Best Supportive Care

For Cancer Related Pain

黃明立 醫師 / 苗栗大千綜合醫院 癌症中心

minglih16@gmail.com

20181026

疼痛

身體症狀

心理面

社會面

文化面 靈性的

Suffering

受苦

Woodruff, 1999

Impact of Pain

on The Dimensions of Quality of Life

Adapted from Ferrell et al. Oncol Nurs Forum. 1991;18:1303–9.

Physical

•Functional ability

•Strength/fatigue

•Sleep and rest

•Nausea

•Appetite

•Constipation

Social

•Caregiver burden

•Roles and relationships

•Affection/sexual function

•Appearance

Psychological

• Anxiety

• Depression

• Enjoyment/leisure

• Pain/distress

• Happiness

• Fear

• Cognition/attention

Spiritual

• Suffering

• Meaning of pain

• Religiosity

止痛的選擇不是只有藥物…

• Multidimensional evaluation

• Pharmacotherapy

– Non-opioids

– Opioids

– Atypical analgesics / co-analgesics / adjuvants

• Interventional Pain Management

• Surgery/ Radiotherapy/ Chemotherapy

• Palliative care

• Psychotherapy

• Physiotherapy / Ergotherapy

• Lifestyle & nutrition

• Cognitive behavioral therapy / ACT

Pain= multimodal treatment approach

We need friends!!

相信病患的疼痛陳述

和開不開嗎啡藥物是兩碼事

(以前)疼痛治療

強效鴉片 Strong Opioids ± Non-Opioids

非鴉片類 Non-Opioids

Ex: NSAID非類固醇消炎藥, COX 2-inhibitors 環氧化酶抑制劑, acetaminophen

Ex: Ultracet, 可待因

Ex: 嗎啡、二氫嗎啡酮、

吩坦尼

Co

-an

alg

esic

s

輔助藥品

弱效鴉片 Weak Opioids ± Non-Opioids

感覺接受性疼痛

BACK-UP SLIDES

弱鴉片類

Codeine / Tramadol

強鴉片類 Oxycodone ≤20mg

Morphine ≤30mg

Hydromorphone ≤4mg

Acetaminophen

NSAID

Oxycodone

Morphine

Hydromorphone

Fentanyl

By the mouth / By the clock / By the ladder [口服/按時/階段] For the individual [個人差異]

Adjuvant Mx [輔助]

Attention to detail [注意細節]

WHO 第二階梯鎮痛藥物的使用存爭議

-無證據顯示弱類鴉片藥物的有效性

-第二階梯藥物療效僅持續30-40天

-弱類鴉片藥物存在“天花板效應”

-許多研究者建議取消WHO第二階梯鎮痛

對於中度疼痛，可考慮以低劑量強類鴉片藥物替代

弱鴉片藥物與非鴉片藥物

Ripamonti CI, et al. Annals of Oncology. 2012;23 (Suppl 7):vii139-vii154.

2012 年 ESMO 癌痛治療指南

9

Recent Guidelines on Weak Opioids

• Does not clearly classify opioids

• Strong opioids can be considered in patients with all pain levels!

NCCN

• For mild to moderate pain, as an alternative,

• low doses of strong opioids should be considered ESMO

• For mild to moderate pain, alternatively,

• low doses of a step III opioid may be used. EAPC

NCCN: National Comprehensive Cancer Network;

ESMO: European Society for Medical Oncology;

EAPC: European Association for Palliative Care

A two-step analgesic approach

12

Step 2

Codeine / Tramadol

+/- Adjuvants

+/-Adjuvants

Step 1

Paracetamol

Increasing pain intensity

Oxycodone, morphine, hydromorphone, fentanyl

New step 2

WHO analgesic ladder

Ladder 1

Non-Opioid ± Adjuvant Ladder 2

Weak Opioid

± Non-Opioid

± Adjuvant

Ladder 3

Strong Opioid

± Non-Opioid

± Adjuvant

13

Ladder 2

low dose Strong Opioid ± Non-Opioid

± Adjuvant Mild to Moderate Pain

Moderator to Severe Pain

Moderator to Severe Pain

Mild to Moderator Pain

NEW

2018/10/23

Re-assess as needed

Initial Assessment

Drug Therapy

Re-assess

Pain persists

Titrate/Switch/Rotate

Re-evaluate

14

Goals:

• Background pain ≤ 3 (NRS)

• Breakthrough pain < 3 times/day

• Manageable side-effects

Time 時間

Pain

In

ten

sity

疼痛強度

Background Cancer Pain

背景癌症疼痛

強效、速效藥物

強效、速效藥物

強效、速效藥物

Cover ongoing and breakthrough pain

按時給予藥物治療 (強效、長效藥物)

15

Rule of 3

• Long-acting after 3天 of short-acting [可以更快些]

• Pain score ≤ 3分

• Breakthrough pain ≤ 3次 in a day

• When breakthrough > 3 times / day

增加“按時給藥”的劑量

16

How Long Should the Titration Period Be?

NCCN

NCCN Guideline 2015

How Long Should the Titration Period Be?

NCCN

Long-acting medication should be started as soon as 24 hours

NCCN Guideline 2015

Overview

Strong Opioids Introduction

New Strong Opioids in Taiwan

Morphine Fentanyl

速效藥物

長效藥物

For the last 10+ years…

Morphine

Injection

Morphine

IR 10mg

MST®

60 mg

MST

30 mg

12

mcg/ hr

25

mcg/ hr

50

mcg/ hr

Morphine Oxycodone Fentanyl Hydromorphone

(Junista)

速效藥物 Breakthrough

Pain

長效藥物 Background

Pain

An Updated Spectrum Now:

強效鴉片 四大天王

Morphine

Injection

Morphine

IR 15mg

MST®

60 mg

MXL®

60 mg

Morphine

SR 30 mg

12

mcg/ hr

25

mcg/ hr

50

mcg/ hr

Buccal Films / Tablet

Hydromorphon

e OROS 8 mg

OxyNorm®

5mg

OxyContin®

10mg

OxyContin®

20mg

Where do strong opioids (四大天王) come from?

OPIUM = dried latex from opium poppy(罌粟果)

Hydromorphone Oxycodone

Naloxone

Buprenorphine

Fentanyl Pethidine Methadone

NATURAL Morphine Codeine Thebaine

SEMI-

SYNTHETIC

Opium poppy

FULLY

SYNTHETIC

Four Major Strong Opiods Updated Spectum

• Morphine ( MXL )

• Oxycodon( Oxycontin, Oxynorm )

• Hydromorphone ( Hydromorphone OROS )

• Fentanyl (Painkyl, Fentora )

23

Morphine: Naturally-occurring opioid

• μ-receptor agonist

• Liver metabolism & renal excretion

– 60% M3G; 5-10% M6G

• Bioavailability: 15-69%

American Medical Directors Association. Pain management in the long term care setting. Columbia MD: 2012

MXL® Controlled Release Capsule

1.多重緩釋微粒技術

2.一天一次、長達24小時持續止痛

3.適合口服、吞嚥困難、管灌病患

25

26

開始作用: 1小時; 高峰期: 2~6小時; 效期: 24小時

27

•用法用量: 請整粒吞服或是打開膠囊，將內含的小顆粒倒入不含酒精的冷飲料內，也可搭配管灌溶液管灌給藥

28

Four Major Strong Opiods Updated Spectum

• Morphine ( MXL )

• Oxycodon( Oxycontin, Oxynorm )

• Hydromorphone ( Hydromorphone OROS )

• Fentanyl (Painkyl, Fentora )

29

Oxycodone

• First developed in 1917 in Germany

• Widespread global use for > 80 years

OxyContin®衛部藥輸字第026432, 026433, 026434, 026435, 026436, 026437, 026438號

OxyNorm®IR Capsules衛部藥輸字第026420, 026421, 026422號

OXYCONTIN, OXYNORM are Registered Trademarks.

OxyNorm® OxyContin®

Oxycodone: An interplay of µ- and k- receptors

Oxycodone µ κ Analgesia- supraspinal +++ -

Analgesia- spinal ++ +

Analgesia- peripheral ++ ++ Respiratory depression +++ -

Pupil constriction ++ +

Reduced GI motility ++ +

Euphoria +++ -

Dysphoria - +++

Sedation ++ ++

Rang HP, et al. Pharmacology, 5th Edition. . London: Churchill Livingstone, 2003

µ receptors

k receptors

1. J Pain Symptom Manage 1993;8:63-67.2. OxyContin® US Prescribing Information; April 2014. Purdue Pharma, LP, Stamford, CT, USA. Reference ID: 3490236 .

3. Leow KP et al. Clin Pharmacol Ther 1992;52:487-495. 4. Baillie SP et al. Age Ageing 1989;18:258-262. 5. Gourlay GK et al. Pain 1986;25:297-312 . 6. Säwe J et al.

Clin Pharmacol Ther 1981;30:629-635. 7. Säwe J et al. Br J Clin Pharmacol 1985;19:495-501. 8. Vallner, et al. J Clin Pharmacol 1981; 21: 152-6. 9. Ritschel et al. J

Clin Pharmacol 1987; 27: 647-53. 10.Parab PV et al. Biopharm Drug Dispos 1988; 9: 187-99. 11. Drover et al. Anesthesiology 2002; 97: 827-36. 12. Dale et al. Acta

Anaesthesiol Scand 2002; 46: 759-70

32

Superior Bioavailability of Oxycodone

60-87%

SUPERIOR ABSORPTION

Morphine 15-69%

Hydromorphone 10-65%

Oxycodone

Side-effects

OR 95% CI P-value Heterogeneity Effects model

I2 P-value

Dizziness 1.04 0.52-2.08 0.9 0% 0.83 Fixed

Nausea 0.52 0.32-0.85 0.009 0% 0.49 Fixed

Vomiting 0.61 0.33-1.13 0.12 0% 0.69 Fixed

Sleepiness 1.19 0.59-2.40 0.62 0% 0.61 Fixed

Pruritus 1.13 0.38-3.40 0.82 0% 0.73 Fixed

Constipation 0.55 0.35-0.87 0.01 11% 0.35 Fixed

Anorexia 0.7 0.14-3.51 0.67 0% 0.81 Fixed

Dysuria 1.45 0.43-4.91 0.55 0% 0.57 Fixed

OR, odds ratio; CI, confidence interval.

Oxycodone Tolerability Profile

Wang et al. Exp Ther Med. 2012; 4:249-254.

Meta-analysis of 7 RCTs with a total of 613 cancer patients with moderate-severe pain

Less nausea & constipation than morphine

Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain:

evidence-based recommendations from the EAPC. Lancet Oncol. Feb 2012;13(2):e58-68.

EAPC: use low-dose oxycodone

to replace weak opioids for moderate pain

34

A two-step analgesic approach

35

Step 2

Codeine / Tramadol

+/- Adjuvants

+/-Adjuvants

Step 1

Paracetamol

Increasing pain intensity

Oxycodone ≤ 20mg

New step 2

Lancet Oncol 2012; 13:e58-e68

Oxycodone Overview

Broad Spectrum Analgesia

Good Tolerability

Superior Bioavailability

SUPERIOR ABSORPTION

Earlier Use in Step II

Four Major Strong Opiods Updated Spectum

• Morphine ( MXL )

• Oxycodon( Oxycontin, Oxynorm )

• Hydromorphone ( Hydromorphone OROS )

• Fentanyl (Painkyl, Fentora )

37

Hydromorphone

• Long clinical history

• μ-(and minor d-) opioid receptor agonist

• 5 times more potent than morphine

• Low relative histamine release

• low protein binding(<30%)

• Metabolism

– M6G isn’t found in its metabolites

Jackie , et al ,Pain Practice, Volume 10, Issue 1, 2010 72–77

CNS Drugs. 2010 Apr;24(4):337-61

Drug Therapy Topics 2006; Vol 35 No 4

OROS ® Hydromorphone 8mg = Morphine 40mg/day

[OROS : Osmotic Release Oral System]

Cross-Sectional View of an

OROS® Push-Pull hydromorphone Tablet

Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19-24.

Laser-Drilled Hole

(point of drug release)

Hard Shell

(clear overcoat,

color overcoat)

Osmotic Pump

(Push layer)

Hydromorphone HCl

Rate-Controlling

Membrane

滲透壓幫浦 (推送層)

硬殼 (透明包衣 有色包衣)

速率控制膜

雷射小孔 (藥物釋出點)

Pharmacokinetic Profile after Multidose

IR Hydromorphone vs. OROS® hydromorphone

16 mg OROS® hydromorphone t72-96

4 mg IR hydromorphone q6h

72 78 84 90 96

Hyd

ro

mo

rp

ho

ne (

ng

/m

L)

0.0

0.5

1.0

1.5

2.0

2.5

Time (hr)

• Concentrations maintained higher than IR Cmin for 24 hours

• Fluctuations in plasma levels reduced by ~40%

16 mg OROS® hydromorphone q24h

Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19-24.

Four Major Strong Opiods Updated Spectum

• Morphine ( MXL )

• Oxycodon( Oxycontin, Oxynorm )

• Hydromorphone ( Hydromorphone OROS )

• Fentanyl (Painkyl, Fentora )

41

Mean absorption of opioids after 10 min in

the oral cavity2

0

15

30

45

60

Morphine Oxycodone Hydromorphone Fentanyl

Me

an a

bso

rpti

on

(%

) Hydrophilic Lipophilic

Potency 1 2 4 100

51%

Fentanyl

90 times stronger than morphine

highly lipophilic 5–8 minutes

Rapid onset

30–60 minutes

Short duration Its oral bioavailability is around 25% to 50%.

42

2018/10/23

Highest Bioavailability

Painkyl® Fentora® OTFC / ACTIQ®

Buccal absorption 51% 48% 22%

GI absorption 20% 17% 25%

Absolute

bioavailability 71% 65% 47%

Generation in

transmucosal fentanyl 1stgeneration 2nd generation 3rd generation

OTFC: oral transmucosal fentanyl citrate

Rapid-Onset-Opioid: delivery systems

1998 OTFC:

Oral trans-mucosal fentanyl citrate

OTFC/Actiq®

2006/2008

FBT:

Fentora® (US)

Effentora® (EU)

2009

FBSF:

Onsolis® (US)

2008 SLF:

Rapinyl®

/Abstral® (EU)

2009 INFS:

Instanyl® (EU)

2009 FPNS:

NasalFen® (EU)

44

Fentanyl buccal tablet Fentanyl buccal

soluble film

Sublingual Fentanyl Intranasal Fentanyl

spray

Fentanyl Pectin

nasal spray

Oral transmucosal

lozenge

1st generation in buccal 2nd generation 3rd generation Sublingual Intra nassal Intra nassal

Painkyl®

Morphine Oxycodone Fentanyl Hydromorphone

Junista

速效藥物 Breakthrough

Pain

長效藥物 Background

Pain

The picture is becoming more complete

Morphine

Injection

Morphine

IR 15mg

MST®

60 mg

MXL®

60 mg

Morphine

SR 30 mg

12.5

mcg/ hr

25

mcg/ hr

50

mcg/ hr

Buccal Films / Tablet

Hydromorphon

e OROS 8 mg

OxyNorm®

5mg

OxyContin®

10mg

OxyContin®

20mg