Documente Academic
Documente Profesional
Documente Cultură
, SpFK
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
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
Step 2
Step 3
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%
40%
0%
1498 patients get
All Pain Patients ladder 2&3 pain killer
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)
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
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
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
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
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)
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
.. ..
67% copies product
mempunyai R-enantiomer
dengan konsentrasi 4x lebih banyak
.. ..
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]
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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