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Aznan Lelo

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran Universitas Sumatera Utara 9 Oktober 2011, MS Pain, Medan

Pain Market
PAIN 100% ACUTE 34% CHRONIC 66% NOCICEPTIVE 80% CANCER 4% NEUROPHATIC 20%

NON-CANCER 96%
Nyoman Kertia, 2010

Common issues of NSAIDs


Different chemical families Different pharmacokinetics and potency Common mechanism of action (COX inhibition) Common clinical indications
Different selectivity to COX-1 and COX-2 Analgesic (CNS and peripheral effect) may involve non-PG related effects Antipyretic (CNS effect) Anti-inflammatory (mainly by PG inhibition) Effective dose for analgesic anti-inflammatory antipyretic

Common analgesic ceiling effect limited efficacy

Factors to consider when choosing NSAID as pain killer


Drug issues Efficacy Tolerability Safety Dosage Cost Patient issues Type, severity Risk factors: GI, platelet, renal and cerebro-cardiovascular system. Co-prescription. Co-morbidity. Compliance.


RISKS safety

BENEFITS efficacy

WHO Analgesic Ladder


NSAID adjuvant analgesic weak opioid (codeine) paracetamol or NSAID adjuvant analgesic
Pain threshold Pain tolerance

Principles of Analgesic Prescribing

Strong opioid NSAID adjuvant analgesic

mild

moderat

severe

1 0

Critical approaches in selecting medicines


Therapeutic NNT effect GREATEST Maximal Minimal SMALLEST
(> 100) SMALLEST (2-4) Maximal GREATEST Minimal

Adverse reaction NNH

Yes ?

? No

here are two reasons to withdraw from the treatment either no efficacy (NNT very high) or serious adverse reactions (NNH very low).

60

55%

Withdrawal (%)

50 40 30 20 10 0
Placebo Celecoxib 200mg Celecoxib 400mg Naproxen 1000mg Diclofenac 150mg

23%

Henti terapi karena tidak merasakan efek terapi

discontinuation rate (%)

25 20 15 10 5 0

gastrointestinal hypertension

19 %

9% 2.3 %
etoricoxib 90 mg

0.7 %
diclofenac 150 mg

Henti 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 doses


NSAID
Ibuprofen

Dose
50 mg 100 mg 200 mg 400 mg 600/800 mg

NNT
4.7 3.7 2.7 2.5 1.7 2.6 2.7 1.8 4.5 3.7 3.0

Percent Responders

5 0 4 0 3 0 2 0 1 0 0
Pcb la e o

Placebo

C2 1 0 x0 C2 2 0 x0 C2 4 0 x0 Celecoxib Celecoxib Celecoxib 2 x 100 2 x 200 2 x 400

10 8 6 4 2 0
R o f e c o xib 1 2 .5 m g (n= 1 2 1 5 ) R o f e c o xib 2 5 .0 m g R o f e c o xib 5 0 .0 m g (n = 4 7 6 ) (n= 1 6 1 4 )

Diclofenac

25 mg 50 mg 100 mg 200 mg 400 mg 600/800 mg

Incidence of Hypertension as adverse effect of Rofecoxib

efficacy-dose response at 6 weeks

Etoricoxib:

Shibuya RB, 2009

Acute vs Chronic Pain


Acute
Drug
Duration of pain

Chronic
Long duration

Rapid onset

Short, self limiting, Persists after healing, 3 well-characterized months

Component

Nociceptive

Nociceptive Neuropathic

Mild vs Severe Pain


Mild
Drug Low dose

Severe
High dose Potent agent

T-max and Onset of action of NSAIDs Onset NSAID T-max (hr) RapidDiclofenac 0.8 Nimesulide 1.2 2.7 SlowCelecoxib 24 Meloxicam 6

T-1/2 and Duration of action of NSAIDs


Duration short moderate long NSAID Diclofenac Nimesulide Celecoxib Naproxen Meloxicam Etoricoxib T-1/2 (hr) 1.1 1.8 4.7 11 14 20 22

NSAID use
Acute inflammatory pain or Breakthrough pain
Short half-life NSAID Ibuprofen, diclofenac, etc

Chronic inflammatory pain


Long half-life NSAID Oxicam, COXIB

Etoricoxib, a long half-life (22 hours): dosage and efficacy Pain Dose Note indications (mg) Chronic pain OA 30 60 Curtis SP, et.al.
2005

Acute pain Gouty arthritis

Maximum 8 days Dysmenorrhea 120 Maximum 8 Acute Pain Severe Pain days

120

How to change the onset of action of the long half-life NSAID


NSAID long half life

Acute

us long duration o By increasing thebut slow onset er ng dose ???: increased a D theonset becomes earlier dose ! but adverse effects c ? i enhanced th concentration Effective E ? ve Sa ? l Time na Slowly Chronic io t

Concentration

DICLOFENA C and all Acidic BBB BBB NSAIDs

HYPERALGESIA
Prostaglandin
BBB BBB BBB BBB BBB INFLAMMATION
MACROPHAGES

BBB

BBB

TNF- IL-6 IL-1


COX-2 FIBROBLASTS

IL-8
SYMPATHETIC NERVE

PG
POLYMORPHS

BK

DICLOFENA C and Ferreira, 1993 Nimesulide

NOCICEPTOR

ALGESIA

DICLOFENA C and all Non-COXIB

Capone ML, et al. Int J Immunopathol Pharmacol. 16(2 Suppl):49-58,2003.

Clinical pharmacology of selective COX-2 inhibitors Acidic COX-2 inhibitors have been hypothesized that this peculiar chemical feature may lead to an enhanced concentration in inflammatory sites that may translate into an 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 paw Concentration of total radiolabeled components (nmol/g) 1 hour 4 hours 8 hours 24 hours T C T C T C T C
tc 1.30 0.10 tc 0.84 0.10 tc 0.20 0.04 nd tc nd

Tissue

Injection site 0.79 0.18 1.20 nape neck 0.12 0.30

Untreated 0.16 0.20 0.15 0.20 footpads 0.04 0.10 Injection site 1.00 0.12 1.30 footpads 0.23 0.5 nd

nd nd

nd nd

Schweitzer A, N Hasler-Nguyen N, Zijlstra J. BMC, 2009

Mekanisme kerja AINS


Mekanis- Ibu- Diclome profen fenac COX-1 COX-2 COX-3 Anti-BK K-opener Tembus BBB ++ + + + ? + + ++ +++ + + + Piroxicam + + ? + ? + Celecoxib ++ ? ? ? ? Etoricoxib +++ ? ? ? ?

platelet aggregation

fewer heart attack

COX-1 inhibitor
GI bleeding

platelet aggregation

GI bleeding

more heart attack COX-2


platelet aggregation

GI bleeding

inhibitor

The Implications of NSAID Selectivity


Cardiovascular Risk Thrombosis, Myocardial Infarction Gastrointestinal Risk Bleeding Ulcer Complications

Discontinuation

Discontinuation

Blood Pressure Increase


Et or ic R o o xi b fe co xi b C Di ele cl c of ox en ib ac Ib up ro fe n Na pr ox en

COX-2

COX-1

Degree of Selectivity
Adapted from Antman EM, et al. Circulation. 2007;115:1634-

Adverse Effects of NSAIDs


Ototoxic Color blindness

Bronchospam

CHF

Hepatotoxic

UGIB UGIB Nephrotoxic

Bleeding

Allergy

Tocolytic

Mechanism of = Mechanism of therapeutic effects adverse effects

phospholipids arachidonic acid


COX-2

COX

COX-1

LOX
5-HPETE

cyclic endoperoxides PGI2


inhibits platelet aggregation, vasodilator,

TXA2
stimulates platelet aggregation, vasoconstriction

LTA4 LTB4
chemotaxis

hyperalgesia PGD2
inhibits platelet aggregation, vasodilator

PGE2
vasodilator,

PGF2alfa
bronchodilatation myometrial contr.

LTC4 LTD4 LTE4

hyperalgesia hyperalgesia

brochoconstriction increase vascular permeability

RESPIRATORY TOXICITY
AA
NSAID

LTs

PGs

bronchoconstriction bronchodilatation

NSAID-induced asthma

Risk Factors of Ulcer Complications from NSAIDs


Prior com plicated PU M ultiple N SAI Ds (including ASA) H igh-dose N SAID Anticoagulant Prior uncom plicated PU Age > 70 yr H .pylori infection Steroid therapy
1

13.5 9 7 6.4 6.1 5.6 3.5 2.2


3 5 7 9 11 13 15

Relative risk

Number of Risk Factors & Incidence of Ulcer Complications


incidence of ulcer (%)
20 15

NNH 5
18

NNH 12
10 5 0 No Risk Factor 1-2 Factors 3 Factors 4 Factors
8

NNH 50 NNH 125


0 .8 2

Silverstein FE. Ann Intern Med 1995;123:241

NSAID GI Toxicity generally varies with halflife of the agent


NSAID
Dose (mg/d) Half-life (hr) 24 hr fecal blood loss (mL)

Lowest GI risk

Shortest half-life

Diclofenac
100 1.5 0.53 +/- 0.21

Naproxen
750 14 2.76 +/- 2.22

Piroxicam
20 50 1.16 +/- 0.62

Henry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med

The pattern of NSAID plasma concentration based on the dose and half-life of drug given
Plasma concentration (mg/L)
1600 1400 1200 1000 800 600 400 200 0 0 2 4 6 8 10 12 14 16 18 20 22 24 500 mg tid, 1500 mg od, 500 mg tid, 1500 mg od, 2 hrs 2 hrs 12 hrs 12 hrs

Drug accumulation 3x11x3 Efek terapeutik Efek samping obat Choose the shortest half-life

Nociceptive VS neuropathic pain


Nociceptive pain
Caused by activity in neural pathway in response to potentially tissuedamaging stimuli

Mixed pain
Caused by a combination of both primary injury or secondary effects

Neuropathic pain
Initiated or caused by primary lesion or dysfunction in the nervous system

Postoperative pain Mechanical LBP

ARTHRITIS

PHN

CRPS

NSAID cell Sickle

crisis

Adjuvant Trigeminal Neuropathic neuralgia LBP ANALGESIC

Distal Central post Sport / polyneuropat stroke pain exercise hy (e.g. injuries diabetic) International Association for the Study of Pain. IASP Pain Terminology. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed.

Adjuvant Analgesics
Defined as drugs with other indications that may be analgesic in specific circumstances Numerous drugs in diverse classes Sequential trials are often needed Multipurpose analgesics

Class
Antidepressants

Adjuvant Analgesics for Neuropathic Pain


Examples
amitriptyline, desipramine, nortriptyline, paroxetine, venlafaxine, citalopram, others gabapentin, phenytoin, carbamazepine, clonazepam, topiramate, oxcarbazepine, others tizanidine, clonidine mexiletine, tocainide dextromethorphan, ketamine, amantadine baclofen, calcitonin lidocaine, lidocaine/prilocaine, capsaicin, NSAIDs prednisone, dexamethasone

Anticonvulsants

Alpha-2 adrenergic agonists Local anesthetics NMDA receptor Antagonists Miscellaneous Topical Steroids

NNT and NNH adjuvant analgesia for chronic noncancer pain


Drug Phenytoin TCAs Carbamazepine Pregabalin Gabapentin Mexiletine Codeine NNT 2.1 2.4 3.3 3.3 5.0 10 18 NNH 9.5 2.7 1.9 7.0 2.5 510 2

The role of neurotropic vitamin in alleviating pain


Investigators
Hanck & Weiser Granados-Soto et al Rocha-Gonzlez et al Medina-Santilln et al Wang et al Caram-Salas et al Song et al

Year
1985 2004 2004 2004 2005 2006 2009

Animal
Rats Rats Rats Rats Rats Rats Rats

Vitamin Bs
B12 B12 + diclofenac B1, B6, B12 + diclofenac B1, B6, B12 + ketorolac B1, B6, B12 B1, B6, B12 + dexametasone B1

The role of neurotropic vitamin in alleviating pain


Investigators
Mazzoni &Valenti Hieber Mder Vetter et al Brggemann et al Abbas & Swai Mauro et al Peters et al Mibielli et al

Year
1964 1974 1988 1988 1990 1997 2002 2006 2009

Subject
Patients Patients Cervicobrachialgia Patients Patients DM LBP Patients Patients

Vitamin Bs
B1 B12 B1, B2, B9 B1, B6, B12 + diclofenac B1, B6, B12 + diclofenac B1, B6 B12 B1, B6, B12, B9 B1, B6, B12 + diclofenac

Percentage of patients discharged with pain score (VAS)

Galvan-Montano A, et al. Cir Cir 2010;78:400-9

Efek Analgetik dan Neuroprotektif Vitamin Neurotropik


(Zimmerman, 2006)

1. NMDA receptor antagonism 2. Block at Ca2+ channels 3. Blok of cytokine formation (eg: TNF-) and receptor binding
Vitamin B complex TNF , growth factors, IL 1, IL 8

Cerebral cortex
Hypothalamus

PAG
Spinoreticular afferents

DESCENDING DESCENDING PATHWAY PATHWAY

Enkephalin

NRM
Spinoreticulothalamic Pain Projection

NRPG

5-HT
Interneuron -

NE
Interneuron -

ASCENDING PATHWAY

C fibers

Neurotropic vitamins increase the production of serotonin and noradrenalin, then inhibit the

NSAID has limited efficacy due to the ceiling effect For acute inflammatory pain For chronic inflammatory pain
Long half-life NSAID (oxicam) Short half-life NSAID (diclofenc)

The best and safest adjuvant analgesic is neurotropic vitamin For mixed pain
With inflammation NSAID + adjuvant analgesic (DOLOFENAC) Without inflammation paracetamol + adjuvant analgesic (DOLONEUROBION)