2 December 1951Bukit TinggiPhD in Clinical PharmacologyFUSA-Flinders Medical Centre Australia, 1988ProfessorHead of DepartmentPharmacology & TherapeuticSchool of Medicine, USUJln. Tridharma 22Kampus USU, Medan SpFK, Clinical PharmacologistPB-IDI & FK UI, 1995MD, FK USU, 1978

Aznan Lelo

Dep. Farmakologi & Terapeutik, Fakultas KedokteranUniversitas Sumatera Utara24 September 2011, MS Pain, Lhokseumawe

Pain MarketPAIN100%ACUTE34%CHRONIC66%NEUROPHATIC20%NOCICEPTIVE80%CANCER4%NON-CANCER96%Nyoman Kertia, 2010

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

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

NSAID adjuvant analgesic weak opioid(codeine)paracetamolor NSAID adjuvant analgesicStrong opioid NSAID adjuvant analgesicPrinciples of Analgesic Prescribing WHO Analgesic LadderPain tolerancePain thresholdmildmoderatesevere

Critical approaches in selecting medicinesNNHSMALLESTGREATEST(> 100)NNTGREATESTSMALLEST(2-4)There are two reasons to withdraw from the treatment either no efficacy (NNT very high) or serious adverse reactions (NNH very low).

Therapeutic effectAdverse reactionMinimalMaximalMaximalYes?Minimal?No

Henti terapi karena tidak merasakan efek terapiHenti terapi karena merasakan efek samping

number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain, all oral analgesics except morphine, pethidine and ketorolac

NNT of NSAIDs at different dosesIncidence of Hypertension as adverse effect of Rofecoxib

NSAIDDoseNNTIbuprofen50 mg4.7100 mg3.7200 mg2.7400 mg2.5600/800 mg1.7Diclofenac25 mg2.650 mg2.7100 mg1.8200 mg4.5400 mg3.7600/800 mg3.0

Etoricoxib: efficacy-dose response at 6 weeksShibuya RB, 2009

Mild vs Severe PainAcute vs Chronic Pain

MildSevereDrug Low doseHigh dosePotent agent

AcuteChronicDrug Rapid onsetLong durationDuration of painShort, self limiting, well-characterizedPersists after healing, 3 monthsComponent NociceptiveNociceptiveNeuropathic

T-max and Onset of action of NSAIDs

OnsetNSAIDT-max (hr)RapidDiclofenac0.8Nimesulide 1.2 2.7SlowCelecoxib 2 4Meloxicam6

T-1/2 and Duration of action of NSAIDs

DurationNSAIDT-1/2 (hr)shortDiclofenac1.1Nimesulide 1.8 4.7moderateCelecoxib 11Naproxen14longMeloxicam20Etoricoxib 22

NSAID useAcute inflammatory pain orBreakthrough painShort half-life NSAIDIbuprofen, diclofenac, etcChronic inflammatory painLong half-life NSAIDOxicam, COXIB

Etoricoxib, a long half-life (22 hours): dosage and efficacyAcute Pain Severe Pain? ?

Pain indicationsDose (mg)NoteChronic painOA30 60Curtis SP, et.al. 2005

Acute painGouty arthritis120Maximum 8 daysDysmenorrhea120Maximum 8 daysDental Pain120 - 240Malmstrom K,et.al. 2004

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 !

PGALGESIAINFLAMMATIONNOCICEPTORPGFerreira, 1993 BBB BBB BBB BBB BBB BBB BBB BBB BBBProstaglandin HYPERALGESIADICLOFENACandNimesulideDICLOFENACand allAcidic NSAIDsDICLOFENACand allNon-COXIB

Capone ML, et al. Int J Immunopathol Pharmacol.16(2 Suppl):49-58,2003. Clinical pharmacology ofselective COX-2 inhibitorsAcidic COX-2 inhibitorshave been hypothesized that this peculiar chemical feature may lead to an enhanced concentration in inflammatory sitesthat may translate intoan improved clinical efficacy

Tissue concentrations of total radiolabeled components at 1, 4, 8 and 24 h after oral administration of [14C] diclofenac sodium at a dose of 2 mg/kg to male rats injected with carrageenan (T) or saline (C) into the left front footpad and the left hind pawSchweitzer A, N Hasler-Nguyen N, Zijlstra J. BMC, 2009

Concentration of total radiolabeled components (nmol/g)1 hour4 hours8 hours24 hoursTissueTCTCTCTCInjection site nape neck0.79 0.120.181.20 0.30tc1.30 0.10tc0.20 0.04ndUntreated footpads0.16 0.040.200.15 0.100.20tcndndndInjection site footpads1.00 0.230.121.30 0.5nd0.84 0.10ndtcnd

Mekanisme kerja AINS

Mekanis-meIbu-profenDiclo-fenacPiro-xicamCele-coxibEtori-coxibCOX-1++++--COX-2+++++++++COX-3++++???Anti-BK+++??K-opener?+???Tembus BBB+++??

plateletaggregationplateletaggregationGIbleedingGIbleedingGIbleedingplateletaggregationCOX-1inhibitorCOX-2inhibitormoreheart attackfewerheart attack

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

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

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

RESPIRATORY TOXICITY

PGsLTsAANSAIDbronchodilatationNSAID-induced asthmabronchoconstriction

Risk Factors ofUlcer Complications from NSAIDsRelative risk

Number of Risk Factors &Incidence of Ulcer ComplicationsSilverstein FE. Ann Intern Med 1995;123:241-9NNH 125NNH 50NNH 12NNH 5incidence of ulcer (%)

NSAID GI Toxicity generally varies with half-life of the agentHenry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med 28(4):436,1998Shortest half-lifeLowest GI risk

NSAIDDiclofenacNaproxenPiroxicamDose (mg/d)10075020Half-life (hr)1.5145024 hr fecal blood loss (mL)0.53 +/- 0.21 2.76 +/- 2.22 1.16 +/- 0.62

Pain in risky population

PATIENT GROUPPREDICTABLE PROBLEMSBabies & InfantsCommunication; drug handlingElderlyCoexisting illness; drug handlingRespiratory diseaseRespiratory depression; NSAIDs & asthmaRenal FailureDrug handling; NSAIDsPregnant womenEarly closure of ductus arteriosus

The pattern of NSAID plasma concentration based on the dose and half-life of drug givenDrug accumulation3 x 1 1 x 3 Efek terapeutik Efek samping obatChoose the shortest half-life

Suggested dosages of some NSAIDs for postoperative pain managementKokki H. Pediatr Drugs 5(2):103-23,2003

NSAIDDoseRouteDiclofenac0.7 - 2 mg/kgOral, Rectal, IMIbuprofen5 - 10 mg/kgoralFlurbiprofen1 mg/kgoralKetorolac0.3 0.5 mg/kgIM, IVKetoprofen1 2 mg/kgIVNaproxen4 - 6 mg/kgoralNimesulide1.5 mg/kgoralTenoxicam0.75 mg/kgIM

Nociceptive VS neuropathic painNeuropathic painInitiated or caused by primary lesion or dysfunction in the nervous systemNociceptive painCaused by activity in neural pathway in response to potentially tissue- damaging stimuliPostoperative painMechanical LBPSport / exercise injuriesSickle cell crisisARTHRITISPHNNeuropathic LBPDistal polyneuropathy (e.g. diabetic)Central post stroke painTrigeminal neuralgiaCRPSInternational Association for the Study of Pain. IASP Pain Terminology.Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57Mixed painCaused by a combination of both primary injury or secondary effectsAdjuvantANALGESICNSAID

Adjuvant AnalgesicsDefined as drugs with other indications that may be analgesic in specific circumstancesNumerous drugs in diverse classesSequential trials are often needed

Multipurpose analgesics

Adjuvant Analgesics for Neuropathic Pain

ClassExamplesAntidepressantsamitriptyline, desipramine, nortriptyline, paroxetine, venlafaxine, citalopram, othersAnticonvulsantsgabapentin, phenytoin, carbamazepine, clonazepam, topiramate, oxcarbazepine, othersAlpha-2 adrenergic agoniststizanidine, clonidineLocal anestheticsmexiletine, tocainideNMDA receptor Antagonistsdextromethorphan, ketamine, amantadineMiscellaneousbaclofen, calcitoninTopicallidocaine, lidocaine/prilocaine, capsaicin, NSAIDsSteroidsprednisone, dexamethasoneNeurotropic VitaminB1, B6, B12 (+B9 Folic acid)

NNT and NNH adjuvant analgesia for chronic non-cancer pain

DrugNNTNNHPhenytoin2.19.5TCAs2.42.7Carbamazepine3.31.9Pregabalin3.37.0Gabapentin5.02.5Mexiletine10510Codeine182

The role of neurotropic vitamin in alleviating pain

InvestigatorsYearAnimalVitamin BsHanck & Weiser1985Rats B12Granados-Soto et al2004Rats B12 + diclofenacRocha-Gonzlez et al2004Rats B1, B6, B12 + diclofenacMedina-Santilln et al2004Rats B1, B6, B12 + ketorolacWang et al2005Rats B1, B6, B12Caram-Salas et al2006Rats B1, B6, B12 + dexametasoneSong et al2009Rats B1

The role of neurotropic vitamin in alleviating pain

InvestigatorsYearSubjectVitamin BsMazzoni &Valenti1964Patients B1Hieber1974Patients B12Mder1988Cervico-brachialgiaB1, B2, B9Vetter et al1988Patients B1, B6, B12 + diclofenacBrggemann et al1990Patients B1, B6, B12 + diclofenacAbbas & Swai1997DMB1, B6Mauro et al2002LBPB12Peters et al2006Patients B1, B6, B12, B9Mibielli et al2009Patients B1, B6, B12 + diclofenac

Peters TJ, et al. Treatment of alcoholic polyneuropathy with vitamin B complex: a randomised controlled trial. Alcohol Alcohol. 2006;41(6):636-42*P < 0.001: new formulation versus placebo (Wilcoxon-Rank Sum Test). *P < 0.001: old formulation versus placebo (Wilcoxon-Rank Sum Test).

McGill's pain question-naireNew form.B1, B2, B6, B12 + B9(N = 85)Old form.B1, B2, B6, B12 (-) B9(N = 83)Placebo(N = 85)Total pain score*, 8.6 (7.55)7.5 (6.76)3.8 (8.18)VAS (mm)*, 35.0 (18.61)34.9 (20.32)9.5 (18.65)

Mibielli MA, et al. Diclofenac plus B vitamins versus diclofenac monotherapy in lumbago: the DOLOR study. Curr Med Res Op 2009;25(11):2589-99A randomized, double blind controlled study in parallel groupsReceived twice-daily po.Group DB (50 mg diclofenac, 50 mg B1, 50 mg B6, 1 mg B12) vs Group D (50 mg diclofenac)Sufficient pain reduction = VAS < 20 mm

The number of patients who meet the confirmative primary study objective at visit 2 (after 3 days of treatment)

Group DB (n=187)Group D (n=185)n%n%Study withdrawal reasonsTreatment success8746.55529.7Treatment failure105.3105.4Side effects (AEs)31.60

Patients with continued intervention8746.512064.9Difference in treatment success. X2 = 12.06; p = 0.0005

Patients response captured between visit 1 and visit 2 to the Visual Analogue Scale (VAS)VAS mm% Patients

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In children who received acetaminophen + B vitamins during the immediate postoperative period, 58% had pain score 2 and 89% were discharged with pain score 1.Acetaminophen + B vitamins showed a better pain score.

Percentage of patients discharged with pain score (VAS)Galvan-Montano A, et al. Cir Cir 2010;78:400-9

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Acetaminophen + B vitamins8911

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Efek Analgetik dan Neuroprotektif Vitamin Neurotropik(Zimmerman, 2006)1. NMDA receptor antagonism2. Block at Ca2+ channels3. Blok of cytokine formation (eg: TNF-) and receptor binding

TNF , growth factors, IL 1, IL 8Vitamin B complex

PAGCerebral cortexHypothalamusSpinoreticularafferentsNRMNRPGInter-neuronInter-neuronSpinoreticulothalamicPain ProjectionC fibersEnkephalin5-HTNE--DESCENDINGPATHWAYASCENDINGPATHWAYNeurotropic vitamins increase the production of serotonin and noradrenalin, then inhibit the transmission of pain

Optimal efficacyRapid onsetHigh potencyMinimal value of ED-50 for analgesic effectMultiple mechanism of actionCOX inhibition, Anti-cytokine, Anti-bradykininK-channel openerOptimal safety (minimal side effect)Not only GI toxicityGood pharmacokinetic profilesShort half-life, Penetrate BBBHas an acidic pKa

For acute inflammatory painShort half-life NSAID (diclofenc)For chronic inflammatory painSlow release short half-life NSAIDLong half-life NSAID (oxicam)For mixed painWith inflammation NSAID + adjuvant analgesic (DOLOFENAC)Without inflammation paracetamol + adjuvant analgesic (DOLONEUROBION)The best and safest adjuvant analgesic is neurotropic vitamin

**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.*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?***The adjuvant analgesic drugs include many drugs in diverse classes. All of these drugs are available for indications other than analgesia, but they may be analgesic in select circumstances. The term adjuvant applies in the management of pain associated with advanced medical illness, in which case they are typically added to an opioid regimen. Overall, the term is a misnomer because these drugs now are commonly used as primary analgesics in many painful disorders. Berbagai sediaan berkhasiat sebagai analgetik adjuvant. Diantara semua sediaan, yang minimal efek sampingnya adalah neurotropic vitamin. Banyak studi membuktikan bahwa neurotropic vitamin berkhasiat sebagai analgetic adjuvant.**