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Perioperative Pain Management

Focus on Parecoxib

Eddy Rahardjo
Pain Continues to be Undertreated
Postoperative pain U.S1,2

1993 (n=135)
1999 (n=250)


49% 47%

19% 21%
20% 18%

Any Slight Moderate Severe Extreme
Pain Pain Pain Pain Pain

Adapted from Apfelbaum J et al. Anesth Analg. 2003;97:534-540.

Contributing Causes of
Inadequate Pain Treatment (in USA)

• Insufficient knowledge of drug pharmacology a ?

among surgeons and nurses *)
d i m
• Uniform “p.r.n.” prescriptions ya
• Lack of concern for optimalspain t-n relief
g i
• Failure to give prescribed
ol o analgesics
• Fear of side effects e si
st h
• e
Fear of addiction
, A
l u *) yang menulis ini pharmacist
Case 1: (5 Des 2001) : Laki 50th post-op struma

• Bila nyeri/sakit: iv Toradol 30 mg diencerkan

• Tidak mempan beri Trunal DX 100mg
dicampur DHBP 1cc
• Tx Ponstan 500 3 x 1
• (ditulis Dr. A) Untuk
satu pasien
yang sama
• Solumedrol 3 x 125mg
• Tramal inj 2 x 1
• (ditulis Dr. B)
• Healthy adults 10-30mg q 4-6 hours,
total daily max 90mg UK, 120mg US
• Total daily max 60mg
– in > 65yo, in BW < 50kg
– creatinine clearance 1.2-3L/hour
• CI : heart failure, hypertension, hypovolemia
• NOT co-administered with
– other NSAIDs
– anti-coagulation (incl. low dose heparin)
3 x 30 mg

• Shock, hematuria, oliguria, dilutional coagulopathy

• Laparotomy, hepar rupture, reseksi usus
10 or 30 mg post-op pain

• Postoperative 10 and 30 mg seemed to

provide similar degree of pain relief,
although in some cases the higher dose
tended to provide better analgesia

• Ny. M, 80 th, Austin Moore Prosthesis

– Toradol 3 x 30 mg
• Ny. I, 62 th, 44 kg, mastectomy
– Toradol 3 x 30 mg
• Tn R, 86 th, 57 kg, batu buli-buli, 2.1
– Toradol 3 x 30 mg

4 Feb 2003
National Patient Safety Foundation
(created by AMA, reported on 9 Oct 1997)

• Forty two percent of 1500 people surveyed had

experienced medical mistakes
– equals to 100 million American public
• From those experienced medical mistakes:
– 40% misdiagnosis and wrong treatments, 28% medication error
• Study from University of Chicago
– Annual approximate of 3 million medical errors with an expense
of US $ 200 billion
• Institute of Medicine, 1999 report:
– Estimate 98,000 people die each year from errors
Pain, what kind of pain ?
Abram SE, Haddox JD: The Pain Clinic Manual, 2000

• Specific pain
• Acute pain – Backpain
– Postoperative pain – Myofascial pain
• Chronic pain – Herpetic Neuralgia
• Cancer pain – Complex Regional
Pain Syndrome
• etc
– Neuropathies
– Headache
– Post Dural Puncture
Dispersi kompleksitas berbagai jenis nyeri

Nyeri post-op

Nyeri kanker

Nyeri khronis

• Opiod / opioid sintetik • Aspirin

– morfin • Paracetamol
– pethidin • Asam mefenamat
– fentanyl • NSAID lain
– codein – puluhan jenis
• Opioid “like”
– tramadol • Low dose ketamine
– dll
Bagaimana memilih analgesik
• Nilai derajat nyeri yang dihadapi
– nyeri fraktura jari vs nyeri fraktura femur
– nyeri operasi fibroadenoma vs laparotomi
– (memang ada variasi subyektif)
• Pilih analgesik dengan potensi yang sesuai
– tonsilektomi apa perlu morfin atau tramadol?
– Fraktura femur apa mungkin dengan paracetamol?
– (perhatikan equi-potency dose)
Postoperative pain is a complex of
unpleasant sensory, emotional,
and mental experiences
associated with autonomic, psychological,
and behavioral responses
precipitated by the surgical injury

Henrik Kehlet, ACS Surgery 2003.

Postoperative pain relief

• Provision of subjective comfort

• Inhibition of trauma-induced nociceptive
– to blunt autonomic and somatic reflex responses
to pain
– to enhance subsequent restoration of function by
allowing the patient to breathe, cough, and move
more easily
– these effects reduce pulmonary, cardiovascular,
thromboembolic events
Nyeri selalu merupakan masalah yang besar bagi pasien.
Tetapi seberapa nyeri menjadi masalah bagi Dokter yang merawat
pasien tersebut ?
Analgesic Ladder WFSA
Post-Operative Pain

COX-2 Inhib

WFSA = World Federation of Societies of Anesthesiologists


COX-2 Inhib
Hierarchy of analgesia
University of Southern California
Los Angeles County Trauma Center

• Acetaminophen oral/rectal, 650-1000mg q 4-6H

• NSAID oral/rectal/im:
– Indomethacin, Ibuprofen
– Ketorolac 30mg iv or im q 6H or 10mg oral q 6H
• Codein 30-60mg q 4-6H
• Morphine oral/sc, iv, epidural 2-20mg/hour
• Fentanyl 2-20cc/hour or epidural
Analgesik apa yang dicari ?
• Morfin, pethidin, fentanyl, suf / alfentanyl
– Gold standard
– Penyulit standard
• Depresi nafas sampai apnea
• Mual muntah
• Vasodilatasi
• Hipotensi
• Reaksi histamin release lain
– Bronchoconstriction
• Aspirin
• Paracetamol
• Potensi bisa sekuat morfin
(dalam hal-hal tertentu)
• Penyulit nafas dan sirkulasi
lebih aman dari morfin
• Tetapi ada penyulit lain yang • GI bleeding
lebih buruk dari morfin
• Angioneurotic edema
• Penyulit tidak dapat
diprediksi • Gagal ginjal
• Efek analgesia tidak lineair • Penyakit jantung
seperti morfin
Pain, a re-look to the problem
How good can Parecoxib
solve the problem ?
Parecoxib Sodium (DYNASTAT™):
an Injectable Prodrug of Valdecoxib

Parecoxib (Prodrug) Valdecoxib (Active)

C H3 CH 3

S O 2N C O C H2 CH3 SO 2 NH 2


(3A4, 2C9)

Glucuronide Glucuronide Active Hydroxylated

(sulfonamide) (Alcohol) Metabolite

Adapted from Karim A et al. J Clin Pharmacol. 2001;41:1112.


10 ---
5 ---- parecoxib
- morfin
- Ceiling effect
- anestesia
- Pada titik ini, menambah dosis tidak
0 menambah analgesia, hanya
menambah komplikasi
NSAIDS can kill, indeed
• Seorang laki 35 th operasi laminektomi L1-3
• Postop diberi resep 6 ampul Ketorolac,
dosis 30 mg x 3 (dr A)
• Hari ke 2 pindah ruangan, Ketorolac diteruskan
3 x 30 mg (dr B)
• Hari ke 10 postop pasien shock, melena 2000 ml
(ternyata masih terus diberi Ketorolac 3 x 30mg)
• Masuk ke ICU selama 7 hari, resusitasi cairan,
transfusi masif sebanyak 20 unit darah
Profile of parecoxib
• 40mg IM ~ morphine 12mg IM ~ ketorolac 60mg IM1,2
• 40mg IV > morphine 4mg IV ~ ketorolac 30mg IV3
• Preoperative* administration: provides postoperative pain relief4
• Onset of action: 7 to 13 minutes8
• Duration of effect: consistent with twice daily dosing8
• Contraindicated in treatment of postoperative pain following
coronary artery bypass graft (CABG) surgery

1Malan TP Jr, Gordon S, Hubbard R, Snabes M. The cyclooxygenase-2-specific inhibitor parecoxib sodiumsodium is as effective as 12 mg of morphine administered

intramuscularly for treating pain after gynecologic laparotomy surgery. Anesth Analg. 2005;100:454-460.
2Daniels SE et al. Clin Ther. 2001;23:1018-1031.
3Rasmussen GL et al. Am J Orthop. 2002;31:336-343.
4Desjardins PJ et al. Anesth Analg. 2001;93:721-727.
5Hubbard RC et al. Br J Anaesth. 2003;90:166-172.
6Malan TP Jr et al. Anesthesiology. 2003;98:950-956.
7Wender RH et al. ASRM. 2001.
8parecoxib sodiumSmPC.
Postoperative Efficacy in Orthopedic Surgery:
Elderly Patients

more relief
Pain Intensity Difference (Mean)

* *
1.2 *

1.0 *
* *
0.8 *
* *
0.6 P-40 single dose
less relief

Morfin 4 mg


0 1 2 3 4 5 6 7 8 10 12

Hours Postdose

Measured as Time
- Specific Pain Intensity Difference (Categorical)
*P <0.05 statistically significantly
different from morphine 4 mg.

Hubbard RC et al. Anesthesiology. 2001;95:A807.
Data on file. Clinical Study #020. July 31, 2000. Pfizer, New York, NY.
Derajat nyeri postop berbeda-beda

• Abdominal Procedures
– Pain after major and upper abdominal operations is severe
– Combined regimen of epidural local anesthetics and opioids
plus systemic NSAIDs or COX-2 inhibitors is

• After gynecologic operations,

– Systemic opioids plus NSAIDs or COX-2 inhibitors are

• Prostatectomy
– Pain is usually not severe and may be treated with systemic
opioids combined with NSAIDs or COX-2 inhibitors and
Opioid-Sparing Effects on PCA Morphine

40 mg IV bid
Percent Reduction In Morphine Use

- 10
P-40 iv single dose vs morphine alone

- 20

- 30 *

Mean morphine consumption was placebo, 43.5 mg; DYNASTAT 20 mg bid, 36.7 mg; DYNASTAT 40 mg bid, 31.4 mg.
PCA morphine was available within 140 minutes following surgery.
1Hubbard RC et al. Br J Anaesth. 2003;90:166-172.
Conventional NSAIDs and COX-2 Inhibitors

NSAIDs are minor analgesics.

The anti-inflammatory effect makes it suitable for postoperative
pain associated with inflammation.
They may have central analgesic effects and thus analgesic
efficacy after all kinds of operations.

Conventional NSAIDs inhibit both COX-1 and COX-2.

Newer agents specifically inhibit COX-2.

The analgesic efficacy is comparable to conventional

NSAIDs but with fewer side effects.
Vioxx Withdrawal Prompts Reevaluation of
COX-2 Inhibitor Safety

Medscape Medical News 2004. © 2004 Medscape Oct. 8, 2004 —

Worldwide withdrawal of rofecoxib (Vioxx) on Sept. 30, concerns are surfacing

over whether the adverse cardiovascular risk documented with rofecoxib may be
a class effect extending to the other cyclooxygenase-2 (COX-2) inhibitors.

"Although the risk that an individual patient would have a heart attack or
stroke related to Vioxx is very small, the study that was halted suggests
that, overall, patients taking the drug chronically face twice the risk of a
heart attack compared to patients receiving a placebo," Dr. Crawford
said in a news release.

"All of the [nonsteroidal anti-inflammatory drugs (NSAIDs)] have risks

when taken chronically, especially of gastrointestinal bleeding, but also
liver and kidney toxicity. They should only be used continuously under
the supervision of a physician."
APPROVe study (Adenomatous Polyp Prevention) was
designed to evaluate rofecoxib, 25 mg, in preventing
recurrence of colorectal polyps in 2,600 patients.

This multicenter, prospective, randomized, double-blind

trial, documented an increased relative risk for
cardiovascular events (myocardial infarction and stroke),
for rofecoxib compared with placebo.

The increased cardiovascular risk began after 18 months

of treatment with rofecoxib.
At three years, cumulative incidence of cardiovascular
events was 7.5 per 1,000 patients receiving placebo
compared with 15 per 1,000 patients receiving rofecoxib.
Parecoxib safety profile
• Parecoxib is given by injection1,
for the short treatment of acute / postop
– Parecoxib inj is administered by health care
– Perioperative use means patients will likely
be monitored closely with follow-up after
2EMEA Questions and Answers on COX-2 Inhibitors; 27 June 2005,
Penanganan nyeri postop sebaiknya dikerjakan
bersama Dokter Spesialis Anestesiologi dan
Tim Perawat.

Agar analgesia optimal dicapai dengan dosis minimal.

Dosis minimal = efek samping yang sangat minimal.
IASP 1979 :
“Pain is
an unpleasant sensory and emotional experience
associated with actual or potential tissue damage,
or described in terms of such damage”.

Perlu kita sadari bahwa

“Pain is always subjective.

Many people report pain in the absence of tissue damage or any
likely pathopysiological cause.
If they regard their experience as pain and if they report it in
the same way as pain caused by tissue damage,
it should be accepted as pain.”


Pain General Anesthesia

Spinal / Peridural Anesthesia

modulation Dorsal Horn

input Dorsal root

Field Block Anesthesia



Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981,

and Kehlet H et al. Anesth Analg. 1993;77:1049.
Jika dengan COX-2 masih ada nyeri tersisa
Tidak boleh ditambah NSAID lain
Rescue medication adalah OPIOID.
Pain Opioid
modulation Dorsal Horn

input Dorsal root


Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981,

and Kehlet H et al. Anesth Analg. 1993;77:1049.
Morphine iv Ketorolac iv
0.1 mg/kg 0.6 mg/kg
Pain relief first hour 56% 57%
Max pain relief in first 2 hours 44% 50%
Treatment failure (no pain relief) 14% 3.7%
Required re-medication in 4 hours 63% 58%

A Randomized Comparison of Ketorolac Tromethamine

And Morphine for Postoperative Analgesia in Critically
Ill Children
Lieh-Lai,MW et al. Crit Care Med Vol 27 (12)
Dec 1999, p 2786-91
Ketorolac for Pain Manangement After Abdominal Surgical
Procedures in Infants
Burd RS, Tobias JD. South Med J, V95(3), 331-333, 2002

10 patients received only ketorolac

4 received received no supplement
6 received morphine supplement
of which 2 had apnea episodes 33%
within first
8 patients received only morphine 12 hours
of which 2 had apnea episodes 25%