1.4.1 Slide Kit Pain & Inflammation

8/3/2019 1.4.1 Slide Kit Pain & Inflammation

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mechanisms of pain andinflammation: the role of NSAIDs


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NSAID effects

Analgesic

Anti-inflammatory

Antipyretic


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Prostaglandin effects: Inflammation Sensitization of nociceptors

(peripheral sensitization) primary hyperalgesia

Sensitization in the spinal cord(central sensitization) secondary hyperalgesia

NSAID +-

+

-COX-

1COX-

2

Tissue injury

inflammation

+

NSAIDs: mechanims of action


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Tissue Damage Inflammation Sympathetic terminals

Sensitizing "Soup"Histamine Nerve growth factor Prostaglandins

Bradykinin Cytokines Neuropeptides (Substance P)

High Threshold Nociceptor

Transduction sensitivity

Low Threshold Nociceptor

Inflammatory pain: peripheralsensitization


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0

sp

ikes/s

012345678

n=13

32C

before BKafter BK

heat ramp 32-46C,20s

spikes/s

Before S(+)-flurbiprofen

0

1

2

3

4

5

6

7

8

n=13

32C

sp

ikes

/s

before BKafter BK

heat ramp 32-46C, 20s

under S(+)-flu

In presence of S(+)-flurbiprofen

Bradykinin-inducedperipheral nociceptor

sensitization: mediated by

prostaglandins

prevented byNSAIDs

Reeh PW, 2002


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Inflammatory pain: central sensitization
http://arjournals.annualreviews.org/na101/home/literatum/ar/journals/production/pharmtox/2002/42/1/annurev.pharmtox.42.092401.143905/images/large/pa42_0553_1.jpeg


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Nociceptor Input

Activity-DependentIncrease in Excitability ofDorsal Horn Neurons

ModifiedResponsiveness

PAIN

(Mechanical Allodynia)

Low ThresholdMechanoreceptors( A beta fibres)

Inflammatory pain: central sensitization


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Prostaglandins, Glutamate and

Substance P in Spinal Sensitization

NSAID


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NSAIDs Crossing Blood-Brain-Barrier

Lowering LPS, IL-1, IL-6 induced fever and

brain PGE2

Inhibiting expression of c-fos (marker of

neuronal stimulation) in supraoptic nucleus

Lowering CSF concentration of inflammatory

protein markers

Orally administered nimesulide results in brain

tissue concentration of 1g/g (3 hours) Reduction of PGE2 in CSF of patients after

thoracotomy


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HGKMcQuay H and Moore A:An evidence-based resource for pain relief. Oxford University Press, Oxford 1998

Postoperative efficacy of oralanalgesics


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NSAID superior to acetaminophen

Pincus et al. Arthritis Rheum 2001;44:1587-1598

* p


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Advantages of NSAIDs in painmanagement

Lack of:

Nausea, constipation

Urinary retention

Sedation/confusion Respiratory depression

Additional effects:

Anti-inflammatory Antipyretic

Desirable properties for day case surgeryand fast rehabilitation!


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Salicylates (acetylsalicylic acid) Arylacetic acids (diclofenac, indomethacin,

ketorolac)

Arylpropionic acids (naproxen, ibu-, keto-,

flurbiprofen) Oxicams (lornoxicam, piroxicam)

Pyrazoles (phenylbutazone)

Fenamates (mefenamic acid, meclofenamate) Sulphonanilides (nimesulide)

Coxibs

NSAIDs


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Differences in

SIDE EFFECTS

CLINICALEFFICACY

PHARMACOKINETICSPHARMACODYNAMICS

CHEMISTRY

COSTS

Differences among NSAIDs


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Selecting an NSAID for anindividual patient remains morean art than a science...

Peter Brooks

Not all NSAIDs are the same!


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Brooks PM, Day RO N Engl J Med. 24: 1716-1725,1991;Bernareggi A Clin Pharmacokinet. 35: 247-274, 1998;

Depre M et al. Eur.J Clin Pharmacol. 56: 167-174, 2000;Davies NM et al. Clin Pharmacokinet 38: 225-242, 2000.

SHORT HALF-LIFE

(< 6 hrs)LONG HALF-LIFE

(> 10 hrs)

ASPIRIN 0.25 0.03 CELECOXIB ~ 11

DICLOFENAC 1.1 0.2 NAPROXEN 14.0 2.0

FLURBIPROFEN 3.8 1.2 OXAPROZIN 58.0 10.0

IBUPROFEN 2.1 0.3 PIROXICAM 57.0 22.0

INDOMETHACIN 4.6 0.7 ROFECOXIB 9.9 - 17.5

LUMIRACOXIB 6.0 SULINDAC 14.0

NIMESULIDE 1.8 4.7

Plasma half-lives of different NSAIDS


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FLURBIPROFEN

KETOPROFEN

INDOMETHACIN

ASPIRIN

NAPROXEN

PIROXICAM

SULINDAC

DICLOFENAC

NIMESULIDE

CELECOXIB

MELOXICAM

ETODOLAC

NS 398

ROFECOXIB

DFP

0 1-1-2 2

log IC80 ratio COX-2/COX-1 (WHMA assay)

> 50-fold COX-2selective

Warner TD et al. Proc Natl Acad Sci. 96: 7563-7568, 1999; mod

Drug selectivity for COX-1 and COX-2

Non-selective NSAIDs


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Nimesulide

Inhibition ofinflammation

Analgesic Effect

COXINHIBITOR

preferential

COX-2INHIBITION

COX-INDEPENDENTACTIVITIES

Inhibition of : TNF release

Histamine release

ROS production

MMP release

Chondrocytedeath

Multifactorial mode of action


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Benefit/risk evaluation forinflammatory pain management

NSAIDs remain good therapeutic option:

Observation of warnings and contraindications

Patient fully informed about risk-benefit ratio

and alternate treatments Monitoring for creatinine/BP, oedema and

congestive heart failure in patients atcardiorenal risk

NSAIDs should be used for the shortestpossible duration, as required by theclinical situation, and at the lowest dose.

1.4.1 Slide Kit Pain & Inflammation

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