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
Arthritis & Back Pain are Leading  Causes of Disability Census data for 1999. CDC. MMWR Morb Mortal Wkly Rep. 2001;50:120-...
History of Pain Management OPIOID NSAIDs OTHERs
Pain Physiology
Stage of Nociception 4. PERCEPTION 3. MODULATION 2. TRANSMISSION 1. TRANSDUCTION Conversion of noxious, or harmful stimuli...
Peripheral Chemical Mediators of Pain
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;...
Acetaminophen / Panadol <ul><li>Always first line drug of choice for pain </li></ul><ul><li>Analgesic and anti-pyretic, bu...
<ul><li>NSAIDs </li></ul><ul><li>Drugs     Trade  dose(mg) Half life  Max dose </li></ul><ul><li>Indomethacin Indocid bid ...
 
Upper GI Bleed Risks for NSAIDs Compared with not Taking NSAIDs Hernández-Diaz & Garcia Rodríguez, Arch Intern Med 2000 Pi...
 
Risk Factors of Ulcer Complications from NSAIDs Relative risk 2.5-4.8 2-4 2-3.5 3 2 2 2
ARAMIS Study 研究發現 1,921 位長期服用 NSAID 的 RA 患者 併用制酸劑或 H 2 -antagonist 反而會增加發生嚴重腸胃併發症的危險性! Singh, et al.  Arch Intern Med . 19...
COXib + PPI COXib NSAID + PPI NSAID +  Hp  eradication Efficacies of GI Preventive Strategies Chan FKL.  NEJM  2002; 347: ...
Concept of COX-2 Jone Vane.  Nature 1994; 367: 215
Osteoarthritis Etoricoxib vs. Diclofenac : WOMAC Pain Subscale* Mean change from baseline in pain level (mm) 2 4 6 S More ...
Rheumatoid Arthritis   Etoricoxib vs. Naproxen :  Tender-Joint Count a SE = standard error a Investigator assessment, tota...
Ankylosing Spondylitis Etoricoxib vs. Naproxen:  Patient Assessment of Spine Pain a  (Parts I and II) Placebo (n=93) Etori...
Acute Gouty Arthritis Etoricoxib vs. Indomethacin   :   Patient Assessment of Pain a LS = least squares; SE = standard err...
NSAIDs = nonsteroidal anti-inflammatory drugs; PUBs = perforations, ulcers, bleeds  *Combined analysis of 10 clinical tria...
Meta-analysis of Randomized Trials of COX-2 Selective NSAIDs vs Placebo Kearney et al.  BMJ.  2006;332:1302.
MEDAL Program Trials <ul><li>3 Trials   46 countries  1380 sites </li></ul><ul><li>EDGE (OA):  N=7,111 </li></ul><ul><li>E...
MEDAL Program: Cumulative Incidence  of Confirmed Thrombotic CV Events (PP) CV = cardiovascular; PP = per protocol; CI = c...
CV safety of NSAID & COXIB Summary : Meta-analysis & Systemic Review  <ul><li>Rofecoxib  <  25 mg/d RR  1.33* -1.73* </li>...
Balancing GI and CV Safety <ul><li>GI events </li></ul><ul><ul><li>Gastric ulcer 20% in 3 mo </li></ul></ul><ul><ul><li>PU...
Strategies to use NSAID tNSAID +cardioprotection <ul><li>tNSAID+PPI </li></ul><ul><li>Coxib at low dose +cardioprotection+...
tNSAID Coxib  or  tNSAID+PPI
<ul><li>Etoricoxib Naproxen </li></ul><ul><li>Placebo 60 or 90 mg daily 1000 mg daily </li></ul><ul><li>(n=1011) (n=1547) ...
Physical measures – patient education Medication Intra - articular Analgesics Anti- inflammatory NSAIDs plus PGE2/PPI, COX...
COX II  抑制劑健保給付規範   <ul><li>COX II  抑制劑(包含 celecoxib, nabumetone, meloxicam, etodolac, nimesulide,  rofecoxib 與  etoricoxi...
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...
Conclusions <ul><li>Combination therapy model </li></ul><ul><li>Balancing benefits and risks of NSAID  </li></ul><ul><ul><...
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7.疼痛治療新紀元Final handout

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  • Arthritis is a leading cause of chronic disability among persons 18 years and older, representing nearly 18% of all such disabilities. Overall, 41.2 million noninstitutionalized US civilians 18 years and older suffer from a disability; 7.2 million (17.5%) suffer from arthritis. Back or spine problems are the second leading cause of chronic disability, representing 6.78 million US adults, or 16.5% of this population. 1 From August 1999 to November 1999, during personal household interviews of a representative sample of the US civilian, noninstitutionalized population (15 years and older), SIPP* (Survey of Income and Program Participation) collected information from 53,636 persons (36,700 households) about disability. Disability was assessed according to the following 8 measures: Ability to perform functional activities Activities of daily living Instrumental activities of daily living Presence of selected impairments Use of assistive devices Limitation in the ability to work around the house Limitation in the ability to work at a job or business (16 – 67 years of age) Receiving federal benefits on the basis of inability to work *The Survey of Income and Program Participation (SIPP) is a subsample of the 1990 US census. CDC. Prevalence of disabilities and associated health conditions among adults—United States, 1999. MMWR Morb Mortal Wkly Rep . 2001;50:120-125.
  • 而併用制酸劑(胃乳片)或 H2-antagonist ,可以解決這方面的問題嗎?從美國重要的風濕病研究 ARAMIS study 的結果來看,答案是否定的。 在研究中發現 1921 位長期服用 NSAID 的 RA 患者併用制酸劑或 H-antagonist 發生嚴重腸胃併發症的危險性比未併用前述藥物的病人還要高!其中原因可能是,這些藥物,只能抑制腸胃不適的症狀,卻無法預防 NSAIDs 引起的潰瘍。由於症狀被遮蔽,因此使醫師、病患對 NSAID 的腸胃毒性,掉以輕心而繼續服用 NSAIDs ,或者甚至加高 NSAIDs 的劑量,最終反而導致更嚴重的腸胃併發症。
  • Etoricoxib 60 mg once daily and diclofenac 50 mg three times daily provided similar, effective, and sustained relief of OA pain over the six-week study. The earliest effect for both drugs, measured on the WOMAC pain subscale, was recorded at the week 2 visit and persisted for the remainder of treatment with the maximum effect occurring at week 6. By the end of the study, VAS scores had decreased from randomization values by 31.3 mm in the etoricoxib 60 mg group and by 30.9 mm in the diclofenac 50 mg three times daily group. 8
  • Etoricoxib was superior to naproxen in one study (p&lt;0.001) and similar to naproxen in another study (p=0.779) in reducing the number of tender joints in RA patients at 12 weeks. In two RA studies, etoricoxib was superior to placebo (p&lt;0.001) in reducing the number of tender joints in RA patients at 12 weeks. In the US trial, 805 patients (n=315 for placebo, n=321 for etoricoxib, and n=169 for naproxen) were analyzed for efficacy, as assessed by investigators. At baseline, patients treated with placebo, etoricoxib 90 mg, and naproxen 1000 mg had an average of 29, 29, and 28 tender joints, which decreased after 12 weeks by 8.05, 14.44, and 10.76, respectively (p&lt;0.001 for etoricoxib vs. placebo; p=0.005 for naproxen vs. placebo; p&lt;0.001 for etoricoxib vs. naproxen). Lack of efficacy led to discontinuations for 54.5% (n=176) of the placebo group, 21.7% (n=70) of the etoricoxib group, and 36.5% (n=62) of the naproxen group. 7,10 In the international trial, 878 patients (n=349 for placebo, n=351 for etoricoxib, and n=178 for naproxen) were included in the primary efficacy analyses. Patients in the placebo, etoricoxib 90 mg, and naproxen 1000 mg groups had a mean of 29, 29, and 28 tender joints at baseline that decreased after 12 weeks by 11.09, 14.37, and 13.42, respectively (p&lt;0.001 vs. placebo for both etoricoxib and naproxen; p=0.779 for etoricoxib vs. naproxen). In this trial, 25.2% (n=90) of the patients who took placebo discontinued because of lack of efficacy, compared with 12.5% (n=44) of those treated with etoricoxib and 10.5% (n=19) of patients given naproxen. 8,10
  • An assessment of the mean change from baseline in patient assessment of spine pain for both part I (six weeks of treatment) and part II (46 weeks of treatment) indicated that the efficacy of etoricoxib was seen at six weeks and was maintained over a 52-week treatment course. Compared with naproxen 1000 mg (500 mg twice daily), etoricoxib 90 and 120 mg were significantly more effective in relieving spinal pain associated with AS during the first six-weeks (p&lt;0.050 for both) and the entire 52-week course (p&lt;0.050 for etoricoxib 90 mg, p&lt;0.010 for etoricoxib 120 mg). In addition, the combined results of the etoricoxib 90 mg and 120 mg groups indicate etoricoxib is superior to naproxen 1000 mg at six-weeks and 52-weeks (p&lt;0.010 for both time points). 1 All active treatments were significantly more effective than placebo (p&lt;0.001) at six weeks. Because patients were randomly assigned again to active treatment after part I, the results for the placebo group do not continue past this time point. 1 There was no significant difference between the etoricoxib 90 mg and 120 mg groups during either the six- or 52-week treatment period. 1
  • Etoricoxib provided considerable pain relief similar to that of indomethacin in patients with acute gouty arthritis (days 1 to 8). Patients with acute gouty arthritis rated their pain at baseline screening, four hours after the initial dose on day 1, and four hours after the morning dose on days 2 to 8. Baseline pain intensity was similar in the etoricoxib 120 mg and indomethacin 150 mg groups, and both drugs afforded similar relief during the seven days of treatment. Both drugs had a rapid onset of action: four hours after the first dose, the patient assessment of pain indicated substantial improvement from baseline (least squares [LS] mean change and 95% CIs: –0.94 [–1.11, –0.76] and –0.91 [–1.09, –0.73] for etoricoxib and indomethacin, respectively, in Study 1 and –1.04 [–1.22, –0.86] and –0.84 [–1.02, –0.66] in Study 2). The response was consistent in patients with polyarticular or monoarticular gout. The LS mean difference between etoricoxib and indomethacin over days 2 to 8 was 0.09 (95% CI, –0.41, 0.33) in Study 1 and –0.07 (95% CI, –0.27, 0.14) in Study 2. 7,8,24
  • The risk of upper GI perforations, ulcers, and bleeds (PUBs) was significantly lower with etoricoxib than with older conventional NSAIDs* (p&lt;0.001). A blinded expert adjudication of investigator-reported upper GI clinical events compared data from the combined analysis of 10 clinical trials in the clinical development program in patients with OA, RA, and chronic low back pain for the occurrence of PUBs in patients treated with etoricoxib 60, 90, or 120 mg once daily (n=3142) or nonselective NSAIDs (n=1828; naproxen 500 mg twice daily, diclofenac 50 mg three times daily, or ibuprofen 800 mg three times daily). Analysis included PUBs occurring during active treatment or within 14 days of stopping treatment. Confirmed PUBs occurred at a rate of 1.16/100 person-years with etoricoxib and 3.05/100 person-years with nonselective NSAIDs. Etoricoxib  60 mg decreased the risk of PUBs by approximately 55% compared with nonselective NSAIDs* (p&lt;0.001). 4,5 *Naproxen 1000 mg/day, ibuprofen 2400 mg/day, or diclofenac 150 mg/day
  • The primary composite thrombotic CV endpoint was the first occurrence of the following fatal and non-fatal events: myocardial infarction (including silent infarction), unstable angina pectoris, intracardiac thrombus, resuscitated cardiac arrest, thrombotic stroke, cerebrovascular thrombosis, transient ischemic attack, peripheral venous thrombosis, pulmonary embolism, peripheral arterial thrombosis, and sudden and/or unexplained death. A composite thrombotic CV endpoint was chosen in an effort to be as comprehensive as possible when capturing adverse cardiac events.
  • In the per protocol analysis, the rate of adjudicated and confirmed thrombotic cardiovascular events (the primary endpoint) with etoricoxib was similar to that with diclofenac. The hazard ratio for etoricoxib versus diclofenac was 0.95 (95% CI: 0.81, 1.11). The upper bound of 1.11 was less than the prespecified bound of 1.3; therefore, the noninferiority (primary) hypothesis was upheld. 1-3 References Cannon CP, Curtis SP, Bolognese JA, et al, for the MEDAL Steering Committee. Clinical trial design and patient demographics of the Multinational Etoricoxib vs. Diclofenac Arthritis Long-Term (MEDAL) Study Program: cardiovascular outcomes with a COX-2 selective inhibitor vs. a traditional NSAID in patients with osteoarthritis and rheumatoid arthritis. Lancet. 2006; in press. Cannon CP, Curtis SP, Bolognese JA, et al, for the MEDAL Steering Committee. Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program: cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis. Am Heart J. 2006;152:237–245. Data on file, MSD ____________.
  • In clinical trials, etoricoxib was evaluated for safety in approximately 4800 individuals, including approximately 3400 patients with OA, RA, or chronic low back pain (approximately 600 patients with OA or RA were treated for one year or longer). The adverse experience profile was similar in patients with OA or RA treated with etoricoxib for one year or longer. In a clinical study of acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for eight days. In clinical studies of acute analgesia, patients were treated with etoricoxib 120 mg once daily for one to seven days. The adverse-experience profile in this study was generally similar to that reported in the combined OA, RA, and chronic low back pain studies. The table lists all adverse events, regardless of causality, occurring in at least 2% of patients receiving etoricoxib at the recommended doses (60 and 90 mg) or naproxen 1000 mg daily in six placebo-controlled studies of 12 weeks’ duration.
  • ACR 關節炎治療規範 建議 , tramadol/APAP 是關節炎治療的主要用藥之一…… .
  • 7.疼痛治療新紀元Final handout

    1. 1. 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
    2. 2. Arthritis & Back Pain are Leading Causes of Disability Census data for 1999. CDC. MMWR Morb Mortal Wkly Rep. 2001;50:120-125. % All Disabilities Stroke Blindness or Vision Diabetes Mental or Emotional Limb/Extremity Stiffness Deafness or Hearing Lung or Respiratory Heart Trouble, Hardening of the Arteries Back or Spine Arthritis 0 2 4 6 8 10 12 14 16 18 2.8% 3.3% 3.4% 3.7% 4.2% 4.4% 4.7% 7.8% 16.5% 17.5% About 39 million physician visits/ yr 1 More than 500,000 hospitalizations/ yr 1 1 CDC, Arthritis Foundation. National Arthritis Action Plan: A Public Health Strategy. 1999.
    3. 3. History of Pain Management OPIOID NSAIDs OTHERs
    4. 4. Pain Physiology
    5. 5. 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
    6. 6. Peripheral Chemical Mediators of Pain
    7. 7. 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 . Opioids Tramadol Anti-spasmodics Anti-depressants Anti-convulsant NSAIDs COX-2 inhibitors Steroid Local therapy Paracetamol/ Acetaminophen Combination Therapy Model of Pain
    8. 8. Acetaminophen / Panadol <ul><li>Always first line drug of choice for pain </li></ul><ul><li>Analgesic and anti-pyretic, but not anti-inflammatory </li></ul><ul><li>Possible COX-3 inhibitor </li></ul><ul><li>Essential for combination therapies </li></ul>
    9. 9. <ul><li>NSAIDs </li></ul><ul><li>Drugs Trade dose(mg) Half life Max dose </li></ul><ul><li>Indomethacin Indocid bid 4.6 200 </li></ul><ul><li>Tiaprofenic acid Surgem bid 3.0 600 </li></ul><ul><li>Tenoxicam Ticotil qd, im,iv 72 </li></ul><ul><li>Ketoprofen Profenid bid, im 2 400 </li></ul><ul><li>Diclofenac Voltaren tid 4 150 </li></ul><ul><li>Sulindac Clinoril bid 16 400 </li></ul><ul><li>Naproxen Naposin bid 14 1500 </li></ul><ul><li>Nabumetone Relifex bid 26 1000 </li></ul><ul><li>Ibuprofen Motrin qid 2 3200 </li></ul><ul><li>Fenbufen Cinopal bid 11 </li></ul><ul><li>Meclofenamate Ponstan tid 2 400 </li></ul><ul><li>Piroxicam Feldene qd 57 20 </li></ul><ul><li>Mepirizole Mebron tid 4 450 </li></ul><ul><li>Acetylsalicyclic acid Aspirin tid 4 6000 </li></ul>
    10. 11. Upper GI Bleed Risks for NSAIDs Compared with not Taking NSAIDs Hernández-Diaz & Garcia Rodríguez, Arch Intern Med 2000 Piroxicam Ketoprofen Indomethacin Naproxen Sulindac Diclofenac Ibuprofen 1 10 Relative risk for upper GI bleed/perforation
    11. 13. Risk Factors of Ulcer Complications from NSAIDs Relative risk 2.5-4.8 2-4 2-3.5 3 2 2 2
    12. 14. ARAMIS Study 研究發現 1,921 位長期服用 NSAID 的 RA 患者 併用制酸劑或 H 2 -antagonist 反而會增加發生嚴重腸胃併發症的危險性! Singh, et al. Arch Intern Med . 1996;156:1530–1536. Patients on antacid/H 2 : GI event risk 3.4% Not on co-therapy : GI event risk 1.4% Odds ratio = 2.14, p < 0.05 ANTACID CAUTION H 2
    13. 15. COXib + PPI COXib NSAID + PPI NSAID + Hp eradication Efficacies of GI Preventive Strategies Chan FKL. NEJM 2002; 347: 2104-10; Chan FKL. Lancet 2007; 369: 1621-6
    14. 16. Concept of COX-2 Jone Vane. Nature 1994; 367: 215
    15. 17. Osteoarthritis Etoricoxib vs. Diclofenac : WOMAC Pain Subscale* Mean change from baseline in pain level (mm) 2 4 6 S More pain Less pain R NSAID washout period 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. Etoricoxib 60 mg once daily (n=253) Diclofenac 50 mg three times daily (n=258)
    16. 18. Rheumatoid Arthritis Etoricoxib vs. Naproxen : Tender-Joint Count a SE = standard error a Investigator assessment, total 68 each; b p=0.005 for naproxen vs. placebo; c p<0.001 for etoricoxib vs. placebo; d p<0.001 for etoricoxib vs. naproxen; e p<0.001 for both etoricoxib and naproxen vs. placebo; f p=0.779 for etoricoxib vs. naproxen; g 500 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. Mean change from baseline (  SE) Weeks in study – 20 – 15 – 10 5 0 – 5 Placebo Etoricoxib 90 mg Naproxen 1000 mg g (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 5 International (n=878) e,f Improved response S R 8 12 Weeks in study 2 4 US (n=805) b c,d Less improved More improved
    17. 19. Ankylosing Spondylitis Etoricoxib vs. Naproxen: Patient Assessment of Spine Pain a (Parts I and II) Placebo (n=93) Etoricoxib 90 mg (n=126) Etoricoxib 120 mg (n=123) Naproxen 1000 mg d (n=125) – 50 – 40 – 30 – 20 – 10 0 Weeks in study S LS mean change from baseline (±SE) 2 8 34 52 b,c a 0- to 100-mm VAS (0 = none to 100 = severe); b p<0.050, etoricoxib 90 mg vs. naproxen; c p<0.010 etoricoxib, 120 mg vs. naproxen; d 500 mg twice daily Adapted from van der Heijde D et al Arthritis Rheum 2005;52:1205–1215. R 16 43 26 6 4 Part I Part II
    18. 20. Acute Gouty Arthritis Etoricoxib vs. Indomethacin : Patient Assessment of Pain a LS = least squares; SE = standard error; R = randomization; CI = confidence interval a 0- to 4-point Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme); b LS mean change from baseline four hours after initial dose = –0.94; 95% CI, –1.11, –0.76; c LS mean difference from indomethacin = 0.09 (–0.14, 0.33) over days 2 to 8; d LS mean change from baseline four hours after initial dose = –1.04, 95% CI, –1.22, –0.86; e LS mean difference from indomethacin = –0.07 (–0.27, 0.14); f 50 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 mean change from baseline (  SE) <ul><li>Etoricoxib produced substantial improvement vs. baseline at 4 hours </li></ul>R 5 – 2.0 – 1.0 – 3.0 2 0.0 6 4 hr 3 4 6 7 8 Day in study – 0.5 – 1.5 – 2.5 Study 1 b,c R 5 – 2.0 – 1.0 – 3.0 2 0.0 6 4 hr 3 4 6 7 8 – 0.5 – 1.5 – 2.5 Day in study Study 2 d,e Etoricoxib 120 mg (n=72 study 1, n=101 study 2) Indomethacin 150 mg f (n=71 study 1, n=83 study 2)
    19. 21. 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/day Adapted from Hunt RH et al Am J Gastroenterol 2003;98:1725–1733; Curtis S et al. Poster presented at EULAR, 2002. Cumulative incidence 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% Risk reduction 450 Etoricoxib vs. Nonselective NSAIDs: GI PUBs Etoricoxib had lower incidence of confirmed PUBs in the clinical development program*
    20. 22. Meta-analysis of Randomized Trials of COX-2 Selective NSAIDs vs Placebo Kearney et al. BMJ. 2006;332:1302.
    21. 23. MEDAL Program Trials <ul><li>3 Trials 46 countries 1380 sites </li></ul><ul><li>EDGE (OA): N=7,111 </li></ul><ul><li>EDGE II (RA): N=4,086 34,701 patients </li></ul><ul><li>MEDAL (OA/RA): N=23,504 </li></ul>n=17,412 R A N D O M I Z E Etoricoxib 60 or 90 mg/d (OA) 90 mg/d (RA) Diclofenac 150 mg/d ( 50 mg tid or 75 mg bid) n=17,289 <ul><li>≥ 50 years of age </li></ul><ul><li>OA of knee, hip, hand, or spine; or RA </li></ul><ul><li>Require long-term therapy with traditional NSAID or COX-2 inhibitor </li></ul><ul><li>Broad CV risk </li></ul><ul><li>Allowed aspirin and PPI use in appropriate patients </li></ul>Mean duration of therapy=18 months
    22. 24. 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. Cumulative Incidence, % (95% CI) Months 0 6 42 24 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 diclofenac HR=0.95 (95% CI: 0.81, 1.11) P =0.496 Primary Endpoint
    23. 25. CV safety of NSAID & COXIB Summary : Meta-analysis & Systemic Review <ul><li>Rofecoxib < 25 mg/d RR 1.33* -1.73* </li></ul><ul><li> > 25 mg/d 2.19* </li></ul><ul><li>Celecoxib > 400 mg/d 1.56* -2.70* </li></ul><ul><li> < 200 mg/d 1.0 </li></ul><ul><li>Naproxen 0.92-0.97 </li></ul><ul><li>Diclofenac 1.40* -1.63* </li></ul><ul><li>Piroxicam 1.06 ( 0.70-1.59 ) </li></ul><ul><li>Ibuprofen 1.07-1.51* </li></ul>
    24. 26. Balancing GI and CV Safety <ul><li>GI events </li></ul><ul><ul><li>Gastric ulcer 20% in 3 mo </li></ul></ul><ul><ul><li>PUB in 10% in 1 yr </li></ul></ul><ul><li>CV events </li></ul><ul><ul><li>26 events in 8000 pts </li></ul></ul><ul><ul><li>4% vs 2% cumulative incidence in 2 yr </li></ul></ul><ul><li>Effect Size (ES) </li></ul><ul><li>Number need to treat (NTT) </li></ul>Identify risk factors is most important!
    25. 27. Strategies to use NSAID tNSAID +cardioprotection <ul><li>tNSAID+PPI </li></ul><ul><li>Coxib at low dose +cardioprotection+/- PPI </li></ul>tNSAID <ul><li>Coxib </li></ul><ul><li>tNSAID+PPI </li></ul>CV risk GI risk
    26. 28. tNSAID Coxib or tNSAID+PPI
    27. 29. <ul><li>Etoricoxib Naproxen </li></ul><ul><li>Placebo 60 or 90 mg daily 1000 mg daily </li></ul><ul><li>(n=1011) (n=1547) (n=790) </li></ul><ul><li>Asthenia/fatigue 1.3 2.2 1.8 </li></ul><ul><li>Dizziness 1.3 2.1 2.5 </li></ul><ul><li>Lower extremity edema 1.9 2.1 2.3 </li></ul><ul><li>Upper respiratory infection 4.0 5.4 6.3 </li></ul><ul><li>Hypertension 1.5 3.6 2.8 </li></ul><ul><li>Diarrhea 4.0 4.6 2.8 </li></ul><ul><li>Epigastric discomfort 1.7 2.0 3.8 </li></ul><ul><li>Heartburn 1.3 2.2 4.2 </li></ul><ul><li>Nausea 2.6 3.5 4.1 </li></ul><ul><li>Sinusitis 2.1 2.0 1.3 </li></ul><ul><li>Headache 4.8 5.9 3.2 </li></ul><ul><li>Urinary tract infection 3.4 2.9 3.0 </li></ul>In  2% of patients treated with etoricoxib Tolerability, Etoricoxib
    28. 30. Physical measures – patient education Medication Intra - articular Analgesics Anti- inflammatory NSAIDs plus PGE2/PPI, COXIB Tramadol Capsaicin Opioids Paracetamol Depot steroids Hyaluronate Antispasmodics / Antidepressants / Anthraquinone / Lipids Surgery Clinical Rheumatol (2006) 25 (Suppl 1): S22-S29 ACR 2006 Guideline for OA Management
    29. 31. COX II 抑制劑健保給付規範 <ul><li>COX II 抑制劑(包含 celecoxib, nabumetone, meloxicam, etodolac, nimesulide, rofecoxib 與 etoricoxib )之使用規範 </li></ul><ul><li>- 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 </li></ul><ul><li>1. 年齡大於等於 60 歲之骨關節病患 </li></ul><ul><li>2. 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 </li></ul><ul><li>3. 合併有急性嚴重創傷、中風、及心血管疾病 </li></ul><ul><li>4. 同時併用腎上腺類固醇之患者 </li></ul><ul><li>5. 曾有消化性潰瘍、上消化道出血或胃穿孔病史者 </li></ul><ul><li>6. 同時併用抗凝血劑者 </li></ul><ul><li>7. 肝硬化患者 </li></ul><ul><li>- 使用本製劑之病患不得 預防性 併用 H2 antagonists 、 PPI 及其他消化性潰瘍用藥,亦不得 合併使用前列腺素劑 ( 如 misoprostol) </li></ul>
    30. 32. 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
    31. 33. Conclusions <ul><li>Combination therapy model </li></ul><ul><li>Balancing benefits and risks of NSAID </li></ul><ul><ul><li>BENEFITS: NSAID ≈ COXIB </li></ul></ul><ul><ul><ul><li>Pain relief </li></ul></ul></ul><ul><ul><ul><li>Anti-inflammation </li></ul></ul></ul><ul><ul><ul><li>Improved QOL, mobility, functional status </li></ul></ul></ul><ul><ul><li>RISKS </li></ul></ul><ul><li>- Gastrointestinal: NSAID > COXIB </li></ul><ul><li>- Cardiovascular: COXIB ≈ NSAID </li></ul><ul><li>- Renal : COXIB ≈ NSAID </li></ul>

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