mechanisms of pain and inflammation: the role of NSAIDs

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NSAID effects

Analgesic Anti-inflammatory Antipyretic

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NSAIDs: mechanims of action

Tissue injury inflammation

COX1

NSAID

COX2

+
Prostaglandin effects: Inflammation Sensitization of nociceptors (peripheral sensitization) primary hyperalgesia Sensitization in the spinal cord (central sensitization) secondary hyperalgesia

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Inflammatory pain: peripheral sensitization

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

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8 7 6

Before S(+)-flurbiprofen
before BK after BK

n=13

spikes/s

5 4 3 2 1 0 32C

s p ike s /s

0
heat ramp 32-46C,20s

Bradykinin-induced peripheral nociceptor sensitization: mediated by prostaglandins

wird durch Prostaglandinsynthesehemmung verhindert

8 7 6

In presence of(S(+)-flurbiprofen under S +) -flu

before BK after BK

n=13

5 4 3 2 1 0 32C
heat ramp 32-46C, 20s

prevented by NSAIDs

spikes/s

Reeh PW, 2002

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Inflammatory pain: central sensitization

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Inflammatory pain: central sensitization

Nociceptor Input

Activity-Dependent Increase in Excitability of Dorsal Horn Neurons

Low Threshold Mechanoreceptors ( A beta fibres)

Modified Responsiveness
PAIN (Mechanical Allodynia)

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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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Postoperative efficacy of oral analgesics

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

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Nonopiod efficacy in osteoarthritis

50 45 40 35 30 25
washout

NSAID superior to acetaminophen

X Acetaminophen X
Acetaminophen 4 x 1000 mg/d versus Diclofenac 2 x 75 mg/d with Misoprostol 2 x 200 mg /d N=227

WOMAC Target Joint Score (mm)

X X

Diclofenac + Misoprostol

Acetaminophen

Greater improvement

*
washout & crossover

Diclofenac + Misoprostol
*
6 Weeks
* p<0.05 vs acetaminophen

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

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Advantages of NSAIDs in pain management

Lack of: Nausea, constipation Urinary retention Sedation/confusion Respiratory depression Additional effects: Anti-inflammatory Antipyretic Desirable properties for day case surgery and fast rehabilitation!
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NSAIDs
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
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Differences among NSAIDs

PHARMACODYNAMICS PHARMACOKINETICS

CHEMISTRY

Differences in

CLINICAL EFFICACY

COSTS

SIDE EFFECTS
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Not all NSAIDs are the same!

Selecting an NSAID for an individual patient remains more an art than a science...
Peter Brooks

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Plasma half-lives of different NSAIDS

SHORT HALF-LIFE (< 6 hrs) LONG HALF-LIFE (> 10 hrs)

ASPIRIN
DICLOFENAC

0.25 0.03
1.1 0.2

CELECOXIB
NAPROXEN

~ 11
14.0 2.0

FLURBIPROFEN
IBUPROFEN

3.8 1.2
2.1 0.3

OXAPROZIN
PIROXICAM

58.0 10.0
57.0 22.0

INDOMETHACIN LUMIRACOXIB
NIMESULIDE

4.6 0.7 6.0

1.8 4.7

ROFECOXIB SULINDAC

9.9 - 17.5 14.0

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.

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Drug selectivity for COX-1 and COX-2

> 50-fold COX-2 selective
DFP ROFECOXIB NS 398 ETODOLAC MELOXICAM CELECOXIB NIMESULIDE DICLOFENAC SULINDAC PIROXICAM NAPROXEN ASPIRIN INDOMETHACIN KETOPROFEN FLURBIPROFEN

Non-selective NSAIDs

-2

-1

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

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

Multifactorial mode of action

Nimesulide
COX INHIBITOR COX-2 INHIBITION

preferential

COXINDEPENDENT ACTIVITIES Inhibition of :

TNF release
Histamine release ROS production MMP release

Inhibition of inflammation

Chondrocyte death

Analgesic Effect

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Benefit/risk evaluation for inflammatory 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 at cardiorenal risk NSAIDs should be used for the shortest possible duration, as required by the clinical situation, and at the lowest dose.
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