Essentials on

Acute Pain
Management
Prof. dr. KRT Lucas Meliala, Sp.KJ,
Sp.S(K)
Curriculum Vitae
Nama : Prof. Dr. KRT. Lucas Meliala, SpKJ, SpS(K) Pendidikan :  Lulus Dokter tahun 1969,
Tempat/tanggal lahir : Membang Muda (Sumut), 22 September 1941 alumnus FK-UGM
Alamat : Jl. Nagan Lor 70, Jogjakarta  Lulus Spesialis Saraf & Jiwa tahun 1974
Telepon : (0274) 450758 alumnus FK-UI, FK-UGM, FK Unair
Fax. : (0274) 374052
Mobile : 0815 687 0584 Pekerjaan :  Staf Fakultas Kedokteran UGM
E-mail : lucasmeliala@yahoo.com bagian IP Saraf dan Jiwa sejak
tahun 1968 sampai sekarang

Organisasi :  Anggota IASP, ENS, IPS dan pokdi nyeri

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

”Pain is perfect misery, the worst of all evils, and, if excessive,

overturns all patience.”
(1667, Paradise Lost, by John Milton)
Pain is an event of
the nervous
system
 PAIN – SERIES OF EVENTS
PERCEPTION

PAIN

MODULATION

TRANSMISSION

TRANSDUCTION
 CURRENT SNAPSHOT ON
PAIN PATIENTS PROFILE IN
INDONESIA : RESULT OF
PAIN SURVEY
By date June 11st , 2011 – Dec 31st, 2012:
1919 patients, MDs: 70 Neurologists
Participating Countries : Indonesia
 SUMMARY
Most of patients suffer moderate to severe pain, but they
are currently treated by ladder 1 analgesic
 Pain is undertreated
Most of patients suffer pain for more than one week
Most of patients with pain are > 40 years old and have
concomitant disease
Older patients relatively have more severe pain, longer
duration of pain, and more risk factors
Physicians should consider patient’s demographic profile
in selecting appropriate analgesics, especially for
patient with risk factors.

7
 The WHO Analgesic Ladder
Hydromorphone
WHO Very severe
Step III Morphine
Oxycodone
Severe Fentanyl
Buprenorphine
Pain intensitiy

Tramadol
Tilidine

Drugs
WHO Codein
Step II Moderate Dextropropoxyphene
NSAIDs
COX II inhibitors

WHO Acetylsalicylic acid

Step I Mild Acetaminophene

Langford, 2002; Proceeding of the Grünenthal symposium

MEKANISME PROTEKSI NYERI SPASME OTOT

C Descending influences
Spinothalamic Joint receptor (nociceptor)
tract
II-IV

B Joint dysfunction
III-IV or pain
I Ia

α Nociceptor
γ
α-Motoaxon A Muscle pain

γ-Motoaxon
NOPAIN
PAIN
Muscle spindle

Eperison
Pain is a complex interaction that involves :
1.Cognitive
2.Emotional
3.Behavioral
Nyeri  multidimensional
1. Sensory discriminative
 Menggambarkan kemampuan penderita menceritakan dari
mana asalnya nyeri.
 Seperti apa nyerinya: panas, cekot2, dll.
 Berat ringannya nyeri.

2. Cognitive dimension
 Kemampuan membanding nyeri sekarang dan masa lalu.
3. Affective or emotional dimension
 Kemampuan penderita menggambarkan nyeri
seperti tidak menyenangkan, menderita sekali,
mengganggu dalam bekerja, dll.

4. Motivational Behaviour
 Menyebabkan penderita mencari pertolongan,
withdrawal reflex, dan escape behaviour.

Nyeri bukan sensasi tunggal, tapi punya

banyak dimensi  tidak ada satu obat
yang mampu mengobati semua jenis nyeri
CENTRAL PATHWAYS
FOR DISCRIMINATIVE
ASPECTS OF PAIN
AND TEMPERATURE
SENSATIONS

Spinothalamic Trigeminal
system from system
body from face

Convey information
about location,
intensity and quality
of stimulus. Project
to ventral posterior
nucleus of
thalamus. Then to
SI and SII.

Purves et al. 2004. Neuroscience. 3rd ed. Sinauer Assoc

 AFFECTIVE-MOTIVATIONAL
PAIN PATHWAYS.

Nociceptive information conveying

the unpleasant quality of pain is
mediated by projections to the
reticular formation and the
intralaminar nuclei of the thalamus
Changes in pain intensity are
accompanied by changes in activity
of neurons in somatosensory
cortex. Changes in pain
unpleasantness are accompanied by
changes in activity of neurons in
cingulate cortex

Purves et al. 2004. Neuroscience. 3rd ed. Sinauer Assoc

Anger Anxiety

Fear
Depression
A

NOCICEPTIVE

Noxious Stimuli MELIALA, 2004

CATEGORIZATION OF PAIN
CONDITIONS
Central Pain Amplification
Nociceptive Pain Neuropathic Pain Inflammatory Pain

(ie, Burn) (ie, Herpes zoster) (ie, Rheumatoid arthritis) (ie, Fibromyalgia)

Noxious stimuli Neuronal damage Inflammation Abnormal pain processing by

CNS

Acute Pain Chronic Pain

Courtesy of Woolf C. Ann Intern Med. 2004;140:441-451.
16
 MECHANISTIC CHARACTERIZATION OF
PAIN
PERIPHERAL
Peripheral C E N T R A L
N E U RO P H AT I C O R
(NOCICEPTIVE “ C E N T R A L I Z E D ”
) (neurophatic) PA I N

• Inflamation or • Damage or Characterized by central

disturbance in pain
mechanical dysfuntion of
processing (diffuse
damage in tissues peripheral nerves hyperalgesia/allodynia
)
• NSAID, opioid • Respond to both
responsive peripheral and
Responsive to neuroactive
centrally acting compounds altering
• Responds to pharmacological levels of
procedures therapies neurotransmitters
involved in pain
transmission
• Classic examples • Classic examples
 Osteoarthritis  Diabetic Classis examples
 Rheumatoid neuropatic  Fibromyalgia
arthritis pain  Irritable bowel syndrome
 Cancer pain  Postherpetic  TMJD
 Tension headache
Clauw, DJ. 2014 neuralgia
 Na+
myelin

Aα K+

Spinal
Aδ Cord

C Peripheral
nerve

Modifikasi Meliala, 2003

myelin Na+ K+ Na++

Node of
K+
Ranvier
Aઠ K+ K+

K+ Na+ K+ +
Na Na+
+ Na
+NaNa Na
+ +
Na++ Na +
Na
+
Na +
Na Na +
Na+ Na
+

K+ K+
K+ K+
C K+ K+
K+ K+ K+ K+ K+
K+ K+ K+

Modifikasi Meliala, 2003

 Ca2+

K+ K+

Na+

1. Transduction 3. Propagation
2. Spike Initiation 4. Transmitter Release

Modified Meliala, 2006

 NOCICEPTIVE PAIN
Noxius Pheripheral Stimuli
Pain
Heat Autonomic Response
Witdrawal Reflex
Cold
Brain

Intense
Mechanical
Nociceptor sensory neuron
Force

Heat

Spinal cord
Cold

Modifikasi Meliala, 2005

 INFLAMMATORY PAIN
Spontaneous Pain
Inflammation Pain Hypersensitivity
Macrophage Reduced Threshold : Aliodyna
Increased Response : Hyperalgesia
Mast Cell

Neutrophil
Granulocyte
Brain

Nociceptor sensory neuron

Tissue Damage

Spinal cord

Modifikasi Meliala, 2005

 NEUROPATHIC PAIN

Spontaneous Pain
Pain Hypersensitivity

Brain

Peripheral Nerve
Damage

Spinal cord Injury

Modifikasi Meliala, 2005

 FUNCTIONAL PAIN
Spontaneous Pain
Pain Hypersensitivity

Brain

Normal Peripheral
Tissue and Nerves

Abnormal Central
Processing

Modifikasi Meliala, 2005

 NORMAL TRANSMISSION KERUSAKAN JARINGAN

MODEL 1 - NORMAL TRANSMISSION INFLAMASI

INNOCOUS OR NOXIOUS STIMULATION
SENSITISASI
SSA MI Pg NOS
Si-Na+
Afferent Input B AKTIFASI
ECT. DISC. 5HT
R-NE Adenosin
Pengalaman KORNU DORSALIS
Kognitif Inhibisi
Behaviour desenden
Psikologik OTAK

PAIN – NO PAIN

SP GluTAMATE

Ca2+

AMPA NK1

Postsyneptic activity

Normal Sensibility
Doubell et al., 1999
Modifikasi Meliala, 2003
 FASCILITATED TRANSMISSION KERUSAKAN JARINGAN
Increased excitation/reduced inhibition
INFLAMASI

SENSITISASI
Afferent Input SSA MI Pg NOS
Si-Na+
B AKTIFASI
ECT. DISC. 5HT
R-NE Adenosin
Pengalaman KORNU DORSALIS
Kognitif Inhibisi
Behaviour desenden
Psikologik OTAK
ATP
Ca2+
Ca2+ PAIN – NO PAIN
P2X3 VSCC GABA Adenocine
Presynaptic NMDA Reduced
MOR Presynaptic
Augmentation Mg2+
SP GDNF GLUTAMATE SHT inhibition
mGluR

Increased transmitter release

Ca2+ Retrograde signale e.g.NO
Ca2+
Ca2+ Reduced
VSCC AMPA NMDA TrkB GABA MOR SHT Postsynaptic
Postsynaptic
NK1 Mg2+ inhibition
facilitation
mGluR S/T
Tyr

PKC Brc GLYCINE

Ca2+
PLC Postsyneptic activity

Reduced Sensibility Doubell et al., 1999

Modifikasi Meliala, 2003
 KERUSAKAN JARINGAN
SUPRESSED TRANSMISSION
INFLAMASI
MODEL 2 – Supressed Transmission
Activation of segmental and descending inhibitory syste
SENSITISASI
SSA MI Pg NOS
Si-Na+ Afferent Input
B AKTIFASI
ECT. DISC. 5HT
R-NE Adenosin
Pengalaman KORNU DORSALIS
Kognitif Inhibisi
Behaviour desenden
Psikologik OTAK
Presynaptic
PAIN – NO PAIN
MOR GABA
SHT Adenocine

SP GluTAMATE Gly

Postsynaptic
Ca2+

NK1 AMPA MCR

GABA SHT GLYCINE
Postsyneptic activity

Reduced Sensibility
Doubell et al., 1999
Modifikasi Meliala, 2003
 KERUSAKAN JARINGAN

Modification : altered conectivity and cell death INFLAMASI

SENSITISASI
SSA MI Pg NOS
Si-Na+
B AKTIFASI
ECT. DISC. 5HT
R-NE Adenosin

C-fiber terminal
KORNU DORSALIS
Pengalaman
Kognitif
Behaviour
Inhibisi
desenden
DISINHIBITION
Psikologik OTAK
Sprouted Aβ fiber Gl PAIN – NO PAIN

terminal u
µ GABA B
adenosine
Glu SP
P2X
NMDA Inhibitory
Ca2+ Ca2+ Interneuron
Gl Cell death
Substance P Mg2+
BDNF
u GABA B
NK1 Ca2+ PGE2
PGE2
Adenosine
Src Ca2+ Na2+ 2+
mGluR TrkB Ca2+ Na 2+Ca Ca2+
µ

KK++ VGCC EP NSC AMPA NMDA GABA-A GLY

IP3 PKC K++
K
KAI
COX2
PGE2
PGE2
PGE2
Woolf & Mitchel, 2001
Induction Modifikasi Meliala, 2003
 DESCENDING INHIBITION
BRAIN DESCENDENS

5HT

ENK
AFFEREN

SP-GLUTAMAT
NEURON TRANSMISI

Kornu Dorsalis

Meliala, 2005
NYERI AKUT Simptom

NYERI KRONIK Disease

Sign : Simptom :
• Merengut • Ansietas
• Postur abnormal • Depresi
• Doctor shopping • Gangguan tidur
• Dll • Marah, dll
 Interaction of Neurons, Astocytes and Microglia Participate in the
Development and Persistance of Chronic Pain

MICROGLIA

PAIN

NEURON
ASTROGLIA

Mika,J;et al : Importance of Glial

Activation in Neuropathic Pain
Eur J Pharmacol (2013)
 ACUTE PAIN
Generally sudden onset
– Certainly recent onset
– Usually has an obvious identifiable cause
• Injury/disease/iatrogenic (eg, surgery)
• Short duration (<1 month)
• Intensity generally variable and indicative of
severity of underlying condition or situation
– Characteristic symptoms
• Redness, swelling, throbbing
– Characteristic behaviors
• Rubbing, moaning, crying, etc
ACUTE PAIN
 ACUTE PAIN MECHANISMS

Postoperative pain similar to trauma

Varies according to:

– Intensity
– Quality
– Duration of stimulus

Involves activation of peripheral nociceptors

GOALS OF PAIN THERAPY

Acute pain Chronic pain

Remove the cause Recondition
Provide rapid and Reduce pain
effective Improve function,
analgesia sleep, & mood
TRANSISI NYERI AKUT  NYERI
KRONIK
Perubahan dari akut menjadi kronik :

Modulasi : Modifikasi :
merupakan perubahan
- reversibel jangka panjang yang dapat
- sentral berupa: ekspresi
neurotransmitter, reseptor,
- perifer saluran ion, struktur
konektivitas
 TREATMENT FOCUS ACUTE VS
CHRONIC PAIN
ACUTE CHRONIC
• Medical model of care • Rehabilitation-disease
management model of care
• Reduced pain intensity
is primary goal in order • Improved function
to facilitate recovery and (physical, psychological and
social) is often primary goal
prevent chronic pain
• Patients must actively
• Generally time limited participate in care
and successful
• Treatment and pain may
• Treatment ends when never end
pain resolves

http://projects.hsl.wisc.edu/GME/PainManagement/tables.html?panel=0
Somatic Pain Forum 37
 Acute Pain (McQuay & Moore, 1999)
TREATMENT METHODS

Remove the cause Medication Regional Physical Psychological

Of pain analgesia methods approaches

Low Tech •relaxation

•Nerve blocks •psychopro-
•Surgery Opioid
•Splinting •Local anaesthetic phylaxis
•Morphine
± opioid •hypnosis
•others

Non-opioid High Tech •physiotherapy

•Aspirin & others •Epidural infusion •manipulation
NSAIDS •Local anaesthetic •TENS
•Paracetamol ± opioid •Acupuncture
•combinations •Ice
 The WHO Analgesic Ladder
Hydromorphone
WHO Very severe
Step III Morphine
Oxycodone
Severe Fentanyl
Buprenorphine
Pain intensitiy

Tramadol
Tilidine

Drugs
WHO Codein
Step II Moderate Dextropropoxyphene
NSAIDs
COX II inhibitors

WHO Acetylsalicylic acid

Step I Mild Acetaminophene

Langford, 2002; Proceeding of the Grünenthal symposium

 Untuk Nyeri Akut Dan Berat

Recommended Significant Toxicity

Initial Dosing
Significant Sedation

Pain/Analgesia Threshold

Some Analgesia

Traditional
Initial Dosing No Analgesia

Analgesia dosing ladder

Pemahaman mekanisme
nyeri sangat bermanfaat
dalam penatalaksanaan
nyeri pada penderita
ANALGESIC MEDICATIONS
PRIMARY ANALGESICS
Acetaminophen
Prostaglandin synthesis inhibitors
 Salicylates
 Traditonal NSAIDs
 COX-2-selective NSAIDs (coxibs)
Tramadol
Opioids
 Traditional
 Mixed

ADJUVANT MEDICATIONS
Antidepressants
Anticonvulsants
Local anesthetics
Miscellaneous agents
THE TASK OF A DOCTOR:

TO CURE IS SOMETIMES
TO TREAT IS OFTEN
TO COMFORT IS ALWAYS
A. Pare (1598)
Key Messages:
1. Dextropropoxyphene has low analgesic efficacy (Level I)
2. Tramadol is an effective treatment in neuropathic pain (Level I)
3. Droperidol, dexamethasone and ondansetron are equally effective in
prophylaxis of postoperative nausea and vomiting (Level I)
4. Naloxone, naltrexone, nalbuphine and droperidol are effective treatments
for opioid-induced pruritus (Level I)
5. In the management of acute pain, one opioid is not superior over others
but some opioids are better in some patients (Level II)
6. The incidence of clinically meaningful adverse effects of opioids is dose-
related (Level II)
7. Tramadol has a lower risk of respiratory depression and impairs
gastrointestinal motor function less than other opioids at equinalgesic
doses (Level II)
8. Pethidine is not superior to morphine in treatment of pain of renal or
biliary colic (Level II)
9. Supplemental oxygen in the postoperative period improves oxygen
saturation and reduces tachycardia and myocardial ishaemia (Level II)
10. In adults, patient age rather than weight is a better predictor of opioid
requirements, although there is a large interpatient variation (Level IV)
11.Impaired renal function and the oral route of administration result in
higher concentrations of the morphine metabolites M3G and M6G (Level
IV)

The following tick boxes √ represent conclusions based on clinical

experience and expert opinion.

√Assessment of sedation level is a more reliable way of detecting early

opioid-induced respiratory depression than a decreased respiratory rate.
√The use of pethidine should be discouraged in favour of other opioids.
Key Messages:

1. Paracetamol is an effective analgesic for acute pain (Level I)

2. NSAIDs and COX-2 inhibitors are effective analgesics of similar efficacy
for acute pain. (Level I)
3. NSAIDs given in addition to paracetamol improve analgesia (Level I)
4. With careful patient selection and monitoring, the incidence of NSAID-
induced perioperative renal impairment is low (Level I)
5. Aspirin and some NSAIDs increase the risk of reoperation for post-
tonsillectomy bleeding (Level I)
6. COX-2 inhibitors and NSAIDs have similar adverse effects on renal
function (Level I)
7. COX-2 selective inhibitors do not appear to produce bronchospasm in
individuals known to have aspirin-exacerbated respiratory disease (Level
I)
8. Paracetamol, NSAIDs and COX-2 inhibitors are valuable components of
multimodal analgesia (Level II).
9. COX-2 inhibitors do not impair platelet function (level II).
10.Short-term use of COX-2 inhibitors results in gastric ulceration rates
similar to placebo (Level II)
11.Use of parecoxib followed by valdecoxib after coronary artery bypass
surgery increases the incidence of cardiovascular events (Level II)
The following tick boxes √ represent conclusions based on clinical
experience and expert opinion.

√Adverse effects of NSAIDs are significants and may limit their use
√The risk of adverse renal effects of NSAIDs and COX-2 inhibitors is
increased in the presence of factors such as pre-existing renal
impairment, hypovolaemia, hypotension, use of other nephtotoxic agents
and ACE inhibitors.
√Serious cardiovascular complications have been reported with the use
of COX-2 inhibitors in some settings and the use of these agents is
currently being assessed; no recommendations about their use can be
made until further evidence is available.
Key Messages:

1. Tricyclic antidepressants are effective in the treatment of chronic

neuropathic pain states, chronic headaches and chronic back pain (Level
I)
2. In neuropathic pain, tricyclic antidepressants are more effective than
selective serotonergic re-uptake inhibitors (Level I)
3. Antidepressants reduce the incidence of chronic neuropathic pain after
acute zoster and breast surgery (Level II).

The following tick boxes √ represent conclusions based on clinical

experience and expert opinion.
√Based on the experience in chronic neuropathic pain states, it would
seem reasonable to use tricyclic antidepressants in the management of
acute neuropathic pain.
√To minimize adverse effects, particularly in elderly people, it is advisable
to initiate treatment with low doses.
Key Messages:

1. Anticonvulsants are effective in the treatment of chronic neuropathic

pain states (Level I)
2. Perioperative gabapentin reduces postoperative pain and opioid
requirements (Level I)

The following tick boxes √ represent conclusions based on clinical

experience and expert opinion.
√Based on the experience in chronic neuropathic pain states, it would
seem reasonable to use anticonvulsants in the management of acute
neuropathic pain.
Key Messages:

1. Membrane stabilisers are effective in the treatment of chronic

neuropathic pain states, particularly after peripheral nerve trauma (Level
I)
2. Periopetive intravenous lignocaine (lidocaine) reduces pain on movement
and morphine requirements following major abdominal surgery (Level II)

The following tick boxes√ represent conclusions based on clinical

experience and expert opinion.
√Based on the experience in chronic neuropathic pain states, it would
seem reasonable to use membrane stabilisers in the management of
acute neuropathic pain.
√lignocaine (lidocaine) (intravenous or subcutaneous) may be a useful
agent to treat acute neuropathic pain.
 TRENDS IN THE MEDICAL USE OF FIVE
OPIOID ANALGESICS IN THE US : 1990-
1996
Year Fentanyl Hydromorphone Meperidine Morphine * Oxycodone
(mg) (mg) (mg) (mg) (mg)
1990 3.263 118.455 5,223.137 2,172.006 1,642.400
1991 12.261 126.251 4,879.898 2,327.881 1,604.605
1992 23.673 129.549 4,407.189 2,483.756 1,573.106
1993 29.668 129.893 4,075.132 2,733.332 1,563.367
1994 28.985 133.428 3,854.929 2,772.441 1,448.599
1995 30.640 127.905 3,483.637 2,869.876 1,426.883
1996 41.371 141.325 3,380.440 3,461.618 2,016.172
% change 1,168 19 -35 59 23

( Wellman,2001 )
PRINCIPLES OF OPIOID THERAPY
Always titrate with short-acting medication.
Convert to long-acting medications with
additional rescue doses if possible.
Use ‘around the clock’ (ATC) medication in
most cases, except primarily incident pain.
Rescue medication should always be made
available to reduce the total dose.
Rescue dose should be 10-25% (usually 10-
15%) of the 24 hour estimated requirement.
Increase ATC long-acting drug if patient uses
>4 rescue doses per day
 PRINCIPLES OF OPIOID THERAPY
(LANJUTAN)
Increase the ATC dose in steps of 33-50%
Decrease the ATC long-acting drug if patient uses only 0-1
rescue doses per day
Decrease the ATC dose in steps of 25-33%
Understand the concept of incident pain and how it alters the
use of rescue doses
Opioids should be considered useful if they reduce pain,
increase function or both with manageable side-effects

(Farrar,2001)
MAIN SIDE-EFFECTS OF OPIOIDS IN
NON-MALIGNANT PAIN PATIENTS
Short-term Long-term
● Sedation ● Constipation

● Constipation ● Excessive sweating

● Nausea ● Oedema (peripheral, non-

dependent)

● Dysphoria ● Cognitive effects

● Reduced cognitive function ● Endocrine abnormalities

(Farrar, 2001)
OPIOIDS
Analgesic Penting
Aman dan efektif bila digunakan dengan tepat.
Masing-masing jenis opioids mempunyai kerja dan efek yang
berbeda.
Efek samping kadang-kadang serius oleh karena itu dicari
strategi baru untuk mengurangi efek samping, misalnya :
 Cara/rute pemberian
 Kombinasi obat

(Kalso, 2012)
INDIKASI PENGGUNAAN OPIOIDS
PADA NYERI KRONIK
Bila semua modalitas gagal dalam mengobati nyeri
Resiko penggunaan opioids lebih rendah dari
pengobatan lainnya.
Banyak untung daripada ruginya.
Oleh karena itu

seleksi pasien sangat ketat untuk pemberian opioid.

Terima Kasih atas Perhatiannya,
Semoga Bermanfaat