Principles in cancer pain management = j ansen 2014

PRINCIPLES IN CANCER PAIN MANAGEMENT

DRADJAT SUARDIKetua PP Perhimpunan Onkologi Indonesia

Ketua PP Masyarakat Paliatif IndonesiaKetua Tim Kanker RSHS/FK UNPADKetua Tim Paliatif RSHS/FK UNPAD

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

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

All AC, Huyce LI, Pain Cancer and older adults 199Ahmedzi 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

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

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






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

Spinothalamictract Peripheral

nerve

Dorsal Horn

Dorsal root ganglion

Pain

Ascendinginput

Descendingmodulation

Peripheralnociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.

PERCEPTION

MODULATION

TRANSMISSION

TRANSDUCTION

OPIOID

Local AnesthesiNSAID/COXIB

No single drug can produce optimal analgesia without adverse effect

Pain pathway and multi-modal mechanism of pain treatment

9

OPIOIDAntidepresan

OPIOIDParacetamol

Trauma: inflammation or

non-inflammation

ParacetamolAdvantages • 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

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)


OpioidsAdvantages • 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


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

Why opioid for severe pain ?

Rapidly titrate short-acting opioid

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

Opioid CharacteristicsCodeine 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 constipationLess 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

dysfunctionSafe 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

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 10Time (hours)

Paracetamol/

Tramadol Para-cetamol

Tramadol

Pain

relie

f

• 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. 2001Ho 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.

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.

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

Barriers to Cancer Pain Management

Barrier %• 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

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

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.

Around-the-ClockMedication

Breakthrough pain

Over Medication

Background pain

Time

Managing Cancer Pain

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.

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.

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






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


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.

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



SwitchingCommonly 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.

Oral and parenteral opioid equivalences and relative potency of drugs as compared with morphine based

on single dose studiesOpioid agonists Parenteral

doseOral dose Factor (IV to

PO)Duration of

actionCodeine 130 mg 200 mg 1.5 3-4 hFentanyl 100 mcg - - 1-3 hMorphine 10 mg 30 mg 3 3-4 hTramadol - 50-100 mg - 3-7 hHydromorphone* 1.5 mg 7.5 mg 5 2-3 hLevorphanol* 2 mg 4 mg 2 3-6 hOxycodone* - 15-20 mg - 3-5 hOxymorphone* 1 mg 10 mg 10 3-6 hHydrocodone* - 30-45 mg - 3-5 h


Recommended dose conversion from other opioid to transdermal Fentanyl

Transdermal

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 7.550 40 120 260 400 60 3 1575 60 180 390 600 90 4.5 22.5

100 80 240 520 500 120 6 30


IV = intravenousSC = subcutaneousO = oral

Opioid side effects• Initial

– Nausea and vomiting– Dizziness– Somnolence– Pruritis – Sweating– Urinary retention

• Late– Constipation

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

http://www.nccn.org/

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

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

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

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 basisOpioid 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

Pain management in opioid naive patients

For ALL pain levels

SeverePain 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



Initiating short acting opioids in opioid naive

patients

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


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



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 ↑



Repeat same dose

Continue at current effective dose as needed over initial 24 h

After 2-3 cycles, for

subsequent management

and treatment



Pain management in opioid tolerant patients

For ALL pain levels

SeverePain 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



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

TERIMA KASIHdradjat_rs@ yahoo.com

Health & Medicine

Principles in cancer pain management = j ansen 2014