Best Supportive Care For Cancer Related Pain · 1. J Pain Symptom Manage 1993;8:63-67.2....
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Transcript of Best Supportive Care For Cancer Related Pain · 1. J Pain Symptom Manage 1993;8:63-67.2....
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!!
(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
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
Long-acting medication should be started as soon as 24 hours
NCCN Guideline 2015
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
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