prinsip penanganan nyeri pada kasus kanker dengan algoritma manajemen tatalaksana nnyeri kronik pada kanker

1. PRINCIPLES IN CANCER PAIN
MANAGEMENT
DRADJAT SUARDI
Ketua PP Perhimpunan Onkologi Indonesia
Ketua PP Masyarakat Paliatif Indonesia
Ketua Tim Kanker RSHS/FK UNPAD
Ketua Tim Paliatif RSHS/FK UNPAD

2. Objectives
Factors that induced cancer
pain
Advantages dan
disadvantages of each
analgesic
Understanding opioid as
a drug for cancer pain
Cancer pain management
To know &
understand

3. OUTLINES
• Overview of cancer pain
• Overview of pain treatment
• Managing cancer pain
– Approach in cancer pain management
• Persistent/baseline pain
• Breakthrough pain
– Opioid in cancer pain
• Opioid phobia
• Advanced formulation in opioid for cancer
pain– practical usage
• Related side effect
– Guidelines of cancer pain management

4. All AC, Huyce LI, Pain Cancer and older adults 199
Ahmedzi S. New approaches to pain control in patients with cancer Eur Journal of Cancer 1997
CANCER PAIN
• PAIN is the symptom most commonly associated with
cancer
– severity increases with the progression of the disease
• 60-90% with advanced cancer report significant pain
• Often a mixed pattern:
– Nociceptive
– Neuropathic
– Cancer specific pain / tumour effects
– Post surgical pain
– Chemotherapy induced pain
• Pain control is a vital component of cancer management
Cancer survivors

5. CANCER ASSOCIATED PAIN
Cancer pain may be induced by:
• Infection AND/ OR Inflammation
• Poor circulation
• Invasion to bone, nerve or other organs
• Psychological or emotional problems

6. 6
International Narcotics Control Board; World Health Organization population data
Pain & Policy Studies Group (PPSG), University of Wisconsin

7. OUTLINES
• Overview of cancer pain
• Overview of pain treatment
• Managing cancer pain
– Approach in cancer pain management
• Persistent/baseline pain
• Breakthrough pain
– Opioid in cancer pain
• Opioid phobia
• Advanced formulation in opioid for cancer
pain– practical usage
• Related side effect
– Guidelines of cancer pain management

8. Tramadol +
Paracetamol
Analgesic classification adapted
from WHO Ladder
- Fentanyl
-COX-2
inhibitor/NSAID
-Aspirin
-Paracetamol
No need to start
from 1st step if the
pain is already
severe
Move to the next
step if there is no
response or the
pain score doesn’t
decreased

9. Spinothalamic
tract
Peripheral
nerve
Dorsal Horn
Dorsal root
ganglion
Pain
Ascending
input
Descending
modulation
Peripheral
nociceptors
Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
PERCEPTION
TRANSMISSION
TRANSDUCTION
OPIOID
Local Anesthesi
NSAID/COXIB
No single drug can produce optimal analgesia without
adverse effect
Pain pathway and multi-modal mechanism of
pain treatment
9
OPIOID
Antidepresan
OPIOID
Paracetamol
Trauma:
inflammation or
non-inflammation

10. Paracetamol
Advantages • Does not produce end-organ toxicity
commonly seen with NSAIDs on the
gastrointestinaltract, kidney and
cardiovascular
• Lack the CNS and opioid-related side
effects
Disadvantages • Lacks antiinflammatory effect
• If used as single drug, its analgesic
potency is less than that of NSAIDs
• Less potent analgesic effect as compared
to NSAIDs
• Has a dose-related hepatotoxicity (in
high dose)
Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. McGraw-Hill Professional; 11th ed: Oct 2005

11. NSAID/COX-2 inhibitors
Advantages • Show antiinflammatory effect
• Lack the CNS and opioid-related side
effects
Disadvantages • Gastrointestinal side effects
(dyspepsia, hemorrhage, ulcer)
• Renal perfusion 
• Blockade of platelet function
• Fluid and sodium retention
• Hypertension
• Risk of cardiovascular events 
(stroke, MCI)
Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics. McGraw-Hill Professional; 11th ed:
Oct 2005

12. Opioids
Advantages • Strong analgesic effect
• Do not produce end-organ toxicity
commonly seen with NSAIDs on the GI
tract, kidney and cardiovascular
• Relatively safe when used in
appropriate doses and when
monitored effectively
• No ceiling effect (strong opioid)
Disadvantages • Opioid related side effects:
nausea, vomiting, constipation,
drowsiness, dizziness, respiratory
depression, tolerance ,risk of abuse
Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics. McGraw-Hill Professional; 11th ed:
Oct 2005

13. Pain treatment based on severity and
presence of inflammation
Inflammation
No
Inflammation
• NSAID or
coxib or
aspirin
• Paracetamol
and (NSAID
or coxib or
aspirin)
Paracetamol
• Weak opioid ±
NSAID or coxib
• Combination of
weak opioid
and
paracetamol ±
NSAID or coxib
Combination of
weak opioid and
paracetamol
Strong opioid ±
NSAID or coxib
Strong opioid
± Adjuvant (antidepressant, corticosteroid, α-2 adrenergic
agonist, neuroleptic, anticonvulsant) if needed
Mild Moderate Severe
Developed by Cancer Pain Management Advisory Board member based on WHO ladder

14. Why opioid for severe pain ?
Rapidly titrate short-acting opioid

15. OPIOID OPTIONS
• As part of multimodal therapy
• IV opioids (morphine, fentanyl)
• Immediate release oral opioid (morphine)#
• Sustained release opioids
– Oral : morphine, oxycodone*, hydromorphone*
– Transdermal : fentanyl, buprenorphine*
# very limited availability in Indonesia
* Not yet available in Indonesia

16. Opioid Characteristics
Codeine 8-9% of Caucasians and up to 40% of Asian people are CYP2D6 poor
metabolizers, and do not experience effective analgesia with codeine.
Tramadol Atypical opioid: additional non-opioid mechanism which inhibits re-uptake of
serotonin and norepinephrine
Morphine Chronic renal disease may be more affected by M3G and M6G metabolite
Fentanyl IV Transdermal/patch
 Less constipation
 Less likely cause nausea/delirium
 Less competition for liver enzymes: drug interactions less likely
 Tiny amounts of fentanyl reach liver so safe in patients with liver
dysfunction
 Safe in renal dysfunction compared to other opioids
 Fewer side effects from interactions with other opioid receptors in CNS
 72-hour supply of fentanyl in patch and skin
for around-the-clock analgesia with no peaks
and troughs
 No first-pass effect of liver: small amounts of
fentanyl needed for analgesia
Weak opioid
Strong opioid

17. Schnitzer. Anaesthesiology. 1996;20(S12):13
Paracetamol and tramadol
complimentary pharmacokinetics
Paracetamol
Paracetamol/Tramadol
Tramadol
0
1
2
3
4
0 2 4 6 8 10
Time
(hours)
Paracetamol/
Tramadol
Para-
cetamol
Tramadol
Painrelief
• Rapid onset of
action of
Paracetamol
• Long-lasting
effect
of tramadol
Medve RA, Wang Julia, Karim . Tramadol and Acetaminophen for dental pain. Anesth prog 48:79-81. 2001
Ho ML, Chung CY, Wang CC et al. Efficacy and safety of tramadol/acetaminophen in the treatment of breakthrough pain in cancer patients. Saudi Med J.
2010 Dec;31(12):1315-9.

18. Combination of tramadol-
paracetamol
• Advantages:
– Have multiple sites of action
– Produce a synergistic effect  dose reduction is
applicable  side effect are less than single components
– Not associated with peptic ulcer, hypertension, CVA, and
renal damage
• Disadvantage:
– Spectrum of side effect includes those from paracetamol
and tramadol as well
18
Ho ML, Chung CY, Wang CC et al. Efficacy and safety of tramadol/acetaminophen in
the treatment of breakthrough pain in cancer patients. Saudi Med J. 2010
Dec;31(12):1315-9.

19. NCCN (National Comprehensive Cancer
Network) Guidelines
• Converting from short-
acting to long-acting
opioids when 24-h opioids
requirement is stable
• Used immediate-release
opioids for breakthrough
pain
– 10–25% (1/6) of 24-h dose*
– Increase rescue dose
proportional to long-acting
*See in case study for detail

20. Barriers to Cancer Pain
ManagementBarrier %
• Inadequate pain assessment 76
• Patient reluctance to report 62
• Patient reluctance to opioids 62
• Physician reluctance 61
• Inadequate staff knowledge 52
• Inadequate nurse knowledge 38
• Excessive state regulations 18
• Lack of access to professional methods 12
• Lack of psychological support services 11
• Lack of equipment 6
• Lack of neurodestructive services 5
• Lack of access of a wide range of analgesics 3
Ann Internal Med 1993

21. Why “Around-the-clock” (ATC)
approach
• Cancer pain is continuous
• Baseline pain in cancer pain is defined as average
pain intensity experienced for 12 hours or more
during a 24-hour period
• ATC dosing should be used when pain itself is ATC
(continuous) or present for 12 or more hours each
day
• Therefore , ATC is a mainstay approach in cancer
pain

22. Drug C Monophasic Extended Release (q24h)
Current Paradigm for the
Relief of Chronic Pain
Pain
Increased Pain Intensity
In overall treatment needs “Around-the-clock”
management with limited “breakthrough pain”
Drug B Biphasic Controlled Release (q12h)
Drug A Immediate Release (q4h)
Time
Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19-24.

23. Around-the-Clock
Medication
Breakthrough pain
Over Medication
Managing Cancer Pain

24. BREAKTHROUGH PAIN
• Defined as transitory exacerbation of pain in
a patient who has relatively stable and
adequately controlled baseline pain (rapid
onset, brief flare of severe pain despite
regular analgesia).
• Common in cancer patients
• Despite around the clock treatment regimen,
patients have approximately 4 episodes/day
Portenoy RK, Hagan NA : Breakthrough pain: definition, prevalance & characteristics. Pain 1990;41:273–281.

25. BREAKTHROUGH PAIN
• In 43% patients, pain reached peak intensity within
3 min
• Mean duration was about 30-40 min
• Immediate released, short-acting analgesic is an
ideal option for breakthrough pain (IV/IM, IR-Oral,
suppositoria, buccal*)
*not yet available in Indonesia
Portenoy RK, Hagan NA : Breakthrough pain: definition, prevalance &
characteristics. Pain 1990;41:273–281.

26. Breakthrough Pain Treatments
• Characteristic of analgesic required for
breakthrough pain:
– Strong opioid
– Immediate release formulation
– Rapid onset time
– Most direct routes
• Buccal / Mucosal / inhaled
• Morphine is preferred in breakthrough pain
treatment

27. OUTLINES
• Overview of cancer pain
• Overview of pain treatment
• Managing cancer pain
– Approach in cancer pain management
• Persistent/baseline pain
• Breakthrough pain
– Opioid in cancer pain
• Opioid phobia
• Advanced formulation in opioid for cancer
pain– practical usage
• Related side effect
– Guidelines of cancer pain management

28. Opioid formulations for cancer pain
• Sustained release formulations
– oral: MST, oxycodone*, hydromorphone
– transdermal: fentanyl, buprenorphine*
• New lower dosage permits ‘start low-go slow’
strategy to reduce side-effects
• Effective in nearly all types of pain including
neuropathic pain
*not yet available in Indonesia

29. Pain patient :
• Not out of control with
medication
• Medications improve quality of
life
• Aware of side effects
• Concerned about medical
problems
• Will follow agreed treatment
plan
• Has medications left over from
previous prescriptions
Differences between a pain patient and
addicted patient
Addicted patient :
• Out of control with medications
• Medications decrease quality
of life
• Wants medication despite side
effects
• In denial about medical
problems
• Does not follow treatment plan
• Does not have medication
remaining and always has ‘a
story’
Heit HA. The truth about pain management: The difference between a pain patient and an addicted
patient. Eur J Pain 2001; 5(suppl A): 27–29.

30. Drug
Equianalgesic
oral dose
Starting
oral dose
Adults ≥ 50 kg Adults ≤ 50 kg
Morphine 30 mg q3-4 h 15-30 mg q3-4 h 0.3 mg/kg q3-4 h
Codeine 130 mg q3-4 h 60 mg q3-4 h 1 mg/kg q3-4 h
Hydromorphone 5 - 7.5 mg q3-4 h 6 mg q3-4 h 0.06 mg/kg q3-4 h
Hydrocodone* 30 mg q3-4 h 10 mg q3-4 h 0.2 mg/kg q3-4 h
Levorphanol* 4 mg q6-8 h 4 mg q6-8 h 0.02 mg/kg q6-8 h
Meperidine 300 mg q2-3 h Not recommended Not recommended
Oxycodone* 20 mg q3-4 h 10 mg q3-4 h 0.2 mg/kg q3-4 h
Oral Opioid Analgesics
Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. McGraw-Hill Professional; 11th ed: Oct 2005
*not yet available in Indonesia

31. Switching
Commonly employed in cancer pain management
for:
• Tolerance causing rapid / high dose escalation
• Suspected opioid induced hyperalgesia
• Intolerable side effects
Dosage usually commenced at 30-40% less than
dose calculated from equivalence table
Hypothesised that incomplete cross tolerance and
differing opioid intracellular effects responsible for
benefit of substitution.

32. Oral and parenteral opioid equivalences and relative
potency of drugs as compared with morphine based
on single dose studies
Opioid agonists Parenteral
dose
Oral dose Factor (IV to
PO)
Duration of
action
Codeine 130 mg 200 mg 1.5 3-4 h
Fentanyl 100 mcg - - 1-3 h
Morphine 10 mg 30 mg 3 3-4 h
Tramadol - 50-100 mg - 3-7 h
Hydromorphone* 1.5 mg 7.5 mg 5 2-3 h
Levorphanol* 2 mg 4 mg 2 3-6 h
Oxycodone* - 15-20 mg - 3-5 h
Oxymorphone* 1 mg 10 mg 10 3-6 h
Hydrocodone* - 30-45 mg - 3-5 h
*not yet available in Indonesia

33. Recommended dose conversion from other opioid
to transdermal Fentanyl
Transder
mal
Fentanyl
(mcg/h)
Morphine
(mg/d)
Codeine
(mg/d)
Oxycodone*
(mg/d)
Hydromorphone*
(mg/d)
IV/SC Oral IV/SC Oral Oral IV/SC Oral
25 20 60 130 200 30 1.5 7.5
50 40 120 260 400 60 3 15
75 60 180 390 600 90 4.5 22.5
100 80 240 520 500 120 6 30
*not yet available in Indonesia
IV = intravenous
SC = subcutaneous
O = oral

34. Opioid side effects
• Initial
–Nausea and vomiting
–Dizziness
–Somnolence
–Pruritis
–Sweating
–Urinary retention
• Late
–Constipation

35. Principles to minimize
the side effects of opioid
• Frequently the side effects are transient, but may
require evaluation and management
• Adverse events, such as constipation, should be
anticipated and treated aggressively and
prophylactically with a stimulant laxative and/or stool
softener.
• ‘Pre-emptive’ use of:
• anti-emetics; laxatives; opioid antagonists
• Haloperidol low dose (1-1.5 mg po every 6-8 hours), proven
to be better than metoclopramide and ondansetron
NCCN Clinical Practice Guideline in Oncology. Adult cancer pain. 2010. www.nccn.org

36. Principles to minimize
the side effects of opioid
• Maximize non-opioid and non pharmacologic
intervention to limit opioid dose and treat side
effects
• Consider opioid rotation  if side effects persist
• Multisystem assesment
• Recognize that side effects may be from other
treatments or cancer itself

37. Constipation
If constipation
develops
Preventive measures
-Prophylatic medications
-Maintain adequate fluid and dietary
fiber intake
-Exercise if feasible
If constipation
persists
-Asses cause and severity
-Rule out obstruction
-Treat other causes
-Titrate stool
softener/laxatives
-Consider co-analgesics to
allow reduction of opioid dose
-Reasses cause and severity
-Check for impaction
-Consider other agent (Mg(OH)2, bisacodyl,
lactulose,sorbitol)
- Saline, or tap water enema
-Consider use of prokinetic agent
-Consider neuraxial analgesics

38. Nausea
If nausea
develops
Preventive measures :
Prophylatic with antiemetic agents are highly recommended for
patients with prior history of opioid induced nausea
If nausea persists
> 1 week
-Asses for other causes of
nausea
-Consider haloperidol or
metoclopramide (as needed
regimen)
-If nausea persist administer
antiemetics around the clock for
1 wk, then change as needed
-Reasses cause
and severity
-Consider
opioid rotation
If nausea persists
after trial of several
opioids
-Reasses cause and
severity
-Consider neuraxial
analgesics or
neuroablative
techniques

39. Managing severe pain in cancer patient*
• Assesment for severe cancer pain:
 Give IV drip morphine 10 mg/ 24 hours for opioid naive
patients and 15 mg/ 24 hours for opioid tolerant patients
 Re-asses efficacy and side effects at 2 hours
 If the pain score is unchanged, patient can be given morphine
bolus 10% from total dose every 2 hour, repeated 10 times at
maximum
 If the pain score↓, maintain the IV morphine dose
 Calculate the 24-hour total opioid requirement and continue
the same dose as needed over the initial 24 hours for the next
day
 Based on the 24 hours total IV morphine dose requirement,
IV morphine should be converted to oral morphine immediate
or sustained released then converted to opioid patch as
indicated (see conversion table)
Opioid naive includes patients who are not chronically receiving opioid analgesic on a daily basis
Opioid tolerant includes patients who are chronically receiving opioid analgesic on a daily basis
*modified based on experience from Advisory Board Member of Cancer Pain Management

40. Pain management in opioid naive patients
For ALL pain
levels
Severe
Pain score 7-10
**
•Recognize and treat
analgesic side effects
•Consider adding co-
analgesic for spesific
pain syndrome
•Provide psychosocial
support
•Provide patient and
family education
•Optimize
nonpharmacologic
• See **AND
•Rapidly
titrate
short-acting
opioid
• Begin
bowel
regimen
Moderate
Pain score 4-6
• See **
AND
•Titrate
short-acting
opioid
•Begin
bowel
regimen
Mild
Pain score 0-3
• See **AND
• Consider NSAID or
paracetamol without opioid if
patient is not on analgesics
•Consider titrating short-
acting opioid
•Begin bowel regimen
Reevaluate pain at each
contact and as needed to
meet patient goals for
comfort and function
NCCN Clinical Practice Guideline in Oncology. Adult cancer pain. 2010. www.nccn.org

41. Initiating short acting opioids in
opioid naive patients

42. Pain score ≥ 4
Oral peak effect (60 min) IV bolus (peak
effect 15 min)
Dose 5-15 mg oral short-acting
morphine sulfate or equivalent
Reasses efficacy and side effects at 60 min
↑ dose by 50-
100%
Pain score
unchanged or ↑
Pain score ↓
to 4-6
Pain score ↓ to 0-3
Repeat same
dose
Continue at
current effective
dose as needed
over initial 24 h
After 2-3
cycles,
consider IV
titration
and/or
subsequent
management
and
treatment
See detail in
next slide
NCCN Clinical Practice Guideline in Oncology. Adult cancer pain. 2010. www.nccn.org

43. Pain score ≥ 4
Oral peak effect
(60 min)
IV bolus (peak effect 15 min)
Dose 2-5 mg IV morphine
sulfate or equivalent
Reasses efficacy and side effects at 15 min
↑ dose by 50-
100%
Pain score
unchanged or ↑
Pain score ↓
to 4-6
Pain score ↓ to 0-3
Repeat same
dose
Continue at
current effective
dose as needed
over initial 24 h
After 2-3
cycles, for
subsequent
management
and treatment
NCCN Clinical Practice Guideline in Oncology. Adult cancer pain. 2010. www.nccn.org

44. Pain management in opioid tolerant patients
For ALL pain
levels
Severe
Pain score 7-10
**
-Provide
psychosocial
support
-Provide
patient and
family
education
• See **AND
• reevaluate opioid
titration
•Reevaluate working
diagnosis with a
comprehensive pain
assesment
•Consider spesific pain
syndrome problems
•Consider pain
specialty consultation
•Reevaluate co-
analgesics as indicated
Moderate
Pain score 4-6
• See **AND
• Continue opioid
titration
• Consider spesific
pain syndrome
problems
• Consider pain
specialty
consultation
• Continue co-
analgesic titration
Mild
Pain score 0-3
• See **AND
• Continue opioid
titration
• reassess and
modify regimen
to minimize side
effects
•Co-analgesics as
needed
NCCN Clinical Practice Guideline in Oncology. Adult cancer pain. 2010. www.nccn.org

45. SUMMARY
• Pain is prevalent, underestimated, debilitating
• Pain is the most common symptom of cancer
– Effective management of moderate to severe cancer
pain requires treatment with opioids
– Cancer pain management is an important factor in
maintaining Quality of Life
• Safe and effective opioid analgesics are available
– However, careful pain assesment and drug titration are
needed
Rich BA. Ethics of opioid analgesia for chronic noncancer pain. Pain Clinical Updates. Dec 2007

46. TERIMA KASIH
dradjat_rs@ yahoo.com