Manajemen Nyeri

dr Ratnawati, SpAn-KMN
 Antara stimulus noksius dan persepsi nyeri terdapat 5
proses yang jelas yaitu;  Nosisepsi (respons saraf terhadap Persepsio
stimulus noksius) n
1.Transduksi
2. Konduksi Neuron III
3. Modulasi Thalamus
4. Transmisi
5. Persepsi

Transduction

Mechanical Conduction
Transmissio
Action potential n
Modulation
Kornu Dorsalis Neuron II
Thermal

Neuron I
Transmission
Chemical

Modified by AHT
 Bagan Perjalanan mekanistik nyeri
5.Perception

1.Transduction 3.Modulation

2.Conduction
action potensial
4.Transmission
Mechanical

Thermal PAIN
Neuron I Neuron II Neuron III
Chemical
Thalamus
Nociceptors Cerebral Cortex
DHN

Modified by AHT
 Target Point of Analgesic Drugs
Ketamin
Paracetamol

Perception
Opioids
CNS Gabapentinoids
Clonidine

Corticosteroids
NSAIDs
Modulation Transduction COXIBs
Local Anesthetic

Transduction
DR
G

Transmission
Modulation
Local
anesthetics
COXIBs
Pathophysiology of Perioperative Pain
Peripheral
Inflamma Sensitizati 1. Primary
tory on hyperalgesia
of
“Soup”
Nocicepto
rs
Surgical Central
Sensitizati
Injury on 2. Secondary
Peripher of Dorsal Hyperalgesia
al Horn
Nerve
Injury Long-
(Acute Term
neurophatic pain) Potentiati
on

Plasticity of the NS

CHRONIC
PERSISTENT POST SURGICAL PAIN PAIN PPSP
 Mechanism of
Perioperative Pain
1. Peripheral
Sensititation It can a
(PRIMARY combination of
HYPERALGESIA)
nociceptive pain
& acute
neuropathic pain
2. Central Sensititation (nerve lesion or
(SECONDARY HYPERALGESIA) injury).
(promoted by nerve lesion or injury during surgery)
 We have only three kinds
ANALGESIC DRUGS

NON OPIOIDS ADJUVANTS

OPIOIDS
• Dexamethason
• Paracetamol • Mild Opioid • Ketamine
• NSAID ( codeine & tramadol ) • Pregabaline &
(nonselective) • Strong Opioid gabapentine
• Coxib (selective ( Morphine, Fentanyl, • Clonidine,
NSAID) Oxycodone, Remifentanil). Dexmedetomidine
• Lidocaine
 Concept of Multimodal
Analgesia
OPIOIDS  Improve
minimal dose (as rescue)
Analgesia
 Reduced
opioid
Potentiation
requirement
 Reduced
Adverse
Paracetamol effects of
Non selective NSAIDs opioid
Selective COXIB
Adjuvand Analgesic ERAS (Enhanced recovery after surgery)
nerve blocks 2019 Global Year against Pain in the Vulnerable

Kehlet dan Dahl. The Value of “Multimodal or

Balanced Analgesia” in Postoperative Pain
Treatment. Anesth Analg 1993;77:1048-56
 PREVENTIVE MULTIMODAL
ANALGESIA
Pra-Incision Intraoperative Postoperative

Preventive Multimodal Analgesia

Combination of NSAIDs, adjuvant
analgesic, regional anesthesia techniques,
and minimal opioid

 Perioperative stress response

 Dynamic Pain (on movement)

 Postoperative Recovery & Improve clinical conditions

 Opiate consumption

 Sides effect of analgesic

 Analgesic Drugs
Primary Secondary Hyperalgesia
- Opioid
Hyperalgesia - Ketamine
‒ Non selective ‒ Gabapentinoid
NSAIDs ‒ Pregabalin
‒ Selective NSAIDs ‒ Gabapentin
(COXIB) ‒ Alpha 2 agonist
- Clonidine
‒ Dexamethasone
- Dexmedetomidine
‒ Infiltration of LA or ‒ Systemic local
NB with LA Anesthetic
‒ Continuous Epidural
with LA
 1. Non Steroidal AntiInflammatory Drugs (NSAIDs)
 “Ceiling effect” to analgesia
 Do not produce tolerance or
physical dependence
 Exhibit antipyretic properties
 Use as adjuvant  in the
perioperative period to
minimize the adverse effects
of analgesic medications

Ref. 1
 Non Steroidal AntiInflammatory Drugs (NSAIDs)

• Ketorolac: 15-30 mg PO/IM/IV

• Diclofenac: 50-100 mg PO/IM/IV
• Ibuprofen: 300-800 mg PO
• Indomethacin: 25-50 mg PO/PR/IM
• Naproxen: 250-500 mg PO
• Celecoxib: 200-400 mg PO
• Rofecoxib: 25-50 mg PO
• Valdecoxib: 20-40 mg PO
• Parecoxib: 20-40 mg IV
 NSAIDs
Block the synthesis of prostaglandins by inhibiting
cyclooxygenase (COX) types I and II, thereby reducing
production of mediators of the acute inflammatory response
 NSAIDs
  Exhibit a spectrum of analgesic, anti-inflammatory,antiplatelet
and antipyretic by inhibition COX enzyme
 Most commonly prescribed analgesic medications in the
world. i.e. Metamizole, Ketorolac, Diclofenac, Ketoprofen
 Many used as the sole method of treatment mild to moderate
pain
 “Opioid sparing effect“ (20–40 %)
Adverse effect due to
Non-selective COX-1 and COX-2 inhibitor

ARACHIDONATE

COX-1 COX-2

prostaglandins prostaglandins

• “Constitutive” • “Inducible”
• Expressed: • Expressed:
– GI mucosa – Site of injury
– Kidneys – CNS
– Platelets
– Vascular
endothelium
 COX-2 Hypothesis (1990s)
Normal Tissue Inflammation Site
Cytokines
Arachidonic Acid + Growth factors

COX-1 COX-2
Constitutive Inducible

COX-2
NSAIDs
Inhibitors
Physiolgical Pathological
Prostaglandin Prostaglandin
Production Production

Normal Functions Inflammation, pain, fever

 Physiological Functions of Prostaglandins:
PGD2 :
 Inflammation
 Vasodilators (edema, erythema)
 Inhibit platelet aggregation

PGE2 :
Sensitize nerve endings to bradykinin, histamine and substane P
Vasodilators (edema, erythema)
Maintenance of renal blood flow
Fever
Keeps ductus arteriosus open following birth

PGI2 :
Sensitize nerve endings to bradykinin, histamine and substance P
Pain
Inflammation
Vasodilators (edema, erythema)
Protection of the gastric mucosa
Platelets

TXA2 stimulates platelet aggregation

 Acid & Pepsin
Prostaglandin &
LUMEN aluminium ion

HCO3 – Mucus
10% from acid pepsin
bicarb
barrier

Cells
Surface
phospholipids Mucosal prostaglandin
physical barrier

Mucus serves as: -

-a lubricant
Mucosal blood flow -retard diffusion of H+ and pepsin
-inhibits of pepsinogen activation
-antibacterial action
 Pharmacokinetics
 Rapid absorption - peak in 2 hours
 Weakly acidic and protein bound (90%)
 NSAIDS cross the blood brain barrier
 Hepatic metabolism and both renal and hepatic excretion
 Adverse Effects of NSAIDs
 More dangerous at therapeutic levels
 Effect many systems
 Longer acting agents are more dangerous -
phenylbutazone and piroxicam
 Indomethacin also found to be more harmful
 Side Effects
Gastrointestinal
 Direct harmful effect plus decreased prostaglandin
mediated protection
 2-5 times higher risk of bleeding than regular population
 Use with caution in people with history of ulcers or gastritis
 Avoid in alcoholics
 Side Effects
Renal System
 Range from mild changes in fluid and electrolytes to renal
insufficiency
 Increase sodium and water resorption
 May cause hyperkalemia
 Inhibit vasodilatation - causing Azotemia and renal
insufficiency - Stress related
 Interstitial nephritis and nephrotic syndrome
 Side Effects
Hepatic dysfunction
 Mild elevation in transaminases to fulminate failure
 Avoid in patients with underlying liver pathology
Hematologic
 Inhibit platelet aggregation, aplastic anemia (indometacin,
phenylbutazone), neutropenia and thrombocytopenia
(indometacin)
 Side Effects
CNS
 Cognitive difficulties, delirium, seizures, tinnitus (motrin and
naproxen) aseptic meningitis and visual disturbances
Pulmonary
 Hypersensitivity pneumonitis
 Bronchospasm- 8-20% of asthmatics and 23% of
asthmatics with nasal polyps
 Side Effects
Dermatologic
 Photo sensitivity , rashes, Stevens-Johnson
Pregnancy
 Cause premature constriction of ductus arteriosus -
pulmonary HTN
 CNS hemorrhage, oligohydramnios, renal dysfunction
mother - increased bleeding during labor
 Drug Interactions
Warfarin
 Naproxen and Phenylbutazone displace warfarin; others
increase risk of bleeding
 Antihypertensive agents and diuretics  Na and water
retention, change vascular tone and alter renin-angiotensin
system
 Inhibit prostaglandins lowering the effect of these drugs
 Drug Interactions
 Sulfonylureas- increase hypoglycemia
 Lithium - decreased clearance
 Digoxin - increased risk of toxicity
 Aminoglycosides- increased risk of toxicity
 Drug Interactions
 Sulfonylureas- increase hypoglycemia
 Lithium - decreased clearance
 Digoxin - increased risk of toxicity
 Aminoglycosides- increased risk of toxicity
 Selective COX-2 inhibitor

 COX-2 in peripheral and central nerve system

 As a part of multimodal analgesia
 Offer significant advantages over NsNSAIDS
with regard to several adverse effect ( not in
renal function )
 COXIB evidence
• Coxibs are effective in the treatment of acute
postoperative pain (N) (Level I [Cochrane
Review]).
• Coxibs were as effective as NsNSAIDs in the
management of postoperative pain (Romsing
& Moiniche, 2004 Level I).
• Preoperative coxibs reduced postoperative pain
and opioid consumption and increased patient
satisfaction (Straube et al, 2005 Level I)
How to choose safest NSAIDs?
 Cox-1 Selective Inhibitor vs Cox-2
Less GI side effects/ but CV AE
COXIB
More GI side effects
Diclofenac Celecoxib
Acetosal Indomethacin Ibuprofen
Meloxicam Rofecoxib
Ketorolac Piroxicam Ketoprofen
Nimesulide Valdecoxib

preferentially non- preferentially

COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

anti-inflammatory
analgesic
 Paracetamol
• Bio availability above 80%
• Peak plasma concentration occur between 15 mins
and 2 hours after ingestion
• Half-life:1-3 hours
• Time to peak concentration: 10-60 min
• Treatment for overdose: →Acetylcystein (mucomyst)
 Paracetamol Site of Action

Acetaminophen ?

Paracetamol = Acetaminophen
N-Acetyl-P-Aminophenol
(APAP)
 Peripheral vs Central effect
 Selective inhibition of COX in CNS support
hypothesis PCT does not possess anti-
inflammatory efficacy similar to NSAIDs
 Not associated with gastric side effect and
inhibition platelet activity
 COX-3 , unlikely to be the elusive target of
PCT in human tissues
 Interaction with endogenous opioid pathway,
serotoninergic and NOS system
 Self-synergistic interaction between spinal dan
supraspinal
 Activation of descending opioid pathways
 Centrally acting component of paracetamol
involves serotoninergic inhibitory descending
pathway
 Inhibitory nitric oxyde synthase ( NOS ) via
inhibited substance P-mediated hyperalgesia
 Plasma concentration
 Minimum plasma concentration for analgesia
and anti-pyresis 10-20 mg/L
 Potential hepatotoxicity 150 mg/L
 Median dose that will developed acute liver
failure is 24 grams

Intravenous 15 mg/kg  7 mg/L and detectable in CSS

at 5 minutes
Intravenous 1 gr  14.4 mg/L in 20 minutes
Oral 1 gr  large and unpredictable variability
( subtherapeutic plasma conc. in 80 min )
Pain relief after IV and Orally

Moller, S. Sindet P. British Journal of Anaesthesia 2005 ; 94 (5): 642–8

 Intravenous Paracetamol
 Faster onset analgesia
 Predictable plasma concentration achieved
 Route of choice when oral administration no
possible
 IV paracetamol was an effective analgesic after
surgery ( Level II, Acute Pain Management: Scientific Evidence, 3 edition, ANZCA,
rd

2010 )
 Safety and toxicity profile
 Safer than NSAIDs
 Small minority  life threatening liver injury
 Toxic metabolite N-acetyl-pbenzoquinine imine
(NAFQI)
 Paracetamol overdoses significant cause toxicity
• Suicide attempts
• Unintentional overdoses
 Risk factor PCT-induced hepatotoxicity
 Excessive dosing
 Increased P-450 activation
 Decreased gluthatione availability
 Chronic severe ethanol abuse
The Metabolism of Acetaminophen and
NAPQI production

N Engl J Med. 2008 July 17; 359(3): 285–292.

PCT, NSAIDs, COXIBs

J Can Dent Assoc 2002; 68(8):476-82

 Lidocaine Intravena
 Lidokain adalah anestesi lokal amida dimana pada
tahun 1951 Gilbert dkk. menerbitkan laporan
bahwa lidokain intravena aman dan efektif dalam
mengurangi nyeri yang resisten terhadap opioid
 Lidokain intravena dapat meningkatkan waktu
permintaan analgesik paska operasi
 Infus lidokain intravena merupakan bagian efektif
dari strategi hemat opioid yang berguna dalam
regimen antiemetik multimodal
 Dosis 1.0–1,5 mg/kg iv, 1 jam sebelum insisi.
 2. Opioids in Perioperative Pain
Management
 Opioid is really very good and effective in post
operative pain management.
 Opioid is golden standard for acute pain
 BUT :
It has significant adverse effects
 Respiratory depression
 Nausea and Vomiting
 Constipation and urinary retention
 Ileus
 Sedation, drowsiness, confusion.
 Pruritus
 Can delay hospital discharge
 Opioid
 The most effective analgesics are the opioid
analgesics
 The opioids  interact with opioid receptors in the
nervous system
 These receptors are the sites of action for the
endorphins, compounds that already exist in the body
 also site of action for the external opioid drugs
 Pharmakokinetics of this specific drugs also
influence its efficacy
Analgesic Effects at Opioid Receptors.

in the limbic and other diencephalic

areas, brain stem, and spinal cord
in the brainstem and medial
thalamus
 Potential problem in  Opioid Therapy
 Opioid induced hyperalgesia : hyperalgesia syndrome
occur following effective opioid administration  the
phenomenon of pharmacological tolerance or may be
mediated through mechanism :
• Central glutamatergic mechanism
• Increase in the synthesis of excitatory neuropeptides such as
dynorphine
• Descending facilitatory mechanism arising in the medula
 Medication overuse headache
 Conclusions
 Opioid  are important drugs used in the pain
management
 Employ appropriate pharmacological choice
by knowing the pharmacology of the drugs
 both pharmacodynamic &
pharmacokinetics
 Provide optimal effect and minimize side
effects
 3. Analgesik Adjuvan
 Analgesik adjuvan adalah obat yang mempunyai sifat
analgesik lemah atau tidak ada sifat analgesik sama sekali
apabila diberikan sendiri, namun dapat meningkatkan efek
agen analgesik lain.

 Obat ini dapat dikombinasikan dengan analgesik primer

sesuai dengan sistem WHO Analgesik Ladder untuk
mengurangi rasa nyeri.

 Sebagian analgesik adjuvant mempunyai efek yang bagus pada

beberapa situasi nyeri tertentu sehingga diberikan nama
multipurpose adjuvant analgesics
 3.1 Kortikosteroid
 Glukokortikoid yang sering digunakan untuk penanganan nyeri
somatik yang tidak berespon terhadap opioid, hipersensitif
terhadap NSAIDs, kompresi pada saraf dan kompresi pada cord
 Glukokortikoid dapat diberikan secara topikal, oral, atau
parenteral
 Waktu paruh panjang (>36 jam), diberikan sekali sehari
 Bersifat minimal mineralocorticoid
 Dosis efektif 2–20 mg/hari
 Pencegahan mual dan muntah (4-5mg IV)
 Anti inflamasi
 Anti-edema
 Dosis terapi untuk nyeri paska bedah dan untuk mengurangi
penggunaan opioid ( >0,1mg/kgBB)
 Kortikosteroid
 Now widely used in anesthetic practice to
prevent PONV, has analgesic effect in
moderate dose 0,11-0,2 mg/kg BW.
improve recovery,
reduce fatigue,
release endorphin
 Hyperglycemia may be seen but this is
likely little clinical significant
 No difference in wound healing & infection
with control groups
 3.3.Ketamine (NMDA Antagonists)
 Ketamine is a non competitive antagonist of NMDA
receptor when used in sub-anesthetic dose.
 Low dose Ketamine around 0,1 mg/kg/ bolus follow
up 0.1 mg/Kg/h drips with resulting
 improved analgesia
 Reduction of opioid side effect.
 Reduced PONV
 A meta-analysis shows a reduction of chronic
postsurgical pain at 3-6 months, If Ketamine is
administered for more than 24 hours
preoperatively.
 Particular Benefits of Ketamine
1. After major surgeries that are suffering severe
pain (VAS >7/10) such as
 Thoracic surgery
 Upper abdominal surgery
 Major orthopedic surgery
2. Ketamine reduces development of opioid
induced hyperalgesia (after remifentanil use)
3. Ketamine is also a useful analgesic for
patients with opioid tolerance
 Ketamine
 Low-dose ketamine is not really an ‘analgesic’,
but better described as:

 ‘anti-hyperalgesic’
 ‘anti-allodynic’
 ‘tolerance-protective’
  Opioid-induced Hyperalgesia
 3.4. Antikonvulsan
 Beberapa guidelines dan systematic review menyatakan
bahwa analgetik adjuvant yaitu antikonvulsan merupakan
terapi lini pertama untuk terapi nyeri neuropatik.

 Gabapentin dan pregabalin merupakan lini pertama untuk

nyeri neuropatik post herpetik dan neuropati diabetes.

 Sedangkan carbamazepine digunakan sebagai lini

pertama untuk kasus neuralgia trigeminal.
 GABA
(Gama-Amino Butiric Acid is an amino acid)

GABA is the major inhibitory neuro-transmitter

in the central nervous system (CNS), with most
neuron undergoing GABA ergic modulation
 Gabapentinoid (Alpha-2 delta ligands)

 Two important drugs e.g. pregabalin and gabapentin

developed for neuropathic pain.
 Shown to have an effect on central sensitization  indicated
the use for postoperative pain as anti nociseptive..
 From meta-analysis supporting their role as a component of
Multimodal Analgesia;
 reduced pain score
 reduced opioid consumption.
 reduced adverse effect of opioid.
(This can be achieved by a single preoperative dose 1 hour before
induction orally).
 Additional beneficial is anxiolytic, make patients calm after
surgery.
 Mekanisme Analgesik
Pregabalin
 Mengikat α2 -δ subunit presynaptic, voltage-
dependent saluran kalsium yang
didistribusikan secara luas di seluruh sistem
saraf pusat dan perifer. Pregabalin mengikat
ke α2 -δ subunit enam kali lebih kuat
daripada gabapentin dan dengan demikian
mengurangi pelepasan beberapa
neurotransmiter
Keuntungan :
• Efektif nyeri post-
stroke atau nyeri
neuropatik perifer.
• Efektif untuk nyeri
kronik termasuk
nyeri
muskuloskeletal,
nyeri leher,
fibromyalgia, dan
tension type
headache.
Dosis 300-3600
• Efek samping : mg/24 jam
• Sedasi
• Light headache
• Dizziness
 GABA Agents

Drug Class Recommended Maximum

Medication T 1/2
and Uses Starting Dose Daily Dose

Anticonvulsant Gabapentin 100-300 mg PO 3,600 mg PO 5-7 hour

(various NP daily /day in 3
types) divided doses
Pregabalin 25-75 mg PO 600 mg PO 12 hour
twice daily per day in 3
divided doses
 3.4.Alpha-2 agonist
 Alpha 2 agonist  used to be panic disorder treatment &
hypertension.
clonidine ( 2 : 1 = 200 : 1)
dexmedetomidine ( 2 : 1 = 1600 : 1)

 These drugs also fulfill the criteria for successful

multimodal analgesia (analgesia, sedation & relaxation).
Potential adverse effect such as
 Hypotension
 Bradycardia
 Sedation
 Clonidine ( Alpha 2 agonist)
 It has been using as antihypertensive drug for long time.
 It has analgesic effect when give centrally, such as:
- spinal analgesia
- epidural analgesia
 Clonidine can selectively blocking conduction of A delta and
C fiber.
 1µ/kg BW clonidine given perioperatively is well
tolerated and little effect of: - hypotesion
- bradycardia
- SEDATION
 Compare to dexmetomidine, dexmetomidine more selective
for alpha-2 receptors and short duration.
 Dexmedetomidine (Alpha 2 Agonist)
• α2 receptor agonist with analgesic and sedative effects.
• At rate of 0.2 to 0.7 μg/kg/min, the drug blunts central
sympathetic responses, and produces CNS depression.
• Lessens opioid-related muscle rigidity, decreases
postoperative shivering, and produces minimal
respiratory depression.
• Adverse effects such as hypotension and bradycardia
 Dexmedetomidine Dose

Intravenous
• Initial 1.0 μg/kg for 10 min + continuous infusion of 0.7 μg/kg/h
approximately 15 min before the induction  effective treatment option for
preventing or attenuating opioid-induced hyperalgesia 1
• Epidural
• 15 mL of 0.5% isobaric bupivacaine 1 μg/kg2 provided better results
compared to 15 mL of 0.5% isobaric bupivacaine with 2 μg/kg clonidine in
patients undergoing lower limb orthopedic surgery. 2
• Intrathecal
• 15 mg of 0.5% isobaric bupivacaine with 5 μg of dexmedetomidine provided
provide compared to bupivacaine alone, in patients undergoing infraumbilical
surgeries.3

1. Lee C, Kim YD, Kim JN. Antihyperalgesic effects of dexmedetomidine on high-dose remifentanil-induced hyperalgesia. Korean J Anesthesiol. 2013;64(4):301–307.
2. Shaikh SI, Mahesh SB. The efficacy and safety of epidural dexmedetomidine and clonidine with bupivacaine in patients undergoing lower limb orthopedic surgeries. J Anaesthesiol Clin
Pharmacol.2016;32(2):203–209.
3. Shaikh SI, Mahesh SB. The efficacy and safety of epidural dexmedetomidine and clonidine with bupivacaine in patients undergoing lower limb orthopedic surgeries. J Anaesthesiol Clin
Pharmacol.2016;32(2):203–209.
TERIMAKASIH