Multimodal Analgesia for

Cancer Pain

Muhammad Ramli Ahmad

Department of Anesthesiology IC and Pain Management

Faculty of Medicine Hasanuddin University
Makassar Indonesia
 INTRODUCTION
PAIN IASP 1979 (International Association for
the Study of Pain) 1979
“an unpleasant sensory and emotional
experience associated with actual or
potential tissue damage or described in
term of such damage”

Pain is whatever the experiencing person says it is,

existing whenever he or she says it does.”( Margo
McCaffrey, RN 1980)
 Defenisi Nyeri
• Nyeri adalah apa saja yang dikatakan seseorang
nyeri, dan terjadi kapan saja ia mengatakannya
terjadi.”
Margo Mc Caffrey, RN 1980

• Sakitnya tuh disini…di sini

 Pain: The 5th vital sign

• Pain should be considered the

“fifth vital sign” Pain: the
(2001 initiative in USA)
5th vital
• Patients should be assessed for
pain every time pulse, blood sign
pressure, core temperature, and
respiration are measured

• Mandatory for hospital

accreditation ($)

American Pain Society Quality Improvement Committee. JAMA. 1995;1847–1880.

 Cancer Pain Prevalence
For many patients pain is the first sign of cancer.
• 30 – 50 % of all cancer patients will
experience moderate to severe
pain.
• 75 – 95 % of patients with advanced stages
will experience severe pain.
• 45 % of cancer patients have
inadequate pain control.
• 25 % Will die in pain.
Nature Reviews Cancer March 2002
 CAUSE OF CANCER PAIN
Can be classified into 3 categories:
1. Pain associated with direct tumor
(tumour infiltration, bone metastases)
2. Pain associated with cancer therapy
(chemotherapy, surgery or radiation)
3. Pain unrelated to cancer
(RA, OA, headache or herpes zoster)
* Due to cancer debility
(decubitus)
 Causes of Cancer Pain
• The tumor itself
 Causes of Cancer Pain
• RELATED TO THERAPY

FROM CHEMOTHERAPY
COBALT RADIATION BURN
 Causes of Cancer Pain
OTHER FACTORS

Acute Herpes Zoster Immunocompromised state

Pathophysiology of Cancer Pain

 Nociceptive pain

•Somatic pain
•Visceral pain Mostly combine form

 Neuropathic pain
Nociceptive pain in Cancer Pain
 Anatomical changes: bone cancer
pain model

13
 Cancer Pain Problems
• Inadequate of Cancer pain management will
impact to
• A.quality of life
• B.quality of dying , of cancer patient.
Target : free of pain.
Management of cancer pain :
1. Non Farmacologic.
2. Farmacologic.
Multimodal Analgesia
What is multimodal analgesia?

Is a combination of two or more

analgesics that act at different
mechanisms, produce additive or
synergistic analgesia
 PERCEPTION

Pain

Descending
modulation Dorsal Horn

Ascending Dorsal root ganglion TRANSMISSION

input

Spinothalamic
Peripheral
tract TRANSDUCTION
nerve

Peripheral Trauma:
nociceptors infalmmation or
non-inflammation
Adapted from Gottschalk A et al. New Concepts in Acute Pain Therapy: Preemptive Analgesia. Am Fam Physician.
2001;63:1981, and Kehlet H et al. The Value of “Multimodal” or “Balanced Analgesia” in Postoperative Pain Treatment.
Anesth Analog. 1993;77:1048-1056.
 Multimodal Analgesia
Kehlet H 1992

polypharmacologic
manipulation of

• Transduction  NSAIDs (COX1 &

COX2)
• Transmission  Local anesthetics
• Modulation  Opioid or NMDA
antagonist and COX2

Using 2 or more drugs which different actions

Better analgesia synergy, additivity, Reduced side effects
1. Synergetic ............. 2+2>4

2. Additive ................ 2+2=4

3. Subadditive ........... 2+2=3

 Benefits of Multimodal Analgesia

Opioids • REDUCED DOSES

of each analgesic

• IMPROVED EFFECACY
due to synergistic effects

• REDUCE SIDE EFFECTS

of each drug

Main goals of Multimodal Analgsia is to reduce the amount of Opioid

1Kehlet H et al. Anesth Analog. 1993;77:1048-1056.

Basic principle of pain management cancar
THREE STEP LADDER WHO, 1986

Severe pain

3
Moderate
pain

2
Mild pain

Concept of Multimodal Analgesia (1993)

 WHO method of cancer pain relief
Three-step analgesic ladder
For moderate to severe pain,
Step III Strong Opioid analgesics
Step II ± Non-opioid analgesics
For mild to moderate pain, ± adjuvant analgesics
Pain level

Mild Opioid analgesics

± Non-opioid analgesics
Step I ± adjuvant analgesics

Non-opioid analgesics
Pain
± adjuvant analgesics

Pain

Codeine
Strong opioids
Tramadol
Tramadol+/APAP
Codein+ APAP APAP/NSAIDs ± adjuvant analgesics

Successive change APAP/NSAIDs ± adjuvant analgesics

Paracetamol = APAP(Acetyl Para Amino Phenol)

 ANALGESIC DRUGS

NONOPIOIDS ADJUVANTS
OPIOIDS • Steroid (dexamethason)
• Paracetamol • Mild Opioid • Antidepressant (tricyclic)
• NSAID (nonselective) ( codeine & tramadol ) • Gabapentinoid
• Coxib (selective NSAID) (gabapentin&pregabaline)
• Strong Opioid
( Morphine, Fetanyl, • Ketamine
oxycodon, hydromorphone)
 Step I (VAS 1-3)Mild Pain
Analgesic Non-opioid
1. 1. Paracetamol
2. NSAIDs non selective
3. Coxibs (celecoxib) selective
 It has celing effect
 ± adjuvants
– Steroid (dexamethasone)
– Anti depressant (tricyclic)
– Gabapentinoid (Gabapentin and
pregabalin)
– Dextrometorphan
– Ketamin
Cantoh pemberian Obat
- By the mouth sebisa mungkin
- By the clock
Pasien harus dituliskan skedulnya
 Jam 06.00  - Paracetamol 500 mg
- Celebrex 200 mg
 Jam 12.00  - Paracetamol 500 mg

 Jam 18.00  - Paracetamol 500 mg

- Celebrex 200 mg
 Jam 22.00  - Paracetamol 500 mg
 ± Adjuvants
 Step I for MILD PAIN
Use paracetamol, aspirin or NSAID

• Use paracetamol , aspirin or NSAID

• NSAIDs have a potential opioid-sparing effect.
• Caution is needed when using NSAIDs for
prolonged periods
• Risk factors such as aging, renal or GI diseases
should be considered.
• It has ceiling effect.
Step II (VAS 4-7) Moderate Pain
 Weak opioids  1. Codeine
2. Tramadol
 Paracetamol
 NSAIDs / Coxib (Celecoxib)
 ±Adjuvants
 Combine  (Codeine +Paracetamol)
 (Codeine + NSAID)
 (Codeine + Celecoxib)
 Codeine is very constipating, less nausea & vomiting
 When use codeine, must be added anti constipation
 Combine (Tramadol+Paracetamol)
 Tramadol is high nausea/vomiting; but less
constipating
Multi Modal Analgesia = Combination of two drugs which has different action
 produce synergic

Codein 30 mg

• Reduced doses
Potentiation • Improved pain relief
• reduce side effects

Paracetamol 500 mg
Coditam®

1Kehlet H et al. Anesth Analog. 1993;77:1048-1056.

Coditam®
Codein 30 mg Paracetamol 500 mg
Multi Modal Analgesia = Combination of two drugs which has different action
 produce synergic

Tramadol 37.5 mg

• Reduced doses
Potentiation • Improved pain relief
• reduce side effects

Paracetamol 325 mg
Ultracet®

1Kehlet H et al. Anesth Analog. 1993;77:1048-1056.

Recent European Recommendations

 For mild to moderate pain, weak opioids such as codeine,

tramadol and dihydrocodeine should be given in combination
with non opioid analgesics.

 As an alternative to weak opioids, low doses of strong opioids

in combination with non-opioid analgesics should be
considered.

Ripamonti et al. Annals of Oncology 23 (suppl 7) 2012

 Step Il for MODERATE PAIN
• Combine Paracetamol/Aspirin/ NSAIDs + Codein
• Formula
Acetaminophen/
Aspirin 500 mg
Codein 10 mg
Dulcolax ¼ tab
mf pulv dtd XXX
6 dd I cap
+ adjuvant
06.00 18.00
10.00 22.00
14.00 02.00 prn

• Constipation is the most common side effect of codein

 Step lll for SEVERE PAIN

• Oral morphine is the mainstay of severe

cancer pain.
• Strong pain needs strong analgesic.
• It is a very safe drugs as long as given properly
• MS contin is one of choice
– Sustained release
– Long acting (twice a day)
– Strong opioid
Step III (VAS 7-10) Strong-Opioid
Strong Opioid  1.Morphine
• Rapid Release
(tablet & liquid)
• Slow Release
(MST Contine)

 Paracetamol
 NSAID/Coxib
 ± Adjuvants

Never apply monomodality , always multimodal analgesia,

get opioid sparing effect
Step lll for SEVERE PAIN
 MST 10 - 15 mg
2 dd I tab
 Celebrex 100–200 mg
2 dd I cap

+ adjuvant
06.00
18.00
Three Step Ladder WHO, 1986
5 essential concepts
 By mouth
 By the clock
 By the ladder
 For individual
 With attention to
detail

By this modality ± 90% of cancer pain can be relieved

 WHO guidelines for the treatment of
cancer pain

• It has been suggested that 90% to 95% of

cancer pain syndromes can be well controlled
by using guidelines established by the World
Health Organization (WHO)1.

1World Health Organization: Cancer pain relief and

palliative care.1990
 WHO guidelines for the treatment of
cancer pain

• 90% to 95% of cancer pain syndromes can be

well controlled by using guidelines established
by the WHO.

• But still…………
• ⇒5% to 10% of patients are still suffering pain.
• ⇒What can be done to these patients?
Adjuvant Drugs for Cancer Pain Treatment
____________________________________________________________________________________________________________

 Steroids
 Antidepressants
 Anticonvulsants
 NMDA receptor antagonists

Mainly for neuropathic pain

 Adjuvant Analgesic Drugs
Drug Category Drug, Dosage
Antidepressants Amitriptyline:
- Initial dose 0.2-0.5 mg/kg PO
- Titrate upward by 0.25 mg/kg
every 2-3 days
- Maintenance: 0.2-3 mg/kg
Alternatives: nortriptyline, doxepin,
or imipramine
Anticonvulsants Gabapentin:
- Initial dose 5 mg/kg/day PO
- Titrate upward over 3-7 days
- Maintenance: 15-50 mg/kg/day
PO divided TID
Carbamazepine:
- Initial dose 10 mg/kg/day PO
divided OD or BID
- Maintenance: up to 20-30 mg/
kg/day PO divided every 8 h.
Increase dose gradually over 2-
4 weeks
Alternatives: clonazepam
Antihistamines Hydroxyzine: 0.5 mg/kg PO every 6
h anxiety, nausea
Diphenhydramine: 0.5-1 mg/ kg
PO/IV every 6 h
Indications Comments
Neuropathic pain (i.e., Usually improved sleep and
vincristine-induced, pain relief within 3–5 days.
radiation plexopathy, Anticholinergic side effects are
tumor invasion, dose-limiting. Use with caution
CRPS-1), insomnia for children with increased risk
for cardiac dysfunction.
Neuropathic pain,
especially shooting,
stabbing pain.
Monitor for hematologic,
hepatic, and allergic reactions.
Side effects include
gastrointestinal upset, ataxia,
dizziness, disorientation, and
somnolence
Opioid-induced pruritus, Sedative side effects may be
helpful
 Adjuvant Analgesic Drugs
Drug Category Drug, Dosage
Sedatives, hypnotics, - Diazepam: 0.025-0.2 mg/kg
anxiolytics PO every 6 h
- Lorazepam: 0.05 mg/kg/dose
SL
- Midazolam: 0.5 mg/kg/dose
PO administered 15-30 min
prior to procedure; 0.05 mg/
kg/dose IV for sedation
Corticosteroids Prednisone, prednisolone, and
dexamethasone dosage depend
son clinical situation.
Dexamethasone:
- Initial dose: 0.2 mg/kg IV.
- Dose limit 10 mg.
- Subsequent dose: 0.3 mg/kg/
day IV divided every 6 h
Psychostimulants Dextroamphetamine,Methylpheni
date: 0.1-0.2 mg/kg BID.
Escalate to 0.3-0.5 mg/kg as
needed
Indications Comments
Acute anxiety, muscle Sedative effect may limit opioid
spasm; premedication for use. Other side effects include
painful procedures depression and dependence
with prolonged use
Headache from increased Side effects include edema,
intracranial pressure, dyspeptic symptoms, and
spinal, or nerve occasional gastrointestinal
compression; bleeding
widespread metastases
Opioid-induced Side effects include agitation,
somnolence sleep disturbance, and
Potentiation of opioid anorexia.
analgesia Administer second dose in the
afternoon to avoid sleep
disturbances
Starting Doses of Opioid Analgesics for Cancer Pain Relief
Drug Equianalgesic Starting dosage IV IV:PO Starting dosage Duration of
dosage ratio PO/Transdermal Action
(parenteral)
Morphine 10 mg - Bolus dose = 0.05-0.1 1:3 0.15-0.3 mg/kg/dose every 4 3-4 h
mg/kg every 2-4 h h
- Continuous infusion
= 0.01-0.04 mg/kg/h

Hydromor- 1.5 mg 0.015-0.02 mg/kg every 1:5 0.06 mg/kg every 3-4 h 2-4 h
phone 4h

Codeine 120 mg Not recommended - 1 mg/kg every 4 h (dose 3-4 h

limit
1.5 mg/kg/dose)

Oxycodone 5-10 mg Not recommended - 0.1-0.2 mg/kg every 3-4 h 3-4 h

Meperidine 75 mg 0.5-1 mg/kg every 3-4 h 1:4 1-2 mg/kg every 3-4 h 1-3 h
(dose
limit 150 mg)

Fentanyl 100 mg 1-2 mg/kg/h as - 25 mg patch 72 h (patch)

continuous infusion

Methadone 10 mg 0.1 mg/kg every 4-8 h 1:2 0.2 mg/kg every 4-8 h 12-50 h
 Long Acting Opioids

Drug Brand Dosing Interval

Morphine MS Contin® 8-12 hrs

Oramorph-SR® 8-12 hrs

Kadian® 12-24 hrs

Avinza® 24 hrs

Oxycodone OxyContin® 8-12 hrs

Oxymorphone Opana ER® 12 hrs

Fentanyl Duragesic® 48-72 hrs

Methadone 6-12 hrs

 Equianalgesic Conversion Chart
Drug Equianalgesic ORAL Equianalgesic IV
Codeine 200 mg 130 mg

Hydrocodone 30 mg ---

Morphine 30 mg 10 mg

Hydromorphone 7.5 mg 1.5 mg

Oxycodone 20 mg ---

Fentanyl (patch ~ ½ morphine) 0.1 mg (100 mcg)

Meperidine 300 mg 75 mg

Methadone 10 mg ACUTE 5 mg ACUTE

 OXYCODONE : Tablet Formulations
• Control release (CR)
– Oxycontin®(CR in ADF) 10, 15 ,20 , 30 , 40, 60, 80 mg
– Onset 30-60 min, Peak effect 1.5 – 3 hr. Duration 8-12 hr.
– Start 10 mg q 12 hr. Titration by increase 25-50 % of current dose
• Immediate release (IR)
– Tablet / capsule 5 mg, solution 5 mg / 5 ml or 20 mg/ml
– Onset 10 -15 min, peak effect 30-60 min. duraion 3-6 hrs.
– Oral prn q 4-5 hr.

• Combine with
paracetamol or
NSAIDs

Multimodal Analgesia
 WHAT IS THE MOST REGIMENTS
There are many regiments for multimodal analgesia,
but the most popular are:

Paracetamol
NSAIDs and Coxibs
Opioid Local Anesthetic

2 (subunit of Ca
NMDA Antagonist -2 antagonist
Channel) agonist
(Ketamin) (Clonidine)
(Gabapentinoid)

All of these drugs targeting to reduce or preventing

sensitization
 Target Point of Analgesic Agents
Ketamin
Acetaminophen

Perception
Opioids
Gabapentinoids
Clonidine

Corticosteroids
NSAIDs
Modulation Transduction COXIBs
Local Anesthetic

Transduction
DRG

Transmission
Modulation
Local anesthetics
Cryotherapy
COXIBs
Modify by AHT
 Some Multimodal Regiments
Parecoxib
Ketamine
Ibuprofen
ivNMDA
COXIBs antagonists
iv

NSAIDs Only LA can produce

iv
 Pain Free and
 Stress Free
Multimodal
Opioid may pain free but
not sress free (PCA).
Gabapentinoids

Local Anaesthetics
NorAdr & iv
Epiduraly or
Opioids 5HT antagonists Nerve block
iv
Tramadol Jin et al. J Clin Anesth;13:524, 2001
Kehlet et al. Anesth Analg;77:1048. 1998
Woolf CJ, Science, 288:1765-1768, 2000
 NSAID

COXIB

Tramadol
OPIOID

Ketamine
PARACETAMOL Gabapentanoid
(Morphine, Fentanyl, Codein)

(Gabapentin, Pregabalin)
 Opioid Dose and Clinically Meaningful
Opioid Related Adverse Events
‘Once threshold reached, every further 3–4 mg increase will be
associated with 1 clinically meaningful opioid-related symptom’
> 3 events
laparoscopic cholecsytectomy
Number of CMEs on day 1 after

Reduction in
clinically meaningful
2 events opioid related ADE

1 event

No event
–33%

0 5 10 15 20 25
Morphine equivalent dose in 24 hours (mg)

ADE = adverse drug Zhao et al, J Pain Symp Manag

event 2004;28:35
 Dibutuhkan obat yang memiliki Opioid
Sparing Effect yang tinggi
Partially desensitised
Sensitised
pain response
pain response

-30%
Normal
(non-opioid) pain
response
Pain intensity

Anti-
hyper
Opioid

Opioid

algesic

X
Stimulus intensity
 WHO three step ladder

Strong Opioid for

severe pain
(Morphine)
Weak Opioid for
mild to moderate  Celecoxib
pain  adjuvants
Paracetamol  Paracetamol
 adjuvants  adjuvants

Increasing pain
 CONCLUSION
• Pain is a common problem and a major symptom of
cancer patients.
• Cancer pain can be organic or psychological pain
• Total pain is a BIOPSYCHOSOCIOCULTUROSPIRITUAL
problem.
• CANCER PAIN management should be treated integrated
and comprehensive by multidisipline doctors.
• About 90% of cancer pain patients can be relieved by
three step ladder of WHO
Thank you!