MANAGEMENT CHRONIC

PAIN WITH NSAID COX-2

INHIBITOR
 What is pain ?
The International Association for the Study of Pain (IASP) defines pain
as an unpleasant sensory and emotional experience which is
primarily associated with tissue damage or described in terms of such
damage, or both.

Definitions of pain
Pain is a complex unpleasant phenomenon composed of
sensory experiences that include time, space, intensity,
emotion, cognition, and motivation
Pain is an unpleasant or emotional experience
originating in real or potential damaged tissue
Pain is an unpleasant phenomenon that is uniquely
experienced by each individual; it cannot be adequately
defined, identified, or measured by an observer
The experience of pain
Three systems interact usually to produce pain:
1. Sensory - discriminative
2. Motivational - affective
3. Cognitive - evaluative
1. Sensory - discriminative system processes information about
the strength, intensity, quality , temporal and spatial
aspects of pain

2. Motivational - affective system determines the individuals

approach-avoidance behaviours

3. Cognitive - evaluative system overlies the individuals learned

behaviour concerning the experience of pain. It may block,
modulate, or enhance the perception of pain
 Pain categories

1. Somatogenic pain is pain with cause (usually

known)
Localised in the body tissue
a/ Nociceptive pain
b/ Neuropatic pain

2. Psychogenic pain is pain for which there is no

known physical cause but processing of sensitive
information in CNS is dysturbed
 Acute and Chronic pain
Acute pain is a protective mechanism that alerts the
individual to a condition or experience that is immediately
harmful to the body
Onset - usually sudden
Psychological and behavioural response to acute pain
- fear
- general sense of unpleasantness or unease
- anxiety

Chronic pain is persistent or intermittent usually defined as

lasting at least 3-6 months
The cause is often unknown, often develops insidiously, very
often is associated with a sense of hopelessness and
helplessness. Depression often results
 Acute Pain Chronic Pain

36 months

Serves a protective function Serves no protective function

Usually apparent noxious insult Degrades health and function
 Categorization of Pain

Acute Pain Chronic Pain

Relatively brief duration
(hours to weeks)
postsurgical pain, trauma,
select disease processes
Longer in duration (months to years)
usually accompanies a disease
process or injury
rheumatoid arthritis, osteoarthritis,
lower back pain, shoulder pain, pain
associated with malignancy
The most common chronic pain

1. Persistent low back pain

result of poor muscle tone,inactivity,
muscle strain, sudden vigorous exercise

2. Chronic pain associated with cancer

Neuropathic pain

It occurs as a result of injury to or dysfunction

of the nervous system itself, peripheral or central

Deaferentation pain - form of neuropathic pain: a term

implying that sensory deficit in the painful area is
a prominent feature (anesthesia dolorosa)

Phantom pain- pain localizei into non-existing organ (tissue)

Long-lasting pain after short-lasting pain stimulus

Table 1. Key Features of Pain Types and Syndromes

Type of Pain Features

Acute pain Pain usually concordant with degree of tissue damage, which remits with resolution of the injury
Reflects activation of nociceptors and/or sensitized central neurons
Often associated with ANS and other protective reflex responses (e.g., muscle spasm,
splinting)
Chronic pain Low levels of identified underlying pathology that do not explain the presence and/or extent of
the pain Perpetuated by factors remote from the cause Continuous or intermittent with or without
acute exacerbations Symptoms of ANS hyperactivity less common Irritability, social withdrawal,
depressed mood and vegetative symptoms (e.g., changes in sleep, appetite, libido),
disruption of work, and social relationships
Cancer pain Strong relationship between tissue pathology and levels of pain Limited time frame that permits
aggressive pain management Rarely involves medical-legal or disability issues
CNCP Weak relationship between tissue pathology and pain levels Prolonged, potentially life-long, pain
May involve medical, legal, disability issues/conflicts, work or relationship problems, physical
deconditioning, psychological symptoms (see chronic pain above) May progress to CPS
CPS Preoccupation with somatic functioning Lifestyle centered on seeking immediate pain relief, with
excessive, nonproductive, and often harmful use of health care services Repeated attempts to
obtain pain-related financial compensation (e.g., Social Security, Veterans benefits)
Numerous symptoms and signs of psychosocial dysfunction that the patient attributes to the pain
(e.g., anger, depression, anxiety, substance abuse, disrupted work or personal relationships)

ANS: autonomic nervous system; CNCP: chronic noncancer pain; CPS: chronic pain syndrome
Example of chronic nociceptive pain:
osteoarthritis of the knee
Neuroanatomy of pain

The portions of the nervous system responsible for the

sensation and perception of pain may be divided into three
areas:
1. afferent pathways

2. CNS

3. efferent pathways

The afferent portion is composed of:

a) nociceptors (pain receptors)
b) afferent nerv fibres
c) spinal cord network
 Posterior root

Spinal ganglion

Anterior root

A,C VViscera

A
Blood vesselsood vessel
Tendon
bundle A

C A

Scletal muscle
MMuscle spindle
Receptor in the skin
Characteristics of primary afferent fibres
Fibre type Ad (finely myelinated) C (unmyelinated)

Fibre diameter 2-5 mm <2 mm

Conduction velocity 5-15 m s 0.5-2 m s 1
Distribution Body surface, Most tissues
muscles, joints
Pain sensation Rapid, pricking well localized
Slow, diffuse, dull,
aching
Position of synapse
within dorsal horn
of spinal cord Laminae I and V Lamina II (substantiagelatinosa
Excitatory and inhibitory interactions at the spinal cord level

Higher centres
NA Perception
5 HT
+ -
Other sensory input
+ Control Neuron

GABA
Enkephalin
-

Pain neuron
+
Subtance P Glutamate

NA = Noradrenalin ; 5HT = 5 hydroxy triptamin ; GABA = g amino butiric acid

 Afferent pathways terminate in the dorsal horn of the
spinal cord (1st afferent neuron)

2nd afferent neuron creates spinal part of afferent

system

The portion of CNS involved in the interpretation of

the pain signals are the limbic system, reticular
formation, thalamus, hypothalamus and cortex

The efferent pathways, composed of the fibers

connecting the reticular formation, midbrain, and
substantia gelatinosa, are responsible for modulating
pain sensation
The Brain first perceives the sensation of pain

The Thalamus, sensitive cortex :

perceiving
describing of pain
localising

Parts of thalamus, brainstem and reticular formation:

- identify dull longer-lasting, and diffuse pain

The reticular formation and limbic system:

- control the emotional and affective response to pain
Because the cortex, thalamus and brainstem are
interconnected with the hypothalamus and autonomic
nervous system, the perception of pain is associated with an
autonomic response
 How to Diagnosis Pain ?
Critical Elements of the Pain History
Charateristic of pain
Prior evaluation of the pain

Prior treatments for the pain

Premorbid and comorbid medical and psychiatric

conditions

Comprehensive medication history

Patients perception of impact of the pain on multiple

domains

Physical functioning
Mood and psychological well being
Social, familial, and marital well being
Role functioning,
 Pain Management Theraphy

1.Diagnosis
2.Diagnosis
3.Diagnosis
4.Intensitas nyeri VAS
5.Fungsi organ : lambung, hati, ginjal,
kardiovaskuler usia pasien
6.Farmakodinamik (potensi, onset, durasi)
7.Farmakokinetik
8.Harga dan ketersediaan
Termasuk pemilihan NSAIDs
Table 2. Classification of common NSAIDs

Class Subclass Drugs

Carboxylic acids Salicylic acids Acetylsalicylic acid (aspirin)

Difl unisal (dolobid)
Trisalicyliate (trilisate)
Salsalate (disalcid, amigesic, salfl ex)
Acetic acids Diclofenac (voltaren, cataflam,arthroteca)
Etodolac (lodine)
Indomethacin (indocin)
Sulindac (clinoril)
Tolmetin (tolectin)
Ketorolac (toradol)
Propionic acids Flurbiprofen (ansaid)
Ketoprofen (orudis, oruvail, axoridb)
Oxaprozin (daypro)
Ibuprofen (motrin, advil, duexisc)
Naproxen (naprosyn, aleve, vimovod)
Fenoprofen (nalfon)
Fenamic acids Meclofenamate (meclomen)
Enolic acids Pyrazolones Phenlbutazone
Oxicams Piroxicam (feldene)
Meloxicam (mobic)
Nonacidic Nabumetone (relafen)
COX-2 selective Sulfonamide Celecoxib (celebrex)
Sulfonylurea Etoricoxib (arcoxia)
Nonacid Lumaricoxib (prexige)
 INDICATION OF NSAIDs
Inflammatory and degenerative forms of rheumatism (RA,
OA, ankylosing spondylitis, juvenile RA etc)
Painful syndromes of the vertebral column
Painful and/or inflammatory conditions in gynaecology
Post-traumatic and post-operative pain, inflammation and
swelling
Acute attacks of gout
Migraine attacks
Renal and biliary colic
Tumour pain
Adjuvant in severe painful inflammatory ENT infections

a Depends on the country, the pharmaceutical form and strength. Refer to local Prescribing Information
for each formulation and dose strength for approved indications
ENT = ear, nose or throat; OA = osteoarthritis; RA = rheumatoid arthritis
26
Table 3. Choosing NSAID therapy in patients with rheumatic diseases
Risk category Treatment recommendations
Low
<65 years old Traditional NSAID
No cardiovascular risk Shortest duration and lowest dose possible
No requirement for high-dose or chronic therapy
No concomitant aspirin, corticosteroids, or anticoagulants
Shortest duration and lowest dose possible

Intermediate
65 years old Traditional NSAID+PPI or H2RB if taking Aspirin
No history of previous complicated gastrointestinal ulceration Once daily Celecoxib +PPI or H2RB if taking Aspirin
Low cardiovascular risk, may be using aspirin for If using aspirin, take low dose (75 to 81 mg)
primary prevention If using aspirin, take traditional NSAID
Requirement for chronic therapy and/or 2 hours prior to aspirin dose
high-dose therapy

High
Older people, especially if frail or if hypertension, Use acetominophen <3 gr/day
renal or liver disease present Avoid chronic NSAID at all possible :
History of previous complicated ulcer or multiple - use intermittent NSAID dosing
gastrointestinal risk Factors - use low dose, short half life NSAID
. Hystory of cardiovascular disease and - Do not use extended realeased NSAID formulation
agent for secondary prevention If chronic NSAID required consider :
History of heart failure - Once daily Celecoxib +PPI
- Naproxen + PPI/misoprostol (cardiovascular > gastroin
- Avoid PPI if using antiplatelet agent such as clopidogre
Monitor and treat blood pressure
Monitor creatinine and electrolytes
Table 4. Shared toxicities of NSAIDs
Organ system Toxicity

Gastrointestinal Dyspepsia
Esophagitis
Gastroduodenal ulcers
Ulcer complications (bleeding, perforation obstruction)
Small bowel erosions and strictures
Colitis
Renal Sodium retention
Weight gain and edema
Hypertension
Type IV renal tubular acidosis and hyperkalemia
Acute renal failure
Papillary necrosis
Acute interstitial nephritis
Accelerated chronic kidney disease
Cardiovascular Heart failure
Myocardial infarction
Stroke
Cardiovascular death
Hepatic Elevated transaminases
Asthma/allergic Aspirin-exacerbated respiratory diseasea
(susceptible patients)
Rash
Hematologic Cytopenias
Nervous Dizziness, confusion, drowsiness
Seizures
Aseptic meningitis
Bone Delayed healing
Table 5. Strategies for reducing cardiovascular risk
If using aspirin, take aspirin dose 2 hours prior to
NSAID doses
Do not use NSAIDs within 3 to 6 months of an acute
cardiovascular event or procedure
Carefully monitor and control blood pressure
Use low-dose, short half-life NSAIDs and avoid extended
release formulations
The prescription of NSAIDs for pain
Types of prescription medicine used for the treatment of chronic paina

Beta/CC blocker
Muscle relaxant
Anti-epileptic
DMARD/steroid
Triptan
Tricyclic/SSRI/SNRI
Barbiturate/ergotamine
Strong opioid
COX-2 inhibitor
Paracetamol
Weak opioid
NSAID

0 10 20 30 40 50
% respondents2
aDatafrom a subgroup of patients (19%) who reported prescription medication use for pain in a large survey
conducted in Europe/Israel (n=46,394). CC = calcium channel blockers; DMARD = disease-modifying anti-
rheumatic drugs
1. IMS 2010
2. Breivik H et al. Eur J Pain 2006;10:287333.
 Pain Killer
NSAID ?

Defenitive Treatment ??
35
 Diclofenac in chronic pain
The GOLD STANDARD of efficacy
No 1 prescribed NSAID1
Used as a reference standard in clinical trials,
including recent several large-scale outcomes studies:
Study (duration) Patients n Treatments Primary outcomes
MEDAL2 OA, RA 34,701 Etoricoxib 60/90 mg qd Safety (CV/GI)
(3 years) Diclofenac 50/75 mg bid
CLASS3 OA, RA 8,059 Celecoxib 400 mg bid Safety (GI/CV)
(65 weeks) Ibuprofen 800 mg tid
Diclofenac 75 mg bid
SUCCESS-14 OA 13,194 Celecoxib 100/200 mg bid Safety (GI/CV)
(12 weeks) Diclofenac 50 mg bid
Naproxen 500 mg bida

aResults were provided for celecoxib versus the combined diclofenac/naproxen group
1. IMS 2010
2. Cannon CP et al. Lancet 2006;368:177181.
3. Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
4. Singh G et al. Am J Med 2006;119:25566.
Diclofenac effective reducing pain of
movement in patients with OA

Non inferiority study during the 12-week, randomized, double-blind, parallel group, double-dummy. The study was
conducted at 40 centers in the UK, the number of patients 249
people. Patients with OA pain on preliminary data (which are valued at 40 VAS 90 mm and a global assessment of the
patient and the physician rating arthritis (bad or very bad) and waiting for joint replacement surgery were randomized to
receive celecoxib 200 mg or diclofenac 150 mg. Previous patient given acetaminophen max 4 g / day

39 Emery et al. Clinical Therapeutics/Volume 30, Number 1, 2008; 70 82.

 CLASS, Pfizer sponsored RCT
No superior efficacy of Celecoxib vs diclofenac is shown

Diclofenac 75 mg bid (n=1,996)

Celecoxib 400 mg bid (n=3,987)
Ibuprofen 800 mg tid (n=1,985)

0 0
Change from baseline

Change from baseline

in mean VAS score
in mean score

2
0.1

4
4.7
0.20
0.2
0.23
6 6.6
0.25 6.7

0.3 8

Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
 MEDAL, MSD sponsored RCT
No superior efficacy of etoricoxib vs diclofenac is shown

Diclofenac 50 or 75 mg bid (n=16,483)

Etoricoxib 60 or 90 mg od (n=16,819)

0
Change from baseline

9.8
9.0
0.2
in Likert units

Patients (%)
0.4

0.6 0.61
0.67

0.8

Cannon CP et al. Lancet 2006;368(9549):177181.

 GI safety profile of diclofenac?
Compared with the selective COX-2 inhibitors ?!

External factors could modify the risk of GI events

GI events are related to non-selective COX-1 inhibition

Diclofenac has more specificity to COX-2 than COX-1

Recent RCTs had shown little or no difference between

COX-2 inhibitors & diclofenac (MEDAL1, CLASS2 &

SUCCESS-13)

1. Cannon CP et al. Lancet 2006;368:177181.

2. Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
3. Singh G et al. Am J Med 2006;119:25566.
THE IMPLICATION OF NSAID SELECTIVITY

6. Antman EM et al. Use of Nonsteroidal Antiinflammatory Drugs : An Update for Clinicians: A Scientific Statement From the American Heart
43 Association . Circulation 2007;115:1634-1642.
GI events are related to COX-1 inhibition?
Diclofenac has more specificity to COX-2 than COX-1
11 Ketoprofen
(increasing COX-2 selectivity)

10 Indomethacin
Relative COX-1/2 selectivity

9 Aspirin
8 Naproxen
7 Tolmetin
6 Ibuprofen
5 Fenoprofen
4 Diflunisal
3 Piroxicam
2 Sulindac
1 Diclofenac
0
0 1 2 3 4 5 6 7 8 9 10 11
Relative GI toxicity
(increasing toxicity)

Hence, diclofenac may have a relatively low GI risk compared with

other traditional NSAIDs

Mitchell JA, Warner TD. Br J Pharmacol 1999;128:112132.

GI events are related to COX-1 inhibition?
Diclofenac has more specificity to COX-2 than COX-1

Concentrations of selected nonsteroidal antiinflammatory drugs required to inhibit 50% of the

cyclooxygenase-1 (COX-1) and COX-2 enzymatic reactions in assays of whole human blood (50%
inhibition concentrations [IC ]).
50

45 Chaiamnuay et al, 2006

 GI comparison for Diclo vs COX-2 inhibitors
RCTs summary: No significant difference for GI complicated ulcers

Trial Drugs (mg/day) Complicated upper GI events P value

N % Rate per 100 PY
MEDAL1 Etoricoxib 78 0.46 0.30 n.s.
(6090)
Diclofenac (150) 79 0.48 0.32
CLASS2 Celecoxib (800) 17 0.43 0.73 C vs D: p=0.640
Diclofenac (150) 10 0.50 0.93 C vs I: p=0.414
Ibuprofen (2400) 11 0.55 0.98
SUCCESS-13 Celecoxib (200) 2 0.022 n.a. C vs D: p=0.14
Diclofenac (100) 3 0.086 n.a.
Naproxen (1000) 4 0.44 n.a.

C=celecoxib; D=diclofenac, I=ibuprofen; N=naproxen; n.a.=not available; n.s.=not statistically significant; PY=patient years
1Results based on per-protocol analysis, n (%) recalculated based on available information on incidence rates; 2number of

events only provided for combined celecoxib group; 3p-values based on Fishers exact test

1. Cannon CP et al. Lancet 2006;368:177181.

2. Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
3. Singh G et al. Am J Med 2006;119:25566.
 MEDAL: Upper & Lower GI event / analysis
Little differences between Voltaren & etoricoxib

Diclofenac 50 or 75 mg bid (n=16,483)

1.2 HR: 0.69 Etoricoxib 60 or 90 mg od (n=16,819)
(95% CI: 0.570.83)
Event rate (per 100 patient years)

1.0
0.97

0.8

0.6 0.67

0.4
0.38
0.32 0.30 0.32
0.2 0.23
0.19

0
Combined Complicated Lower Lower
symptomatic and GI events GI events GI bleeding
complicated upper
GI events

Cannon CP et al. Lancet 2006;368(9549):177181.

Laine L et al. Gastroenterology 2008;135(5):151725.
 CLASS: Upper GI events / Analysis
No differences between Voltaren and celecoxib

Clinically significant Clinically significant

upper GI eventsb upper GI events or
gastroduodenal ulcers
Diclofenac 75 mg bid (n=1,996)
Celecoxib 400 mg bid (n=3,987)
0.8 Ibuprofen 800 mg tid (n=1,985) 2.0
* ***
* 1.76 1.72
Week 52 crude ratea

Week 52 crude ratea

0.55
0.6 0.62
1.5
0.55 1.30
0.50
0.4 0.43 1.0 1.05

0.2 0.26 0.26 0.5 0.64 0.68

0 0
Overall Patients not Overall Patients not
population taking aspirin population taking aspirin

*p<0.05, ***p<0.001 versus celecoxib. aRates and p values from uncensored data
bUpper GI bleeding, perforation or gastric outlet obstruction

Witter J. Celebrex Capsules (Celecoxib) NDA 20-998/S-009 Medical Officer Review 2000.
 Diclofenac sustained release (SR) may
increase patients compliance and convenience

Serum levels of three forms of diclofenac

49
Nasir M Idkaidek, Gordon L Amidon, David E Smith et al. Biopharm. Drug Dispos.19: 169-174 ( 1998)
 Synovial Fluid Concentrations of Diclofenac in
Patients With Rheumatoid Arthritis or Osteoarthritis

Concentration of diclofenac in plasma and synovial fluid after oral

administration (75 mg every 12 hours) to rheumatoid arthritis and
osteoarthritis patients: day 8

Benson MD, Aldo-Benson M, Brandt KD. Synovial Fluid Concentrations of Diclofenac in Patients with Rheumatoid Arthritis or Osteoarthritis.
Seminars in Arthritis and Rheumatism 1985; 15 (2 Suppl 1): 65-67
 NSAID in Chronic Pain Treatment
Chronic pain has a worldwide prevalence of 1055%1
Non-steroidal anti-inflammatory drugs (NSAIDs) are
effective analgesic, anti-inflammatory and antipyretic drugs2
Inhibit cyclo-oxygenase (COX) enzymes, leading to reduced
production of prostaglandins, which activate pain/inflammatory
responses

NSAIDs inhibit COX-1 and COX-2

COX-1-derived prostanoids may be needed for regulatory functions
throughout the body, especially GI tract, kidney, platelets3
COX-2, found in joints and muscles, contributes to pain and
inflammation3,4
1. Harstall C, Opsina M. IASP: Clinical Updates 2003;XI(2):14.
2. Rang HP et al. Pharmacology 2007, 6th Edition, Churchill Livingstone, London. Section 2; Page 228.
3. Hinz B, Brune K. J Pharmacol Exp Ther 2002;300(2):36775.
4. Chou R et al. Drug Class Review. Portland (OR): Oregon Health & Science University; 2006.
 Patients with increased GI risk
Different strategies for reducing GI toxicity with NSAIDs

1. Use lowest effective doses, shortest duration of

treatment
According to drugs prescribing information
2. Use a selective COX-2 inhibitor
BUT several withdrawn due to cardiovascular/other risks1,2
3. Co-administer NSAID + prostaglandin analogue
Supplements stomach in prostaglandins not synthesized due to
COX inhibition3
4. Co-administer NSAID + proton pump inhibitor (PPI)
Suppresses gastric acid secretion, protecting upper GI tract
Reduces NSAID-associated dyspepsia and gastric injury4

1. FDA. Information for Healthcare Professionals: Valdecoxib (marketed as Bextra). 2005. (ww.fda.gov)
2. FDA. Vioxx (rofecoxib) Questions and Answers. 2004. (ww.fda.gov)
3. Miller DR. Clin Pharm 1992;11(8):690704.
4. Lanas A, Sopea F. Gastroenterol Clin North Am 2009;38:33352.
How to choose NSAID for chronic rheumatic pain ?

Consider the diagnosis ?

Diclofenac SR the right choice for chronic pain due to nociceptive,

Consider the past and present history, especially GI and cardiovascular

events?
Diclofenac SR has GI safety is similar or with little difference compared to COX-2
inhibitors

Choose NSAID due to pharmacokinetic and pharmacodynamics profile (onset

of action, half life, COX selectivity, risk of side effect)
After administration diclofenac sustained release, the amount absorbed can be
recorded at 24 hours.

Dose and Duration of treatment

Diclofenac sustained release (SR) recommended administered is 1 tablet or 2 tablets
per day

Patient compliance
Diclofenac sustained release (SR) may increase patients compliance and
53 convenience.
 Conclusion

Voltaren has been used to treat pain for >3 decades

Vast body of evidence supports its efficacy, safety and
continued use
Number 1 prescribed NSAID
The Gold standard reference for many clinical studies
including RCTs

Voltaren SR effective reducing pain and increase patients

compliant.

Recent RCTs didnt show any superior efficacy for COX-2

inhibitors vs diclofenac

GI safety is similar or with little difference compared to COX-2

inhibitors