疼痛治療新紀元疼痛治療新紀元

魏正宗

中山醫學大學附設醫院過敏免疫風濕科主任

Census data for 1999.Census data for 1999.CDC. MMWR Morb Mortal Wkly Rep. 2001;50:120-125.CDC. MMWR Morb Mortal Wkly Rep. 2001;50:120-125.

% All Disabilities% All Disabilities

StrokeStroke

Blindness or VisionBlindness or Vision

DiabetesDiabetes

Mental or EmotionalMental or Emotional

Limb/Extremity StiffnessLimb/Extremity Stiffness

Deafness or HearingDeafness or Hearing

Lung or RespiratoryLung or Respiratory

Heart Trouble, Hardening of the ArteriesHeart Trouble, Hardening of the Arteries

Back or SpineBack or Spine

Arthritis Arthritis

00 22 44 66 88 1010 1212 1414 1616 1818

2.8%2.8%

3.3%3.3%

3.4%3.4%

3.7%3.7%

4.2%4.2%

4.4%4.4%

4.7%4.7%

7.8%7.8%

16.5%16.5%

17.5%17.5%

Arthritis & Back Pain are LeadingArthritis & Back Pain are Leading Causes of Disability Causes of Disability

About 39 million physician visits/ yr1

More than 500,000 hospitalizations/ yr1

1 1 CDC, Arthritis Foundation. National Arthritis Action Plan: A Public Health Strategy. 1999. CDC, Arthritis Foundation. National Arthritis Action Plan: A Public Health Strategy. 1999.

History of Pain Management

OPIOID

NSAIDs

OTHERs

4

Pain Physiology

Stage of Nociception

4. PERCEPTION

3. MODULATION

2. TRANSMISSION

1. TRANSDUCTION Conversion of noxious, or harmful stimuli (mechanical, thermal, chemical) into nervous impulse, or action potential

Communication of the nerve impulse from the periphery to the spinal cord, up the spinothalamic track to the thalamus and cerebral cortex

Process by which impulse travel from the brain back down to the spinal cord to selectively inhibit (or sometimes amplify) pain impulses

Net result of three events – the subjective experience of pain

5

Peripheral Chemical Mediators of Pain

6

D’Amours RH et al. JOSPT 1996;24(4):227-36. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.Pini LA et al. JPET 1997;280(2):934-40.Chandrasekharan NV et al. PNAS 2002;99(21):13926-31.

OpioidsTramadol

Anti-spasmodicsAnti-depressants Anti-convulsant

NSAIDsCOX-2 inhibitors

SteroidLocal therapy

Paracetamol/Acetaminophen

Combination Therapy Model of PainCombination Therapy Model of Pain

Acetaminophen / PanadolAcetaminophen / Panadol

Always first line drug of choice for painAlways first line drug of choice for pain

Analgesic and anti-pyretic, but not anti-Analgesic and anti-pyretic, but not anti-inflammatoryinflammatory

Possible COX-3 inhibitorPossible COX-3 inhibitor

Essential for combination therapiesEssential for combination therapies

NSAIDsNSAIDsDrugsDrugs Trade Trade dose(mg)dose(mg) Half life Half life Max doseMax doseIndomethacinIndomethacin IndocidIndocid bidbid 4.64.6 200200Tiaprofenic acidTiaprofenic acid SurgemSurgem bidbid 3.03.0 600600TenoxicamTenoxicam TicotilTicotil qd, im,ivqd, im,iv 7272KetoprofenKetoprofen ProfenidProfenid bid, imbid, im 22 400400DiclofenacDiclofenac Voltaren Voltaren tidtid 44 150150SulindacSulindac Clinoril Clinoril bidbid 1616 400400

NaproxenNaproxen NaposinNaposin bidbid 1414 15001500NabumetoneNabumetone RelifexRelifex bidbid 2626 10001000IbuprofenIbuprofen MotrinMotrin qidqid 22 32003200FenbufenFenbufen CinopalCinopal bidbid 1111MeclofenamateMeclofenamate PonstanPonstan tidtid 22 400400

PiroxicamPiroxicam FeldeneFeldene qdqd 5757 2020MepirizoleMepirizole MebronMebron tidtid 44 450450

Acetylsalicyclic acidAcetylsalicyclic acid AspirinAspirin tidtid 44 60006000

Upper GI Bleed Risks for NSAIDsCompared with not Taking NSAIDs

Hernández-Diaz & Garcia Rodríguez, Arch Intern Med 2000

Piroxicam

Ketoprofen

Indomethacin

Naproxen

Sulindac

Diclofenac

Ibuprofen

1 10Relative risk for upper GI bleed/perforation

1 2 3 4 5 6

H.pylori infection

Co-morbid illness

Steroid therapy

Anticoagulant

Age (>65)

Multiple NSAIDs(including ASA)

Prior GI events

Risk Factors ofRisk Factors ofUlcer Complications from Ulcer Complications from

NSAIDsNSAIDs

Relative risk

2.5-4.8

2-4

2-3.5

3

2

2

2

ARAMIS StudyARAMIS Study

研究發現研究發現 1,9211,921位長期服用位長期服用 NSAIDNSAID的的 RARA患患者者併用制酸劑或併用制酸劑或 HH22-antagonist-antagonist反而會增加發反而會增加發生嚴重腸胃併發症的危險性！生嚴重腸胃併發症的危險性！

Singh, et al. Arch Intern Med. 1996;156:1530–1536.

ANTACID

CAUTIONH2

Patients on antacid/H2： GI event risk 3.4%

Not on co-therapy ： GI event risk 1.4%

Odds ratio = 2.14, p < 0.05

COXib + PPICOXib + PPI

COXibCOXib

NSAID + PPINSAID + PPI

NSAID + NSAID + HpHp eradication eradication

Efficacies of GI Preventive StrategiesEfficacies of GI Preventive Strategies

Chan FKL. NEJM 2002; 347: 2104-10; Chan FKL. Lancet 2007; 369: 1621-6

Concept of COX-2Concept of COX-2

Jone Vane. Nature 1994; 367: 215

OsteoarthritisOsteoarthritis

Etoricoxib vs. Diclofenac :Etoricoxib vs. Diclofenac :WOMAC Pain Subscale*WOMAC Pain Subscale*

Mea

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ase

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p

ain

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vel

(mm

)

2 4 6S

Morepain

Lesspain

Etoricoxib 60 mg once daily (n=253)Diclofenac 50 mg three times daily (n=258)

R

NSAIDwashoutperiod

Weeks postrandomization

–40

–30

–20

–10

0

–5

–15

–25

–35

Etoricoxib provided effective and sustained pain relief similar to diclofenac

*0- to 100-mm VAS (0 = no pain to 100 = extreme pain)

Adapted from Zacher J et al Curr Med Res Opin 2003;19(8):725–736.

SE = standard error

aInvestigator assessment, total 68 each; bp=0.005 for naproxen vs. placebo; cp<0.001 for etoricoxib vs. placebo; dp<0.001 for etoricoxib vs. naproxen; ep<0.001 for both etoricoxib and naproxen vs. placebo; fp=0.779 for etoricoxib vs. naproxen; g500 mg twice daily

Adapted from Matsumoto AK et al J Rheumatol 2002;29:1623–1630; Collantes E et al BMC Fam Pract 2002;3(1):10.

Rheumatoid ArthritisRheumatoid Arthritis Etoricoxib vs. Naproxen : Etoricoxib vs. Naproxen : Tender-Joint CountTender-Joint Countaa

Mea

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han

ge

fro

m

bas

elin

e (

SE

)

Weeks in study

–20

–15

–10

5

0

–5

Placebo Etoricoxib 90 mg Naproxen 1000 mgg

(n=315 US, n=349 Int) (n=321 US, n=351 Int) (n=169 US, n=178 Int)

S R 8 12

–20

–15

–10

0

–5

2 4

5International (n=878)

e,f

Improvedresponse

S R 8 12

Weeks in study2 4

US (n=805)

b

c,d

Lessimproved

Moreimproved

Ankylosing SpondylitisEtoricoxib vs. Naproxen: Patient Assessment of Spine Paina (Parts I and II)

Placebo(n=93)

Etoricoxib 90 mg(n=126)

Etoricoxib 120 mg(n=123)

Naproxen 1000 mgd

(n=125)

–50

–40

–30

–20

–10

0

Weeks in study

S

LS

mea

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han

ge

fro

mb

asel

ine

(

±SE

)

2 8 34 52

b,c

a0- to 100-mm VAS (0 = none to 100 = severe); bp<0.050, etoricoxib 90 mg vs. naproxen; cp<0.010 etoricoxib, 120 mg vs. naproxen; d500 mg twice daily

Adapted from van der Heijde D et al Arthritis Rheum 2005;52:1205–1215.

R 16 432664

Part I Part II

LS = least squares; SE = standard error; R = randomization; CI = confidence intervala0- to 4-point Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme); bLS mean change from baseline four hours after initial dose = –0.94; 95% CI, –1.11, –0.76; cLS mean difference from indomethacin = 0.09 (–0.14, 0.33) over days 2 to 8; dLS mean change from baseline four hours after initial dose = –1.04, 95% CI, –1.22, –0.86; eLS mean difference from indomethacin = –0.07 (–0.27, 0.14); f50 mg three times daily

Adapted from Schumacher HR Jr et al BMJ 2002;324:1488–1492; Rubin BR et al Arthritis Rheum 2004;50:598–606.

LS

mea

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fro

m

bas

elin

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SE

)

Etoricoxib produced substantial improvement vs. baseline at 4 hoursEtoricoxib produced substantial improvement vs. baseline at 4 hours

R 5

–2.0

–1.0

–3.02

0.0

64 hr 3 4 6 7 8

Day in study

–0.5

–1.5

–2.5

Acute Gouty ArthritisAcute Gouty Arthritis

Etoricoxib vs. IndomethacinEtoricoxib vs. Indomethacin :: Patient Assessment of PainPatient Assessment of Painaa

Study 1b,c

R 5

–2.0

–1.0

–3.02

0.0

64 hr 3 4 6 7 8

–0.5

–1.5

–2.5

Day in study

Study 2d,e

Etoricoxib 120 mg (n=72 study 1, n=101 study 2)

Indomethacin 150 mgf

(n=71 study 1, n=83 study 2)

NSAIDs = nonsteroidal anti-inflammatory drugs; PUBs = perforations, ulcers, bleeds *Combined analysis of 10 clinical trials in OA, RA, and chronic low back pain; **Naproxen 1000 mg/day, ibuprofen 2400 mg/day, or diclofenac 150 mg/dayAdapted from Hunt RH et al Am J Gastroenterol 2003;98:1725–1733; Curtis S et al. Poster presented at EULAR, 2002.

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cid

en

ce

Days (active treatment period)

0 90 180 270 360 540

0.02

0.04

0.06

0.00

Etoricoxib 60 mg (n=3142)Nonselective NSAIDs combined** (n=1828)

p<0.001~ 55%

Riskreduction

450

EtoricoxibEtoricoxib vs. Nonselective NSAIDs: GI PUBs vs. Nonselective NSAIDs: GI PUBs

Etoricoxib had lower incidence of confirmed PUBs in the Etoricoxib had lower incidence of confirmed PUBs in the clinical development program*clinical development program*

Meta-analysis of Randomized Trials ofCOX-2 Selective NSAIDs vs Placebo

Kearney et al. BMJ. 2006;332:1302.

3 Trials 46 countries 1380 sites EDGE (OA): N=7,111 EDGE II (RA): N=4,086 34,701

patients MEDAL (OA/RA): N=23,504

MEDAL Program Trials

n=17,412RANDOMIZE

Etoricoxib60 or 90 mg/d (OA)

90 mg/d (RA)

Diclofenac150 mg/d

(50 mg tid or 75 mg bid)

n=17,289

≥ 50 years of age OA of knee, hip, hand,

or spine; or RA Require long-term therapy

with traditional NSAID orCOX-2 inhibitor

Broad CV risk Allowed aspirin and PPI

use in appropriate patients

Mean duration of therapy=18 months

MEDAL Program: Cumulative Incidence of Confirmed Thrombotic CV Events (PP)

CV = cardiovascular; PP = per protocol; CI = confidence interval; HR = hazard ratio

Adapted from Cannon CP et al. Lancet. 2006; in press.

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, %

(95

% C

I)

Months

0 6 4224

Etoricoxib 60 and 90 mg pooled (320 events)Diclofenac 150 mg (323 events)

7

0

Patients at risk Etoricoxib 16,819 13,359 10,733 8277 6427 4024 805 Diclofenac 16,483 12,800 10,142 7901 6213 3832 815

12 18 30 36

6

5

4

3

2

1

Etoricoxib vs diclofenacHR=0.95 (95% CI: 0.81, 1.11)

P=0.496

Primary Endpoint

CV safety of NSAID & COXIBCV safety of NSAID & COXIBSummary : Meta-analysis & Systemic Review Summary : Meta-analysis & Systemic Review

• Rofecoxib Rofecoxib << 25 mg/d 25 mg/d RR RR 1.33* -1.73*1.33* -1.73*

> 25 mg/d> 25 mg/d 2.19* 2.19*• Celecoxib Celecoxib >> 400 mg/d 400 mg/d 1.56* -2.70* 1.56* -2.70*

<< 200 mg/d 200 mg/d 1.0 1.0• NaproxenNaproxen 0.92-0.97 0.92-0.97• DiclofenacDiclofenac 1.40* -1.63*1.40* -1.63*• PiroxicamPiroxicam 1.06 ( 0.70-1.59 ) 1.06 ( 0.70-1.59 )• IbuprofenIbuprofen 1.07-1.51*1.07-1.51*

Balancing GI and CV Safety

• GI events– Gastric ulcer 20%

in 3 mo– PUB in 10% in 1 yr

• CV events– 26 events in 8000 pts– 4% vs 2% cumulative

incidence in 2 yr

•Effect Size (ES)

•Number need to treat (NTT)

Identify risk factors is most important!

Strategies to use NSAIDStrategies to use NSAID

tNSAID tNSAID +cardioprotection+cardioprotection

tNSAID+PPItNSAID+PPI

Coxib at low dose Coxib at low dose +cardioprotection+cardioprotection+/- PPI+/- PPI

tNSAIDtNSAID CoxibCoxib

tNSAID+PPItNSAID+PPI

CV risk

GI risk

tNSAID Coxib or tNSAID+PPI

In In 2% of patients treated with etoricoxib2% of patients treated with etoricoxib

Etoricoxib NaproxenPlacebo 60 or 90 mg daily 1000 mg daily(n=1011) (n=1547) (n=790)

Asthenia/fatigue 1.3 2.2 1.8Dizziness 1.3 2.1 2.5Lower extremity edema 1.9 2.1 2.3Upper respiratory infection 4.0 5.4 6.3Hypertension 1.5 3.6 2.8Diarrhea 4.0 4.6 2.8Epigastric discomfort 1.7 2.0 3.8Heartburn 1.3 2.2 4.2Nausea 2.6 3.5 4.1Sinusitis 2.1 2.0 1.3Headache 4.8 5.9 3.2Urinary tract infection 3.4 2.9 3.0

Tolerability, Tolerability, EtoricoxibEtoricoxib

Physical measures – patient educationPhysical measures – patient education

MedicationMedication

Intra - articularIntra - articularAnalgesicsAnalgesicsAnti- inflammatoryAnti- inflammatory

NSAIDs plus PGE2/PPI, COXIB

NSAIDs plus PGE2/PPI, COXIB Tramadol

Capsaicin Opioids

Tramadol Capsaicin Opioids

ParacetamolParacetamolDepot steroids

HyaluronateDepot steroids

Hyaluronate

Antispasmodics / Antidepressants / Anthraquinone / Lipids Antispasmodics / Antidepressants / Anthraquinone / Lipids

SurgerySurgery

Clinical Rheumatol (2006) 25 (Suppl 1): S22-S29

ACR 2006 Guideline for OA Management

COX II COX II 抑制劑健保給付規範抑制劑健保給付規範

COX II COX II 抑制劑（包含抑制劑（包含 celecoxib, nabumetone, meloxicam, celecoxib, nabumetone, meloxicam, etodolac, nimesulide, rofecoxibetodolac, nimesulide, rofecoxib 與 與 etoricoxibetoricoxib）之使用規範）之使用規範

- - 本類製劑之使用需合乎衛生主管機關所核准之適應症本類製劑之使用需合乎衛生主管機關所核准之適應症範圍，並符合下列之一者範圍，並符合下列之一者

1.1.年齡大於等於年齡大於等於 6060歲之骨關節病患歲之骨關節病患2.2.類風濕性關節炎、僵直性脊椎炎、乾癬性關節炎等慢類風濕性關節炎、僵直性脊椎炎、乾癬性關節炎等慢

性發炎性關節病變，需長 期使用非類固醇抗發炎劑者 性發炎性關節病變，需長 期使用非類固醇抗發炎劑者3.3.合併有急性嚴重創傷、中風、及心血管疾病合併有急性嚴重創傷、中風、及心血管疾病4.4.同時併用腎上腺類固醇之患者同時併用腎上腺類固醇之患者5.5.曾有消化性潰瘍、上消化道出血或胃穿孔病史者曾有消化性潰瘍、上消化道出血或胃穿孔病史者6.6.同時併用抗凝血劑者同時併用抗凝血劑者7.7.肝硬化患者肝硬化患者 - - 使用本製劑之病患不得使用本製劑之病患不得預防性預防性 併用 併用 H2 H2

antagonistsantagonists 、 、 PPIPPI 及其他消化性潰瘍用藥，亦不得 及其他消化性潰瘍用藥，亦不得 合併使用前列腺素劑 合併使用前列腺素劑 ((如如 misoprostol)misoprostol)

COXIB商品名 ARCOXIA CELEBREX MOBIC LONINE

藥名（學名） Etoricoxib Celecoxib Meloxicam Etodolac

選擇性分級 專一性 Specific 專一性 Specific 選擇性 Preferential 選擇性 Preferential

Onset 24 mins 1 hrs Lack of data 30 mins

Half-life 22 hrs 11 hrs 15~20 hrs 11 hrs

T (max) * 1 1 hrs 2.8 hrs 4~5 hrs 2.8 hrs

GI Safety Data 顯著優於傳統 NSAID 50%

顯著優於傳統 NSAID 50%

稍低於傳統 NSAID 稍低於傳統 NSAID

懷孕危險 NA C C C

適應症 骨關節炎 (OA)與類風濕性關節炎 (RA) 、痛風性關節炎、原發性經痛

骨關節炎、類風濕性關節炎、急性疼痛、原發性經痛、減少家族性腺瘤息肉症之息

肉數目

類風濕性關節炎，骨關節炎及僵直性脊椎

炎

骨關節炎及類風濕性關節炎，止痛

用法 OA: 60 mg QD; RA: 90 mg QD; 急性痛風和經痛 : 120 mg QD

<8天

OA: 100 mg BID RA: 100-200 mg BID 原

發性經痛 : 400mg/day

RA:15mg/day OA:7.5-15 mg/day

AS:15mg/day

OA: 100mg BID or 200 mg QD RA: 100-

200 mg BID

每日藥費 (NT) 26.9 26.9~52.8 17.8~35.6 24

ConclusionsConclusions

• Combination therapy modelCombination therapy model• Balancing benefits and risks of NSAID Balancing benefits and risks of NSAID

– BENEFITS: NSAID BENEFITS: NSAID ≈≈ COXIB COXIB • Pain relief Pain relief • Anti-inflammationAnti-inflammation• Improved QOL, mobility, functional statusImproved QOL, mobility, functional status

– RISKS RISKS - - Gastrointestinal: NSAID > Gastrointestinal: NSAID > COXIBCOXIB- Cardiovascular: COXIB ≈ NSAID- Cardiovascular: COXIB ≈ NSAID- Renal : COXIB ≈ NSAID- Renal : COXIB ≈ NSAID