Antiinflammatory: 50-75 mg 3-4 times/dayCommon adverse effectsApproximately 30% of patients experience mild gastrointestinal side effects Fluid retention and increased plasma concentrations of creatinine.Renal function should be monitored in such patients.COX 1 SELECTIVEGoodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Ibuprofen PharmacokineticsAbsorbed rapidly, bound avidly to protein, and undergoes hepatic metabolismRenal excretion of metabolites. Peak 15-30 minutes, half-life is roughly 2-4 hoursSlow equilibration with the synovial space means that its antiarthritic effects may persist after plasma levels decline In experimental animals, ibuprofen and its metabolites readily cross the placentaDoseAnalgesia 200-400 mg every 4-6 hoursAntiinflammatory 300 mg every 6-8 hours or 400-800 mg 3-4 times/dayCommon adverse effects 5% to 15% of patients experience gastrointestinal side effects.Can be used occasionally by pregnant women; however, the concerns apply regarding third-trimester effects, including delay of parturitionExcretion into breast milk is thought to be minimal, so ibuprofen also can be used with caution by women who are breastfeeding.

Pref. COX-1

Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Mefenamic AcidPharmacological PropertiesPeak plasma 2-4 hours, half life 3-4 hoursMay have central actionThe fenamates are a family of NSAIDs first discovered in the 1950s that are derivatives of N-phenylanthranilic acid. They include mefenamic, meclofenamic, and flufenamic acids.The fenamates are typical tNSAIDs. Mefenamic acid has central and peripheral actions, and meclofenamic acid (and perhaps other fenamates) may antagonize directly certain effects of prostaglandins, although it is not clear that receptor blockade is attained at therapeutic concentrations.These drugs are absorbed rapidly and short durations of action. Approximately 50% of a dose of mefenamic acid is excreted in the urineTwenty percent of the drug is recovered in the feces,Dose500-mg load, then 250 mg every 6 hoursCommon Adverse Effects and PrecautionsApproximately 25% of users develop gastrointestinal side effects at therapeutic doses.The fenamates are contraindicated in patients with a history of gastrointestinal diseasenonselectiveGoodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Piroxicam Pharmacological PropertiesPiroxicam is effective as an antiinflammatory agent Absorbed completely after oral administration and undergoes enterohepatic recirculation;Peak concentrations in plasma 3-5 hours, Half life 45-50 minutesFood may delay absorptionEstimates of the half-life in plasma have been variable; the average is roughly 50 hours Extensively (99%) bound to plasma proteinsLess than 5% of the drug is excreted into the urine unchanged60% of the drug excreted in the urine and feces.DoseThe usual daily dose is 20 mg and because of the long half-life, steady-state blood levels are not reached for 7 to 12 daysCommon adverse effectsToxicity includes gastrointestinal symptoms (20% of patients), dizziness, tinnitus, headache, and rash. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered. nonselectiveGoodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

MeloxicamPharmacological PropertiesSome COX-2 selectivity, especially at lower dosesPeak 5-10 hours, Hall life 15-20 hoursProtein binding 99%Meatbolisme di hati melalui HydroxylationDose7.5-15 mg/day7.5 to 15 mg once daily for osteoarthritis and 15 mg once daily for rheumatoid arthritis Pref.COX-2Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Celecoxib Pharmacological PropertiesPeak 2-4 hours, Half-life 6-12 hours, protein binding 97%Metabolites Carboxylic acid and glucuronide conjugatesCelecoxib is metabolized predominantly by CYP2C9.Little drug is excreted unchanged; most is excreted as carboxylic acid and glucuronide metabolites in the urine and fecesRenal insufficiency is associated with a modest, clinically insignificant decrease in plasma concentrationDoseCelecoxib is approved in the United States for the treatment of osteoarthritis and rheumatoid arthritisThe recommended dose for treating osteoarthritis is 200 mg per day as a single dose or as two 100-mg doses. Common Adverse Effects and PrecautionsStudies in mice and some epidemiological evidence suggest that the likelihood of hypertension on NSAIDs reflects the degree of inhibition of COX-2 and the selectivity with which it is attained.Risk of thrombosis, hypertension, and accelerated atherogenesis are mechanistically integrated. The coxibs should be avoided in patients prone to cardiovascular or cerebrovascular disease. Pref.COX-2Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

DiclofenacPharmacological PropertiesDiclofenac has analgesic, antipyretic, and antiinflammatory activitiesDiclofenac has rapid absorption, Peak 2-3 hours, a short half-life, Half-life 1-2 hoursThere is a substantial first-pass effect, such that only about 50% of diclofenac is available systemically.Diclofenac accumulates in synovial fluid after oral administration, which may explain why its duration of therapeutic effect is considerably longer than the plasma half-lifeDiclofenac is metabolized in the liver Metabolites are excreted in the urine (65%) and bile (35%)Dose100 to 200 mg, given in several divided doses50 mg 3 times/day or 75 mg 2 times/dayshort-term treatment of acute musculoskeletal pain, postoperative pain, and dysmenorrheaCommon Adverse EffectsDiclofenac produces side effects (particularly gastrointestinal) in about 20% of patientsModest elevation of hepatic transaminases in plasma occurs in 5% to 15% of patientsCNS effects, rashes, allergic reactions, fluid retention, and edema, and rarely impairment of renal function.The drug is not recommended for children, nursing mothers, or pregnant womenPref.COX-2Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Paracetamol Pharmacological PropertiesAnalgesic-antipyretic agent Weak COX-1 and COX-2 inhibitor and no significant anti-inflammatory effectPeak blood in 30-60 minutes, half-life is 2-3 hours Relatively unaffected by renal function.With toxic doses or liver disease, the half-life may be increased twofold or more.Less than 5% is excreted unchanged. Dose10-15 mg/kg every 4 hours (maximum of 5 doses/24 hours)Common Adverse Effects and PrecautionsRash and other allergic reactions occur occasionallyThe use of acetaminophen has been associated anecdotally with neutropenia, thrombocytopenia, and pancytopenia.Overdosage: Fatal hepatic necrosis. Renal tubular necrosis and hypoglycemic coma also may occur.

Slowly ChronicCorrelation between absorption, T-max and onset of actionTimeConcentrationEffective concentrationAcute NSAID short half liferapid onset but short durationNSAID long half lifelong duration but slow onset

Slowly ChronicHow to change the onset of action of the long half-life NSAIDTimeConcentrationAcute NSAID long half lifelong duration but slow onset increased the dose !By increasing the dose ???:onset becomes earlierbut adverse effects enhancedRational ? Save ? Ethic ? Dangerous !

Adapted from Antman EM, et al. Circulation. 2007;115:1634-1642.Bleeding Ulcer ComplicationsDegree of SelectivityBlood Pressure IncreaseDiscontinuationThrombosis, Myocardial InfarctionEtoricoxibCelecoxib DiclofenacRofecoxibNaproxenIbuprofenDiscontinuationCardiovascular RiskGastrointestinal RiskCOX-2COX-1The Implications of NSAID Selectivity

***************Dari kaskade pembentukan prostaglandin diketahui bahwa baik COX-1 (yang diperlukan dalam pembentukan tromboxan dan PGF2-alfa pencetus nyeri) dan COX-2 (yang diperlukan dalam pembentukan pencetus nyeri PGI2 dan PGE2) harus dihambat aktivitasnya dalam mengurangi nyeri. Bukan hanya menghambat COX-2. dengan demikian adakah perbedaan khasiat NSAID non-COXIB dengan COXIB?*PNI Cabang MedanMedan Pain Management 2011*****************It has been postulated that the differences in relative selectivity for COX inhibition affect the likelihood of a patient experiencing adverse CV or GI complications as a consequence of using NSAIDsThis figure illustrates the implication of the relative degrees of NSAID selectivityIncreasing degrees of selectivity for COX-2 are associated with augmented cardiovascular risk, whereas increasing degrees of selectivity for COX-1 are associated with augmented GI riskThis has important implications for interpretation of clinical trials. For example, a trial such as VIGOR (Vioxx Gastrointestinal Outcomes Research) is more likely to yield a signal of harm from a COX-2selective agent given the comparison with naproxenIn contrast, a comparison of etoricoxib with diclofenac, as in EDGE (part of the larger MEDAL program), is likely to yield similar risk profiles of the 2 agents but is unable to provide insight into other clinically important issues such as the relative risk of either etoricoxib or diclofenac against placebo or less COX-2selective NSAIDs

CLASS=Celecoxib Long-Term Arthritis Safety Study

ReferenceAntman EM, et al. Circulation. 2007;115:1634-1642.*PNI Cabang MedanMedan Pain Management 2011