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ANALGESIC

Opioid dan non-opioid


• An unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or
described in terms of such damage (IASP, 1994)

 A protective mechanism to warn of damage or the


presence of disease
 Part of the normal healing process

PAIN definition
Noxious
Stimulus
Stimulus nyeri yang
disebabkan oleh :
• Kimia
• Mekanik
• Termal
• Panas (>42̊ C)
• Dingin (<10̊ C)

3
Klasifikasi  berdasarkan lama nyeri
Klasifikasi  berdasarkan asalnya
Pain pathway
TATA LAKSANA TERAPI
• Menghilangkan rasa nyeri
• Membuat perasaan lebih nyaman
• Dapat beraktivitas secara normal
• Meningkatkan kualitas hidup

Tujuan Terapi
Pharmacotherapy
1. Non-opioid analgesics
2. Opioid analgesics
3. Adjuvant analgesics
LA = Local anesthetic
ASA = Asetil salysilic acid
TCA = Tricyclic Antidepressant
SSRI = Selective serotonin reuptake inhibitor
SNRI = Selective norepinephrine reutake inhibitor

Target Terapi
PAIN SCALE
 adjuvan

 non-opioid  adjuvan

 non-opioid  adjuvan
NON-OPIOID ANALGESIC
(NSAID, asetaminophen)
• Analgesik
1

• Antipiretik
2

• Antiinflamasi
3 (kec.parasetamol)

Pharmacology Effects
• depression of cyclooxygenases activity
• decreasing of prostaglandins synthesis in peripheral
tissues and in central nervous system
• decreasing of sensitivity of nervous endings and
depression of transmission of nociceptive impulses
on the level of CNS structures
• pain-relieving action of non-opioid analgesics is
partly connected with their anti-inflammatory
activity

Mechanism of action of non-opioid


analgesics
potency NSAID mg/formula
strong Meloxicam 7.5, 15
Piroxicam 10, 20
Diclofenac 25, 50, 75
moderate Celecoxib 100, 200
Nimesulide 100
Ibuprofen 200, 400
weak Mefenamic acid 500
Naproxen 500
Asetaminofen 500

Potency of NSAID
onset NSAID T-max (hr)
Rapid Diclofenac 0.8
Nimesulide 1.2 – 2.7
Slow Celecoxib 2–4
Meloxicam 6

duration NSAID T-1/2 (hr)


short Diclofenac 1.1
Nimesulide 1.8 – 4.7
moderate Celecoxib 11
Naproxen 14
long Meloxicam 20
Piroxicam 57

Onset & duration of action of NSAID


Asetaminofen

• Acetaminophen (paracetamol (PCT) ; N-acetyl-p-aminophenol;


TYLENOL, others) is the active metabolite of phenacetin
• a weak COX-1 and COX-2 inhibitor, PCT may inhibit a third
enzyme, COX-3, in the central nervous system (COX-3
appears to be a splice variant product of the COX-1 gene)
• Indikasi
• Mempunyai efek analgesik dan antipiretik yang setara dengan
asetosal, namun efek anti-inflamasinya rendah
• Digunakan untuk pasien yang kontraindikasi dengan aspirin (cth : pasien
dengan keluhan saluran cerna, hipersensitivitas thd asetosal)
• Antipiretik pilihan untuk anak-anak
Differences between NSAIDs
and Acetaminophen
Asetaminofen

• Dosis : Acute pain and fever may be effectively treated with


325-500 mg four times daily and proportionately less for
children
• Farmakokinetik :
• Cepat dan sempurna diabsorbsi dari saluran cerna
• T ½ plasma = 1-3 jam
• Mengalami metabolisme oleh enzim mikrosomal hati menjadi bentuk
glukoronida dan metabolit sulfat yang tidak aktif
• Sebagian asetaminofen dihidroksilasi menjadi N-asetil
benzoquinomeinin (NAPQI) yang toksik terhadap ginjal dan hati. Pada
dosis normal NAPQI bereaksi dengan grup sulfhidril glutation
membentuk substansi nontoksik
Asetaminofen

• Efek samping
• Pada dosis terapi normal bebas dari efek samping bermakna
• Kemerahan pada kulit dan reaksi alergi yang lain sering terjadi
• Penggunaan dosis besar jangka lama dapat menyebabkan nekrosis
tubular ginjal dan nekrosis hati
• Hepatotoksik
• In adults, hepatotoxicity may occur after ingestion of a single dose of 10
to 15 g (150 to 250 mg/kg) of acetaminophen; doses of 20 to 25 g or
more are potentially fatal  Symptoms occur during the first 2 days of
acute poisoning by acetaminophen reflect gastric distress (nausea,
abdominal pain, and anorexia)
OPIOID ANALGESIC
Opioid Receptors
• Group of G-protein coupled receptors with opioids as
ligands.
• Subtypes of opiod receptors:
mu, delta, kappa, epsilon, sigma

Endogenous ligands Exogenous ligands


• dynorphins • Drugs
• enkephalins
• endorphins
• endomorphins
• nociceptin
Opiod Receptor Activation

Response Mu-1 Mu-2 Kappa Delta Sigma


Analgesia    
Respiratory 
depression
Euphoria  
Dysphoria 
Decrease GI motility 

Physical Dependence 

Mania, hallucination 
• Opium is extracted from poppy seeds (Papaver
somniforum)
• Used for thousands of years to produce:
• Euphoria
• Analgesia
• Sedation
• Relief from diarrhea
• Cough suppression

History of Opioids
Morpheus
is the Greek god of
dreams and sleep.

Friedrich Wilhelm Adam


Sertürner,
 a German
pharmacist, isolated
Morphine from opium,
in 1805.
Available Opioids
Natural Semi-Synthetic Fully Synthetic
• Morphine • Hydromorphone • Pethidine
• Codeine • Oxycodone (meperidine)
• Diacetylmorphine • Tramadol
(heroin) • Nalbuphine
• Naloxone • Methadone
(antagonist) • Pentazocine
• Fentanyl
• Alfentanil
Opioids on the WHO essential drug list • Sufentanil
• Morphine • Remifentanil
• Codeine
• Pethidine
• Oxycodone
• Tramadol
Opioids can be classified as:
• Strong opioids used for severe pain
• Morphine, Oxycodone, Pethidine, Fentanyl

• Weak Opioids used for moderate pain


• Codeine, Tramadol
1. Agonists of opioid receptors – morphine
hydrochloride, promedol, omnopon, fentanyl, codeine;
2. Agonists – antagonists or partial agonists of opioid
receptors – pentazocin, buprenorphine
3. Antagonist – Nalokson (no analgesic effect)

Classification
Tolerance and
Dependence
Depressant effects Stimulate effects
• Sedation  Analgesia • CTZ (nausea, vomiting)
• Indifference to surroundings
• Edinger Wesphal nucleus
• Mood and subjective effects
• Depression of respiration (III nerve –producing
• Cough centre miosis)
• Vasomotor centre  dilatation • Vagal centre
• Decrease GI motility  (bradycardia)
constipation
• Urine retention

1. Morphine
MORPHINE HYDROCHLORIDE
routes of administration
 subcutaneously and intramuscularly
(analgesic action after 10-15 min)
 oral administration – presystemic elimination
( 20-60 % enters general blood circulation)
 sublingually – quick absorption
 i.v. is indicated even in emergency
 Epidural or intrathecal ( into the spinal canal ) injection
produces segmental analgesia lasting 12 hours without
affecting other sensory, motor or autonomic modalities
Duration of analgesic action – 4-6 hours
Maximum single dose of morphine is 0,02 g,
maximum daily dose – 0,05 g
2. Fentanyl
• synthetic opioid analgesic of short action
• analgesic activity is 300 times higher than of morphine
• analgesic effect after intravenous introduction – after 1-3
min, lasts for 15-30 min
• Transdermal route: should be used for long-term (chronic)
pain requiring continuous narcotic pain
• Is designed to release the drug into the skin at a constant rate
ranging from 25 to 100 micrograms/h,
3. Codeine
 opium alkaloid
 analgesic action is not strong, but anticough effect is
considerable
 administered as an anticough drug of central action
 combination with non opiod analgesics
(eg. Paracetamol) is supra-additive
• Central analgesic
• Terikat pada reseptor N opiat dan secara lemah
menghambat reuptake norepinefrin dan serotonin
• ESO = opioid lain, tetapi potensi depresi pernafasan <<
• Digunakan untuk nyeri kronis (neuropati), bukan akut.

4. Tramadol
• Terapi tambahan bukan analgesik, tetapi dapat
meningkatkan respon terhadap analgesik
• Contoh:
• Antidepresan, misal: gol. Amin trisiklik/TCA (amitriptilin,
imipramin), Inhibitor MAO, SSRI, SNRI
• Antikonnvulsan, misal : phenobarbital, diazepam
• Anestesi lokal, misal: lidokain

Adjuvan Analgesic
AAFP, 2013