Prof.dr. Aznan Lelo, PhD.

, SpFK

2 December 1951 SpFK, Clinical Pharmacologi

Bukit Tinggi PB-IDI & FK UI, 1995
Professor
MD, FK USU, 1978 Head of Department
Pharmacology & Therapeut
PhD in Clinical PharmacologySchool of Medicine, USU
FUSA-Flinders Medical Centre
Australia, 1988 Jln. Tridharma 22
Kampus USU, Medan
Role of Multimodal Anal
ain Patient with Risk Fa
Aznan Lelo
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera
Utara
21 May 2016, HISFARSI, Banda Aceh
Pain =
NYERI
. adalah KEGAWATAN MEDIS
. dapat MEMBUNUH
. merupakan penyebab tersering
seseorang dibawa ke UGD
Bebas NYERI merupakan HAK AZASI
manusia
Saat ini keluhan NYERI merupakan
Tanda Vital ke-5
Consequences of Inadequate
Pain Management

Lamont LA, Tranquilli WJ, Grimm KA. Physiology of pain. Management of Pain 2000; 30(4) :703-28.
Faktor-faktor yang harus
dipertimbangkan bila menangani
nyeri
Isue Obat Isu Pasien
Jenis, keparahan
Khasiat Kausa nyeri
Tolerabilitas Faktor risiko: saluran
cerna, platelet, renal dan
Keamanan
cerebro-cardio-vascular
Dosis system.
Biaya Obat tambahan.
Penyakit penyerta
Kepatuhan .
BENEFITS RISKS
efficacy safety
 Kelasifikasi Nyeri
Akut

Durasi
Kronis
Nosiseptif
Pato-
fisiologi Neuropatik
Ringan

Keparahan
Berat
Kelasifikasi Analgetik
Analgetik

Opioid Non-opioid

Anti- Anti-
Kuat Lemah piretik inflamasi
Adjuvan

AINS
Morphine Codeine Parasetamol Celecoxib Antidepressant
Diclofenac Anticonvulsant
Fentanyl Tramadol Metampyrone Ibuprofen Local anesthetic

Dresden, Germany, 12th June 2012

 WHO Analgesic Step
Ladder
Prinsip Peresepan Analgetik Berdasarkan Keparahan
Nyeri
Opioid kuat
AINS
Analgetik adjuvan

Opioid
lemah
Non-opioid AINS
paracetamol Analgetik
or AINS adjuvan
Analgetik adjuvan
Treshold nyeri Toleransi nyeri

0 1 2 3 4 5 6 7 8 9 1
ringan sedang berat 0
 Pegal
etc, Linu Nyeri
etc,etc haid
etc
Asam Sakit
Sakit ?
mefenamat in-partu
Nyeri Sakit
bisul Nyeri gigi
dada
Isue umum tentang AINS
Mekanisme kerja sama (menghambat aktivitas
cyclooxygenase)
Berbeda selektivitas thdp COX-1 dan COX-2
Berbeda struktur kimia
Berbeda farmakokinetik dan potensi
Sama indikasi klinis
Analgetik (efek CNS dan perifer) bisa
melibatkan efek yang tidak berkait dengan PG
Antipiretik (efek CNS)
Anti-inflamasi (terutama melalui inhibisi PG)
Sama memiliki analgesic ceiling effect
Tidak bermanfaat untuk nyeri neuropatik
Adverse Effects of NSAIDs
Ototoxic Color blindness

Bronchospam CHF

Hepatotoxic UGIB
UGIB

Bleeding Nephrotoxic

Allergy Tocolytic

Mechanism of = Mechanism of
therapeutic effects adverse effects
 PAIN
ALZHEIMER
CANCER DISEASE

NSAID

Iatrogenic diseases
Fluid
Retention
Incease
PUB
BP
Heart
burn

Rp Rp Rp Rp
Anti-
diureticIatrogenic COST antacid
hypertensive misoprostol

PRESCRIBING
Prescribing Cascade
Petunjuk penggunaan analgetik AINS

Memiliki banyak efek samping

Pada banyak kondisi klinis dapat
diganti dengan analgeik lain
Hindari penggunaan berlama-lama,
teristimewa pada pasien berisiko tinggi
Tidak bermanfaat untuk nyeri
neuropatik
nsNSAID-related deaths &
admissions to hospital
Event Annual UK USA CANADA
NSAID
prescriptions 25 million 70 million 10 million
NSAID-related
admissions 12,000 100,000 3,900
NSAID-related
deaths 2,600 16,500 365

Blower AL, Brooks A, Fenn CG et al. Aliment Pharmacol Ther 1997;11:28391.

Hawkey CJ, Cullen DJ, Greenwood DC et al. Aliment Pharmacol Ther 1997;11:2938.
MacDonald TM, Morant SV, Robinson GC et al. BMJ 1997;315:13337.
Step 1

Step 2

Step 3

Antman EM, Bennet JS, Daugherty A, et al. Use of nonsteroidal anti-inflammatory

drugs: an update for clinicians: a scientific statement from the American Heart
 FDA & EMEA had given strong
caution for use of NSAIDs in
patients with CV & GI risks
Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs), including COX-2
selective NSAID, have to include
a Black Box Warning, highlighting
the potential for increased risk of
cardiovascular (CV) events and
the well described, serious,
potential life-threatening
gastrointestinal (GI) bleeding
associated with their use.
Carefully consider the potential
benefits and risks of NSAIDs and
other treatment options before
deciding to use NSAIDs. Use the
lowest effective dose for the
shortest duration consistent with
individual patient treatment
goals
Source: May 15, 2005, AJHP (Am J Health-Syst
Pharm)
The majority of studies with sufficient data have
demonstrated a strong association between
increasing dose and increasing risk of gastrointestinal
toxicity. Other risk factors identified, namely
increasing age, a history of peptic ulcer disease, male
gender, the use of oral anticoagulants or oral
corticosteroids, treatments for heart disease and
diabetes or being a smoker/heavy drinker, are
generally well recognised.
New epidemiological evidence and updated clinical
trial data (APC, PreSAP, APPROVe and metaanalyses)
continue to point towards an increased thrombotic
risk with Cox-2 inhibitors compared to non-use (in
epidemiological studies) and compared to placebo (in
clinical studies) possibly accounting for about 3 extra
events per 1000 patient-years. This relates mainly to
myocardial infarction, and includes cerebrovascular
and peripheral vascular events in some studies
20.PUBLIC CHMP ASSESSMENT REPORT FOR MEDICINAL PRODUCTS
CONTAINING NON-SELECTIVE NON STEROIDAL ANTIINFLAMMATORY
DRUGS (NSAIDs). EMEA/CHMP/442130/2006
Therapeutic options for treating
moderate-to-severe low back
pain

Schnitzer TJ. Update on guidelines for the treatment of chronic musculoskeletal pain. Clin Rheumatol
2006;25(Suppl 1):S22-S29
Treating moderate to severe pain
in OA patients WITH risk factor

Schnitzer TJ. Update on guidelines for the treatment of chronic musculoskeletal pain. Clin Rheumatol
2006;25(Suppl 1):S22-S29
 Pain Patient Demography
in Indonesia
100%

16% Pain 74% of patients suffer

Intensity moderate-severe pain
80%
7-10 (Severe)
but theres only 17%
4-6
60% (Moderate) patients get ladder 2&3
58%
0-3 (Mild)
painkiller

40%

20% 73% 16% 1% 4% 6%

Ladder 1 Ladder 2 Ladder 3 Adjuvant NA
26%

0%
1498 patients get
All Pain Patients ladder 2&3 pain killer

9108 patients suffer WHO Ladder:

Ladder 1 for Mild Pain : Non-opioid, e.g. paracetamol, NSAIDs, coxib, aspirin
moderate-severe pain Ladder 2 for Moderate Pain : Weak opioid, e.g. tramadol, codein
Ladder 3 for Severe Pain : Strong opioid, e.g. Morphine, Fentanyl

National Pain Survey, Understanding pain patient profile,14218 patients, 528 MDs all countries in Indonesia,2012
 Inflammatory
PAIN

SEVERE
PAIN
Paracetamol
PURE
ANALGESIC + NSAID + STEROID
OPIOID
+
NSAID
Multimodal Analgesia
Menggunakan lebih dari satu jenis obat untuk
mengatur nyeri
Berbeda obat dengan mekanisme kerja berbeda
Tiap obat dengan dosis lebih rendah dibanding bila
digunakan tersendiri
Dapat memberikan efek additif atau sinergis
Memberikan efek analgetik yang lebih baik dengan
efek samping yang lebih sedikit (terutama yang
berhubungan dengan efek samping oipioid)

Always consider multimodal analgesia when treating pain

 Multimodal Analgesia
Non-
selective selective
COXIB COXIB
Ketamin

COXIB Administration of two

parace NMDA analgesic agents that act
tamol antagonist
by different mechanism
for providing superior
ANESTESI
LOKAL
PAIN GABA
agonist analgesic efficacy with
equivalent or reduced
mu 5-HT adverse effects
agonist Nadr Reuptake
inhibitor REDUCED DOSES
Reuptake
inhibitor of each analgesic
OPIOID IMPROVED PAIN
RELIEF due to
synergistic effects
TRAMADOL
TRAMADOL REDUCE SIDE
Jin et al. J Clin Anesth;13:524, 2001 EFFECTS of each
Kehlet et al. Anesth Analg;77:1048. 1998
Woolf CJ, Science, 288:1765-1768, 2000 drug
Rational Combination of
Acetaminophen + Tramadol

One of the most popular

multimodal fixed combination
is Tramadol + Paracetamol

Acetaminophen Tramadol
 Acetaminophen
Centrally acting analgesic and antipyretic
Usually 1st line
Unclear mechanism
Inhibits COX-3 in the hypothalamus, very low activity on
COX-1, possible 5-HT activity.
partly inhibiting nitric oxide (pain neurotransmitter)
formation
No anti-inflammatory properties.
Drug of choice for OA
Rapidly absorbed from GI tract, reaches a peak
plasma level in 30 to 60 min, rectally: 2-2.5 h.
Onset: 15-30 min
do not give to alcoholic patients and those with liver disease 2 grams/day limit
 Acetaminophen
Metabolized in liver;
half life is ~ 2 hours.
Dose: 325-1000mg Q4-6h (4g daily max)
Reduce dose 50-70% in patient with significant
hepatic impairment
associated with hepatotoxicity (fatal hepatic
necrosis) when taken in large doses (10 to 15
g).
Measure serum level of acetaminophen
after 4 hours of ingestion
Antidote: acetylcysteine
 Tramadol
Centrally acting analgesic with a dual MOA
1st - opioid effects similar to morphine (mu)
Active Metabolite M1
M1 - 6x tramadol as analgesic, 200x binding
2nd - inhibit re-uptake of NA / 5-HT
descending pain inhibitory pathway
Tramadols strength lies in its weakness as an
opioid
Poor Mu receptor affinity
does not antagonize the action of classic mu
agonists like morphine, dilaudid or fentanyl
Other mu agonist may be added
moderate to moderately severe pain
do not give these medications to patients who are dependent on narcotics
 Tramadol
Dose exceeding 400 mg daily are not
recommended
Hepatic Metabolism via CYP 2D6
similar to codeine
renal or hepatic impairment: decreasing the frequency
of administration
Interactions:
SSRI, TCA, carbamazepine, MAOI, warfarin ( INR)
Can cause serotonin syndrome by itself!
Minimal opioid effect
Less constipation, faster return to normal bowel
function, Less N/V
No sig. respiratory depression
No sig. risk for abuse (not classified as narcotic)
 Site of Action of
1 3 acetaminohen-tramadol
combination

Tramadol
activates
opioid
receptors

Tramadol
1 3 inhibits re-
uptake of
2 norepinephrine
and serotonin

Acetaminophen
weakly inhibits
prostaglandin
biosynthesis

Sohita Dhillon et al, Tramadol/Paracetamol Fixed-Dose Combination. Clin drug Investig, 2010.
Pharmacokinetics of Tramadol and
Acetaminophen
Tramadol Acetaminophen
Onset of action 20 30 minutes 15 30 minutes
Peak serum conc. Approx. 2 hours 0.5 1 hours
Elimination half life 6 hours 2 hours
Bioavailability 90 100% Up to 90%
with multiple doses depending on the
formulation

Protein binding Approx. 20% Approx. 20%

Metabolism liver liver
Rate of Approx. 70% > 90%
metabolism
Metabolite Active Toxic
Tramadol and Acetaminophen
measured in single and
combination formula
Tramadol Acetaminophen
measured measured
Comb. Single Single Comb.
C-max 148 148 12.3 13.2
(ng/ml)
T-max 1.9 2.1 1.1 1.0
(hour)
AUC 1.385 1.504 50.8 51.7
(ng.h/ml)
 Contribution of Tramadol, Acetaminophen, and the
combination to the rate of the pain relief probability as
a function of time

Paracetamol/Tram
3 Paracetamol/Tramadol
adol
Pain relief

T1/2 = 7-9 h
Paracetamol
2 Paracetamol
peak = Paracetamol
30
min
T1/2 = 2 h
1
TRAMADOL
Tramadol
Tramadol
peak = 2-3 hrs
T1/2 = 6 h
0
0 2 4 6 8 10
Time, h
Fast onset of action and
prolonged action
Ultracet (package insert). Raritan (NJ): Ortho-McNeil Pharmaceutical Inc, 2007
Tramadol/APAP have fast onset vs
single Tramadol or APAP

Estimeted time to onset of pain relief (min.)

70
60
50
40
30
20
10
0
tramadol/APAP tramadol APAP ibuprofen placebo

Medve, RA, Julia Wang., et al. Tramadol and Acetaminophen Tablets for Dental Pain.
American Dental Society of Anaesthesiology. 2001
Tramadol/APAP have long duration
vs single Tramadol or APAP

Duration of pain relief (hour)

6

0
tramadol/APAP tramado APAP ibuprofen placebo

Medve, RA, Julia Wang., et al. Tramadol and Acetaminophen Tablets for Dental Pain.
American Dental Society of Anaesthesiology. 2001
 Efficacy Acetaminophen 325 mg +
Tramadol 37.5 mg on OA
References Study design Efficacy Adverse reactions
Rosenthal et al. R CT, combination vs. Combination significantly Nausea, vomiting and
J Am Geriatr placebo in painful OA better than placebo dizziness (10-18%)
Soc flare, added to NSAID
2004;52:374-80 for 10 days
Emkey et al. J RCT, combination vs. Significantly lower pain Somnolence, nausea,
Rheumatol placebo in add-on score for combination and constipation (3-
2004;31:150-6 therapy to coxib in OA plus coxib than coxib 7%)
for 91 days alone, and pain relief
significantly higher
Silverfield et al. RCT, combination vs. Combination significantly No serious adverse
Clin Ther placebo in painful OA reduced pain and events
2002;24:282-97 flare, added to NSAID improved pain relief
for 10 days compared with placebo
Mullican et al. RCT, combinataion Two treatment were Higher somnolence
Clin Ther A+T vs. A300+C30 in equivalent and constipation with
2001;23:1429- chronic back pain or A300+C30, and more
45 OA headache with A+T
 Combination Tramadol/Paracetamol
significant effective as add on therapy
with COXIB in patient OA

Vs placebo

Emkey R.Rosenthal N. Wu SH, Jordan D.Kamin M. CAPSS-114 Study Group. Efficacy

and Safety of Tramadol/Acetaminophen tablets (Ultracet) as Add-on Therapy for
Osteoarthritis Pain in Subjects Receiving a COX-2 Non-steroidal Anti-Inflammatory
Drug: A multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. J rheumatol
2004:31:150-6
 Tramadol/Paracetamol is effective for
better pain relief in post-surgical
patients
Effectivity for first four hours (Score for Sum of Pain Relief
and Pain Intensity Difference over first 4 hours)

TRAM/APAP Kodein/APAP Placebo

(n = 98) (n = 109) (n = 98)
Day 1,inHours
P-value is for the specific treatment contrast 14
a two-way analysis of covariance with
surgery type and treatment as factors and baseline pain intensity as a covariate.
*4-Hour Sum (SPRID) of Total Pain Relief (TOTPAR) and Sum of Pain Intensity Differences
(SPID).

P = .005 vs placebo.

P = .033 vs placebo.
 Tramadol/Paracetamol shows better
tolerability for vomiting and
constipation in post-surgical patients
Adverse Events (n, %)
TRAM/APAP
Adverse Kodein/APAP Placebo
Event (n = 98) (n = 109) (n = 99)

Nausea 21 (21.4) 26 (23.9) 16 (16.2)

Dizziness 10 (10.2) 9 (8.3) 3 (3.0)
Vomiting 9 (9.2) 16 (14.7) 9 (9.1)
Headache 8 (8.2) 8 (7.3) 8 (8.1)
Somnolen 5 (5.1) 4 (3.7) 1 (1.0)
Constipation 4 (4.1) 11 (10.1) 5 (5.1)

Smith AB, et al. Combination tramadol plus acetaminophen for postsurgical pain. Am J Surg 187,
2004;521-527
 Incidence of most common side
effects (> 5%)
Preferred term Tramadol/APAP Tramadol P value
Nausea 14% 35% <0.01
Vertigo 2% 17% <0.01
Somnolence 10% 17%
Constipation 5% 15% <0.05
Vomiting 3% 13% <0.05
Dry moth 12% 13%
Sweating 5% 10%
Drowsiness 2% 8% -0.05
Dizziness 2% 8%
Pruritus 7% 2%
Headache 5% 2%
Any adverse event 51% 73% <0.01
 Comparison of non steroidal anti-inflammatory
drugs (NSAIDs) with tramadol/paracetamol fix
dose combination

Pergolizzi Jr et al. Tramadol/paracetamol fixed-dose combination in the treatment of moderate to severe pain. Journal of pain
research,2012
Original vs generic or
branded generic
 .. 61% copies products
mengandung lebih banyak

.. .. senyawa produk yang ter-hydrolysi

.. ..
67% copies product
mempunyai R-enantiomer
dengan konsentrasi 4x lebih banyak

.. .. 72% copies product

mempunyai ketidak murnian

.. ..
4x lebih banyak daripada originalny

.. ..
. .
....... . . . .
. . .. ... .
.
 Change in phenytoin excipients
resulted in epidemic toxicity
obat yang berdasar uji la
mempunyai BA/BE yang
sama, ternyata
secara klinis berbeda da
ditemukan efek samping
[PHENYTOIN]

yang lebih besar

g/mL

WEEKS
Bochner F, et al. Proc Aust Assoc Neurol 1973;9:165-70
 The Role of Multimodal Analgesia
in Pain Patient with Risk Factor
Tidak semua nyeri dapat diatasi dengan AINS, terlebih lagi pada pasien
dengan faktor risiko tinggi
Multimodal analgesia memberikan khasiat yang lebih nyata dan
toleransi yang lebih optimal
Fixed combination acetaminophen 325 mg dan tramadol 37.5 mg
adalah salah satu multimodal analgesia dengan berbagai
keunggulan
Penggunaan tramadol yang dikurangi 25% menurunkan kejadian efek
samping tramadol,
Penambahan acetaminophen mempercepat mula kerja obat dan
meningkatkan khasiat analgesia.
Memperpanjang masa kerja analgesia
Fixed combination acetaminophen 325 mg dan tramadol 37.5 mg
terbukti lebih unggul dibandingkan dengan multimodal analgesia lain
seperti acetaminophen + kodein atau dibandingkan dengan COXIB
Kombinasi ini terbukti efektif dalam menanggulangi berbagai nyeri
termasuk nyeri pasca operasi
 tak ada ROTAN,
AKAR pun jadi

Thank you
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