THE ROLE COX-2 INHIBITOR IN

NEUROLOGICAL PAIN MANAGEMENT

HENNY ANGGRAINI SADELI
Neurological Department Hasan Sadikin Hospital/
Faculty of Medicine Universitas Padjadjaran
Bandung
 Curriculum Vitae
• N a m a                        : dr. Henny Anggraini Sadeli SpS(K)
• Pekerjaan : dokter pendidik klinis SMF/Dep. Neurologi
RS Hasan Sadikin/FK  UNPAD Bandung
Subdiv. Nyeri/Nyeri Kepala
Subdiv. Neurorestorasi
• Pendidikan : lulus dr umum FKUI 1979
lulus spesialis FK UNPAD 1991
Konsultan Nyeri PERDOSSI 2006
• Kordinator Pokdi Nyeri PERDOSSI Cabang Bandung
 P A I N
Pain is unpleasant sensory and emotional experience associated with 
actual or potential tissue damage, or described in term of such damage 
( IASP, 1986 )

Types of pain : 
• Nociceptive pain
• Inflammatory pain            Mixed pain
Spontaneous pain
• Neuropathic pain
Stimulus‐evoked pain
• Dysfunctional pain Woolf CJ,2004
NSAIDs TREATMENT IN DAILY NEUROLOGICAL PRACTICE
• Musculoskeletal Pain
• Back Pain,Low Back Pain ± leg pain
• Neck Pain ± arm pain
• Carpal Tunnel Syndrome
• Cancer Pain
• Headache
CHOOSING PAIN KILLER AND ITS COMBINATIONS

Pain Intensity Scale (0-10)

0 1 2 3 4 5 6 7 8 9 10
Mild Moderate Severe
paracetamol NSAID Strong opioid
or/+ ± ±
NSAID weak opioid NSAID
± ± ±
adjuvant adjuvant adjuvant
analgesic analgesic analgesic
CURRENT VIEW IN SELECTING ANALGESIC AND 
ANTI‐INFLAMMATORY DRUGS

 Efficacy (indication)
 Safety (side effects)
 GI toxicity
 Cardiovascular toxicity
 Renal toxicity
 etc
 Suitability (contra‐indication)
 Availability
 Pharmacokinetics and drug interaction
 Daily cost
 Evidence Based Medicine (EBM)
HAS/Neuro Bandung

CYCLO‐OXYGENASE  PATHWAY
Arachidonic Acid

Endothelial cell Synovial membrane Kidney Gastric mucosa Platelets

COX‐1
COX‐1
COX‐2 COX‐2 COX‐1` COX‐1
COX‐2

Prostacyclin ‐ PGI2 Prostaglandins ‐PGE2/PGI2 Prostaglandins PGE2/PGI2 Tromboxane‐TXA2

Vasodilatation Pain Gastric protection Vasocontraction
Platelet aggregration↙ Inflammation Platelet aggregration↗

Antithrombotic state GI side 
Prothrombotic state
Prostaglangins‐PGE2 effects
Na/H2O resoption↙ (COX‐2)
Renal homeostasis (COX‐1)
 PERIPHERALLY AND CENTRALLY INDUCED COX‐2
PERIPHERAL CENTRAL
Trauma/inflammation Central sensitization

Arachidonic acid release PAIN

IL‐1β
COX‐2
Prostaglandin
Prostaglandin
COX‐2 
inhibitor

PAIN
COX‐2
Peripheral sensitization Samad TA,2001
 Development of COXIBS
• Theoretically, selective inhibition of COX‐2 would 
provide

• Anti‐inflammatory effects

• Without disrupting gastric cytoprotection and 
platelet function
 Less GI side effects
More GI side effects
Diclofenac Celecoxib
Acetosal Indomethacin Ibuprofen
Ketorolac Piroxicam Ketoprofen
Meloxicam COXIB
Rofecoxib
Nimesulide Valdecoxib

preferentially non- preferentially

COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

Etoricoxib
 Etoricoxib showed 24 minutes Fast Onset of action
& 24 hours Long Last
Pain Relief Score* Over 24 Hours
Etoricoxib 120 mg had a 24-Minute onset of action**
(Dose ranging study)
3.5
3.0
Mean PR score (±SE)*

Etoricoxib 180 mg (n=74)

2.5 Etoricoxib 120 mg (n=76)
Etoricoxib 240 mg (n=76)
2.0 Etoricoxib 60 mg (n=75)
1.5
Ibuprofen 400 mg (n=47)
1.0
Placebo (n=49)
0.5
0.0
0 1 2 3 4 5 6 7 8 12 24
Time (hour) postdose
• Etoricoxib 120 mg had a 24-minute or less onset of action in 50% of patients
• Etoricoxib 120 mg sustained a longer duration of action than ibuprofen
SE = standard error
p<0.001 for etoricoxib 60 and 120 mg and ibuprofen 400 mg vs. placebo over eight hours; p≤0.025 for etoricoxib 120 mg vs. ibuprofen 400 mg
over eight hours
Study included 60, 120, 180, and 240 mg dose for etoricoxib.
*Pain relief (PR) rated on a 0- to 4-point scale (0 = none, 1 = a little, 2 = some, 3 = a lot, 4 = complete); **Median time to onset in 50% of patients
Adapted from Malmstrom K et al. Clin Ther 2004;26:667-79
Etoricoxib at either dose led to significant improvement in other endpoints, including RMDQ scores,
bothersomeness scores and global assessments. Etoricoxib given once daily provided significant
relief of symptoms, and disability associated with chronic LBP that was observed 1 week after
initiating therapy, was maximal at 4 weeks, and was maintained over 3 months.
MEDAL PROGRAM

Unsurpassed safety
profile of Etoricoxib :
- Better GI safety
- Comparable CV
safety

Proven by MEDAL
Program with:
- Biggest number
patients enrollment
- Longest duration of
treatment
 Cumulative Incidence of Arterial
Thrombotic CV and APTC Events

Arterial Thrombotic CV Events APTC Events (CVD/MI/Stroke)
7.0 7.0
Etoricoxib (272 events) Etoricoxib (216 events)
Cumulative incidence (%) with 95% CI 

Cumulative incidence (%) with 95% CI 
6.0 Diclofenac (272 events) 6.0 Diclofenac (216 events)
Etoricoxib vs diclofenac Etoricoxib vs diclofenac
5.0 HR = 0.96  5.0 HR = 0.96 
95% CI = (0.81‐1.13) 95% CI = (0.79‐1.16)
4.0 4.0

3.0 3.0

2.0 2.0

1.0 1.0

0 0
0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42
Months Months
No. of patients at risk No. of patients at risk
Etoricoxib 16,819 13,362 10,735 8277 6427 4024 805 Etoricoxib 16,819 13,366 10,745 8282 6429 4026 805
Diclofenac Diclofenac 14
16,483 12,801 10,144 7903 6214 3832 815 16,483 12,814 10,155 7906 6218 3832 816
MEDAL PROGRAM: Confirmed Upper GI Events 
3.0
Etoricoxib 60 and 90 mg pooled (176 events)
Diclofenac 150 mg (246 events) All confirmed
2.5
Cumulative Incidence, eventsa
Etoricoxib vs diclofenac
HR=0.69 (95% CI: 0.57, 0.83) P=0.0001
2.0
% (95% CI)

1.5

1.0 Complicated
events
P=0.561
0.5
Etoricoxib vs diclofenac
HR=0.91 (95% CI: 0.67, 1.24)
0
0 6 12 18 24 30 36 42
Months
Patients at risk for upper GI events, no.
Etoricoxib 17,412 13,704 10,972 8400 6509 4063 821
Diclofenac 17,289 13,190 10,396 8027 6306 3867 820

GI=gastrointestinal; ITT=intention-to-treat; CI=confidence interval; HR=hazard ratio.

aThese included uncomplicated (perforation, ulcer, and bleeds) and complicated (perforation, obstruction, and bleeds) events.
Adapted from Laine L, et al. Lancet. 2007;369:465–473; Cannon CP, et al. Lancet. 2006;368:1771–1781.
 “Our results show that patients with arthritis treated with the 
COX‐2 selective NSAID etoricoxib and those given the 
traditional NSAID diclofenac have nearly identical rates of 
thrombotic cardiovascular events.”

Dr. Loren Laine is presenting preliminary GI subgroup data at Am. Coll. 
Rheumatology in Wash DC today
For the lower risk upper GI clinical events with etoricoxib:
 Generally consistent benefit in ASA and PPI subgroups

Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368 (published online)   www.thelancet.com  16
 BALANCING THE RISKS: 
USE OF NSAIDs IN PATIENTS WITH GI and CV RISKS
GASTROINTESTINAL RISK

LOW MODERATE HIGH

CARDIOVASCULAR  LOW  Traditional NSAID Traditional NSAID COX2 inhibitor+

RISK (does not require  +gastroprotective gastroprotective
aspirin) agent agent

Or  Or  Or

COX2 inhibitor COX2 inhibitor Consider alternative

non‐NSAID therapy
HIGH  Naproxen  Naproxen  Alternative non‐
(requires aspirin) +gastroprotective +gastroprotective NSAID therapy
agent agent

Modif Atchison JW,2013
 ORINOX BIOEKUIVALENCE STUDY
Mean plasma concentration‐time profiles of etoricoxib in human subjects (n = 27) after
a single dose oral administration etoricoxib tablet ORINOX® and the reference drug
(Originator) : comparable / similar  Orinox bioekuivalen vs originator

Putri, RSI et al. 2016. Summary Report of Bioequivalence Study. Data on Dexa Medica file

 CONCLUSION

Etoricoxib :
 selective COX‐2 inhibitor
 showed 24 minutes Fast Onset of action
 has the longest duration of analgesic action
 has good efficacy
 has a good safety and tolerability profile

ORINOX® (etoricoxib) bioequivalent to the reference drug 
THANK YOU