Dr Pramono Apriawan Wijayanto Sekolah Tinggi Ilmu Kesehatan ICSADA Bojonegoro

Pendahuluan
Nyeri adalah pengalaman sensorik dan emosional yang tidak menyenangkan terkait kerusakan jaringan, baik aktual maupun potensial atau yang digambarkan dalam bentuk kerusakan tersebut.

Pendahuluan
Nyeri adalah anugerah Sesungguhnya nyeri adalah anugerah yg besar dari maha pencipta (Allah SWT)
Pain is alarm protection tell us that something wrong in

our body.
Sulit dibayangkan seandainya tubuh kita tidak

dilengkapi dgn reseptor nyeri, sehingga kita tidak pernah menyadari kalau tubuh kita telah terancam kerusakan.

Pendahuluan
Pain can occur due to

Potential tissue damage --- > Physiological Pain

Actual tissue damage ----- > Nociceptive pain or Acute pain or inflammation pain
Described in term of such damage ----- > Chronic Pain

1. PHYSIOLOGICAL PAIN
Pain that occur to stimulate withdrawals reflex To prevent tissue damage To prevent our body from harmful things.

REFLEK

2. Acute or Nociceptive Pain

Acute Pain or Nociceptive Pain is pain that elicited by activation of nociceptors There are 4 distinct process involved: 1. Transduction 2. Transmission 3. Modulation and 4. Perception

The Pain Pathway

Brain Dorsal Root Ganglion Dorsal Horn

Pain Perception

Spinal Cord Nociceptor

Gottschalk A et al. Am Fam Physician. 2001;63:1979-84. Fields HL et al. Harrisons Principles of Internal Medicine. 1998:53-8.

Stage of Nociception
1.

Transduction

Conversion of noxious stimuli (mechanical, thermal, chemical into electrical activation Communication of the nerve impulse from the periphery to the spinal cord, up to spinothalamic track to the thalamus and cerebral cortex Process by which impulse travel from the brain back down to the spinal cord to selectiveley inhibit (or sometimes amlpify) pain impulse Net result of three events the subjective experience of pain

Transmission

Modulation

Perception

4. Pain Perception
Pain perception much depend on modulation ---- > 3 possibilities
1. Nociception without pain (ada nosisepsi tanpa nyeri) 2. Nociception with pain (ada nosisepsi dengan nyeri). 3. Pain without Nociception (ada nyeri tanpa nosisepsi)

The Somatosensory System

Somatosensory cortex

Frontal cortex
Descending pathway Periaqueductal gray matter

Thalamus Hypothalamus Ascending tracts Midbrain

Medulla

Dorsal horn area

Spinal cord

Noxious stimuli activate receptors in periphery

The Pain Response

Tissue Damage

Activation of the Peripheral Nervous System

Transmission of the Pain Signal to the Brain

Activation of the Central Nervous System at the Spinal Cord Level

Pain
Samad TA et al. Nature. 2001;410:471-5.

Nyeri dibedakan atas: Nyeri Neuropatik: Nyeri yang disebabkan oleh lesi (kerusakan) sistem saraf. Nyeri Nosiseptif: Nyeri yang disebabkan oleh proses inflamasi dan kerusakan jaringan

Pd keadaan sakit, tubuh merasakan nyeri Nyeri merupakan mekanisme pertahanan tubuh sehingga individu memindahkan stimulus nyeri Ada 2 jenis rasa nyeri: Nyeri cepat: tajam, menusuk, rasa kesetrum dan akut. Nyeri lambat: rasa terbakar, pegal, berdenyut, nyeri mual dan khronik

Peripheral Activation
VR1

Extern al Stimuli

Heat Mechanical Chemical

Ca2+

Voltage-Gated Sodium Channels

Action Potentials

Adapted from Woolf CJ et al. Science. 2000;288:1766.

Pendahuluan
Reseptor nyeri dan rangsangannya: Semua reseptor adalah ujung saraf bebas. Tersebar dipermukaan kulit dan jaringan seperti: - periosteum - dinding dalam arteri - permukaan sendi - falks / tentorium serebri Ada 3 macam stimulus: - mekanik - suhu - kimiawi

Peripheral Modulation
External Stimulus HEAT Sensitizing Stimulus
PGE
2

VR1

EP Recept or

PK A
SNS/PN3

PKCeTTX-Resistant
Sodium Channel

Bradykinin
BK Recept or

EP = prostaglandin E; BK = bradykinin.

Adapted from Woolf CJ et al. Science. 2000;288:1766.

Sensasi Nyeri
Nyeri berperan melindungi tubuh Nosiseptor adalah suatu reseptor nyeri pada ujung saraf bebas yg ditemukan pada jaringan tubuh, kecuali otak. Rangsangan termal, kimia dan mekanik akan mengaktifkan nosiseptor, dengan jalan melepaskan prostaglandin, kinin dan ion kalium

Jenis Nyeri:
Impuls nyeri cepat - berlangsung cepat (0,1 dtk pasca rangsangan - disepanjang saraf tipe A bermielin - nyeri bersifat akut, tajam atau menusuk - tdk dijumpai pd struktur dalam

Jenis Nyeri:
Impuls nyeri lambat terjadi disepanjang saraf tipe C tdk bermielin - nyeri sangat menyiksa, dan menjadi khronik spt; rasa terbakar, tumpul dan berdenyut. spt sakit gigi dan infeksi kuku, - nyeri pd rangsangan reseptor kulit disebut dgn; superficial somatic pain - pd rangsangan otot skeletal, sendi, tendon disebut; deep somatic pain

Jenis Nyeri:
- nyeri viseral; akibat rangsangan nosiseptor organ pd viseral spt distensi abdomen dan iskhemia organ internal. - zat kimia yg merangsang nyeri adalah bradikinin, serotonin, ion kalium, asetil kholine dan enzim proteolitik

Jaras rangkap penjalaran sinyal nyeri

Dua jaras penyaluran sinyal nyeri ke sistem saraf pusat Nyeri cepat dan tajam dirangsang oleh mekanik dan suhu. - disalurkan ke medula spinalis oleh serabut tipe A - kecepatan 6-10 m/detik. Nyeri lambat dirangsang secara kimia, mekanik dan suhu - disalurkan melalui saraf tipe C - kecepatan 0,5-2 m/dtk

There are Two Sensory Afferent Neurons

1. Large myelinated A fibers, very fast conduction velocity. Respond to innocuous stimuli 2. Small myelinated A & C unmyelinated fibers, have slow conduction velocity. Respond to noxious stimuli

Large A fibers

A Small fibers C Peripheral sensory Nerve fibers

Dorsal root ganglion

Dorsal Horn

Physiological Pain
NOXIOUS STIMULUS INNOCUOUS STIMULUS

C fiber

DHN

DHN
INNOCUOUS SENSATION

PAIN First Pain Second Pain

Touch Tactile Pressure

Jaras nyeri di MS dan batang otak

Dari kornu dorsalis menuju otak, sinyal nyeri disalurkan di MS melalui: Tr. Neo-spinotalamikus - untuk nyeri cepat berakhir di lamina I (lamina marginalis) kolumna anterolat. - sebgn berakhir di kompleks ventrobasal dan sebgn lagi di korteks somatosensorik

Jaras nyeri di MS dan batang otak

Tr. Paleo-spinotalamikus

- utk nyeri lambat dan khronik melalui saraf tipe C dan sebgn saraf tipe A - berakhir di lamina II dan III subs. Gelatinosa dan lamina V dan VII kornu dorsalis - Neurotransmiternya Subst. P dan Glutamat - Berakhir di tiga tempat Nc. Retikularis medula, pons dan mesensefalon Area tekt. mesensefalon dan kol. Sup dan Inf Subst. grisea peri akuadukt

Activation of Central Neurons

C-Fiber Terminal
Glutamate

Substance P AMPA
P

NMD A

(-)

Ca2+

(+) PKC

Dorsal Horn Neuron

(+)

Woolf CJ et al. Science. 2000;288:1765-8. Schwartzman RJ et al. Arch Neurol. 2001;58:1547-50.

1965 MELZACK and WALL Introduce Hypothesis of GATE CONTROL THEORY

Brain

GATE CONTROL SYSTEM A

+
SG -

DHN

ACTION SYSTEM

The beginning of MODULATION

Sistim Inhibisi Sensasi Nyeri

Reaksi seseorang terhadap nyeri bervariasi. Dipengaruhi otak melakukan inhibisi (sistem analgesia). Ada 3 komponen: 1. Area periakuadukt grisea dan periventr. mesensefalon., sinyal dikirim ke 2. Nukl. Raphe magnus dibawah pons diatas medula obl. Dan disalurkan ke 3. Kompleks penghambat rasa nyeri radiks dorsalis MS kemudian dipancarkan ke-otak

Sistim Inhibisi Sensasi Nyeri

Enkefalin disekresikan oleh nc. periventrik, area peri

akuadukt dan raphe magnus. menghambat pd pre dan post sinaps serabut nyeri tipe C dan A
Serotonin oleh radiks dorsalis MS menghambat pd pre-

sinaptik terhadap ion kasium.

Sistim Inhibisi Sensasi Nyeri

Sistim Opium Otak, Endorfin dan Enkefalin Morphin like subst. bekerja pd sebagian sistem analgesia. Ada 12 macam opium like subst di-otak Berasal dari pemecahan 3 mol. Protein, y.i proopiomelanokortin, pro-enkefalin dan pro-dinorfin. Bhn yg penting adalah -endorfin, met-enkefalin dan leu-endorfin.

Proses Sensasi Nyeri

Pd reseptor sensasi diseleksi dan di-olah jadi 4 tahap 1. Rangsangan reseptor sensorik - Hrs tepat dan adekuat hingga terjadi respons. 2. Transduksi stimulus. - terjadi pd kornu dorsalis MS (dikonversi) menjadi energi rangsangan (gradasi pot tergantung kuat rangsangan dan ampl

Proses Sensasi Nyeri

3. Membangkitkan impuls saraf. - Pd grad. potensial mencapai ambang tercetus 1 impuls atau lebih, kmdian menyebar ke pusat. 4. Integrasi input sensorik. Daerah tertentu di-otak akan menerima dan meng-integrasikan impuls sensorik dan diterima pd area tertentu di korteks

Diagnosis
Acute and chronic pain

Drug Treatment
NSAIDS (al Meloxicam/ Movi-cox), Opioids, Paracetamol

Myofascial pain dysfunction

Neuropathic pain, neuralgias

Analgesics (Movi-cox), tricyclics, centrally-acting muscle relaxants, glucocorticoids Carbamazepine, phenytoin, baclofen, tricyclics, gabapentin, others?

Targets of Pain Therapies

Pharmacotherapy
Non-opioid analgesics Opioid analgesics Nerve Blocks Adjuvant analgesics (neuropathic, musculoskeletal)

Acetaminofen

Electrical Stimulation
Transcutaneous electrical nerve stimulation (TENS) Percutaneous electrical nerve stimulation (PENS)

Alternative methods
(NSAID)
Gottschalk et al., 2001

Acupuncture Physical Therapy Chiropractics Surgery

Thick, myelinated, fast conducting neurons Mediate the feeling of initial fast, sharp, highly localized pain.

Very thin, unmyelinated, slowconducting Mediate slow, dull, more diffuse, often burning pain.

Rabaan Tekanan

Nerve Fibers
Class A- A- A- A- B C Velocity Fast Fast Intermediate Intermediate Small Small Function Motor
Touch, pressure Muscle tone Pain, temperature

Motor Pain

Chemical mediators are released from damaged tissue and inflammatory cells. Some inflammatory mediators directly activate nociceptors, while others act together to sensitize the pain pathway.

Inflammation
l biological response to injury or

foreign substances l acute and chronic inflammation l components:

cellular response biochemical mediators

Mechanisms of Inflammation Cellular Mechanisms:

Acute inflammation
PMN

Chronic inflammation
lymphocytes monocytes

Mechanisms of Inflammation
Biochemical Mediators
vasoactive amines
plasma proteases (complement, kinins) arachidonic acid metabolites (PG, LT) lysosomal constituents oxygen derived free radicals cytokines growth factors

Mediators of Inflammation
Arachidonic Acid Metabolites

Prostaglandins Leukotrienes

Generation of Eicosonoids
Phospholipids
Phospholipase

Arachidonic Acid
5-lipoxygenase cyclooxygenase

5-HPTE
peroxidase

PGG2 LTC4 PGH2

LTB4

TXA2 PGI2 PGE2 PGF2 PGD2

Biological Effects of Prostaglandins

PGE2 Vasodilatation, pain sensitization, gastric cytoprotection PGF2 Bronchoconstriction, uterine contraction PGI2 Inhibit platelet aggregation, gastric cytoprotection TxA2 Platelet aggregation

Roles of COX-1 and COX-2

Arachidonic acid COX-1 Constitutive COX-2

PGs PGs Inducible Constitutive

GI cytoprotection Platelet activity Renal function

Inflammation Pain Fever

Renal function

Non-COX selective inhibitors of cyclooxygenase

Selective COX-2 inhibitors

Leukotriene inhibitors

Non-COX Selective NSAIDs

l Carboxylic acids

[salicylates, meclofenamate, diflunisal] l Indoleacetic acids [indomethacin, sulindac] l Propionic acids [ibuprofen, fenoprofen, ketoprofen, flurbiprofen] l Naphthalene acetic acids [naproxen]

Non-COX Selective NSAIDs [contd]

l Diclofenac
l Etodolac l Nabumetone l Oxaprozin l Ketorolac

COX - 2 Inhibitors
l Celecoxib l Rofecoxib l Valdecoxib l Meloxicam (Movi-cox)*

*[less COX-2 selective]

Golongan Coxib

resiko kardiovaskuler + stroke

Physicians prescribing celecoxib or valdecoxib should consider the

emerging cautionary data "when weighing the benefits against risks for individual patients." The most appropriate candidates for coxib therapy are patients at a high risk of GI bleeding or who have a history of intolerance to "or are not doing well on" nonselective NSAIDs. "Individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation." Consumers should use all over-the-counter analgesics, "including NSAIDs," strictly according to the label instructions and consult a physician if using them for longer than 10 days.

Justification for the Development of COX-2 Selective Inhibitors

COX-2: A New Anti-inflammatory Drug Target
Arachidonic acid Glucocorticoids COX-1 (Constitutive) () NSAIDs Stomach Intestine Kidney Platelet Inflammatory site: Macrophages Synoviocytes Endothelial cells COX-2 (Inducible) ()

TARGET FOR A SPECIFIC COX-2 INHIBITOR

COX-2 Selectivity: Molecular Basis

NSAID Binding Clefts COX-1 COX-2

Chemical Structures of Oxicams and Coxibs

OXICAMS
Linear, enolic acid
CH3

COXIBS
Y-shaped, Tricyclic NH2 O O
N

Meloxicam

Celecoxib
N N

OH

O N H

S O

N CH3 O

CF3

H3C CH3 O S O
O
N H N

Piroxicam

OH

Rofecoxib

S N
O

CH3
O

COX-2 Selectivity
DRUG Rofecoxib Celecoxib Meloxicam Diclofenac Indomethacin COX-2 IC50/COX-1 IC50 .013 .080 .200 .170 1.500

Efficacy as an emerging concern of NSAID used

Potency (strong) Onset of action (rapid) Duration of action (long)

Efek samping minimal Harga terjangkau

Meloxicam (MOVI-COX) was approved recently by the FDA for use in osteoarthritis. The recommended dose for meloxicam is 7.5 to 15 mg once daily for osteoarthritis and 15 mg once daily for rheumatoid arthritis. Meloxicam demonstrates roughly tenfold COX-2 selectivity on average in ex vivo assays. However, this is quite variable, and a clinical advantage or hazard has yet to be established. There is significantly less gastric injury compared to piroxicam (20 mg/day) in subjects treated with 7.5 mg/day of meloxicam, but the advantage is lost with 15 mg/day
(Goodman & Gilman, 2006)

Potency of NSAID
milligram basis of active compound for each formula

potency

NSAID

mg/formula
7.5, 15 10, 20 25, 50, 75 100, 200 100 100, 200 500 500 500

strong Meloxicam Piroxicam Diclofenac moderate Celecoxib Nimesulide Ketorpofen weak Mefenamic acid Naproxen Nabumetone

Onset of action of NSAID

onset NSAID T-max (hr) Rapid Diclofenac 0.8 Nimesulide 1.2 2.7 Slow Celecoxib 24 Meloxicam 6

Duration of action of NSAID

duration NSAID short Diclofenac Nimesulide moderate Celecoxib Naproxen long Meloxicam Piroxicam T-1/2 (hr)
1.1 1.8 4.7 11 14 20 57

TOXICITY OF NSAIDs
Ototoxic Color blindness

Bronchospam

CHF

Hepatotoxic

UGIB Perdarahan GI Nephrotoxic

Bleeding

Allergy

Tocolytic

Mechanism of = Mechanism of therapeutic effects adverse effects

Table IV. Incidence of gastrointestinal (GI) adverse events

Drug exposure (days)
56 33

Treatment Placebo Meloxicam 7.5mg

No. of patients 736 10158

Patients/ byear 113 918

No. of GI adverse events

0 3

Percentage per 100 patients/year

0 0.3

Meloxicam 15mg
Meloxicam 22.5mg Diclofenac

2960
910 5464

179
241 35

1451
600 524

9
6 9

0.6
1 1.7

Naproxen

243

117

78

1.3

Efficacy and Tolerability of Meloxicam, a COX-2 Preferential Nonsteroidal Anti-Inflammatory Drug [Clin Drug Invest 22(12):799-818, 2002. 2002 Adis International Limited]

Kombinasi OAINS
Kombinasi 2 OAINS:
Tidak dianjurkan Efek samping meningkat Tidak menambah efikasi

Kombinasi OAINS dengan Pelindung Lambung:

Ditujukan untuk sedikit

Kombinasi OAINS dan Analgetik:

Masih dapat dipertanggungjawabkan

mengatasi masalah efek samping terhadap lambung. Dapat diberikan bersama golongan PPI, Misoprostol

Pain: A conceptual approach to treatment

(Biopsycosocial approach)
Cognitive therapies Functional restoration
Pain Behaviors Suffering

Anti-depressants / psychotropics
Relaxation Spiritual

Opioid

Pain Perception

Adjuvants
NSAIDs? Acetaminophene Neural augmentation
Nociception

Local block

NSAIDs (Movicox )
Surgery Physical modalities

Ablative surgery

1. Looser JD, Cousins MJ. Med J aust 1990;216: 153-208; 2. van den Hout JH, et al. Clin J Pain. 2003;19:87-96.; 3. Mynors-Wallis L, et al. Br J Psychiatry. 1997;170:113-119.; 4. Morley S, et al. Pain. 1999;80:1-13.

Anamnesa nyeri secara sistematik dan

teratur Berprasangka baik (percaya) terhadap keluhan pasien atau keluarga Carilah metode kontrol nyeri yang nyaman untuk pasien dan keluarga Dilakukan intervensi yang tepat waktunya, logis dan terkoordinasi Edukasi pasien dan keluarga untuk mengatasi nyeri sekuat mungkin